89 results on '"phase I trial"'
Search Results
2. Time‐to‐event calibration‐free odds design: A robust efficient design for phase I trials with late‐onset outcomes.
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Jin, Huaqing and Yin, Guosheng
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GAME theory , *CHIEF financial officers - Abstract
Compared with most of the existing phase I designs, the recently proposed calibration‐free odds (CFO) design has been demonstrated to be robust, model‐free, and easy to use in practice. However, the original CFO design cannot handle late‐onset toxicities, which have been commonly encountered in phase I oncology dose‐finding trials with targeted agents or immunotherapies. To account for late‐onset outcomes, we extend the CFO design to its time‐to‐event (TITE) version, which inherits the calibration‐free and model‐free properties. One salient feature of CFO‐type designs is to adopt game theory by competing three doses at a time, including the current dose and the two neighboring doses, while interval‐based designs only use the data at the current dose and is thus less efficient. We conduct comprehensive numerical studies for the TITE‐CFO design under both fixed and randomly generated scenarios. TITE‐CFO shows robust and efficient performances compared with interval‐based and model‐based counterparts. As a conclusion, the TITE‐CFO design provides robust, efficient, and easy‐to‐use alternatives for phase I trials when the toxicity outcome is late‐onset. [ABSTRACT FROM AUTHOR]
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- 2023
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3. Flexible use of copula‐type model for dose‐finding in drug combination clinical trials.
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Hashizume, Koichi, Tshuchida, Jun, and Sozu, Takashi
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DRUG design , *ANTINEOPLASTIC agents - Abstract
Identification of the maximum tolerated dose combination (MTDC) of cancer drugs is an important objective in phase I oncology trials. Numerous dose‐finding designs for drug combination have been proposed over the years. Copula‐type models exhibit distinctive advantages in this task over other models used in existing competitive designs. For example, their application enables the consideration of dose‐limiting toxicities attributable to one of two agents. However, if a particular combination therapy demonstrates extremely synergistic toxicity, copula‐type models are liable to induce biases in toxicity probability estimators due to the associated Fréchet–Hoeffding bounds. Consequently, the dose‐finding performance may be worse than those of other competitive designs. The objective of this study is to improve the performance of dose‐finding designs based on copula‐type models while maintaining their advantageous properties. We propose an extension of the parameter space of the interaction term in copula‐type models. This releases the Fréchet–Hoeffding bounds, making the estimation of toxicity probabilities more flexible. Numerical examples in various scenarios demonstrate that the performance (e.g., the percentage of correct MTDC selection) of the proposed method is better than those exhibited by existing copula‐type models and comparable with those of other competitive designs, irrespective of the existence of extreme synergistic toxicity. The results obtained in this study could motivate the real‐world application of the proposed method in cases requiring the utilization of the properties of copula‐type models. [ABSTRACT FROM AUTHOR]
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- 2022
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4. A semi‐mechanistic dose‐finding design in oncology using pharmacokinetic/pharmacodynamic modeling.
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Su, Xiao, Li, Yisheng, Müller, Peter, Hsu, Chia‐Wei, Pan, Haitao, and Do, Kim‐Anh
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DRUG administration routes , *PHARMACOKINETICS , *PHARMACODYNAMICS , *ONCOLOGY - Abstract
While a number of phase I dose‐finding designs in oncology exist, the commonly used ones are either algorithmic or empirical model‐based. We propose a new framework for modeling the dose–response relationship, by systematically incorporating the pharmacokinetic (PK) data collected in the trial and the hypothesized mechanisms of the drug effects, via dynamic PK/PD modeling, as well as modeling of the relationship between a latent cumulative pharmacologic effect and a binary toxicity outcome. This modeling framework naturally incorporates the information on the impact of dose, schedule and method of administration (e.g., drug formulation and route of administration) on toxicity. The resulting design is an extension of existing designs that make use of pre‐specified summary PK information (such as the area under the concentration‐time curve [AUC] or maximum serum concentration [Cmax]). Our simulation studies show, with moderate departure from the hypothesized mechanisms of the drug action, that the performance of the proposed design on average improves upon those of the common designs, including the continual reassessment method (CRM), Bayesian optimal interval (BOIN) design, modified toxicity probability interval (mTPI) method, and a design called PKLOGIT that models the effect of the AUC on toxicity. In case of considerable departure from the underlying drug effect mechanism, the performance of the design is shown to be comparable with that of the other designs. We illustrate the proposed design by applying it to the setting of a phase I trial of a γ‐secretase inhibitor in metastatic or locally advanced solid tumors. We also provide R code to implement the proposed design. [ABSTRACT FROM AUTHOR]
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- 2022
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5. A Comparative Study of Model-Based Dose-Finding Methods for Two-Agent Combination Trials
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Hirakawa, Akihiro, Sato, Hiroyuki, Matsui, Shigeyuki, editor, and Crowley, John, editor
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- 2017
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6. Phase I Trial of [99mTc]Tc-maSSS-PEG2-RM26, a Bombesin Analogue Antagonistic to Gastrin-Releasing Peptide Receptors (GRPRs), for SPECT Imaging of GRPR Expression in Malignant Tumors
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Vladimir Chernov, Anastasiya Rybina, Roman Zelchan, Anna Medvedeva, Olga Bragina, Nadejda Lushnikova, Artem Doroshenko, Evgeniy Usynin, Liubov Tashireva, Sergey Vtorushin, Ayman Abouzayed, Sara S. Rinne, Jens Sörensen, Vladimir Tolmachev, and Anna Orlova
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phase I trial ,Cancer och onkologi ,Cancer Research ,GRPR ,antagonist ,99mTc ,Oncology ,Cancer and Oncology ,Radiologi och bildbehandling ,Radiology, Nuclear Medicine and Medical Imaging - Abstract
The gastrin-releasing peptide receptor (GRPR) is overexpressed in prostate cancer (PCa) and in hormone-driven breast cancer (BCa). The aim of this phase I clinical trial was to evaluate safety, biodistribution, and dosimetry after the administration of the recently developed GRPR-targeting antagonistic bombesin analogue [99mTc]Tc-maSSS-PEG2-RM26 in PCa and BCa patients. Planar and whole-body SPECT/CT imaging was performed in six PCa patients and seven BCa patients 2, 4, 6, and 24 h post the intravenous administration of 40 µg of [99mTc]Tc-maSSS-PEG2-RM26 (600–700 MBq). No adverse events or pathological changes were observed. The rapid blood clearance of [99mTc]Tc-maSSS-PEG2-RM26 was observed with predominantly hepatobiliary excretion. The effective doses were 0.0053 ± 0.0007 for male patients and 0.008 ± 0.003 mSv/MBq for female patients. The accumulation of [99mTc]Tc-maSSS-PEG2-RM26 in tumors was observed in four out of six PCa and in seven out of seven BCa patients. In four BCa patients, a high uptake of the agent into the axillary lymph nodes was detected. Immunohistochemistry revealed positive GRPR expression in 60% of primary PCa, 71.4% of BCa tumors, and 50% of examined BCa lymph nodes. In conclusion, a single administration of [99mTc]Tc-maSSS-PEG2-RM26 was safe and well tolerated. [99mTc]Tc-maSSS-PEG2-RM26 SPECT may be useful for tumor detection in PCa and BCa patients, pending further studies.
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- 2023
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7. Health-related quality of life as an endpoint in oncology phase I trials: a systematic review.
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Fiteni, Frédéric, Ray, Isabelle Le, Ousmen, Ahmad, Isambert, Nicolas, Anota, Amélie, and Bonnetain, Franck
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QUALITY of life , *META-analysis , *STATISTICAL measurement , *ONCOLOGY - Abstract
Background: Phase I trials aim to identify the recommended dose for further development. Health-related quality of life (HRQoL) could be a complement to the usual National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) scale to detect adverse events and define the doses. The objective of this study is to review the phase I in oncology which used HRQoL as endpoint.Methods: A search in PubMed database identified phase I trials in oncology with HRQoL as endpoint, published between January 2012 to May 2016. Hematological and pediatric phase I were excluded.Results: A total of 1333 phase I were identified and 15 trials were identified with HRQoL as endpoint (1.1%). The European Organisation for Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30) was the most frequently used instrument: 5 studies (33.3%). The targeted dimensions of HRQoL and the minimal clinically important difference were prespecified in 1 study (6.7%) and 2 studies (13.3%), respectively. Twelve studies (80%) described the statistical approach to analyze HRQoL data. Eight studies used the mean change from baseline (60%) to analyse longitudinal HRQoL data, two the mean score at certain times (13.3%), one the linear mixed model for repeated measures (6.7%), one the time to HRQoL score deterioration (6.7%), one percentage of patient-reported symptoms (6.7%). None of the studies used HRQoL to determine the recommended doses.Conclusion: Few phase I studies used HRQoL as endpoint and among studies with HRQoL as endpoint, the methodology of HRQoL measurement and statistical analysis was heterogeneous. HRQoL. endpoint not used for assessing the recommended phase II doses. [ABSTRACT FROM AUTHOR]- Published
- 2019
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8. Global trends in the distribution of cancer types among patients in oncology phase I trials, 1991-2015.
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Itahashi, Kota, Shimizu, Toshio, Koyama, Takafumi, Kondo, Shunsuke, Fujiwara, Yutaka, and Yamamoto, Noboru
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BREAST tumors ,CANCER patients ,CLINICAL trials ,COLON tumors ,KIDNEY tumors ,LUNG tumors ,MEDLINE ,ONCOLOGY ,ONLINE information services ,RECTUM tumors ,SARCOMA ,TUMORS ,TUMOR classification ,SYSTEMATIC reviews - Abstract
Background Systematic analyses regarding cancer types of patients enrolled in oncology phase I trials are scarce. The global distribution, time-dependent change, and regional differences were evaluated. Methods A systematic search of the PubMed database, in which all single-agent phase I trials permitting the enrollment of all-comer patients with any type of solid tumor published between January 1991 and December 2015 were specified, was performed. Trials expected to enroll specific patient populations were excluded according to predefined criteria. Results Eight hundred and sixty-six eligible trials, which had enrolled 29,112 advanced solid tumor patients, were identified. Colorectal (n = 7510; 25.8%) and lung cancer (n = 3212; 11.0%) were the most prevalent solid tumors, followed by sarcoma (n = 1756; 6.0%), breast cancer (n = 1623; 5.6%), and renal cancer (n = 1589; 5.5%). The proportion of patients with either colorectal or lung cancer tended to decrease over time. The proportion of trials, in which patients with either of these two cancers accounted for ≥50.0% of the total number of patients in each trial, also decreased: 33 of 67 trials (31/67) (46.3%) in 1991-1995, 58/142 (40.8%) in 1996-2000, 59/223 (26.5%) in 2001-2005, 38/189 (20.1%) in 2006-2010, and 41/245 (16.7%) in 2011-2015. Instead, the proportion of patients with various types of cancer increased, leading to diversification of enrolled patients. Conclusions The distribution of cancer types among patients in phase I trials has changed. The comprehensive review of the distribution of solid tumor types could contribute to flexible trial designs and optimal patient recruitment. [ABSTRACT FROM AUTHOR]
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- 2019
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9. Proton Image-guided Radiation Assignment for Therapeutic Escalation via Selection of locally advanced head and neck cancer patients [PIRATES]
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Abdallah S.R. Mohamed, Jack Phan, Kathryn E. Preston, David I. Rosenthal, William H. Morrison, Steven J. Frank, Clifton D. Fuller, Johannes A. Langendijk, Adam S. Garden, Lisanne V. van Dijk, Anna Lee, Michael T. Spiotto, Brandon Gunn, Amy C. Moreno, Ying Yuan, Yun Qing, University of Groningen, Damage and Repair in Cancer Development and Cancer Treatment (DARE), and Guided Treatment in Optimal Selected Cancer Patients (GUTS)
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medicine.medical_specialty ,Osteoradionecrosis ,medicine.medical_treatment ,Radiation dose-escalation ,R895-920 ,Article ,CHEMORADIOTHERAPY ,CISPLATIN ,Phase I trial ,Medical physics. Medical radiology. Nuclear medicine ,Image guided RT ,medicine ,Mucositis ,Clinical endpoint ,INDUCTION CHEMOTHERAPY ,Radiology, Nuclear Medicine and imaging ,FDG-PET ,Head and neck cancer ,Proton therapy ,RC254-282 ,III TRIAL ,Toxicity ,business.industry ,CONCURRENT ,FRACTIONATION ,HUMAN-PAPILLOMAVIRUS ,Induction chemotherapy ,Hyper-fractionation ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,medicine.disease ,RANDOMIZED-TRIAL ,Radiation therapy ,Oncology ,SURVIVAL ,Radiology ,business ,Chemoradiotherapy - Abstract
Highlights • The PIRATES protocol is a novel tumor radiation dose-escalation approach. • PIRATES integrates proton therapy, image guided RT and hybrid hyper-fractionation. • It targets only head and neck cancer patients at high risk of treatment failure. • This Phase I trial aims to test the feasibility and safety of PIRATES., Introduction Radiation dose-escalation for head and neck cancer (HNC) patients aiming to improve cure rates is challenging due to the increased risk of unacceptable treatment-induced toxicities. With “Proton Image-guided Radiation Assignment for Therapeutic Escalation via Selection of locally advanced head and neck cancer patients” (PIRATES), we present a novel treatment approach that is designed to facilitate dose-escalation while minimizing the risk of dose-limiting toxicities for locally advanced HPV-negative HNC patients. The aim of this Phase I trial is to assess the safety & feasibility of PIRATES approach. Methods The PIRATES protocol employs a multi-faceted dose-escalation approach to minimize the risk of dose-limiting toxicities (DLTs): 1) sparing surrounding normal tissue from extraneous dose with intensity-modulated proton therapy, 2) mid-treatment hybrid hyper-fractionation for radiobiologic normal tissue sparing; 3) Magnetic Resonance Imaging (MRI) guided mid-treatment boost volume adaptation, and 4) iso-effective restricted organ-at-risk dosing to mucosa and bone tissues. The time-to-event Bayesian optimal interval (TITE-BOIN) design is employed to address the challenge of the long DLT window of 6 months and find the maximum tolerated dose. The primary endpoint is unacceptable radiation-induced toxicities (Grade 4, mucositis, dermatitis, or Grade 3 myelopathy, osteoradionecrosis) occurring within 6 months following radiotherapy. The second endpoint is any grade 3 toxicity occurring in 3–6 months after radiation. Discussion The PIRATES dose-escalation approach is designed to provide a safe avenue to intensify local treatment for HNC patients for whom therapy with conventional radiation dose levels is likely to fail. PIRATES aims to minimize the radiation damage to the tissue surrounding the tumor volume with the combination of proton therapy and adaptive radiotherapy and within the high dose tumor volume with hybrid hyper-fractionation and not boosting mucosal and bone tissues. Ultimately, if successful, PIRATES has the potential to safety increase local control rates in HNC patients with high loco-regional failure risk. Trial registration: ClinicalTrials.gov ID: NCT04870840; Registration date: May 4, 2021. Netherlands Trial Register ID: NL9603; Registration date: July 15, 2021.
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- 2022
10. Low-Dose Metronomic Topotecan and Pazopanib (TOPAZ) in Children with Relapsed or Refractory Solid Tumors: A C17 Canadian Phase I Clinical Trial
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Arif Manji, Yvan Samson, Rebecca J. Deyell, Donna L. Johnston, Victor A. Lewis, Alexandra P. Zorzi, Jason N. Berman, Kathy Brodeur-Robb, Ellen Morrison, Lynn Kee, Sushil Kumar, Sylvain Baruchel, James A. Whitlock, and Daniel A. Morgenstern
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Cancer Research ,Oncology ,phase I trial ,pediatric ,children ,pazopanib ,topotecan ,metronomic ,angiogenesis - Abstract
Oral metronomic topotecan represents a novel approach to chemotherapy delivery which, in preclinical models, may work synergistically with pazopanib in targeting angiogenesis. A phase I and pharmacokinetic (PK) study of this combination was performed in children with relapsed/refractory solid tumors. Oral topotecan and pazopanib were each administered daily without interruption in 28-day cycles at five dose levels (0.12 to 0.3 mg/m2 topotecan and 125 to 160 mg/m2 pazopanib powder for oral suspension (PfOS)), with dose escalation in accordance with the rolling-six design. PK studies were performed on day 1 and at steady state. Thirty patients were enrolled, with 26 evaluable for dose-limiting toxicity (DLT), with median age 12 years (3–20). Toxicities were generally mild; the most common grade 3/4 adverse events related to protocol therapy were neutropenia (18%), thrombocytopenia (11%), lymphopenia (11%), AST elevation (11%), and lipase elevation (11%). Only two cycle 1 DLTs were observed on study, both at the 0.3/160 mg/m2 dose level comprising persistent grade 3 thrombocytopenia and grade 3 ALT elevation. No AEs experienced beyond cycle 1 required treatment discontinuation. The best response was stable disease in 10/25 patients (40%) for a median duration of 6.4 (1.7–45.1) months. The combination of oral metronomic topotecan and pazopanib is safe and tolerable in pediatric patients with solid tumors, with a recommended phase 2 dose of 0.22 mg/m2 topotecan and 160 mg/m2 pazopanib. No objective responses were observed in this heavily pre-treated patient population, although 40% did achieve stable disease for a median of 6 months. While this combination is likely of limited benefit for relapsed disease, it may play a role in the maintenance setting.
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- 2022
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11. Phase I Study of a Combination of Fluvastatin and Celecoxib in Children with Relapsing/Refractory Low-Grade or High-Grade Glioma (FLUVABREX)
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Pierre Leblond, Emmanuelle Tresch-Bruneel, Alicia Probst, Nadège Néant, Caroline Solas, Arthur Sterin, Thomas Boulanger, Isabelle Aerts, Cécile Faure-Conter, Anne-Isabelle Bertozzi, Pascal Chastagner, Natacha Entz-Werlé, Emilie De Carli, Marie-Cécile Le Deley, Gauthier Bouche, and Nicolas André
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Cancer Research ,Oncology ,high-grade pediatric glioma ,low-grade pediatric glioma ,phase I trial ,drug repurposing - Abstract
Preclinical data support the activity of celecoxib and fluvastatin in high-grade (HGG) and low-grade gliomas (LGG). A phase I trial (NCT02115074) was designed to evaluate the safety of this combination in children with refractory/relapsed HGG and LGG using four dose levels of fluvastatin with a fixed daily dose of celecoxib. A Continual Reassessment Method was used for fluvastatin dose escalation. Dose-limiting toxicities (DLT) were determined on the first treatment cycle. Twenty patients were included. Ten LGG and ten HGG patients received a median of 3.5 treatment cycles. Two DLTs were reported: one grade 3 maculopapular rash (4 mg/kg dose level) and one grade 4 increase of Creatine Phospho-Kinase (6 mg/kg dose level). We identified the dose of 6 mg/kg/day as the recommended phase II dose (RP2D) of fluvastatin with celecoxib. Four patients with LGG continued treatment beyond 12 cycles because of stable disease, including one patient who received 23 treatment cycles. In children with refractory/relapsed glioma, the RP2D of fluvastatin with celecoxib is 6 mg/kg/day. The long-term stable diseases observed in LGG suggest a possible role of the combination in a maintenance setting, given its good tolerance and low cost for children living in low- and middle-income countries.
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- 2023
12. Phase I pharmacokinetic study of single agent trametinib in patients with advanced cancer and hepatic dysfunction
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Lee-Anne Stayner, Ulka N. Vaishampayan, Daniel J. Renouf, Solmaz Sahebjam, Helen X. Chen, Karen Kelly, Aaron R. Hansen, Philippe L. Bedard, Vivek Subbiah, Eric X. Chen, Pei Jye Voon, Sebastien J. Hotte, Albiruni R. Razak, S. Percy Ivy, Albert C. Lockhart, Lillian L. Siu, Arti Singh, Lisa Wang, and Anna Spreafico
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Oncology ,Adult ,Male ,Hepatic dysfunction ,medicine.medical_specialty ,Cancer Research ,Pyridones ,Pyrimidinones ,Phase I trial ,Pharmacokinetics ,Trametinib ,Internal medicine ,Neoplasms ,medicine ,Humans ,cancer ,Single agent ,In patient ,study ,pharmacokinetic ,RC254-282 ,Aged ,Dose escalation ,business.industry ,Liver Diseases ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Middle Aged ,Advanced cancer ,Female ,business - Abstract
BackgroundTrametinib is an oral MEK 1/2 inhibitor, with a single agent recommended phase 2 dose (RP2D) of 2 mg daily (QD). This study was designed to evaluate RP2D, maximum tolerated dose (MTD), and pharmacokinetic (PK) profile of trametinib in patients with advanced solid tumors who had various degrees of hepatic dysfunction (HD).MethodsAdvanced cancer patients were stratified into 4 HD groups based on Organ Dysfunction Working Group hepatic function stratification criteria: normal (Norm), mild (Mild), moderate (Mod), severe (Sev). Dose escalation was based on “3 + 3” design within each HD group. PK samples were collected at cycle 1 days 15-16.ResultsForty-six patients were enrolled with 44 evaluable for safety [Norm=17, Mild=7, Mod (1.5 mg)=4, Mod (2 mg)=5, Sev (1 mg)=9, Sev (1.5 mg)=2] and 22 for PK analysis. Treatment related adverse events were consistent with prior trametinib studies. No treatment related deaths occurred. Dose limiting toxicities (DLTs) were evaluable in 15 patients (Mild=6, Mod (1.5 mg)=3, Mod (2 mg)=2, Sev (1 mg)=3 and Sev (1.5 mg)=1). One DLT (grade 3 acneiform rash) was observed in a Sev patient (1.5 mg). Dose interruptions or reductions due to treatment related adverse events occurred in 15 patients (34%) [Norm=9, 53%; Mild=2, 29%; Mod (1.5 mg)=1, 33%; Mod (2 mg)=2, 33%; Sev (1 mg)=1, 11%; Sev (1.5 mg)=1; 50%]. There were no significant differences across HD groups for all PK parameters when trametinib was normalized to 2 mg. However, only limited PK data were available for the Mod (n = 3) and Sev (n = 3) groups compared to Norm (n = 10) and Mild (n = 6) groups. Trametinib is heavily protein bound, with no correlation between serum albumin level and unbound trametinib fraction (p = 0.26).ConclusionsRP2D for trametinib in Mild HD patients is 2 mg QD. There are insufficient number of evaluable patients due to difficulty of patient accrual to declare RP2D and MTD for Mod and Sev HD groups. DLTs were not observed in the highest dose cohorts that reached three evaluable patients – 1.5 mg QD in Mod group, and 1 mg QD in Sev group.Trial registrationThis study was registered in the ClinicalTrials.gov website (NCT 02070549) on February 25, 2014. .
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- 2022
13. Phase I dose-escalation study of the safety, tolerability, and pharmacokinetics of aflibercept in combination with S-1 in Japanese patients with advanced solid malignancies
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Yusuke Onozawa, Narikazu Boku, Toshihiko Doi, Atsushi Ohtsu, Keishiro Takahashi, and Osamu Kawaguchi
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Adult ,Male ,0301 basic medicine ,Antimetabolites, Antineoplastic ,medicine.medical_specialty ,Pleural effusion ,Recombinant Fusion Proteins ,Urology ,Angiogenesis Inhibitors ,Antibodies ,Phase I trial ,03 medical and health sciences ,0302 clinical medicine ,Asian People ,Pharmacokinetics ,Phase I Studies ,Neoplasms ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,Pharmacology (medical) ,Infusions, Intravenous ,Aged ,Tegafur ,Aflibercept ,Pharmacology ,Proteinuria ,business.industry ,Standard treatment ,Incidence (epidemiology) ,S-1 ,Middle Aged ,medicine.disease ,Drug Combinations ,Oxonic Acid ,Receptors, Vascular Endothelial Growth Factor ,Treatment Outcome ,030104 developmental biology ,Oncology ,Tolerability ,030220 oncology & carcinogenesis ,Toxicity ,Japanese ,Female ,medicine.symptom ,business ,VEGF trap ,medicine.drug - Abstract
SummaryBackground Aflibercept, a recombinant fusion protein binding VEGF-A, VEGF-B and placental growth factor, inhibits tumor growth by blocking angiogenesis. The aim of this phase I dose-escalation study was to determine the recommended phase II dose (RP2D) of aflibercept in combination with S-1 in Japanese patients with solid tumors. Patients and methods Sequential cohorts of 3–6 patients with metastatic or unresectable solid tumors, who had failed at least one prior line of standard treatment or who were not suitable for such treatment, were to receive escalating doses of aflibercept every 2 weeks, starting at 2 mg/kg, combined with S-1 at 40 mg/m2 twice daily (80 mg/m2/day; 4 weeks on/2 weeks off). Dose-escalation was to be based on the incidence of dose-limiting toxicity (DLT). Blood samples were collected for pharmacokinetic analysis. Results At the first dose level (aflibercept 2 mg/kg plus S-1) 1 of 6 patients experienced a DLT (grade 4 proteinuria). The aflibercept dose was consequently escalated to 4 mg/kg; 1 of 3 patients treated at this dose level had a DLT (grade 2 pleural effusion), and another patient experienced grade 3 reversible posterior leukoencephalopathy syndrome after the DLT assessment period. Additional patients were therefore enrolled into the first dose level to explore safety and tolerability. The study was subsequently terminated prematurely. The maximum tolerated dose was not reached and the RP2D was not determined in Japanese patients. Conclusions The tolerability and safety of aflibercept 2 mg/kg in combination with S-1 was confirmed in Japanese patients with advanced solid tumors.
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- 2020
14. Access to early‐phase clinical trials for children with relapsed and refractory neuroblastoma: A multicentre international study
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Marta Cortes, Fernando Carceller, Alba Rubio‐San‐Simón, Sucheta J. Vaidya, Francisco Bautista, and Lucas Moreno
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access to innovation ,relapsed neuroblastoma ,clinical trial ,Hematology ,Prognosis ,drug development ,Drug Administration Schedule ,Phase I trial ,Neuroblastoma ,Oncology ,Antineoplastic Combined Chemotherapy Protocols ,Pediatrics, Perinatology and Child Health ,Humans ,Phase II trial ,Neoplasm Recurrence, Local ,Child - Abstract
Neuroblastoma is the most common extracranial tumour in children, and prognosis for refractory and relapsed disease is still poor. Early-phase clinical trials play a pivotal role in the development of novel drugs. Ensuring adequate recruitment is crucial. The primary aim was to determine the rate of participation trials for children with refractory/relapsed neuroblastoma in two of the largest drug development European institutions. Data from patients diagnosed with refractory/relapsed neuroblastoma between January 2012 and December 2018 at the two institutions were collected and analysed. Overall, 48 patients were included. A total of 31 (65%) refractory/relapsed cases were enrolled in early-phase trials. The main reasons for not participating in clinical trials included not fulfilling eligibility criteria prior to consent (12/17, 70%) and screening failure (2/17, 12%). Median time on trial was 4.3 months (range 0.6-13.4). Most common cause for trial discontinuation was disease progression (67.7%). Median overall survival was longer in refractory (28 months, 95% CI: 20.9-40.2) than in relapsed patients (14 months, 95% CI: 8.1-20.1) (p = .034). Although two thirds of children with refractory/relapsed neuroblastoma were enrolled in early-phase trials, recruitment rates can still be improved. The main cause for not participating on trials was not fulfilling eligibility criteria prior to consent, mainly due to performance status and short life expectancy. This study highlights the hurdles to access to innovative therapies for children with relapsed/refractory neuroblastomas, and identifies key areas of development to improve recruitment to early-phase trials.
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- 2022
15. Phase I clinical trial of the combination of eribulin and everolimus in patients with metastatic triple-negative breast cancer
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Norma Martinez, Kim Robinson, Aileen Tang, Yuan Yuan, Susan E. Yost, Thehang Luu, Daniel Schmolze, Wei Wen, Joanne E. Mortimer, Hongwei Holly Yin, Heather Ann Brauer, Jana Portnow, John H. Yim, Suzette Blanchard, Jin Sun Lee, Raju Pillai, and Yuqi Ren
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Adult ,Oncology ,medicine.medical_specialty ,Neutropenia ,Phases of clinical research ,Triple Negative Breast Neoplasms ,Kaplan-Meier Estimate ,lcsh:RC254-282 ,Drug Administration Schedule ,03 medical and health sciences ,chemistry.chemical_compound ,Phase I trial ,0302 clinical medicine ,Breast cancer ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,Humans ,Medicine ,Eribulin ,Everolimus ,Furans ,Fatigue ,Triple-negative breast cancer ,Aged ,030304 developmental biology ,Metastatic TNBC ,Stomatitis ,0303 health sciences ,Leukopenia ,Dose-Response Relationship, Drug ,business.industry ,Gene Expression Profiling ,Ketones ,Middle Aged ,medicine.disease ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,3. Good health ,Gene Expression Regulation, Neoplastic ,Tolerability ,chemistry ,030220 oncology & carcinogenesis ,Female ,medicine.symptom ,business ,Research Article ,medicine.drug - Abstract
Background Alteration of the PI3K/AKT/mTOR pathway is a common genomic abnormality detected in triple-negative breast cancer (TNBC). Everolimus acts synergistically with eribulin in TNBC cell lines and xenograft models. This phase I trial was designed to test the safety and tolerability of combining eribulin and everolimus in patients with metastatic TNBC. Methods The primary objective of this study was to evaluate the safety and toxicities of the combination. Patients with metastatic TNBC who had up to four lines of prior chemotherapies were enrolled. The combination of eribulin and everolimus was tested using three dosing levels: A1 (everolimus 5 mg daily; eribulin 1.4 mg/m2 days 1 and 8 every 3 weeks), A2 (everolimus 7.5 mg daily; eribulin 1.4 mg/m2, days 1 and 8 every 3 weeks), and B1 (everolimus 5 mg daily; eribulin 1.1 mg/m2 days 1 and 8 every 3 weeks). Results Twenty-seven patients with median age 55 years were enrolled. Among 8 evaluable patients who received dose level A1, 4 had dose-limiting toxicities (DLTs). Among 3 evaluable patients treated with dose level A2, 2 had DLTs. Among 12 evaluable patients who received dose level B1, 4 had DLTs. The DLTs were neutropenia, stomatitis, and hyperglycemia. Over the study period, 59% had a ≥ grade 3 toxicity, 44% had ≥ grade 3 hematologic toxicities, and 22% had grade 4 hematologic toxicities. The most common hematological toxicities were neutropenia, leukopenia, and lymphopenia. Thirty-three percent had grade 3 non-hematologic toxicities. The most common non-hematological toxicities were stomatitis, hyperglycemia, and fatigue. The median number of cycles completed was 4 (range 0–8). Among 25 eligible patients, 9 patients (36%) achieved the best response as partial response, 9 (36%) had stable disease, and 7 (28%) had progression. The median time to progression was 2.6 months (95% CI [2.1, 4.0]), and median overall survival (OS) was 8.3 months (95% CI [5.5, undefined]). Conclusion Eribulin 1.1 mg/m2 days 1 and 8 every 3 weeks with everolimus 5 mg daily was defined as the highest dose with acceptable toxicity (RP2D). The combination is safe, and efficacy is modest. A post hoc analysis showed that participants that used dexamethasone mouthwash stayed on treatment for one additional cycle. Trial registration ClinicalTrials.gov, NCT02120469. Registered 18 April 2014
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- 2019
16. The rapid enrollment design for Phase I clinical trials.
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Ivanova, Anastasia, Wang, Yunfei, and Foster, Matthew C.
- Subjects
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CLINICAL trials , *DRUG dosage , *DOSE-effect relationship in pharmacology , *DRUG toxicity , *EXPERIMENTAL design , *ONCOLOGY , *PATIENT selection - Abstract
We propose a dose-finding design for Phase I oncology trials where each new patient is assigned to the dose most likely to be the target dose given observed data. The main model assumption is that the dose-toxicity curve is non-decreasing. This method is beneficial when it is desirable to assign a patient to a dose as soon as the patient is enrolled into a study. To prevent assignments to doses with limited toxicity information in fast accruing trials we propose a conservative rule that assigns temporary fractional toxicities to patients still in follow-up. We also recommend always using a safety rule in any fast accruing dose-finding trial. Copyright © 2016 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]
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- 2016
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17. Clinical Predictors of Early Trial Discontinuation for Patients Participating in Phase I Clinical Trials in Oncology
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Ramy Sedhom, Mikkjal Skardhamar, Michael A. Carducci, Henk M.W. Verheul, Joeri A. J. Douma, Divya Dharmaraj, Anthony De Felice, Mariette Labots, Laurien M. Buffart, Esther Lee, Willemien C. Menke-van der Houven van Oordt, Nilofer S. Azad, APH - Health Behaviors & Chronic Diseases, CCA - Cancer Treatment and quality of life, and Internal medicine
- Subjects
0301 basic medicine ,Cancer Research ,medicine.medical_specialty ,Early discontinuation ,hyponatremia ,Lower limit ,Article ,phase I trial ,03 medical and health sciences ,Tumours of the digestive tract Radboud Institute for Health Sciences [Radboudumc 14] ,0302 clinical medicine ,Internal medicine ,medicine ,RC254-282 ,business.industry ,Sodium level ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,clinical predictors ,medicine.disease ,drug development ,Current analysis ,Elevated alkaline phosphatase ,Discontinuation ,Clinical trial ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,medicine.symptom ,Hyponatremia ,business ,early trial discontinuation - Abstract
Despite stringent eligibility criteria for trial participation, early discontinuation often occurs in phase I trials. To better identify patients unlikely to benefit from phase I trials, we investigated predictors for early trial discontinuation. Data from 415 patients with solid tumors who participated in 66 trials were pooled for the current analysis. Early trial discontinuation was defined as (i) trial discontinuation within 28 days after start of treatment or (ii) discontinuation before administration of the first dosage in eligible patients. Multilevel logistic regression analyses were conducted to identify predictors for early trial discontinuation. Eighty-two participants (20%) demonstrated early trial discontinuation. Baseline sodium level below the lower limit of normal (OR = 2.95, 95%CI = 1.27–6.84), elevated alkaline phosphatase level >, 2.5 times the upper limit of normal (OR = 2.72, 95%CI = 1.49–4.99), performance score ≥ 1 (OR = 2.07, 95%CI = 1.03–4.19) and opioid use (OR = 1.82, 95%CI = 1.07–3.08) were independent predictors for early trial discontinuation. Almost 50% of the patients with hyponatremia and all four patients in whom all four predictors were present together discontinued the trial early. Hyponatremia, elevated alkaline phosphatase level, performance score ≥1 and opioid use were identified as significant predictors for early trial discontinuation. Hyponatremia was the strongest predictor and deserves consideration for inclusion in eligibility criteria for future trials.
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- 2021
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18. Phase I trial of concurrent chemoradiotherapy with docetaxel, cisplatin and 5-fluorouracil (TPF-CRT) for locally advanced squamous cell carcinoma of the external auditory canal
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Natsumi Uehara, Naomi Kiyota, Takeshi Fujita, Ken-ichi Nibu, Akinobu Kakigi, Masanori Teshima, Yoshinori Imamura, Hirotaka Shinomiya, Daisuke Miyawaki, and Ryohei Sasaki
- Subjects
Oncology ,medicine.medical_specialty ,TPF ,medicine.medical_treatment ,Locally advanced ,Docetaxel ,Recommended dose ,Phase I trial ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,Cisplatin ,business.industry ,Cancer ,General Medicine ,Chemoradiotherapy ,medicine.disease ,Radiation therapy ,Otorhinolaryngology ,Fluorouracil ,Head and Neck Neoplasms ,Carcinoma, Squamous Cell ,Taxoids ,business ,External auditory canal cancer ,Febrile neutropenia ,Ear Canal ,medicine.drug - Abstract
Purpose: Chemoradiotherapy with docetaxel (DOC), cisplatin (CDDP), and 5-FU (TPF-CRT) for locally advanced external auditory canal cancer (EACC) has favorable oncological and functional outcomes. To establish TPF-CRT as a standard of care for advanced EACC, we conducted this study to determine the maximum tolerated (MTD) and recommended dose (RD) of DOC in TPF-CRT for locally advanced EACC. Methods: To determine the recommended (RD) and maximum tolerated dose (MTD) of DOC in TPF-CRT for EACC, a phase I trial was conducted using the standard “3 + 3” design for maximum dose finding. DOC was administered twice every 4 weeks, CDDP at 70 mg/m² and 5-FU at 700 mg/m²; patients were also receiving radiotherapy (66 Gy). Eight patients with T3 or T4 EACC were prospectively enrolled. Results: Two patients treated with DOC, 50 mg/m², and one out of six patients treated with DOC, 40 mg/m², had dose-limiting toxicities. Prolonged febrile neutropenia was observed in three patients. Grade 3 non-hematological toxicities were observed in only three patients. At study completion, six patients survived, five of whom were disease free. Conclusion: The RD and MTD of DOC in TPF-CRT for locally advanced EACC are 40 mg/m² when doses of CDDP and 5-FU are 70 mg/m² and 700 mg/m², respectively.
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- 2021
19. A comparative study of adaptive dose-finding designs for phase I oncology trials of combination therapies.
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Hirakawa, Akihiro, Wages, Nolan A., Sato, Hiroyuki, and Matsui, Shigeyuki
- Abstract
Little is known about the relative performance of competing model-based dose-finding methods for combination phase I trials. In this study, we focused on five model-based dose-finding methods that have been recently developed. We compared the recommendation rates for true maximum-tolerated dose combinations (MTDCs) and over-dose combinations among these methods under 16 scenarios for 3 × 3, 4 × 4, 2 × 4, and 3 × 5 dose combination matrices. We found that performance of the model-based dose-finding methods varied depending on (1) whether the dose combination matrix is square or not; (2) whether the true MTDCs exist within the same group along the diagonals of the dose combination matrix; and (3) the number of true MTDCs. We discuss the details of the operating characteristics and the advantages and disadvantages of the five methods compared. [ABSTRACT FROM AUTHOR]
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- 2015
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20. Competing designs for drug combination in phase I dose-finding clinical trials.
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Riviere, M.‐K., Dubois, F., and Zohar, S.
- Abstract
The aim of phase I combination dose-finding studies in oncology is to estimate one or several maximum tolerated doses (MTDs) from a set of available dose levels of two or more agents. Combining several agents can indeed increase the overall anti-tumor action but at the same time also increase the toxicity. It is, however, unreasonable to assume the same dose-toxicity relationship for the combination as for the simple addition of each single agent because of a potential antagonist or synergistic effect. Therefore, using single-agent dose-finding methods for combination therapies is not appropriate. In recent years, several authors have proposed novel dose-finding designs for combination studies, which use either algorithm-based or model-based methods. The aim of our work was to compare, via a simulation study, six dose-finding methods for combinations proposed in recent years. We chose eight scenarios that differ in terms of the number and location of the true MTD(s) in the combination space. We then compared the performance of each design in terms of correct combination selection, patient allocation, and mean number of observed toxicities during the trials. Our results showed that the model-based methods performed better than the algorithm-based ones. However, none of the compared model-based designs gave consistently better results than the others. Copyright © 2014 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]
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- 2015
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21. A Bayesian dose-finding design for drug combination clinical trials based on the logistic model.
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Riviere, Marie‐Karelle, Yuan, Ying, Dubois, Frédéric, and Zohar, Sarah
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CLINICAL trials , *DRUG dosage , *ANTINEOPLASTIC agents , *CANCER treatment , *DRUG toxicity , *ONCOLOGY - Abstract
In early phase dose-finding cancer studies, the objective is to determine the maximum tolerated dose, defined as the highest dose with an acceptable dose-limiting toxicity rate. Finding this dose for drug-combination trials is complicated because of drug-drug interactions, and many trial designs have been proposed to address this issue. These designs rely on complicated statistical models that typically are not familiar to clinicians, and are rarely used in practice. The aim of this paper is to propose a Bayesian dose-finding design for drug combination trials based on standard logistic regression. Under the proposed design, we continuously update the posterior estimates of the model parameters to make the decisions of dose assignment and early stopping. Simulation studies show that the proposed design is competitive and outperforms some existing designs. We also extend our design to handle delayed toxicities. Copyright © 2014 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]
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- 2014
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22. Outcome analysis of Phase I trial patients with metastatic KRAS and/or TP53 mutant non-small cell lung cancer
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Naiyi Shi, Funda Meric-Bernstam, David S. Hong, Zhijie Wang, Vali Papadimitrakopoulou, Aung Naing, John V. Heymach, Russell Broaddus, Charles Lu, Vivek Subbiah, Daniel D. Karp, Apostolia Maria Tsimberidou, Yudong Wang, Kenneth R. Hess, Baoen Shan, Filip Janku, Siqing Fu, and Sarina Anne Piha-Paul
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0301 basic medicine ,Oncology ,medicine.medical_specialty ,endocrine system diseases ,overall survival ,STK11 ,medicine.disease_cause ,Metastasis ,03 medical and health sciences ,Phase I trial ,0302 clinical medicine ,CDKN2A ,Internal medicine ,medicine ,KRAS ,Missense mutation ,Epidermal growth factor receptor ,TP53 ,Lung cancer ,neoplasms ,non-small cell lung cancer ,biology ,business.industry ,medicine.disease ,digestive system diseases ,respiratory tract diseases ,030104 developmental biology ,030220 oncology & carcinogenesis ,biology.protein ,business ,Carcinogenesis ,Research Paper - Abstract
KRAS and TP53 mutations, which are the most common genetic drivers of tumorigenesis, are still considered undruggable targets. Therefore, we analyzed these genetic aberrations in metastatic non-small cell lung cancer (NSCLC) for the development of potential therapeutics. One hundred eighty-five consecutive patients with metastatic NSCLC in a phase 1 trial center were included. Their genomic aberrations, clinical characteristics, survivals, and phase 1 trial therapies were analyzed. About 10%, 18%, 36%, and 36% of the patients had metastatic KRAS+/TP53+, KRAS+/TP53-,KRAS-/TP53+, and KRAS-/TP53- NSCLC, respectively. The most common concurrent genetic aberrations beside KRAS and/or TP53 (>5%) were KIT, epidermal growth factor receptor, PIK3CA, c-MET, BRAF, STK11, ATM, CDKN2A, and APC. KRAS+/TP53+ NSCLC did not respond well to the phase 1 trial therapy and was associated with markedly worse progression-free (PFS) and overall (OS) survivals than the other three groups together. KRAS hotspot mutations at locations other than codon G12 were associated with considerably worse OS than those at this codon. Gene aberration-matched therapy produced prolonged PFS and so was anti-angiogenesis in patients with TP53 mutations. Introduction of the evolutionary action score system of TP53 missense mutations enabled us to identify a subgroup of NSCLC patients with low-risk mutant p53 proteins having a median OS duration of 64.5 months after initial diagnosis of metastasis. These data suggested that patients with metastatic dual KRAS+/TP53+ hotspot-mutant NSCLC had poor clinical outcomes. Further analysis identified remarkably prolonged survival in patients with low-risk mutant p53 proteins, which warrants confirmatory studies.
- Published
- 2018
23. A novel allogeneic off-the-shelf dendritic cell vaccine for post-remission treatment of elderly patients with acute myeloid leukemia
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Ada M. Kruisbeek, Tanja D. de Gruijl, Malika Koppes, Jorn Kaspers, Sandra van Wetering, Gert J. Ossenkoppele, Arjan A. van de Loosdrecht, Saskia J. A. M. Santegoets, Yvonne den Hartog, Corien Eeltink, Satwinder Kaur Singh, CCA - Cancer biology and immunology, AII - Cancer immunology, Hematology, Medical oncology, Molecular cell biology and Immunology, VU University medical center, and Medical oncology laboratory
- Subjects
Male ,Oncology ,Cancer Research ,medicine.medical_specialty ,T-Lymphocytes ,medicine.medical_treatment ,T cell ,Immunology ,Cancer Vaccines ,Dendritic cells ,Phase I trial ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Antigen ,Internal medicine ,Humans ,Immunology and Allergy ,Medicine ,Aged ,Acute myeloid leukemia ,business.industry ,Remission Induction ,Myeloid leukemia ,Immunotherapy ,Dendritic cell ,Middle Aged ,medicine.disease ,Comorbidity ,3. Good health ,Vaccination ,Leukemia, Myeloid, Acute ,Treatment Outcome ,medicine.anatomical_structure ,Immune therapy ,030220 oncology & carcinogenesis ,Original Article ,Female ,business ,030215 immunology - Abstract
In elderly acute myeloid leukemia (AML) patients post-remission treatment options are associated with high comorbidity rates and poor survival. Dendritic cell (DC)-based immunotherapy is a promising alternative treatment strategy. A novel allogeneic DC vaccine, DCP-001, was developed from an AML-derived cell line that uniquely combines the positive features of allogeneic DC vaccines and expression of multi-leukemia-associated antigens. Here, we present data from a phase I study conducted with DCP-001 in 12 advanced-stage elderly AML patients. Patients enrolled were in complete remission (CR1/CR2) (n = 5) or had smoldering disease (n = 7). All patients were at high risk of relapse and ineligible for post-remission intensification therapies. A standard 3 + 3 dose escalation design with extension to six patients in the highest dose was performed. Patients received four biweekly intradermal DCP-001 injections at different dose levels (10, 25, and 50 million cells DCP-001) and were monitored for clinical and immunological responses. Primary objectives of the study (feasibility and safety) were achieved with 10/12 patients completing the vaccination program. Treatment was well tolerated. A clear-cut distinction between patients with and without detectable circulating leukemic blasts during the vaccination period was noted. Patients with no circulating blasts showed an unusually prolonged survival [median overall survival 36 months (range 7–63) from the start of vaccination] whereas patients with circulating blasts, died within 6 months. Long-term survival was correlated with maintained T cell levels and induction of multi-functional immune responses. It is concluded that DCP-001 in elderly AML patients is safe, feasible and generates both cellular and humoral immune responses. Electronic supplementary material The online version of this article (10.1007/s00262-018-2198-9) contains supplementary material, which is available to authorized users.
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- 2018
24. Are phase I trials safe for older patients?
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Capucine Baldini, Antoine Hollebecque, Jean-Charles Soria, Carole Helissey, Olivier Mir, Sandrine Aspeslagh, Olivia Le Saux, Anas Gazzah, Christophe Massard, Eduardo Castanon, Andrea Varga, Rastilav Bahleda, Medical Oncology, and Laboratory of Molecular and Medical Oncology
- Subjects
Male ,Aging ,medicine.medical_specialty ,Pediatrics ,Population ,Medical Oncology ,Phase I trial ,03 medical and health sciences ,0302 clinical medicine ,Older patients ,Neoplasms ,medicine ,Humans ,030212 general & internal medicine ,education ,Geriatric Assessment ,Toxicity profile ,Aged ,Cancer ,Aged, 80 and over ,education.field_of_study ,Clinical Trials, Phase I as Topic ,business.industry ,Clinical study design ,Age Factors ,toxicity ,Phase i trials ,drug development ,Clinical trial ,Cancer rate ,Oncology ,Drug development ,030220 oncology & carcinogenesis ,Polypharmacy ,Physical therapy ,Female ,Safety ,Geriatrics and Gerontology ,business - Abstract
Phase I clinical trials in oncology primarily aim to assess the toxicity profile of new drugs and determine recommended phase II doses (RP2D). Since the cancer rate increases with age and our population is continually aging, RP2D must necessarily be assessed in older patients. Few clinical studies include older patients, however, and particularly few Phase I trials. We reviewed published data on the safety and efficacy of Phase I trials in older patients. The majority of studies included primarily young, fit patients, with age thresholds varying widely from 65 to 80years. However, age does not seem to be associated with more toxicity or less efficacy. While Phase I trials seem feasible in fit older patients, geriatric-medicine score systems should be included in the clinical trial design in order to better characterize this population.
- Published
- 2018
25. Neoadjuvant therapy for resectable pancreatic cancer
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Robin Urquhart, Michele Molinari, and Sheikh Hasibur Rahman
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Oncology ,Resectable Pancreatic Cancer ,medicine.medical_specialty ,medicine.medical_treatment ,Locally advanced ,Decision analysis ,Neoadjuvant chemotherapy ,Borderline resectable ,law.invention ,Phase I trial ,03 medical and health sciences ,0302 clinical medicine ,Quality of life ,Randomized controlled trial ,law ,Internal medicine ,Neoadjuvant chemoradiation therapy ,medicine ,Preoperative chemotherapy ,Neoadjuvant therapy ,business.industry ,Gastroenterology ,Minireviews ,Meta-analysis ,030220 oncology & carcinogenesis ,030211 gastroenterology & hepatology ,Phase II trial ,Phase III trial ,business ,Pancreatic adenocarcinoma - Abstract
The use of neoadjuvant therapies has played a major role for borderline resectable and locally advanced pancreatic cancers (PCs). For this group of patients, preoperative chemotherapy or chemoradiation has increased the likelihood of surgery with negative resection margins and overall survival. On the other hand, for patients with resectable PC, the main rationale for neoadjuvant therapy is that the overall survival with current strategies is unsatisfactory. There is a consensus that we need new treatments to improve the overall survival and quality of life of patients with PC. However, without strong scientific evidence supporting the theoretical advantages of neoadjuvant therapies, these potential benefits might turn out not to be worth the risk of tumors progression while waiting for surgery. The focus of this paper is to provide the readers an overview of the most recent evidence on this subject.
- Published
- 2017
26. Creatinine Clearance Is Associated with Toxicity from Molecularly Targeted Agents in Phase I Trials.
- Author
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Basu, B., Vitfell-Pedersen, J., Moreno Garcia, V., Puglisi, M., Tjokrowidjaja, A., Shah, K., Malvankar, S., Anghan, B., de Bono, J.S., Kaye, S.B., Molife, L.R., and Banerji, U.
- Subjects
- *
CREATININE , *TOXICOLOGY , *CLINICAL trials , *HETEROCYCLIC compounds , *ONCOLOGY - Abstract
Objectives: This study aimed to evaluate any correlations between baseline creatinine clearance and the development of grade 3/4 toxicities during treatment within oncology phase I trials of molecularly targeted agents where entry criteria mandate a serum creatinine of ≤1.5 × the upper limit of normal. Methods: Documented toxicity and creatinine clearance (calculated by the Cockcroft-Gault formula) from all patients treated with molecularly targeted agents in the context of phase I trials within our centre over a 5-year period were analyzed. Results: Data from 722 patients were analyzed; 116 (16%) developed at least one episode of grade 3/4 toxicity. Patients who developed a late-onset (>1 cycle) grade 3/4 toxicity had a lower creatinine clearance than those who did not (82.69 ml/min vs. 98.97 ml/min; p = < 0.001). Conclusion: Creatinine clearance (even when within normal limits) should be studied as a potential factor influencing late toxicities in the clinical trials of molecularly targeted anti-cancer drugs. Copyright © 2012 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]
- Published
- 2012
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27. PET imaging of hypoxia using [18F]HX4: a phase I trial.
- Author
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van Loon, Judith, Janssen, Marco H. M., Öllers, Michel, Aerts, Hugo J. W. L., Dubois, Ludwig, Hochstenbag, Monique, Dingemans, Anne-Marie C., Lalisang, Roy, Brans, Boudewijn, Windhorst, Bert, Dongen, Guus A., Kolb, Hartmuth, Zhang, James, De Ruysscher, Dirk, and Lambin, Philippe
- Subjects
- *
POSITRON emission tomography , *HYPOXEMIA , *NITROIMIDAZOLES , *TOXICITY testing , *RADIATION-sensitizing agents , *ONCOLOGY , *DIAGNOSIS - Abstract
Noninvasive PET imaging of tumour hypoxia could help in the selection of those patients who could benefit from chemotherapy or radiation with specific antihypoxic treatments such as bioreductive drugs or hypoxic radiosensitizers. In this phase I trial, we aimed to determine the toxicity of [18F]HX4, a member of the 2-nitroimidazole family, at different dose levels. The secondary aim was to analyse image quality related to the HX4 dose and the timing of imaging. Patients with a histologically proven solid cancer without curative treatment options were eligible for this study. A study design with two dose steps was used in which a single dose of a maximum of 222 MBq (step 1) or 444 MBq (step 2) [18F]HX4 was injected. Toxicity was scored on day 0 and on days 3 and 7 after injection, according to the CTCAE 3.0 scoring system. PET/CT images of the largest tumour site were acquired 30, 60 and 120 min after injection. Six patients with stage IV carcinoma were included, four with non-small-cell lung carcinoma, one with thymus carcinoma, and one with colon carcinoma. No toxicity was observed in any of the patients at either dose level. The median tumour to muscle ratio 120 min after injection was 1.40 (range 0.63–1.98). The findings of this study showed that [18F]HX4 PET imaging for the detection of hypoxia is not associated with any toxicity. Imaging was successful; however, future trials are needed to determine the optimal image parameters. [ABSTRACT FROM AUTHOR]
- Published
- 2010
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28. Phase I trial of the androgen receptor modulator CR1447 in breast cancer patients
- Author
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Martin Zweifel, Beat Thürlimann, Salome Riniker, Patrik Weder, Roger von Moos, Olivia Pagani, Martin Bigler, Karin M Rothgiesser, Christiane Pilop, Hanne Hawle, Peter Brauchli, Coya Tapia, Wolfgang Schoenfeld, and Cristiana Sessa
- Subjects
0301 basic medicine ,Oncology ,medicine.medical_specialty ,Nausea ,Endocrinology, Diabetes and Metabolism ,Urinary system ,610 Medicine & health ,Gastroenterology ,lcsh:Diseases of the endocrine glands. Clinical endocrinology ,phase I trial ,03 medical and health sciences ,0302 clinical medicine ,Endocrinology ,Breast cancer ,breast cancer ,Internal medicine ,Internal Medicine ,medicine ,CR1447 ,Adverse effect ,lcsh:RC648-665 ,business.industry ,Research ,Cancer ,androgen receptor modulator ,medicine.disease ,Rash ,Androgen receptor ,030104 developmental biology ,030220 oncology & carcinogenesis ,Joint pain ,medicine.symptom ,business ,4-OH-testosterone - Abstract
CR1447 (4-hydroxytestosterone, 4-OHT) binds to the androgen receptor and has antiproliferative activity in both ER-positive and ER-negative/AR-positive breast cancer cells in preclinical studies. The objective of this first-in man trial was to evaluate the safety and to determine the dose of CR1447, administered as an ointment, for Phase II. Escalating doses (100, 200, 400 mg) of CR1447 were administered topically on a daily basis to patients with ER-positive/AR-positive/HER2-negative advanced breast cancer pretreated with several lines of therapy. 14 patients have been treated for a total of 42 cycles. Two patients, one at dose level 100 mg and one at dose level 200 mg, showed early tumour progression and were replaced. Related adverse events were all ≤ grade 2 and included fatigue, bone and joint pain, stiffness, dry skin and mouth, nausea, sweating, urinary tract infection, rash, headache and distress. No drug-related dose-limiting toxicities (DLTs) were seen. Two patients (17%) achieved stable disease at 3 months. Pharmacokinetic analysis confirmed dose-dependent transdermal uptake of CR1447. 4-OH-androstenedione (4-OHA), a key metabolite of 4-OHT, was undetectable in most of the plasma samples. Urine metabolites of 4-OHT and 4-OHA indicate high exposure of 4-OHT after topical administration. Oestradiol serum concentrations did not increase, confirming preclinical data that CR1447 is not converted to estrogens in vivo. In conclusion, CR1447 administered transdermally as an ointment is well tolerated and appears to have single-agent activity in heavily pretreated ER-positive/HER2-negative breast cancer patients. The recommended phase II dose is 400 mg/day.
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- 2017
29. Outcomes of phase I clinical trials for patients with advanced pancreatic cancer: update of the MD Anderson Cancer Center experience
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Apostolia Maria Tsimberidou, Milind Javle, David R. Fogelman, Filip Janku, Ralph Zinner, Siqing Fu, Aung Naing, Vivek Subbiah, Daniel D. Karp, Sarina Anne Piha-Paul, Jennifer Brooke Goldstein, Gauri R. Varadhachary, Chad Tang, Kenneth R. Hess, Funda Meric-Bernstam, Robert A. Wolff, Jennifer J. Wheler, and David S. Hong
- Subjects
Gerontology ,medicine.medical_specialty ,medicine.medical_treatment ,pancreatic cancer ,chemotherapy ,Targeted therapy ,phase I trial ,03 medical and health sciences ,0302 clinical medicine ,Cancer Medicine ,Pancreatic cancer ,Radiation oncology ,Medicine ,030304 developmental biology ,0303 health sciences ,business.industry ,General surgery ,Cancer ,targeted therapy ,medicine.disease ,Gemcitabine ,3. Good health ,Clinical trial ,Oncology ,030220 oncology & carcinogenesis ,biomarker ,Erlotinib ,business ,Research Paper ,medicine.drug - Abstract
// Jennifer B. Goldstein 1 , Chad Tang 2 , Kenneth R. Hess 3 , David Hong 4 , Vivek Subbiah 4 , Filip Janku 4 , Siqing Fu 4 , Daniel D. Karp 4 , Aung Naing 4 , Apostolia Maria Tsimberidou 4 , Jennifer Wheler 4 , Ralph Zinner 4 , Milind Javle 5 , Gauri R. Varadhachary 5 , Robert A. Wolff 5 , David R. Fogelman 5 , Funda Meric-Bernstam 4 and Sarina A. Piha-Paul 4 1 Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA 2 Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA 3 Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA 4 Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA 5 Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA Correspondence to: Jennifer B. Goldstein, email: jbgoldstein@mdanderson.org Keywords: pancreatic cancer, phase I trial, biomarker, chemotherapy, targeted therapy Received: November 02, 2016 Accepted: July 17, 2017 Published: August 03, 2017 ABSTRACT Background: In 2011, we reported the outcomes of pancreatic cancer (PC) patients enrolled in phase I trials at our institution from 2004 through 2009. At the time, gemcitabine and erlotinib were the only Food and Drug Administration-approved drugs for PC and median overall survival (OS) from consultation in the phase I clinic was 5 months. We sought to determine the impact of novel therapeutics on PC patients in phase I trials. Methods: We reviewed records of PC patients treated in phase I trials at our institution from January 2009 through December 2014. Survival was analyzed using the Kaplan-Meier method. Results: Ninety-five patients were identified. The median age was 61 years (range, 40-84), 59% were men, and 41% had stage IV disease. The median OS from consultation in the phase I clinic was 5.8 months (95% confidence interval [CI], 4.5-6.8), and the 1-year OS rate was 9% (95% CI, 4%-17%). Three patients had partial responses and 18 had stable disease ≥ 4 months. Conclusion: We observed no improvement in OS between PC patients enrolled in phase I trials in 2004-2009 and 2009-2015. To substantially improve OS in this challenging disease, improved patient selection and science-driven, innovative trial designs will be key.
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- 2017
30. Antiangiogenesis and gene aberration-related therapy may improve overall survival in patients with concurrent KRAS and TP53 hotspot mutant cancer
- Author
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James C. Yao, Jing Gong, Kenneth R. Hess, Zhijie Wang, Funda Meric-Bernstam, Siqing Fu, Kenna R. Mills Shaw, Filip Janku, Sarina Anne Piha-Paul, Naiyi Shi, Apostolia Maria Tsimberidou, David S. Hong, Aung Naing, Russell Broaddus, Daniel D. Karp, Chetna Wathoo, and Vivek Subbiah
- Subjects
0301 basic medicine ,Oncology ,Male ,Pathology ,chronic inflammation ,endocrine system diseases ,Angiogenesis Inhibitors ,Kaplan-Meier Estimate ,medicine.disease_cause ,phase I trial ,0302 clinical medicine ,Neoplasms ,Antineoplastic Combined Chemotherapy Protocols ,Hypoalbuminemia ,TP53 ,Neoplasm Metastasis ,gene aberration-related therapy ,Aged, 80 and over ,Neovascularization, Pathologic ,Middle Aged ,Prognosis ,Treatment Outcome ,030220 oncology & carcinogenesis ,Female ,KRAS ,Research Paper ,Adult ,medicine.medical_specialty ,Adolescent ,Antineoplastic Agents ,03 medical and health sciences ,Young Adult ,Internal medicine ,medicine ,Overall survival ,Humans ,neoplasms ,Aged ,Neoplasm Staging ,Thrombocytosis ,business.industry ,medicine.disease ,Clinical trial ,030104 developmental biology ,Concomitant ,Mutation ,ras Proteins ,Tumor Suppressor Protein p53 ,Carcinogenesis ,business ,Body mass index - Abstract
// Zhijie Wang 1, 6 , Sarina Piha-Paul 1 , Filip Janku 1 , Vivek Subbiah 1 , Naiyi Shi 1 , Jing Gong 1 , Chetna Wathoo 2 , Kenna Shaw 2 , Kenneth Hess 3 , Russell Broaddus 4 , Aung Naing 1 , David Hong 1 , Apostolia M. Tsimberidou 1 , Daniel Karp 1 , James Yao 5 , Funda Meric-Bernstam 1 and Siqing Fu 1 1 Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA 2 Institute of Personalized Cancer Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA 3 Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA 4 Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA 5 Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA 6 National Cancer Center/Cancer Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China Correspondence to: Siqing Fu, email: siqingfu@mdanderson.org Keywords: KRAS, TP53, chronic inflammation, phase I trial, gene aberration-related therapy Received: October 15, 2016 Accepted: March 16, 2017 Published: April 05, 2017 ABSTRACT Purpose: Genetic alterations such as activating KRAS and/or inactivating TP53 are thought to be the most common drivers to tumorigenesis. Therefore, we assessed phase I cancer patients with KRAS+ / TP53+ mutations. Results: Approximately 8% of patients referred to phase I clinical trials harbored concurrent KRAS and TP53 mutations. Patients who received a phase I trial therapy (n = 57) had a median OS of 12 months, compared with 4.6 months in those who were not treated (n = 106; p = 0.003). KRAS G13 and TP53 R273 mutations were associated with poor overall survival (OS), while antiangiogenesis and gene aberration-related therapies were associated with prolonged OS. A prognostic model using neutrophilia, thrombocytosis, hypoalbuminemia, body mass index
- Published
- 2017
31. Phase I/II trial of weekly docetaxel and concomitant radiotherapy for squamous cell carcinoma of the head and neck.
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Fujii, Masato, Tsukuda, Mamoru, Satake, Bunsuke, Kubota, Akira, Kida, Akinori, Kohno, Naoyuki, Okami, Kenji, and Inuyama, Yukio
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CANCER , *DOCETAXEL , *RADIOTHERAPY , *CLINICAL trials , *ONCOLOGY - Abstract
Background. A phase I/II trial of concurrent docetaxel and radiation for head and neck cancer was conducted to estimate the recommended dose schedule of docetaxel, and then to evaluate the therapeutic benefit. Methods. Patients received radiation in 2.0-Gy single daily fractions to a total dose of 60Gy. Docetaxel was administered weekly for 6 consecutive weeks. Results. Docetaxel 15mg/m² was considered the maximum tolerated dose (MTD). The recommended dose was decided as 10mg/m². The phase II study was conducted using docetaxel at 10mg/m². Thirty-nine patients were enrolled. The overall response rate was 96.9%. The prognosis of the complete response (CR) patients was significantly better than that of the partial response (PR) patients. Grade 3 or 4 adverse events consisted of lymphopenia, stomatitis, and anorexia. Thirty-two of the 35 eligible patients showed high compliance, of over 90%, and their toxicities were manageable. Conclusion. Even low-dose docetaxel shows a strong effect in combination with radiation, with a high survival rate in CR patients. The effect on survival will be assessed by further follow-up. [ABSTRACT FROM AUTHOR]
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- 2004
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32. Phase I trial of<scp>GBS</scp>‐01 for advanced pancreatic cancer refractory to gemcitabine
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Kayo Toyosaki, Satoshi Yomoda, Hiroyasu Esumi, Masafumi Ikeda, Nobuo Mochizuki, Hideaki Takahashi, Hiromi Hasegawa, Izumi Ohno, Rumi Fujioka, Shuichi Mitsunaga, Yusuke Hashimoto, Chika Miyoshi, Shogo Nomura, Akihiro Sato, Katsuya Tsuchihara, Ryuji Takahashi, and Satoshi Kishino
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Male ,0301 basic medicine ,Oncology ,Cancer Research ,medicine.medical_treatment ,pancreatic cancer ,chemotherapy ,Deoxycytidine ,Gastroenterology ,phase I trial ,chemistry.chemical_compound ,0302 clinical medicine ,Neoplasm Metastasis ,gemcitabine ,General Medicine ,Middle Aged ,Treatment Outcome ,030220 oncology & carcinogenesis ,Toxicity ,Original Article ,Female ,Drug Monitoring ,medicine.drug ,Adult ,medicine.medical_specialty ,Maximum Tolerated Dose ,03 medical and health sciences ,Pharmacokinetics ,Clinical Research ,natural anticancer compound ,Internal medicine ,Pancreatic cancer ,Biomarkers, Tumor ,medicine ,Humans ,Adverse effect ,Arctigenin ,Aged ,Neoplasm Staging ,Chemotherapy ,business.industry ,Original Articles ,medicine.disease ,Antineoplastic Agents, Phytogenic ,Survival Analysis ,Gemcitabine ,Bioavailability ,Pancreatic Neoplasms ,030104 developmental biology ,chemistry ,Drug Resistance, Neoplasm ,Neoplasm Recurrence, Local ,Tomography, X-Ray Computed ,business - Abstract
GBS-01, an extract from the fruit of Arctium lappa L. is an orally administered drug rich in arctigenin, which has been reported to exert antitumor activity by attenuating the tolerance of cancer cells to glucose deprivation. We investigated the maximum tolerated dose of GBS-01 based on the frequency of the dose-limiting toxicities (DLTs) and pharmacokinetics in patients with advanced pancreatic cancer refractory to gemcitabine. GBS-01 was given orally at escalating doses from 3.0 g (containing 1.0 g burdock fruit extract) to 12.0 g q.d. A DLT was defined as a grade 4 hematological toxicity and grade 3 or 4 non-hematological toxicity appearing during the first 28 days of treatment. Fifteen patients (GBS-01 dose level 1 [3.0 g], three patients; dose level 2 [7.5 g], three patients; and dose level 3 [12.0 g], nine patients) were enrolled. None of the patients at any of the three dose levels showed any sign of DLTs. The main adverse events were increased serum γ-glutamyl transpeptidase, hyperglycemia, and increased serum total bilirubin; however, all the toxicities were mild. Of the 15 patients, 1 showed confirmed partial response and 4 patients had stable disease. The median progression-free and overall survival of the patients were 1.1 and 5.7 months, respectively. The pharmacokinetic study revealed a high bioavailability of arctigenin and rapid conjugation of the drug with glucuronic acid. The recommended dose of GBS-01 was 12.0 g q.d, and favorable clinical responses were obtained. This trial was registered at UMIN-CTR (http://www.umin.ac.jp/ctr/index-j.htm), identification number UMIN000005787.
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- 2016
33. Health-related quality of life as an endpoint in oncology phase I trials: a systematic review
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Amélie Anota, Ahmad Ousmen, Franck Bonnetain, Isabelle Le Ray, Nicolas Isambert, Frédéric Fiteni, Department of Medical Oncology [Nîmes], Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Université de Montpellier (UM), Department of Neonatology [Strasbourg], CHU Strasbourg, Department of Medical Epidemiology and Biostatistics (MEB), Karolinska Institutet [Stockholm], Unité de Méthodologie et de Qualité de Vie en Cancérologie (UMQVC), Carcinogénèse épithéliale : facteurs prédictifs et pronostiques - UFC (EA 3181) (CEF2P / CARCINO), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Pôle cancérologie (CHRU Besançon), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Institut Régional Fédératif du Cancer (IRFC), Département d'oncologie médicale [Centre Georges-François Leclerc], Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER-UNICANCER, French National Platform Quality of Life and Cancer [Dijon], Bodescot, Myriam, Carcinogénèse épithéliale : facteurs prédictifs et pronostiques - UFC (UR 3181) (CEF2P / CARCINO), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Institut Régional Fédératif du Cancer (IRFC), and Plateforme nationale qualité de vie et cancer
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0301 basic medicine ,Oncology ,Cancer Research ,medicine.medical_specialty ,Health-related quality of life ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,lcsh:RC254-282 ,Phase I trial ,03 medical and health sciences ,0302 clinical medicine ,[SDV.CAN] Life Sciences [q-bio]/Cancer ,Quality of life ,Surgical oncology ,Neoplasms ,Surveys and Questionnaires ,Internal medicine ,Outcome Assessment, Health Care ,Recommended phase II dose ,Genetics ,medicine ,Humans ,Adverse effect ,Neoplasm Staging ,Health related quality of life ,Clinical Trials, Phase I as Topic ,business.industry ,Minimal clinically important difference ,Repeated measures design ,Common Terminology Criteria for Adverse Events ,Phase i trials ,[SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Endpoint ,Combined Modality Therapy ,humanities ,3. Good health ,[SDV.SP] Life Sciences [q-bio]/Pharmaceutical sciences ,Treatment Outcome ,030104 developmental biology ,[SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie ,030220 oncology & carcinogenesis ,Quality of Life ,[SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie ,business ,Research Article - Abstract
International audience; BACKGROUND:Phase I trials aim to identify the recommended dose for further development. Health-related quality of life (HRQoL) could be a complement to the usual National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) scale to detect adverse events and define the doses. The objective of this study is to review the phase I in oncology which used HRQoL as endpoint.METHODS:A search in PubMed database identified phase I trials in oncology with HRQoL as endpoint, published between January 2012 to May 2016. Hematological and pediatric phase I were excluded.RESULTS:A total of 1333 phase I were identified and 15 trials were identified with HRQoL as endpoint (1.1%). The European Organisation for Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30) was the most frequently used instrument: 5 studies (33.3%). The targeted dimensions of HRQoL and the minimal clinically important difference were prespecified in 1 study (6.7%) and 2 studies (13.3%), respectively. Twelve studies (80%) described the statistical approach to analyze HRQoL data. Eight studies used the mean change from baseline (60%) to analyse longitudinal HRQoL data, two the mean score at certain times (13.3%), one the linear mixed model for repeated measures (6.7%), one the time to HRQoL score deterioration (6.7%), one percentage of patient-reported symptoms (6.7%). None of the studies used HRQoL to determine the recommended doses.CONCLUSION:Few phase I studies used HRQoL as endpoint and among studies with HRQoL as endpoint, the methodology of HRQoL measurement and statistical analysis was heterogeneous. HRQoL. endpoint not used for assessing the recommended phase II doses.
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- 2019
34. A Phase I, Dose-Escalation Trial of Pazopanib in Combination with Cisplatin in Patients with Advanced Solid Tumors: A UNICANCER Study
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Florence Joly, Christophe Le Tourneau, Christine Orsini, Emmanuelle Bompas, Pierre Fumoleau, Thomas Bachelot, Véronique Diéras, Etienne Chatelut, Marta Jimenez, Sabine Noal, Nicolas Isambert, Diane Charlotte Imbs, Mario Campone, and Philippe A. Cassier
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0301 basic medicine ,Oncology ,medicine.medical_specialty ,Pharmacology ,Pazopanib ,03 medical and health sciences ,Phase I trial ,0302 clinical medicine ,Internal medicine ,Solid tumors ,medicine ,Dose escalation ,In patient ,Aprepitant ,Original Research ,Cisplatin ,business.industry ,030104 developmental biology ,030220 oncology & carcinogenesis ,Safety ,business ,medicine.drug - Abstract
Introduction To determine the feasibility, maximum-tolerated dose (MTD), and dose-limiting toxicities (DLT) of pazopanib in combination with cisplatin. Methods Patients with advanced malignancies were included in a 3 + 3 dose-escalation phase I study. Pazopanib administration started 8 days before the first infusion of cisplatin; some patients were treated according to a reverse sequence (cisplatin first). Five dose levels (DLs) were planned. MTD was based on DLT observed during cycles 1 and 2. Results Thirty-five patients were enrolled. The MTD was reached at the first DL, (pazopanib 400 mg daily + cisplatin 75 mg/m2 every 21 days). Main DLTs were pulmonary embolism, neutropenia, thrombocytopenia, and elevation of liver enzymes. Overall, most common adverse events were anemia (83%), fatigue (80%), thrombocytopenia (80%), neutropenia (73%), hypertension (59%), neurotoxicity (56%), and anorexia (53%). Sixteen patients (46%) discontinued the study due to toxicity. One patient (sarcoma) had a complete response, and three patients (one with breast cancer and two with ovarian cancers) had a partial response. Pharmacokinetic (PK) analyses showed interactions with aprepitant, resulting in increased exposure to pazopanib, which might explain partly the poor tolerance of the combination. Conclusion Cisplatin and pazopanib could not be administered at their single agent full doses, partly due to a PK interaction between pazopanib and aprepitant. Funding This work was funded by GlaxoSmithKline and by the charity Ligue Nationale de Lutte Contre le Cancer. Trial registered ClinicalTrials.gov identifier, NCT01165385.
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- 2016
35. A multicenter phase I study of preoperative chemoradiotherapy with S-1 and irinotecan for locally advanced lower rectal cancer (SAMRAI-1)
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Kazushige Hayakawa, Masafumi Noda, Masahiko Watanabe, Masahiro Hiraoka, Daiki Kato, Yoshiharu Sakai, Naohiro Tomita, Takeo Sato, Hitoshi Ikushima, Masahiro Takeuchi, Hideo Baba, Keiko Nemoto-Murofushi, Toshiaki Watanabe, Norihiko Kamikonya, Natsuo Oya, Masatoshi Oya, and Mitsuo Shimada
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0301 basic medicine ,Oncology ,Male ,Colorectal cancer ,medicine.medical_treatment ,0302 clinical medicine ,Antineoplastic Combined Chemotherapy Protocols ,Rectal cancer ,Neoadjuvant therapy ,Standard treatment ,Hematology ,Chemoradiotherapy ,S-1 ,Middle Aged ,Magnetic Resonance Imaging ,Neoadjuvant Therapy ,Neoadjuvant chemoradiotherapy ,Drug Combinations ,Radiology Nuclear Medicine and imaging ,030220 oncology & carcinogenesis ,Female ,Radiology ,medicine.drug ,Adult ,Diarrhea ,medicine.medical_specialty ,Maximum Tolerated Dose ,Irinotecan ,Tegafur ,Drug Administration Schedule ,03 medical and health sciences ,Phase I trial ,Internal medicine ,medicine ,Humans ,Radiology, Nuclear Medicine and imaging ,Aged ,business.industry ,Rectal Neoplasms ,Radiotherapy Planning, Computer-Assisted ,medicine.disease ,digestive system diseases ,Regimen ,Oxonic Acid ,030104 developmental biology ,Camptothecin ,business ,Tomography, X-Ray Computed - Abstract
Background and purpose: Preoperative 5-fluorouracil-based chemoradiotherapy is a standard treatment for locally advanced lower rectal cancer (LALRC). We performed a phase I study to develop a new regimen combining irinotecan and S-1. Materials and methods: Patients with LALRC (T3-4, N0-2) were studied. The radiation dose was 45 Gy in 25 fractions. S-1 (80 mg/m2/day) was administered on days 1–5, 8–12, 22–26, and 29–33. Irinotecan was administered on days 1, 8, 22, and 29. The dose of irinotecan was initially 60 mg/m2 (level 1). Surgery was performed 6–10 weeks after the chemoradiotherapy. Results: Twenty patients were enrolled, of whom 18 patients were analyzed. Dose-limiting toxicity (DLT) did not occur in the first 3 patients treated with irinotecan at 80 mg/m2 (level 2), but developed in 3 of the 6 patients who received irinotecan at 90 mg/m2 (level 3). Then DLT occurred in 3 other patients at level 2. At level 2 or 3, DLT comprised neutropenia, thrombocytopenia, and diarrhea. Level 2 was designated as the maximum tolerated dose, and level 1 as a recommended dose (RD). The pathological complete response rate was 28%, and the down-staging rate was 56%. Conclusions: Our results suggested that the RD of irinotecan when combined with preoperative S-1 and pelvic radiation was 60 mg/m2.
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- 2016
36. Pragmatic dose-escalation methods incorporating relative dose intensity assessment for molecularly targeted agents in phase I trials
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Akihiro Hirakawa, Yuichi Tanaka, and Shuhei Kaneko
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Pharmacology ,lcsh:R5-920 ,Toxicity data ,Phase i trials ,General Medicine ,Dose intensity ,Article ,Phase I trial ,03 medical and health sciences ,Dose finding ,0302 clinical medicine ,Oncology ,Statistics ,Assessment methods ,Dose escalation ,030212 general & internal medicine ,Relative dose intensity ,lcsh:Medicine (General) ,030217 neurology & neurosurgery ,Mathematics - Abstract
The recommended phase 2 doses of molecularly targeted agents, determined by using an ordinal dose-finding method that only uses toxicity data at first cycle, may not be optimal. Some researchers have proposed the use of relative dose intensity that can account for late-onset, cumulative, and low-grade toxicities to determine the recommended phase 2 dose (RP2D). In this study, we proposed two dose escalation methods based on the observed relative dose intensities (RDIs) between the pre-specified intervals (cycles) for toxicity evaluation used in combination with DLT evaluation in the first cycle. First, we propose the modified 3 + 3 design that incorporates longitudinal RDI assessment. Second, we propose the sequential assessment method for longitudinal RDI (SARDI) to achieve faster dose escalation compared to that of the modified 3 + 3 design. Simulation studies demonstrated that the SARDI was, in many cases, superior to the ordinal and modified 3 + 3 designs in respect to the selection rate of true RP2D and study period. The two proposed methods could also in some cases decrease the average number of patients enrolled in the trial compared to that of the ordinary 3 + 3 design. Incorporation of the RDI assessment into the 3 + 3 design is not difficult and does not require the use of complex statistical techniques. Therefore, we believe that investigators who routinely use the 3 + 3 design in practice can easily use our proposed methods. Keywords: Dose finding, Oncology, Relative dose intensity, Phase I trial
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- 2019
37. The advantage of Flash radiotherapy confirmed in mini-pig and cat-cancer patients
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Maud Jaccard, Marie-Catherine Vozenin, Jean Bourhis, Marco Burki, Patrick Devauchelle, Claude Bailat, Kristoffer Petersson, François Bochud, Jean François Germond, Gisele Ferrand, David Patin, Pauline de Fornel, Benoit Petit, Vincent Favaudon, Hanan Bouchaab, Mahmut Ozsahin, Centre Hospitalier Universitaire Vaudois [Lausanne] ( CHUV ), Génotoxicologie, signalisation et radiothérapie expérimentale, Institut National de la Santé et de la Recherche Médicale ( INSERM ) -INSTITUT CURIE, Université de Lausanne ( UNIL ), Institut de Génétique et Développement de Rennes ( IGDR ), Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Centre National de la Recherche Scientifique ( CNRS ) -Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Lausanne = University of Lausanne (UNIL), Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), nd, ISREC fundation/Biletema, CR32I3L_156924, Lead Agency FNS/ANR, Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Curie [Paris], Université de Lausanne (UNIL), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)
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Cancer Research ,medicine.medical_specialty ,medicine.medical_treatment ,Urology ,Locally advanced ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,cat-patients ,030218 nuclear medicine & medical imaging ,phase I trial ,03 medical and health sciences ,0302 clinical medicine ,FLASH-RT ,medicine ,Mucositis ,Carcinoma ,CATS ,business.industry ,Cancer ,differential effect ,normal tissue protection ,medicine.disease ,Acute toxicity ,Radiation therapy ,Oncology ,030220 oncology & carcinogenesis ,Toxicity ,business ,[ SDV.GEN ] Life Sciences [q-bio]/Genetics - Abstract
Purpose: Previous studies using FLASH radiotherapy (RT) in mice showed a marked increase of the differential effect between normal tissue and tumors. To stimulate clinical transfer, we evaluated whether this effect could also occur in higher mammals. Experimental Design: Pig skin was used to investigate a potential difference in toxicity between irradiation delivered at an ultrahigh dose rate called “FLASH-RT” and irradiation delivered at a conventional dose rate called “Conv-RT.” A clinical, phase I, single-dose escalation trial (25–41 Gy) was performed in 6 cat patients with locally advanced T2/T3N0M0 squamous cell carcinoma of the nasal planum to determine the maximal tolerated dose and progression-free survival (PFS) of single-dose FLASH-RT. Results: Using, respectively, depilation and fibronecrosis as acute and late endpoints, a protective effect of FLASH-RT was observed (≥20% dose-equivalent difference vs. Conv-RT). Three cats experienced no acute toxicity, whereas 3 exhibited moderate/mild transient mucositis, and all cats had depilation. With a median follow-up of 13.5 months, the PFS at 16 months was 84%. Conclusions: Our results confirmed the potential advantage of FLASH-RT and provide a strong rationale for further evaluating FLASH-RT in human patients. See related commentary by Harrington, p. 3
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- 2018
38. Dose-finding study of hepatic arterial infusion of irinotecan-based treatment in patients with advanced cancers metastatic to the liver
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Filip Janku, Jennifer J. Wheler, Michael J. Wallace, Savita Bidyasar, Joann Lim, David S. Hong, Aung Naing, Razelle Kurzrock, Siqing Fu, Sarina Anne Piha-Paul, Rabih Said, Apostolia Maria Tsimberidou, and Bryan K. Kee
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Male ,Oncology ,Organoplatinum Compounds ,Cetuximab ,Hepatic Artery ,Phytogenic ,Antineoplastic Combined Chemotherapy Protocols ,80 and over ,Medicine ,Pharmacology (medical) ,Infusions, Intravenous ,6.2 Cellular and gene therapies ,Liver metastasis ,Cancer ,Aged, 80 and over ,Liver Disease ,Liver Neoplasms ,Pharmacology and Pharmaceutical Sciences ,Middle Aged ,Rash ,Bevacizumab ,Oxaliplatin ,6.1 Pharmaceuticals ,Female ,medicine.symptom ,Intravenous ,medicine.drug ,Adult ,Infusions ,medicine.medical_specialty ,Maximum Tolerated Dose ,Combination therapy ,Clinical Trials and Supportive Activities ,Antineoplastic Agents ,Neutropenia ,Irinotecan ,Article ,Phase I trial ,Hepatic arterial infusion ,Clinical Research ,Internal medicine ,Infusions, Intra-Arterial ,Humans ,Oncology & Carcinogenesis ,neoplasms ,Aged ,Pharmacology ,Intra-Arterial ,business.industry ,Evaluation of treatments and therapeutic interventions ,medicine.disease ,Antineoplastic Agents, Phytogenic ,UGT1A ,Camptothecin ,Digestive Diseases ,business - Abstract
Background Liver metastases are associated with a poor prognosis. We investigated the use of hepatic arterial infusion (HAI) of irinotecan combination therapy in patients with liver metastases. Patients and methods Patients with histologically confirmed advanced cancer with liver metastases that was refractory to standard therapy were eligible. A standard “3 + 3” phase I study design was used to determine the dose-limiting toxicity (DLT) and the maximum tolerated dose (MTD). Three cohorts were evaluated: HAI of irinotecan with systemic intravenous (IV) (a) bevacizumab, (b) oxaliplatin and bevacizumab, or (c) bevacizumab and cetuximab. Results From October 2009 through December 2013, 98 patients with various tumor types were enrolled (median age, 62 years, range, 34-85; and median number of prior therapies, 4, range, 1–11). In cohorts A and C, dose escalation continued until the highest dose level—considered the MTD—was reached. In cohort B, dose escalation continued until dose level 3, and dose level 2 was considered the MTD. Rates of grade 3/4 adverse events were as follows: diarrhea, 8 %; fatigue, 4 %; neutropenia, 4 %; thrombocytopenia, 2 %; and skin rash, 2 %. Seventy-seven patients were evaluable for response. Partial response was noted in 5 (6.5 %) patients (neuroendocrine cancer, n = 2; CRC, n = 2; NSCLC, n = 1); and stable disease ≥ 6 months in 17 (22.1 %) patients (CRC, n = 13; breast, n = 1; neuroendocrine, n = 1; NSCLC, n = 1; pancreatic, n = 1). Conclusions HAI irinotecan in combination with bevacizumab; oxaliplatin plus bevacizumab; or cetuximab plus bevacizumab was safe and may be a treatment option for selected patients with advanced cancer and liver involvement.
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- 2015
39. First report of a Japanese phase I study of triplet plus bevacizumab for chemotherapy-naive metastatic colorectal cancer (J1-TRIBE study)
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Akihito Tsuji, Takeshi Kotake, Hironaga Satake, Yukimasa Hatachi, and Yoshihiro Okita
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Oncology ,medicine.medical_specialty ,FOLFOXIRI ,Bevacizumab ,business.industry ,Colorectal cancer ,Neutropenia ,medicine.disease ,Gastroenterology ,Triplet ,Oxaliplatin ,Irinotecan ,Phase I trial ,Regimen ,Fluorouracil ,Internal medicine ,medicine ,Advanced colorectal cancer ,business ,medicine.drug - Abstract
Background The aim of this study was to determine the recommended dose of irinotecan (CPT-11) with fixed regimen of oxaliplatin (L-OHP)/fluorouracil (5-FU)/leucovorin (LV) (FOLFOXIRI) plus bevacizumab in Japanese patients with metastatic colorectal cancer. Patients and methods Patients received CPT-11 followed by L-OHP 85mg/m 2 , LV 200mg/m 2 , and 5-FU 3200mg/m 2 infused as a 48-h continuous infusion and bevacizumab 5mg/kg, repeated every 2 weeks. A decrease of the CPT-11 dose was planned (started at level 1: CPT-11 165mg/m 2 ). This trial was registered with the University Hospital Medical Information Network (number UMIN000012991). Results Six patients were enrolled, and MTD was not reached at level 1. CPT-11 165mg/ in combination with L-OHP 85mg/m 2 , LV 200mg/m 2 , 5-FU 3200mg/m 2 infused as a 48-h continuous infusion and bevacizumab 5mg/kg could be administered with acceptable toxicity, and all patients were treated at these dose levels. The most common grade 3 or 4 toxicities were neutropenia (67%) and leukopenia (50%). No treatment death was observed. The overall response rate was 67% (95% confidence interval: 30.0–90.3 %). Conclusion This biweekly triplet plus bevacizumab regimen was well tolerated by Japanese patients with metastatic colorectal cancer. The recommended phase II dose was determined to be the same as the standard doses for this regimen used worldwide. Micro abstract The efficacy of the FOLFOXIRI plus bevacizumab regimen for patients with metastatic colorectal cancer has been proven in a recent phase III study. However, there is no report of the FOLFOXIRI plus bevacizumab regimen in Japanese patients, and recommended doses of this regimen for Japanese patients have not been determined. The present study demonstrates that the recommended doses of FOLFOXIRI plus bevacizumab for Japanese patients are the same as the standard doses used worldwide.
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- 2015
40. Langerhans-type dendritic cells electroporated with TRP-2 mRNA stimulate cellular immunity against melanoma: Results of a phase I vaccine trial
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Sandra P. D'Angelo, Justin A. Shyer, Mark A. Dickson, Sneh Sharma, Michael A. Postow, Katherine B. Pronschinske, Richard D. Carvajal, David J. Chung, Shahnaz V. Singh-Kandah, James W. Young, and Jedd D. Wolchok
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0301 basic medicine ,lcsh:Immunologic diseases. Allergy ,Cellular immunity ,Immunology ,lcsh:RC254-282 ,Proinflammatory cytokine ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,langerhans-type dendritic cell ,melanoma ,Immunology and Allergy ,Cytotoxic T cell ,Medicine ,business.industry ,Immunogenicity ,Vaccine trial ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,Cytokine secretion ,phase i trial ,business ,lcsh:RC581-607 ,CD8 ,cancer vaccines ,clinical immunology ,Research Article - Abstract
Purpose: We conducted a phase I vaccine trial to determine safety, toxicity, and immunogenicity of autologous Langerhans-type dendritic cells (LCs), electroporated with murine tyrosinase-related peptide-2 (mTRP2) mRNA in patients with resected AJCC stage IIB, IIC, III, or IV (MIa) melanoma. Experimental Design: Nine patients received a priming immunization plus four boosters at three week intervals. Vaccines comprised 10 × 106 mRNA-electroporated LCs, based on absolute number of CD83+CD86brightHLA-DRbrightCD14neg LCs by flow cytometry. Initial vaccines used freshly generated LCs, whereas booster vaccines used viably thawed cells from the cryopreserved initial product. Post-vaccination assessments included evaluation of delayed-type hypersensitivity (DTH) reactions after booster vaccines and immune response assays at one and three months after the final vaccine. Results: All patients developed mild DTH reactions at injection sites after booster vaccines, but there were no toxicities exceeding grade 1 (CTCAE, v4.0). At one and three months post-vaccination, antigen-specific CD4 and CD8 T cells increased secretion of proinflammatory cytokines (IFN-γ, IL-2, and TNF-α), above pre-vaccine levels, and also upregulated the cytotoxicity marker CD107a. Next-generation deep sequencing of the TCR-V-β CDR3 documented fold-increases in clonality of 2.11 (range 0.85-3.22) for CD4 and 2.94 (range 0.98-9.57) for CD8 T cells at one month post-vaccines. Subset analyses showed overall lower fold-increases in clonality in three patients who relapsed (CD4: 1.83, CD8: 1.54) versus non-relapsed patients (CD4: 2.31, CD8: 3.99). Conclusions: TRP2 mRNA-electroporated LC vaccines are safe and immunogenic. Responses are antigen-specific in terms of cytokine secretion, cytolytic degranulation, and increased TCR clonality, which correlates with clinical outcomes.
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- 2017
41. A phase I trial of the MEK inhibitor selumetinib (AZD6244) in pediatric patients with recurrent or refractory low-grade glioma: a Pediatric Brain Tumor Consortium (PBTC) study
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Jason Fangusaro, Shengjie Wu, Arie Perry, Joanna J. Phillips, Stewart Goldman, Clinton F. Stewart, Ibrahim Qaddoumi, Theodore Nicolaides, Roger J. Packer, Tina Young Poussaint, Larry E. Kun, Anuradha Banerjee, Regina I. Jakacki, Michael D. Prados, James M. Boyett, Ian F. Pollack, Lawrence A. Doyle, Arzu Onar-Thomas, Maryam Fouladi, David C. Turner, and Sridharan Gururangan
- Subjects
Male ,Cancer Research ,Pathology ,Gastroenterology ,phase I trial ,0302 clinical medicine ,Child ,Cancer ,Pediatric ,low-grade glioma ,Brain Neoplasms ,MEK inhibitor ,Area under the curve ,Glioma ,Rash ,Oncology ,Local ,030220 oncology & carcinogenesis ,Child, Preschool ,Female ,medicine.symptom ,Mitogen-Activated Protein Kinases ,Drug ,medicine.medical_specialty ,Maximum Tolerated Dose ,Adolescent ,Clinical Trials and Supportive Activities ,Oncology and Carcinogenesis ,Clinical Investigations ,Disease-Free Survival ,Dose-Response Relationship ,03 medical and health sciences ,Rare Diseases ,Refractory ,Clinical Research ,Internal medicine ,medicine ,Mucositis ,Humans ,Progression-free survival ,Oncology & Carcinogenesis ,Preschool ,Protein Kinase Inhibitors ,selumetinib ,Dose-Response Relationship, Drug ,business.industry ,Neurosciences ,medicine.disease ,Brain Disorders ,Brain Cancer ,Neoplasm Recurrence ,Selumetinib ,Benzimidazoles ,Neurology (clinical) ,Neoplasm Recurrence, Local ,Neoplasm Grading ,business ,030217 neurology & neurosurgery - Abstract
Background Activation of the mitogen-activated protein kinase pathway is important for growth of pediatric low-grade gliomas (LGGs). The aim of this study was to determine the recommended phase II dose (RP2D) and the dose-limiting toxicities (DLTs) of the MEK inhibitor selumetinib in children with progressive LGG. Methods Selumetinib was administered orally starting at 33 mg/m2/dose b.i.d., using the modified continual reassessment method. Pharmacokinetic analysis was performed during the first course. BRAF aberrations in tumor tissue were determined by real-time polymerase chain reaction and fluorescence in situ hybridization. Results Thirty-eight eligible subjects were enrolled. Dose levels 1 and 2 (33 and 43 mg/m2/dose b.i.d.) were excessively toxic. DLTs included grade 3 elevated amylase/lipase (n = 1), headache (n = 1), mucositis (n = 2), and grades 2-3 rash (n = 6). At dose level 0 (25 mg/m2/dose b.i.d, the RP2D), only 3 of 24 subjects experienced DLTs (elevated amylase/lipase, rash, and mucositis). At the R2PD, the median (range) area under the curve (AUC0-∞) and apparent oral clearance of selumetinib were 3855 ng*h/mL (1780 to 7250 ng × h/mL) and 6.5 L × h-1 × m-2 (3.4 to 14.0 L × h-1 × m-2), respectively. Thirteen of 19 tumors had BRAF abnormalities. Among the 5 (20%) of 25 subjects with sustained partial responses, all at the RP2D, 4 had BRAF aberrations, 1 had insufficient tissue. Subjects received a median of 13 cycles (range: 1-26). Fourteen (37%) completed all protocol treatment (26 cycles [n = 13], 13 cycles [n = 1]) with at least stable disease; 2-year progression-free survival at the RP2D was 69 ± SE 9.8%. Conclusion Selumetinib has promising antitumor activity in children with LGG. Rash and mucositis were the most common DLTs.
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- 2017
42. PET imaging of zirconium-89 labelled cetuximab: A phase I trial in patients with head and neck and lung cancer
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Kim M. Smits, Véronique Winnepenninckx, Frank J. P. Hoebers, Eric Thunnissen, Boudewijn Brans, Roy I. Lalisang, Pascal Kempers, Michel Öllers, Ernst-Jan M. Speel, Anne-Marie C. Dingemans, Philippe Lambin, Danielle J. Vugts, Ronald Boellaard, Hugo J.W.L. Aerts, Wouter van Elmpt, Aniek J.G. Even, Ludwig Dubois, Dirk De Ruysscher, Judith van Loon, RS: GROW - R3 - Innovative Cancer Diagnostics & Therapy, Radiotherapie, Promovendi ODB, Pulmonologie, MUMC+: MA Med Staf Spec Longziekten (9), Interne Geneeskunde, MUMC+: MA Medische Oncologie (9), Faculteit FHML Centraal, Pathologie, MUMC+: DA Pat Pathologie (9), RS: GROW - R2 - Basic and Translational Cancer Biology, Radiology and nuclear medicine, and CCA - Imaging
- Subjects
Male ,0301 basic medicine ,EGFR-INHIBITION ,Lung Neoplasms ,medicine.medical_treatment ,Cetuximab ,0302 clinical medicine ,Carcinoma, Non-Small-Cell Lung ,PLUS CETUXIMAB ,Hematology ,Middle Aged ,ErbB Receptors ,Oncology ,Head and Neck Neoplasms ,030220 oncology & carcinogenesis ,Toxicity ,SURVIVAL ,Immuno-PET ,Female ,Zr-89-cetuximab ,medicine.drug ,RADIOTHERAPY ,EXPRESSION ,CARCINOMA ,EGFR ,Antineoplastic Agents ,03 medical and health sciences ,Phase I trial ,medicine ,Carcinoma ,Humans ,Radiology, Nuclear Medicine and imaging ,In patient ,Lung cancer ,neoplasms ,Aged ,business.industry ,Cancer ,Pet imaging ,1ST-LINE CHEMOTHERAPY ,medicine.disease ,digestive system diseases ,Radiation therapy ,030104 developmental biology ,Positron-Emission Tomography ,Zirconium ,MONOCLONAL-ANTIBODIES ,business ,Nuclear medicine ,GROWTH-FACTOR RECEPTOR - Abstract
Background and purpose: PET imaging of cetuximab uptake may help selecting cancer patients with the highest chance of benefit. The aim of this phase I trial was to determine the safety of the tracer (89)zr-cetuximab and to assess tumour uptake.Methods: Two dose schedules were used; two consecutive doses of 60 MBq Zr-89-cetuximab or a single dose of 120 MBq, both preceded by 400 mg/m(2) of unlabelled cetuximab. Toxicity (CTCAE 3.0) was scored twice weekly. PET-CT scans were acquired on days 4, 5 and 6 (step 1) or 5, 6, 7 (step 2). Because tumour uptake could not be assessed satisfactorily, a third step was added including EGFR overexpressing tumours.Results: Nine patients were included (6 NSCLC; 3 HNC). No additional toxicity was associated with administration of 89Zr-cetuximab compared to standard cetuximab. A tumour to blood ratio (TBR) > 1 was observed in all but one patient, with a maximum of 4.56. TBR was not different between dose schedules. There was a trend for higher TBR at intervals > 5 days after injection.Conclusions: Both presented 89Zr-cetuximab administration schedules are safe. The recommended dose for future trials is 60 MBq, with a minimum time interval for scanning of 6 days. (C) 2016 Elsevier Ireland Ltd. All rights reserved.
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- 2017
43. A phase I trial of ganetespib in combination with paclitaxel and trastuzumab in patients with human epidermal growth factor receptor-2 (HER2)-positive metastatic breast cancer
- Author
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Gabriella D'Andrea, David B. Solit, Shanu Modi, Karen Cadoo, James L. Speyer, Rui Wang, Francisco J. Esteva, Eleonora Teplinsky, Sylvia Adams, Sofia Haque, Tara O'Neill, Komal Jhaveri, Clifford A. Hudis, Sarat Chandarlapaty, Sujata Patil, and Kent Friedman
- Subjects
0301 basic medicine ,Oncology ,Adult ,medicine.medical_specialty ,HSP90 inhibitor ,Combination therapy ,Maximum Tolerated Dose ,Paclitaxel ,Receptor, ErbB-2 ,Ganetespib ,Breast Neoplasms ,lcsh:RC254-282 ,Disease-Free Survival ,03 medical and health sciences ,chemistry.chemical_compound ,Phase I trial ,0302 clinical medicine ,Breast cancer ,Trastuzumab ,Internal medicine ,HER2 ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,Neoplasm Metastasis ,skin and connective tissue diseases ,Aged ,Neoplasm Staging ,Dose-Response Relationship, Drug ,business.industry ,Middle Aged ,Triazoles ,medicine.disease ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Metastatic breast cancer ,Regimen ,030104 developmental biology ,chemistry ,030220 oncology & carcinogenesis ,Female ,Pertuzumab ,business ,medicine.drug ,Research Article - Abstract
Background Targeted therapies in HER2-positive metastatic breast cancer significantly improve outcomes but efficacy is limited by therapeutic resistance. HER2 is an acutely sensitive Heat Shock Protein 90 (HSP90) client and HSP90 inhibition can overcome trastuzumab resistance. Preclinical data suggest that HSP90 inhibition is synergistic with taxanes with the potential for significant clinical activity. We therefore tested ganetespib, a HSP90 inhibitor, in combination with paclitaxel and trastuzumab in patients with trastuzumab-refractory HER2-positive metastatic breast cancer. Methods In this phase I dose-escalation study, patients with trastuzumab-resistant HER2-positive metastatic breast cancer received weekly trastuzumab (2 mg/kg) and paclitaxel (80 mg/m2) on days 1, 8, 15, and 22 of a 28-day cycle with escalating doses of ganetespib (100 mg/m2, 150 mg/m2, and a third cohort of 125 mg/m2 if needed) on days 1, 8, and 15. Therapy was continued until disease progression or toxicity. The primary objective was to establish the safety and maximum tolerated dose and/or recommended phase II dose (RP2D) of this therapy. The secondary objectives included evaluation of the effects of ganetespib on the pharmacokinetics of paclitaxel, and to make a preliminary assessment of the efficacy of the combination therapy. Results Dose escalation was completed for the two main cohorts without any observed dose-limiting toxicities. Nine patients received treatment. The median prior lines of anti-HER2 therapy numbered three (range 2–4), including prior pertuzumab in 9/9 patients and ado-trastuzumab emtansine (T-DM1) in 8/9 patients. The most common grade 1/2 adverse events (AEs) were diarrhea, fatigue, anemia, and rash. There were no grade 4 AEs related to ganetespib. The overall response rate was 22% (2/9 patients had partial response) and stable disease was seen in 56% (5/9 patients). The clinical benefit rate was 44% (4/9 patients). The median progression-free survival was 20 weeks (range 8–55). Conclusion The RP2D of ganetespib is 150 mg/m2 in combination with weekly paclitaxel plus trastuzumab. The combination was safe and well tolerated. Despite prior taxanes, pertuzumab, and T-DM1, clinical activity of this triplet regimen in this heavily pretreated cohort is promising and warrants further study in HER2-positive metastatic breast cancer. Trial registration ClinicalTrials.gov NCT02060253 . Registered 30 January 2014.
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- 2017
44. Do all patients in the phase I oncology trials need to be hospitalized? Domestic but outstanding issues for globalization of drug development in Japan
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Shunsuke Kondo, Yutaka Fujiwara, Akihiko Shimomura, Kenji Tamura, Noriko Kobayashi, Noboru Yamamoto, Shigehisa Kitano, and Satoru Iwasa
- Subjects
Adult ,Male ,medicine.medical_specialty ,Internationality ,Adolescent ,Maximum Tolerated Dose ,Domestic guideline ,Antineoplastic Agents ,Cancer Care Facilities ,03 medical and health sciences ,Young Adult ,Phase I trial ,0302 clinical medicine ,Toxicity management ,Nursing ,Pharmacokinetics ,Japan ,Surgical oncology ,Internal medicine ,Neoplasms ,Outpatient clinic ,Medicine ,Humans ,Severe toxicity ,Aged ,Clinical Trials, Phase I as Topic ,Dose-Response Relationship, Drug ,business.industry ,Clinical study design ,Hematology ,General Medicine ,Middle Aged ,Clinical trial ,Oncology ,Drug development ,030220 oncology & carcinogenesis ,Toxicity ,Surgery ,Female ,Original Article ,business ,030215 immunology - Abstract
Introduction Most trials investigating new drugs around the world, including phase I trials, are conducted in outpatient clinics. However, in Japan, regulatory authority requirements and traditional domestic guidelines often require hospitalization of phase I study participants. Patients and methods Patients participating in single-agent phase I clinical trials at National Cancer Center Hospital between December 1996 and August 2014 were monitored. Toxicity requiring hospitalization is defined as toxicity that needs intensive treatment. Study designs were classified into three types: first-in-human (FIH) study, dose-escalation study (conventional dose-escalation study to determine maximum tolerated dose (MTD) in Japanese patients), and dose-finding study (to assess safety and pharmacokinetic profiles up to the MTD previously determined in the West). Results A total of 945 patients who participated in a variety of single-agent phase I clinical trials between December 1996 and August 2014 were included in this study. Patients participated in one of three study types: dose-escalation (n = 582, 62%), first-in-human (n = 129, 14%), or dose-finding (n = 234, 25%). A total of 76 study drugs were evaluated as part of this pool of phase I studies. Subdivided by mechanism of action, 20 (26%) were cytotoxic, 50 (66%) were molecularly targeted, and 6 (8%) were immune checkpoint inhibitor. Thirty-six patients (3.8%) had severe toxicities requiring hospitalization during the first cycle. The overall number of toxicities requiring hospitalization and/or grade 4 toxicities during any cycle was 5.0%. Conclusions The frequency of severe toxicity that needs to be hospitalized was unexpectedly low. The data did not demonstrate the need for hospitalization in the phase I trials, suggesting that phase I trials in Japan could be conducted in outpatient settings.
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- 2017
45. A first-in-human study of the anti-α5β1 integrin monoclonal antibody PF-04605412 administered intravenously to patients with advanced solid tumors
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Vicki L. Keedy, Roger B. Cohen, Ganesh Mugundu, Lianglin Zhang, Hossein Borghaei, Joaquin Mateo, Jordan Berlin, Craig Davis, J.S. de Bono, C. Gallo Stampino, and Antonello Abbattista
- Subjects
Adult ,Male ,Cancer Research ,medicine.drug_class ,Angiogenesis ,Metabolic Clearance Rate ,Integrin ,Pharmacology ,Monoclonal antibody ,Toxicology ,Antibodies, Monoclonal, Humanized ,Drug Administration Schedule ,Phase I trial ,Pharmacokinetics ,Neoplasms ,medicine ,Flushing ,Humans ,Pharmacology (medical) ,Infusions, Intravenous ,Antibody ,Fatigue ,Aged ,Antibody-dependent cell-mediated cytotoxicity ,biology ,Dose-Response Relationship, Drug ,business.industry ,Nausea ,Middle Aged ,Treatment Outcome ,Tolerability ,Oncology ,Pharmacodynamics ,First-in-human ,Area Under Curve ,Monoclonal ,biology.protein ,Original Article ,Female ,Hypotension ,business ,ADCC ,Integrin alpha5beta1 - Abstract
Purpose A first-in-human clinical trial of a fully human, Fc-engineered IgG1 monoclonal antibody targeting integrin α5β1 was conducted to evaluate tolerability, maximum tolerated dose, pharmacokinetics, pharmacodynamics and preliminary anti-tumor activity. Methods Escalating doses of PF-04605412 were given IV on day 1, 28 and every 2 weeks thereafter to patients with advanced solid tumors until disease progression or unacceptable toxicity. Sequential dose cohorts were evaluated based on a modified 3 + 3 dose-escalation design. The starting dose was 7.5 mg based on preclinical data. Results Thirty-three patients were enrolled to six dose levels (7.5, 11.25, 16.9, 34, 68 and 136 mg). Twenty-three patients were evaluable for the primary endpoint (determination of the maximum tolerated dose). Five patients required permanent drug discontinuation due to acute infusion-related reactions, which occurred as grade 3 events in two patients. PK analysis indicated that the targeted drug exposure based on preclinical models was not achieved by the tolerated doses and PK modeling suggesting that doses at least fivefold higher would be necessary. No anti-tumor activity was observed. Conclusion Based on the safety data, the risks associated with the likelihood of significant cytokine-mediated infusion reactions at higher doses, the projected high dose necessary to affect on the biological target and the lack of anti-tumor activity at the doses explored, the trial was prematurely terminated without determining a formal maximum tolerated dose. Further clinical development of PF-04605412 has been discontinued. Electronic supplementary material The online version of this article (doi:10.1007/s00280-014-2576-8) contains supplementary material, which is available to authorized users.
- Published
- 2014
46. First-in-human phase I clinical trial of RG7356, an anti-CD44 humanized antibody, in patients with advanced, CD44-expressing solid tumors
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Dominik Rüttinger, Florian Heil, Randolph Christen, Christophe Le Tourneau, Devalingam Mahalingam, Michael Brewster, Antje Walz, C. Willemien Menke-van der Houven van Oordt, Michael A. Cannarile, Tapan K. Nayak, Ernesto Guarin, Valerie Meresse, Henk M.W. Verheul, Winette T. A. van der Graaf, Carlos Gomez-Roca, Stefan Weigand, Carla M.L. van Herpen, Andrew L. Coveler, Medical oncology, and CCA - Clinical Therapy Development
- Subjects
0301 basic medicine ,Adult ,Male ,medicine.medical_specialty ,Maximum Tolerated Dose ,Phases of clinical research ,Pilot Projects ,Humanized antibody ,Antibodies, Monoclonal, Humanized ,phase I trial ,03 medical and health sciences ,0302 clinical medicine ,Antineoplastic Agents, Immunological ,Internal medicine ,Neoplasms ,advanced CD44-expressing solid malignancies ,medicine ,Humans ,In patient ,Tissue Distribution ,Dosing ,Adverse effect ,Aged ,Aged, 80 and over ,business.industry ,Middle Aged ,medicine.disease ,030104 developmental biology ,Clinical research ,Hyaluronan Receptors ,Oncology ,030220 oncology & carcinogenesis ,Maximum tolerated dose ,Positron-Emission Tomography ,Immunology ,Disease Progression ,anti-CD44 humanized antibody ,Female ,advanced solid tumors ,Zirconium ,Clinical Research Paper ,Radiopharmaceuticals ,business ,RG7356 ,Febrile neutropenia - Abstract
// C. Willemien Menke-van der Houven van Oordt 1 , Carlos Gomez-Roca 2 , Carla van Herpen 3 , Andrew L. Coveler 4 , Devalingam Mahalingam 5 , Henk M. W. Verheul 1 , Winette T. A. van der Graaf 3 , Randolph Christen 6 , Dominik Ruttinger 7 , Stefan Weigand 7 , Michael A. Cannarile 7 , Florian Heil 7 , Michael Brewster 8 , Antje-Christine Walz 9 , Tapan K. Nayak 9 , Ernesto Guarin 9 , Valerie Meresse 9 and Christophe Le Tourneau 10 1 Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands 2 Clinical Research Unit, Department of Medical Oncology, Institut Claudius Regaud, Institut Universitaire du Cancer de Toulouse – Oncopole, Toulouse, France 3 Radboud University Medical Center, Nijmegen, The Netherlands 4 Department of Medicine, Division of Oncology, University of Washington, Seattle, WA, USA 5 Cancer Therapy and Research Center, University of Texas Health Science Center, San Antonio, TX, USA 6 Product Development, Safety Risk Management, Roche, Basel, Switzerland 7 Pharma Research & Early Development, Roche Innovation Center, Penzberg, Germany 8 Pharma Research & Early Development, Roche Innovation Centre, Welwyn, UK 9 Pharma Research & Early Development, Roche Innovation Center Basel, Basel, Switzerland 10 Department of Medical Oncology, Institut Curie, Saint-Cloud & Paris, France, and Versailles-Saint-Quentin-en-Yvelines University, Versailles, France Correspondence to: C. Willemien Menke-van der Houven van Oordt, email: // Keywords : RG7356, anti-CD44 humanized antibody, advanced solid tumors, advanced CD44-expressing solid malignancies, phase I trial Received : March 28, 2016 Accepted : July 10, 2016 Published : August 05, 2016 Abstract Transmembrane glycoprotein CD44 is overexpressed in various malignancies. Interactions between CD44 and hyaluronic acid are associated with poor prognosis, making CD44 an attractive therapeutic target. We report results from a first-in-human phase I trial of RG7356, a recombinant anti-CD44 immunoglobulin G1 humanized monoclonal antibody, in patients with advanced CD44-expressing solid malignancies. Sixty-five heavily pretreated patients not amenable to standard therapy were enrolled and received RG7356 intravenously biweekly (q2w) or weekly (qw) in escalating doses from 100 mg to 2,250 mg. RG7356 was well tolerated. Most frequent adverse events were fever, headache and fatigue. Dose-limiting toxicities included headache (1,500 mg q2w and 1,350 mg qw) and febrile neutropenia (2,250 mg q2w). The maximum tolerated dose with q2w dosing was 1,500 mg, but was not defined for qw dosing due to early study termination. Clinical efficacy was modest; 13/61 patients (21%) experienced disease stabilization lasting a median of 12 (range, 6–35) weeks. No apparent dose- or dose schedule-dependent changes in biological activity were reported from blood or tissue analyses. Tumor-targeting by positron emission tomography (PET) using 89 Zr-labeled RG7356 was observed for doses ≥200 mg (q2w) warranting further investigation of this agent in combination regimens.
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- 2016
47. Phase I clinical study of RG7356, an anti-CD44 humanized antibody, in patients with acute myeloid leukemia
- Author
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Jacques Delaunay, Peter Paschka, Valeria Runza, Maxim Kebenko, Cristina Papayannidis, Ernesto Guarin, Michael Brewster, Norbert Vey, Ann-Marie E Bröske, Carlos Gomez-Roca, Valerie Meresse, Giovanni Martinelli, Emmanuel Raffoux, Thomas Prebet, Randolph Christen, Antje-Christine Walz, Monika Baehner, Francesca Michielin, Christian Recher, Walter Fiedler, Vey, Norbert, Delaunay, Jacque, Martinelli, Giovanni, Fiedler, Walter, Raffoux, Emmanuel, Prebet, Thoma, Gomez Roca, Carlo, Papayannidis, Cristina, Kebenko, Maxim, Paschka, Peter, Christen, Randolph, Guarin, Ernesto, Bröske, Ann Marie, Baehner, Monika, Brewster, Michael, Walz, Antje Christine, Michielin, Francesca, Runza, Valeria, Meresse, Valerie, and Recher, Christian
- Subjects
Adult ,Male ,0301 basic medicine ,Pediatrics ,medicine.medical_specialty ,Dose ,Exacerbation ,Antibodies, Monoclonal, Humanized ,Humanized antibody ,Gastroenterology ,Young Adult ,03 medical and health sciences ,Phase I trial ,0302 clinical medicine ,Relapsed/refractory acute myeloid leukemia ,Pharmacokinetics ,Refractory ,Internal medicine ,medicine ,Humans ,Adverse effect ,Aged ,Aged, 80 and over ,Dose-Response Relationship, Drug ,business.industry ,Myeloid leukemia ,Induction chemotherapy ,Cell adhesion ,Middle Aged ,Leukemia, Myeloid, Acute ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,Anti-CD44 humanized antibody ,Female ,business ,RG7356 ,Research Paper - Abstract
RG7356, a recombinant anti-CD44 immunoglobulin G1 humanized monoclonal antibody, inhibits cell adhesion and has been associated with macrophage activation in preclinical models. We report results of a phase I dose-escalation study of RG7356 in relapsed/refractory acute myeloid leukemia (AML). Eligible patients with refractory AML, relapsed AML after induction chemotherapy, or previously untreated AML not eligible for intensive chemotherapy were enrolled and received intravenous RG7356 at dosages ≤ 2400 mg every other week or ≤ 1200 mg weekly or twice weekly; dose escalation started at 300 mg. Forty-four patients (median age, 69 years) were enrolled. One dose-limiting toxicity occurred (grade 3 hemolysis exacerbation) after one 1200 mg dose (twice-weekly cohort). The majority of adverse events were mild/moderate. Infusion-related reactions occurred in 64% of patients mainly during cycle 1. Two patients experienced grade 3 drug-induced aseptic meningitis. Pharmacokinetics increased supraproportionally, suggesting a target-mediated drug disposition (TMDD) at ≥ 1200 mg. Two patients achieved complete response with incomplete platelet recovery or partial response, respectively. One patient had stable disease with hematologic improvement. RG7356 was generally safe and well tolerated. Maximum tolerated dose was not reached, but saturation of TMDD was achieved. The recommended dose for future AML evaluations is 2400 mg every other week.
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- 2016
48. First-in-human phase I study of the DNA-repair inhibitor DT01 in combination with radiotherapy in patients with skin metastases from melanoma
- Author
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Pierre Bey, Bernard Asselain, C. Le Tourneau, Marie Dutreix, Youlia M. Kirova, Philippe Saiag, Michel Marty, Pascal Joly, Luc Thomas, J.-J. Grob, Jian-Sheng Sun, C. Dutriaux, Thomas Jouary, Flavien Devun, Eve Maubec, Laurent Mortier, M.-F. Avril, Jean-Marc Cosset, Brigitte Dréno, Céleste Lebbé, Risques cliniques et sécurité en santé des femmes et en santé périnatale (RISCQ), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Institut Curie [Paris], Centre hospitalier universitaire de Nantes (CHU Nantes), Hôpital de la Timone [CHU - APHM] (TIMONE), Service de dermatologie Hôpital Saint-André Bordeaux, CHU Bordeaux [Bordeaux], Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Hôpital Ambroise Paré [AP-HP], Hôpital Cochin [AP-HP], AP-HP - Hôpital Bichat - Claude Bernard [Paris], CHU Rouen, Normandie Université (NU), DNA-therapeutics, Université Paris-Sud - Paris 11 (UP11), Roche, BD reports grants and personal fees from Roche, grants and personal fees from Bristol-Myers Squibb, grants and personal fees from GlaxoSmithKline, outside the submitted work. CL reports personal fees from Roche, GlaxoSmithKline, Merck Sharp and Dhome, Bristol-Myers Squibb outside the submitted work. FD is employee of DNA Therapeutics, and JMC, JSS and MD are cofounders of DNA Therapeutics, the company which holds the patent for DT01. MEM served as a consultant for DNA Therapeutics, Oncoethics, Merck Sharp and Dhome, Pfizer and Roche laboratories. The other authors declare no conflict of interest.
- Subjects
0301 basic medicine ,Male ,Cancer Research ,Radiation-Sensitizing Agents ,Skin Neoplasms ,medicine.medical_treatment ,[SDV]Life Sciences [q-bio] ,Salvage therapy ,phase I trial ,0302 clinical medicine ,skin metastases ,Aged, 80 and over ,Melanoma ,Chloroquine ,Chemoradiotherapy ,Middle Aged ,Combined Modality Therapy ,3. Good health ,Neoplasm Proteins ,Tumor Burden ,Cholesterol ,Treatment Outcome ,Oncology ,030220 oncology & carcinogenesis ,Toxicity ,Female ,Adult ,medicine.medical_specialty ,Maximum Tolerated Dose ,Urology ,DNA repair ,Antineoplastic Agents ,03 medical and health sciences ,Pharmacokinetics ,medicine ,melanoma ,Humans ,Adverse effect ,radiotherapy ,Aged ,Salvage Therapy ,Dose-Response Relationship, Drug ,business.industry ,DT01 ,DNA ,medicine.disease ,Surgery ,Clinical trial ,Radiation therapy ,030104 developmental biology ,Clinical Study ,business - Abstract
International audience; Background: DT01 is a DNA-repair inhibitor preventing recruitment of DNA-repair enzymes at damage sites. Safety, pharmacokinetics and preliminary efficacy through intratumoural and peritumoural injections of DT01 were evaluated in combination with radiotherapy in a first-in-human phase I trial in patients with unresectable skin metastases from melanoma.Methods:Twenty-three patients were included and received radiotherapy (30 Gy in 10 sessions) on all selected tumour lesions, comprising of two lesions injected with DT01 three times a week during the 2 weeks of radiotherapy. DT01 dose levels of 16, 32, 48, 64 and 96 mg were used, in a 3+3 dose escalation design, with an expansion cohort at 96 mg.Results:The median follow-up was 180 days. All patients were evaluable for safety and pharmacokinetics. No dose-limiting toxicity was observed and the maximum-tolerated dose was not reached. Most frequent adverse events were reversible grades 1 and 2 injection site reactions. Pharmacokinetic analyses demonstrated a systemic passage of DT01. Twenty-one patients were evaluable for efficacy on 76 lesions. Objective response was observed in 45 lesions (59%), including 23 complete responses (30%).Conclusions:Intratumoural and peritumoural DT01 in combination with radiotherapy is safe and pharmacokinetic analyses suggest a systemic passage of DT01.
- Published
- 2016
49. Evaluation of cell death mechanisms induced by the vascular disrupting agent OXi4503 during a phase I clinical trial
- Author
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Mark R. Middleton, Caroline Dive, Nigel K Smith, P Ross, G.J.S. Rustin, Martin Zweifel, Timothy H Ward, Patricia M Price, Jane Peters, and Jeffrey Cummings
- Subjects
Cancer Research ,Programmed cell death ,Pathology ,medicine.medical_specialty ,Phases of clinical research ,Antineoplastic Agents ,Apoptosis ,Enzyme-Linked Immunosorbent Assay ,Keratin 18 ,phase I trial ,cell death mechanisms ,Text mining ,OXi4503 ,Neoplasms ,Stilbenes ,Biomarkers, Tumor ,Humans ,Medicine ,Keratin-18 ,Neovascularization, Pathologic ,business.industry ,M30 ELISA ,M65 ELISA ,Peptide Fragments ,Diphosphates ,Oncology ,Cancer research ,vascular disrupting agent ,Translational Therapeutics ,business - Abstract
Background: OXi4503 is a tubulin-binding vascular disrupting agent that has recently completed a Cancer Research UK-sponsored phase I trial. Preclinical studies demonstrated early drug-induced apoptosis in tumour endothelial cells at 1-3 h and secondary tumour cell necrosis between 6 and 72 h. Methods: To capture both possible outcomes of OXi4503 treatment on cell death, plasma samples for analysis by M30 and M65 ELISAs, which measure different circulating forms of cytokeratin 18 as biomarkers of apoptosis and necrosis, respectively, were collected from patients entered into the trial at early (4/6 h) and later time points (24 h, day 8 and day 15). Results: OXi4503 induced a selective dose-dependent elevation in M30 antigen levels (apoptosis) at 4/6 h and a similar elevation in M65 antigen levels at 24 h (necrosis) consistent with its preclinical cell death profile. For the purposes of investigating potential biomarker relationships to patient characteristics, the trial population was divided into three groups based on radiological and clinical response: (a) early progression, (b) progressive disease and (c) stable disease (SD)/partial response. A significant increase in antigen concentrations was measured by M65 at 24 h in the SD group compared with the two other groups (P=0.015, mean increase 30.9%). Conclusion: These results provide pharmacodynamic evidence of drug mechanism of action in cancer patients and highlight the M65 ELISA as a potentially useful biomarker assay of response to OXi4503. © 2012 Cancer Research UK.
- Published
- 2012
50. Functional imaging: what evidence is there for its utility in clinical trials of targeted therapies?
- Author
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Stan B. Kaye, Nandita M. deSouza, and Nina Tunariu
- Subjects
Diagnostic Imaging ,Cancer Research ,medicine.medical_specialty ,targeted agents ,multiparametric imaging ,Key issues ,Multimodal Imaging ,Drug Administration Schedule ,phase I trial ,Neoplasms ,medicine ,Medical imaging ,imaging biomarker ,Humans ,Medical physics ,Molecular Targeted Therapy ,Clinical efficacy ,Clinical Trials as Topic ,medicine.diagnostic_test ,business.industry ,Magnetic resonance imaging ,Magnetic Resonance Imaging ,Functional imaging ,Clinical trial ,Dynamic contrast ,Oncology ,Positron emission tomography ,Positron-Emission Tomography ,Minireview ,Tomography, X-Ray Computed ,business - Abstract
Key issues in early clinical trials of targeted agents include the determination of target inhibition, rational patient selection based on pre-treatment tumour characteristics, and assessment of tumour response in the absence of actual shrinkage. There is accumulating evidence that functional imaging using advanced techniques such as dynamic contrast enhanced (DCE)-magnetic resonance imaging (MRI), DCE-computerised tomography (CT) and DCE-ultrasound, diffusion weighted-MRI, magnetic resonance spectroscopy and positron emission tomography-CT using various labelled radioactive tracers has the potential to address all three. This article reviews this evidence with examples from trials using targeted agents with established clinical efficacy and summarises the clinical utility of the various techniques. We therefore recommend that input from specialist radiologists is sought at the early stages of trial design, in order to ensure that functional imaging is incorporated appropriately for the agent under study. There is an urgent need to strengthen the evidence base for these techniques as they evolve, and to ensure standardisation of the methodology.
- Published
- 2012
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