68 results on '"Kumar Sankhala"'
Search Results
2. Supplementary Figure from A Phase I Study of an MPS1 Inhibitor (BAY 1217389) in Combination with Paclitaxel Using a Novel Randomized Continual Reassessment Method for Dose Escalation
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Martijn P. Lolkema, Ingmar Bruns, Jaap Verweij, Ron H.J. Mathijssen, Simon Langer, Isabelle Genvresse, Prabhu Rajagopalan, Kumar Sankhala, Martin Gutierrez, Joseph P. Eder, Patricia M. LoRusso, Anthony W. Tolcher, Sant P. Chawla, Jennifer R. Diamond, Vivek Subbiah, Oliver Boix, and Florence Atrafi
- Abstract
Supplementary Figure from A Phase I Study of an MPS1 Inhibitor (BAY 1217389) in Combination with Paclitaxel Using a Novel Randomized Continual Reassessment Method for Dose Escalation
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- 2023
3. Supplementary Data from A Phase I Study of an MPS1 Inhibitor (BAY 1217389) in Combination with Paclitaxel Using a Novel Randomized Continual Reassessment Method for Dose Escalation
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Martijn P. Lolkema, Ingmar Bruns, Jaap Verweij, Ron H.J. Mathijssen, Simon Langer, Isabelle Genvresse, Prabhu Rajagopalan, Kumar Sankhala, Martin Gutierrez, Joseph P. Eder, Patricia M. LoRusso, Anthony W. Tolcher, Sant P. Chawla, Jennifer R. Diamond, Vivek Subbiah, Oliver Boix, and Florence Atrafi
- Abstract
Supplementary Data from A Phase I Study of an MPS1 Inhibitor (BAY 1217389) in Combination with Paclitaxel Using a Novel Randomized Continual Reassessment Method for Dose Escalation
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- 2023
4. Data from A Phase I Study of an MPS1 Inhibitor (BAY 1217389) in Combination with Paclitaxel Using a Novel Randomized Continual Reassessment Method for Dose Escalation
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Martijn P. Lolkema, Ingmar Bruns, Jaap Verweij, Ron H.J. Mathijssen, Simon Langer, Isabelle Genvresse, Prabhu Rajagopalan, Kumar Sankhala, Martin Gutierrez, Joseph P. Eder, Patricia M. LoRusso, Anthony W. Tolcher, Sant P. Chawla, Jennifer R. Diamond, Vivek Subbiah, Oliver Boix, and Florence Atrafi
- Abstract
Purpose:Monopolar spindle 1 (MPS1) kinase inhibitor, BAY 1217389 (BAY) synergizes with paclitaxel. This phase I study assessed the combination of BAY with paclitaxel using a novel randomized continuous reassessment method (rCRM) to improve dose determination.Patients and Methods:Patients with solid tumors were randomized to receive oral BAY (twice daily 2-days-on/5-days-off) with weekly paclitaxel (90 mg/m2) or paclitaxel monotherapy in cycle 1. Dose escalation was guided by CRM modeling. Primary objectives were to assess safety, establish the MTD of BAY, and to evaluate the pharmacokinetic profiles for both compounds. Simulations were performed to determine the contribution of the rCRM for dose determination.Results:In total, 75 patients were enrolled. The main dose-limiting toxicities were hematologic toxicities (55.6%). The MTD of BAY was established at 64 mg twice daily with paclitaxel. Inclusion of a control arm enabled the definitive attribution of grade ≥3 neutropenia to higher BAY exposure [AUC0–12 (P< 0.001)]. After determining the MTD, we included 19 patients with breast cancer at this dose for dose expansion. Other common toxicities were nausea (45.3%), fatigue (41.3%), and diarrhea (40.0%). Overall confirmed responses were seen in 31.6% of evaluable patients. Simulations showed that rCRM outperforms traditional designs in determining the true MTD.Conclusions:The combination of BAY with paclitaxel was associated with considerable toxicity without a therapeutic window. However, the use of the rCRM design enabled us to determine the exposure–toxicity relation for BAY. Therefore, we propose that the rCRM could improve dose determination in phase I trials that combine agents with overlapping toxicities.
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- 2023
5. A Phase i Study of an MPS1 Inhibitor (BAY 1217389) in Combination with Paclitaxel Using a Novel Randomized Continual Reassessment Method for Dose Escalation
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Kumar Sankhala, Simon Langer, Martijn P. Lolkema, Jennifer R. Diamond, Ingmar Bruns, Isabelle Genvresse, Patricia LoRusso, Martin Gutierrez, Vivek Subbiah, Jaap Verweij, Anthony W. Tolcher, Sant P. Chawla, Prabhu Rajagopalan, Ron H.J. Mathijssen, Florence Atrafi, Joseph Paul Eder, Oliver Boix, and Medical Oncology
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Oncology ,Cancer Research ,medicine.medical_specialty ,Maximum Tolerated Dose ,Paclitaxel ,Breast Neoplasms ,Mps1 Inhibitor BAY 1217389 ,Neutropenia ,chemistry.chemical_compound ,Pharmacokinetics ,SDG 3 - Good Health and Well-being ,Internal medicine ,Neoplasms ,Antineoplastic Combined Chemotherapy Protocols ,Dose escalation ,medicine ,Humans ,Dose-Response Relationship, Drug ,business.industry ,medicine.disease ,Phase i study ,chemistry ,Toxicity ,Female ,business ,Bay - Abstract
Purpose: Monopolar spindle 1 (MPS1) kinase inhibitor, BAY 1217389 (BAY) synergizes with paclitaxel. This phase I study assessed the combination of BAY with paclitaxel using a novel randomized continuous reassessment method (rCRM) to improve dose determination. Patients and Methods: Patients with solid tumors were randomized to receive oral BAY (twice daily 2-days-on/5-days-off) with weekly paclitaxel (90 mg/m2) or paclitaxel monotherapy in cycle 1. Dose escalation was guided by CRM modeling. Primary objectives were to assess safety, establish the MTD of BAY, and to evaluate the pharmacokinetic profiles for both compounds. Simulations were performed to determine the contribution of the rCRM for dose determination. Results: In total, 75 patients were enrolled. The main dose-limiting toxicities were hematologic toxicities (55.6%). The MTD of BAY was established at 64 mg twice daily with paclitaxel. Inclusion of a control arm enabled the definitive attribution of grade ≥3 neutropenia to higher BAY exposure [AUC0–12 (P< 0.001)]. After determining the MTD, we included 19 patients with breast cancer at this dose for dose expansion. Other common toxicities were nausea (45.3%), fatigue (41.3%), and diarrhea (40.0%). Overall confirmed responses were seen in 31.6% of evaluable patients. Simulations showed that rCRM outperforms traditional designs in determining the true MTD. Conclusions: The combination of BAY with paclitaxel was associated with considerable toxicity without a therapeutic window. However, the use of the rCRM design enabled us to determine the exposure–toxicity relation for BAY. Therefore, we propose that the rCRM could improve dose determination in phase I trials that combine agents with overlapping toxicities.
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- 2021
6. A study to improve the fog/visibility forecast at IGI Airport, New Delhi during the winter season 2020–2021
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S H Arun, Charan Singh, Sebin John, Sumant Kumar Diwakar, Dinesh Kumar Sankhala, Narendra Nigam, Chander S Tomar, and Gajendra Kumar
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General Earth and Planetary Sciences - Published
- 2022
7. Correction: A Phase I Study of an MPS1 Inhibitor (BAY 1217389) in Combination with Paclitaxel Using a Novel Randomized Continual Reassessment Method for Dose Escalation
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Florence Atrafi, Oliver Boix, Vivek Subbiah, Jennifer R. Diamond, Sant P. Chawla, Anthony W. Tolcher, Patricia M. LoRusso, Joseph P. Eder, Martin Gutierrez, Kumar Sankhala, Prabhu Rajagopalan, Isabelle Genvresse, Simon Langer, Ron H.J. Mathijssen, Jaap Verweij, Ingmar Bruns, and Martijn P. Lolkema
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Cancer Research ,Oncology - Published
- 2022
8. Phase I Assessment of Safety and Therapeutic Activity of BAY1436032 in Patients with IDH1-Mutant Solid Tumors
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Joachim P. Steinbach, Catya Munhoz, Carol Peña, Volker Heinemann, Susanne Reschke, Cristiana Roggia, Yoshitaka Narita, Michael C. Burger, Sant P. Chawla, Katharina J. Wenger, Simon Langer, Antje Wick, Ulrik Lassen, Stefan Kaulfuss, Michael Jeffers, Kamalesh Kumar Sankhala, Christine Rentzsch, Filip Janku, Heinz-Josef Lenz, Yuichi Ando, Martin Schuler, Masafumi Ikeda, Markus Wagner, Isabelle Genvresse, Eleni Lagkadinou, Oliver Bähr, Kristoffer Staal Rohrberg, Charles Cai, Wolfgang Wick, David Schiff, and Ghazaleh Tabatabai
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0301 basic medicine ,Adult ,Male ,Cancer Research ,medicine.medical_specialty ,IDH1 ,Mutant ,DNA Mutational Analysis ,Medizin ,Antineoplastic Agents ,Gastroenterology ,03 medical and health sciences ,0302 clinical medicine ,Pharmacokinetics ,Internal medicine ,Glioma ,Neoplasms ,medicine ,Biomarkers, Tumor ,Humans ,Intrahepatic Cholangiocarcinoma ,Alleles ,Aged ,Neoplasm Staging ,Aged, 80 and over ,Aniline Compounds ,business.industry ,Disease Management ,Middle Aged ,medicine.disease ,Isocitrate Dehydrogenase ,030104 developmental biology ,Isocitrate dehydrogenase ,Oncology ,030220 oncology & carcinogenesis ,Pharmacodynamics ,Cohort ,Mutation ,Benzimidazoles ,Female ,Disease Susceptibility ,Neoplasm Grading ,business - Abstract
Purpose: BAY1436032, an inhibitor of mutant isocitrate dehydrogenase 1 (mIDH1), was active against multiple IDH1-R132X solid tumors in preclinical models. This first-in-human study was designed to determine the safety and pharmacokinetics of BAY1436032, and to evaluate its potential pharmacodynamics and antitumor effects. Patients and Methods: The study comprised of dose escalation and dose expansion cohorts. BAY1436032 tablets were orally administered twice daily on a continuous basis in subjects with mIDH1 solid tumors. Results: In dose escalation, 29 subjects with various tumor types were administered BAY1436032 across five doses (150–1,500 mg twice daily). BAY1432032 exhibited a relatively short half-life. Most evaluable subjects experienced target inhibition as indicated by a median maximal reduction of plasma R-2-hydroxyglutarate levels of 76%. BAY1436032 was well tolerated and an MTD was not identified. A dose of 1,500 mg twice daily was selected for dose expansion, where 52 subjects were treated in cohorts representing four different tumor types [lower grade glioma (LGG), glioblastoma, intrahepatic cholangiocarcinoma, and a basket cohort of other tumor types]. The best clinical outcomes were in subjects with LGG (n = 35), with an objective response rate of 11% (one complete response and three partial responses) and stable disease in 43%. As of August 2020, four of these subjects were in treatment for >2 years and still ongoing. Objective responses were observed only in LGG. Conclusions: BAY1436032 was well tolerated and showed evidence of target inhibition and durable objective responses in a small subset of subjects with LGG.
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- 2020
9. 416 SQ3370–001 is a multi-center open-label phase I dose-escalation study to test a novel intratumoral and systemic approach to treat advanced solid tumors
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M. Wayne Saville, Vivek Subbiah, Ding Wang, Ravi Murthy, Sangeetha Srinivasan, Vivek Bhadri, Jose M. Mejia Oneto, Nam Bui, Alexander Guminski, Kamalesh Kumar Sankhala, Robert J. Steffner, and Nathan Yee
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Oncology ,Cardiotoxicity ,medicine.medical_specialty ,Chemotherapy ,Anthracycline ,business.industry ,medicine.medical_treatment ,Immunosuppression ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Institutional review board ,lcsh:RC254-282 ,Tolerability ,Internal medicine ,medicine ,Doxorubicin ,Adverse effect ,business ,medicine.drug - Abstract
Background Cancer immunotherapies have been very successful in recent times; however, they benefit only a subset of patients and have varying response rates across tumor types. Conversely, conventional chemotherapies are effective in a large group of patients, but have limited dosing capabilities, lack specificity, and often result in systemic adverse events. Here, we present SQ3370, a novel approach that activates doxorubicin (Dox) at the tumor site while avoiding systemic toxicities commonly associated with the therapy, and also potentially activates an immune response against tumors. SQ3370 is based on a local intratumoral injection of a prodrug-capturing biomaterial (SQL70) followed by 5 daily systemic infusions of an attenuated form of Dox (SQP33). Mutually-reactive click chemistry groups in the 2 components allow the capture and release of active Dox at the tumor site. While conventional Dox is known to induce immune activation1 and enhance tumor responsiveness to checkpoint inhibitors,2 its benefit is limited by cumulative dose cardiotoxicity. We safely administered SQ3370 in dogs at 8.95-times the veterinary clinical dose of Dox with minimal side effects including cardiotoxicity and immunosuppression. In syngeneic mouse models, SQ3370 improved overall survival and induced a robust anti-tumor response against the biomaterial-injected lesion compared to conventional Dox. Surprisingly, SQ3370 also induced regression of the non-injected tumor and enhanced T-cell infiltration in both injected and noninjected tumors. We hypothesize that activating Dox at a local site with SQ3370 promotes activation of the native immune system against the tumor. Thus, SQ3370 represents a new therapeutic modality to treat solid tumors by using a drug with known efficacy, Dox, and expanding its therapeutic window. SQ3370 could potentially also benefit patients with widely disseminated or micro-metastatic lesions. Methods SQ3370-001 (NCT04106492), the first-in-human Phase 1 study, is currently open in the United States and Australia to treat patients with advanced solid tumors. SQ3370-001 is enrolling patients ≥ 18 years of age with an injectable local or metastatic lesion, for which published data indicates responsiveness to anthracyclines. Patients must be relapsed or refractory following standard of care therapy and must not have received more than 225 mg/m2 of Dox (or equivalent anthracycline). Each cycle will be for 21 days with no limit on total cycles. Primary objectives include determining the safety, tolerability, and recommended Phase 2 dose. Additional objectives include assessment of the pharmacokinetic profile, preliminary efficacy per RECIST 1.1, and immune response. Results N/A Conclusions N/A Acknowledgements The authors would like to thank the National Institutes of Health (NIH), the National Science Foundation (NSF), and Y Combinator. Ethics Approval This study was approved by:1. The Institutional Review Board (IRB) of Stanford University; eProtocol Number: 54928.2. The IRB of The University of Texas MD Anderson Cancer Center; IRB ID Number: 2020-0185_MOD001.3. Western IRB, on behalf of The Angeles Clinic and Research Institute and Henry Ford Health System IRB Office; IRB Tracking Number: 20200758.4. Bellberry Limited Human Research Ethics Committee, on behalf of Royal North Shore Hospital and Chris O’Brien Lifehouse; Application Number: 2019-10-848. References Mattarollo SR, Loi S, Duret H, Ma Y, Zitvogel L, Smyth MJ. Pivotal role of innate and adaptive immunity in anthracycline chemotherapy of established tumors. Cancer Res 2011;71:4809–4820. Zitvogel L, Galluzzi L, Smyth MJ, Kroemer G. Mechanism of action of conventional and targeted anticancer therapies: reinstating immunosurveillance. Immunity 2013;39:74–88.
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- 2020
10. A Phase 1b Study Evaluating the Safety, Tolerability, and Immunogenicity of CMB305, a Lentiviral-Based Prime-Boost Vaccine Regimen, in Patients with Locally Advanced, Relapsed, or Metastatic Cancer Expressing NY-ESO-1
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Joseph Kim, Robin L. Jones, Sant P. Chawla, Mahlet Yishak, Khanh T. Do, Sacha Gnjatic, Kevin Tuballes, Michael Chen, Seunghee Kim-Schulze, Neeta Somaiah, Seth M. Pollack, John C. Morris, Chet Bohac, Richard T. Kenney, Adam Yakovich, Hailing Lu, Kamalesh Kumar Sankhala, Mihaela Druta, Jan ter Meulen, Patrick Hwu, and Matthew S. Block
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LV305 ,0301 basic medicine ,Oncology ,medicine.medical_specialty ,medicine.medical_treatment ,Immunology ,Priming (immunology) ,synovial sarcoma ,Cancer Vaccines ,complex mixtures ,prime-boost ,Viral vector ,03 medical and health sciences ,0302 clinical medicine ,Adjuvants, Immunologic ,Antigens, Neoplasm ,lentivirus ,vaccine ,Internal medicine ,medicine ,Humans ,NY-ESO-1 ,Immunology and Allergy ,myxoid liposarcoma ,RC254-282 ,Original Research ,biology ,business.industry ,Immunogenicity ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Membrane Proteins ,Sarcoma ,G305 ,Prime boost ,Immunotherapy ,RC581-607 ,biology.organism_classification ,Regimen ,030104 developmental biology ,030220 oncology & carcinogenesis ,Lentivirus ,immunotherapy ,Immunologic diseases. Allergy ,business ,Research Article - Abstract
Preclinical data suggest that a “prime-boost” vaccine regimen using a target-expressing lentiviral vector for priming, followed by a recombinant protein boost, may be effective against cancer; however, this strategy has not been evaluated in a clinical setting. CMB305 is a prime-boost vaccine designed to induce a broad anti-NY-ESO-1 immune response. It is composed of LV305, which is an NY-ESO-1 expressing lentiviral vector, and G305, a recombinant adjuvanted NY-ESO-1 protein. This multicenter phase 1b, first-in-human trial evaluated CMB305 in patients with NY-ESO-1 expressing solid tumors. Safety was examined in a 3 + 3 dose-escalation design, followed by an expansion with CMB305 alone or in a combination with either oral metronomic cyclophosphamide or intratumoral injections of a toll-like receptor agonist (glucopyranosyl lipid A). Of the 79 patients who enrolled, 81.0% had sarcomas, 86.1% had metastatic disease, and 57.0% had progressive disease at study entry. The most common adverse events were fatigue (34.2%), nausea (26.6%), and injection-site pain (24.1%). In patients with soft tissue sarcomas, a disease control rate of 61.9% and an overall survival of 26.2 months (95% CI, 22.1–NA) were observed. CMB305 induced anti-NY-ESO-1 antibody and T-cell responses in 62.9% and 47.4% of patients, respectively. This is the first trial to test a prime-boost vaccine regimen in patients with advanced cancer. This approach is feasible, can be delivered safely, and with evidence of immune response as well as suggestion of clinical benefit.
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- 2020
11. Two phase I, pharmacokinetic, and pharmacodynamic studies of DFP-10917, a novel nucleoside analog with 14-day and 7-day continuous infusion schedules
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Scott Kopetz, Kenzo Iizuka, Kamalesh Kumar Sankhala, Amir Mehrvarz Sarshekeh, Jordi Rodon, Chris H. Takimoto, Alain C. Mita, K. Burns, and Henry Xiong
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Adult ,Male ,Isoflurophate ,Maximum Tolerated Dose ,Nausea ,Antineoplastic Agents ,Neutropenia ,Pharmacology ,Deoxycytidine ,Article ,Drug Administration Schedule ,chemistry.chemical_compound ,Pharmacokinetics ,Refractory ,Neoplasms ,Humans ,Medicine ,Tissue Distribution ,Pharmacology (medical) ,Infusions, Intravenous ,Aged ,business.industry ,Middle Aged ,Prognosis ,medicine.disease ,Oncology ,chemistry ,Pharmacodynamics ,Vomiting ,Female ,medicine.symptom ,business ,Febrile neutropenia ,Follow-Up Studies - Abstract
Purpose DFP-10917 is a novel deoxycytidine analog with a unique mechanism of action. Brief exposure to high concentrations of DFP-10917 inhibits DNA polymerase resulting in S-phase arrest, while prolonged exposure to DFP-10917 at low concentration causes DNA fragmentation, G2/M-phase arrest, and apoptosis. DFP-10917 demonstrated activity in tumor xenografts resistant to other deoxycytidine analogs. Experimental design Two phase I studies assessed the safety, pharmacokinetic, pharmacodynamic and preliminary efficacy of DFP-10917. Patients with refractory solid tumors received DFP-10917 continuous infusion 14-day on/7-day off and 7-day on/7-day off. Enrollment required age > 18 years, ECOG Performance Status 0–2 and adequate organ function. Results 29 patients were dosed in both studies. In 14-day infusion, dose-limiting toxicities (DLT) consisting of febrile neutropenia and thrombocytopenia occurred at 4.0 mg/m2/day. At 3.0 mg/m2/day, 3 patients experienced neutropenia in cycle 2. The dose of 2.0 mg/m2/day was well tolerated in 6 patients. In 7-day infusion, grade 4 neutropenia was DLT at 4.0 mg/m2/day. The maximum tolerated dose was 3 mg/m2/day. Other toxicities included nausea, vomiting, diarrhea, neutropenia, and alopecia. Eight patients had stable disease for >12 weeks. Paired comet assays performed for 7 patients showed an increase in DNA strand breaks at day 8. Pharmacokinetic data showed dose-proportionality for steady-state concentration and AUC of DFP-10917 and its primary metabolite. Conclusion Continuous infusion of DFP-10917 is feasible and well tolerated with myelosuppression as main DLT. The recommended doses are 2.0 mg/m2/day and 3.0 mg/m2/day on the 14-day and 7-day continuous infusion schedules, respectively. Preliminary activity was suggested. Pharmacodynamic data demonstrate biological activity at the tested doses.
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- 2018
12. Denosumab in advanced/unresectable giant-cell tumour of bone (GCTB): For how long?
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Silvia Ferrari, Neal Shiv Chawla, Michela Pierini, Imran S. Syed, William E. Mendanha, Emanuela Marchesi, Anna Paioli, Kumar Sankhala, Madhuri Sudan, M. Piccinni Leopardi, Prarthana Parthasarathy, Sant P. Chawla, Emanuela Palmerini, P. Picci, Palmerini, E, Chawla, N.S., Ferrari, S., Sudan, M., Picci, P., Marchesi, E., Leopardi, M. Piccinni, Syed, I., Sankhala, K.K., Parthasarathy, P., Mendanha, W.E., Pierini, M., Paioli, A., and Chawla, S.P.
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Male ,Cancer Research ,Lung Neoplasms ,Time Factors ,Receptor activator of nuclear factor κB ligand ,Cohort Studies ,0302 clinical medicine ,GCTB ,Giant Cell Tumor of Bone ,Bone Density Conservation Agents ,Femoral Neoplasms ,Middle Aged ,Primary tumor ,Rash ,Radius ,medicine.anatomical_structure ,Denosumab ,Oncology ,030220 oncology & carcinogenesis ,Toxicity ,Disease Progression ,Bisphosphonate-Associated Osteonecrosis of the Jaw ,Female ,medicine.symptom ,medicine.drug ,Adult ,Sacrum ,medicine.medical_specialty ,Adolescent ,ONJ ,Skull Neoplasms ,Bone Neoplasms ,Young Adult ,03 medical and health sciences ,Ischium ,medicine ,Giant-cell tumour of the bone ,Humans ,Adverse effect ,Aged ,Retrospective Studies ,Spinal Neoplasms ,Lung ,Dose-Response Relationship, Drug ,Tibia ,business.industry ,medicine.disease ,Surgery ,Peripheral neuropathy ,Giant cell ,business ,030217 neurology & neurosurgery - Abstract
Background Giant-cell tumours of bone (GCTB) are RANK/RANK-ligand (RANKL) positive, aggressive and progressive osteolytic tumours. Denosumab, a RANKL inhibitor, was FDA-approved for adults and skeletally mature adolescents with unresectable GCTB or when surgical resection is likely to result in severe morbidity. Data on long-term toxicity and activity of denosumab monthly ‘GCTB-schedule’ (120 mg per 12/year, 1440 mg total dose/year) are lacking. Methods Patients with GCTB receiving denosumab, 120 mg on days 1, 8, 15, 29 and every 4 weeks thereafter, from 2006 to 2015 treated in two centres were included. Long-term toxicity was evaluated. Results Ninety-seven patients were identified. 43 patients underwent resection of the tumour with a median time on denosumab treatment of 12 months (range 6–45 months). Fifty-four patients had unresectable GCTB's (male/female 23/31, median age 35 years [range: 13–76 years], 26% presented with lung metastases, 31% had primary tumor located to the spine, 63% were relapsed after previous surgery) with a median time on denosumab of 54 months (9–115 months). In the unresectable GCTB group, tumour control and clinical benefits were observed in all patients undergoing denosumab, whereas 40% of patients discontinuing denosumab had tumour progression after a median of 8 months (range 7–15 months). Adverse events Overall, six (6%) patients developed osteonecrosis of jaw (ONJ): 1/43 (2%) in the resectable group, 5/54 (9%) in the unresectable group, with a 5-year ONJ-free survival of 92% (95% CI 84–100). Only patients with prolonged treatment experienced mild peripheral neuropathy (6/54, 11%), skin rash (5/54, 9%), hypophosphataemia (2/54, 4%) and atypical femoral fracture (2/54, 4%). Conclusions Prolonged treatment with denosumab has sustained activity in GCTB, with a mild toxicity profile. The dose-dependent toxicity observed recommends a careful and strict monitoring of patients who need prolonged treatment. Decreased dose-intensity schedules should be further explored in unresectable GCTB.
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- 2017
13. Clinical development landscape in GIST: from novel agents that target accessory pathways to revisiting non-targeted therapies
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Kamalesh Kumar Sankhala
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0301 basic medicine ,MAPK/ERK pathway ,Gastrointestinal Stromal Tumors ,Antineoplastic Agents ,Biology ,Bioinformatics ,03 medical and health sciences ,0302 clinical medicine ,Growth factor receptor ,medicine ,Humans ,Receptors, Platelet-Derived Growth Factor ,Pharmacology (medical) ,Molecular Targeted Therapy ,Protein Kinase Inhibitors ,PI3K/AKT/mTOR pathway ,Gastrointestinal Neoplasms ,Pharmacology ,GiST ,Kinase ,Antibodies, Monoclonal ,Imatinib ,General Medicine ,Proto-Oncogene Proteins c-kit ,030104 developmental biology ,Drug Design ,030220 oncology & carcinogenesis ,Mutation ,Signal transduction ,Tyrosine kinase ,medicine.drug - Abstract
Activating mutations in the genes encoding the tyrosine receptor kinases KIT and platelet-derived growth factor receptor occur in 85%-90% of patients with gastrointestinal stromal tumors (GIST). Although imatinib and other tyrosine kinase inhibitors have revolutionized the treatment of GIST, most patients progress within a few years. Areas covered: Monoclonal antibodies and small-molecule inhibitors targeting specific signaling pathways or proteins associated with resistance to existing treatments are being explored as alternative treatment approaches for GIST. Other alternative approaches include inhibiting more general regulators of protein folding, chromatin packaging, and cell-cycle regulation; nontargeted approaches are also being evaluated in select patient populations. This review summarizes preclinical and clinical data from agents using these accessory pathways. Expert opinion: As we learn more about GIST biology, it is becoming clear that treatment strategies will become more personalized, as reflected by the fact that several trials are enrolling specific subpopulations of patients with GIST. Going forward, researchers should evaluate these new drugs alone or in combination with other types of drugs to better meet patient needs.
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- 2017
14. Trabectedin for Soft Tissue Sarcoma: Current Status and Future Perspectives
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Sant P. Chawla, Kumar Sankhala, Erlinda M. Gordon, and Neal Shiv Chawla
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0301 basic medicine ,Oncology ,medicine.medical_specialty ,Neutropenia ,Alkylating agent ,Phases of clinical research ,Review ,Dioxoles ,Ecteinascidia turbinata ,Disease-Free Survival ,03 medical and health sciences ,0302 clinical medicine ,Clinical trials ,Internal medicine ,Germany ,Tetrahydroisoquinolines ,medicine ,Chemotherapy ,Humans ,Pharmacology (medical) ,Adverse effect ,Antineoplastic Agents, Alkylating ,Trabectedin ,Randomized Controlled Trials as Topic ,Medicine(all) ,Soft tissue sarcoma ,biology ,business.industry ,Sarcoma ,General Medicine ,ET-743 ,biology.organism_classification ,medicine.disease ,Surgery ,Clinical trial ,Europe ,Regimen ,DNA minor groove binder ,030104 developmental biology ,030220 oncology & carcinogenesis ,business ,medicine.drug - Abstract
Trabectedin (ET743, Yondelis®, manufactured by Baxter Oncology GmbH, Halle/Westfalen, Germany, for Janssen Products, LP, Horsham, PA), derived from the marine ascidian, Ecteinascidia turbinata, is a natural alkaloid with multiple complex mechanisms of action. On 23 October 2015, 15 years after the results of the first Phase 1 clinical trial using trabectedin for chemotherapy-resistant solid malignancies was reported, and 8 years after its approval in Europe, the United States Food and Drug Administration (USFDA) finally approved trabectedin for the treatment of unresectable or metastatic liposarcoma or leiomyosarcoma that has failed a prior anthracycline-containing regimen. Approval was based on the results of a pivotal Phase 3 trial involving a 2:1 randomization of 518 patients (who were further stratified by soft tissue sarcoma subtype), in which a significant improvement in progression-free survival was reported in the trabectedin-treated group vs. the dacarbazine-treated group (p
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- 2016
15. Aldoxorubicin for the treatment of advanced soft tissue sarcoma
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Sant P. Chawla, Kamalesh Kumar Sankhala, and Neal Shiv Chawla
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Drug ,Cardiotoxicity ,biology ,business.industry ,Health Policy ,media_common.quotation_subject ,Soft tissue sarcoma ,Serum albumin ,Aldoxorubicin ,Prodrug ,Pharmacology ,medicine.disease ,Pharmacokinetics ,Cancer research ,medicine ,biology.protein ,Pharmacology (medical) ,Doxorubicin ,business ,Pharmacology, Toxicology and Pharmaceutics (miscellaneous) ,medicine.drug ,media_common - Abstract
Introduction: Soft tissue sarcomas (STS) comprise a group of uncommon mesenchymal tumors of heterogeneous differentiation. For advanced STS, single-agent doxorubicin or doxorubicin-based combinations are commonly used, but at serious risk of cumulative cardiotoxicity. In addition, doxorubicin is the sheet anchor drug for many malignancies, both solid and hematologic.Areas covered: Aldoxorubicin, a doxorubicin prodrug currently in development, was designed to bind covalently to serum albumin and remains conjugated until transported to an acidic environment, such as the tumor site. We review the novel mechanism of action and the published pharmacokinetic, safety and efficacy data from Phase I, Ib/II and II clinical studies of aldoxorubicin in patients with advanced solid tumors, including advanced STS.Expert opinion: Chemical modification of doxorubicin, an effective but cardiotoxic chemotherapy drug, to aldoxorubicin has yielded a notable improvement in patient outcomes. This small step in drug chemistry m...
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- 2015
16. A phase 1B/2 study of aldoxorubicin in patients with soft tissue sarcoma
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Neelesh Soman, D. Scott Wieland, Sant P. Chawla, Andrew F. Hendifar, Kamalesh Kumar Sankhala, Victoria S. Chua, Daniel J. Levitt, and Doris Quon
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Adult ,Male ,Cancer Research ,medicine.medical_specialty ,Neutropenia ,Maximum Tolerated Dose ,Vomiting ,Nausea ,Aldoxorubicin ,Kaplan-Meier Estimate ,Severity of Illness Index ,Gastroenterology ,Drug Administration Schedule ,Bone Marrow ,Internal medicine ,medicine ,Humans ,Prodrugs ,Adverse effect ,Aged ,Febrile Neutropenia ,Neoplasm Staging ,Stomatitis ,Antibiotics, Antineoplastic ,business.industry ,Soft tissue sarcoma ,Cancer ,Alopecia ,Sarcoma ,Middle Aged ,medicine.disease ,Treatment Outcome ,Oncology ,Doxorubicin ,Anesthesia ,Female ,Neoplasm Recurrence, Local ,medicine.symptom ,business ,Febrile neutropenia - Abstract
BACKGROUND Aldoxorubicin, a prodrug of doxorubicin, covalently binds to serum albumin, allowing for the administration of much higher doses of doxorubicin in a previous clinical study. The current phase 1B/2 study evaluated the safety of aldoxorubicin, including preliminary efficacy and safety of its maximum tolerated dose (MTD). METHODS Patients aged 18 to 70 years with recurrent/refractory malignant solid tumors received aldoxorubicin at a dose of 230 mg/m2, 350 mg/m2, or 450 mg/m2 (170 mg/m2, 260 mg/m2, or 335 mg/m2 doxorubicin equivalents, respectively) by intravenous infusion once every 21 days for up to 8 consecutive cycles. RESULTS A total of 25 patients were enrolled, including 17 patients (68%) with advanced soft tissue sarcoma (STS). The MTD of aldoxorubicin was 350 mg/m2; dose-limiting toxicities included grade 4 neutropenia and grade 3 febrile neutropenia (NCI CTCAE v4.0). Drug-related adverse events included myelosuppression, nausea, fatigue, alopecia, stomatitis, vomiting, and oropharyngeal pain. No clinically significant cardiac toxicities were reported. Seven patients (28%) had elevated serum troponin levels while taking part in the study, but these elevations were not clinically significant or associated with cardiac findings. A partial response was achieved in 20% of patients, and stable disease was reported in 40% of patients. The median progression-free survival was 4.80 months, and the median overall survival was 11.25 months. Among patients with STS who were treated at the MTD (13 patients), a partial response was achieved in 38% and stable disease in 46%; the median progression-free survival was 11.25 months and the median overall survival was 21.71 months. CONCLUSIONS Aldoxorubicin at a dose of 350 mg/m2 administered once every 21 days for up to 8 cycles was found to be acceptably safe and demonstrated preliminary efficacy in patients with advanced solid tumors, including STS. Further investigation of aldoxorubicin is ongoing. Cancer 2015;121:570–579. © 2014 American Cancer Society.
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- 2014
17. Phase I study of intravenously administered ATI-1123, a liposomal docetaxel formulation in patients with advanced solid tumors
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Jessica Hart, Alain C. Mita, John Sarantopoulos, Ahmed Kousba, Kamalesh Kumar Sankhala, Laeeq Malik, Neil Senzer, John Charles, Nicole S. Gallegos, Gavin Anderson, Steven D. Weitman, Devalingam Mahalingam, Jon M. Rogers, and John Nemunaitis
- Subjects
Adult ,Male ,Cancer Research ,medicine.medical_specialty ,Maximum Tolerated Dose ,Nausea ,Antineoplastic Agents ,Docetaxel ,Pharmacology ,Neutropenia ,Toxicology ,Gastroenterology ,Pharmacokinetics ,Neoplasms ,Internal medicine ,medicine ,Humans ,Pharmacology (medical) ,Infusions, Intravenous ,Adverse effect ,Aged ,Aged, 80 and over ,Dose-Response Relationship, Drug ,business.industry ,Middle Aged ,medicine.disease ,Treatment Outcome ,Oncology ,Tolerability ,Liposomes ,Female ,Taxoids ,medicine.symptom ,Liposomal Docetaxel ,business ,Febrile neutropenia ,medicine.drug - Abstract
ATI-1123 is a liposomal formulation of docetaxel and may be administered without the premedications and hypersensitivity reactions. This Phase I study examines the safety, tolerability, pharmacokinetics (PKs), and antitumor activity of ATI-1123.Patients with advanced solid malignancies received escalating doses of ATI-1123 intravenously over 1-h every 3 weeks. The dosing commenced using an accelerated titration design and was followed by a modified 3 + 3 Fibonacci schema to determine maximally tolerated dose (MTD). Plasma was analyzed for encapsulated/non-encapsulated docetaxel; PK analyses were performed using model independent method. Response was assessed using RECIST criteria.In total, 29 patients received doses ranging from 15 to 110 mg/m(2). At 110 mg/m(2), two of six patients experienced dose-limiting toxicities including grade 3 stomatitis and febrile neutropenia. The 90 mg/m(2) cohort was expanded to ten patients and identified as the MTD. The most common adverse events were fatigue, nausea, neutropenia, anemia, anorexia, and diarrhea. ATI-1123 exhibited linear and dose proportional PKs. One patient with lung cancer had confirmed partial response, and stable disease was observed in 75 % patients.ATI-1123 demonstrated an acceptable tolerability and favorable PK profile in patients with solid tumors. Our results provide support for Phase II trials to determine the antitumor activity of this drug.
- Published
- 2014
18. Randomized Phase II Trial of the Cyclin-Dependent Kinase Inhibitor Dinaciclib (MK-7965) Versus Capecitabine in Patients With Advanced Breast Cancer
- Author
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Monica M. Mita, Karen Small, Ying Ming Jou, Da Zhang, Anil A. Joy, Charles L. Shapiro, Kamalesh Kumar Sankhala, Alain C. Mita, Siu Long Yao, Rajat Bannerji, Yali Zhu, and Paul Statkevich
- Subjects
Adult ,Oncology ,Cancer Research ,medicine.medical_specialty ,Population ,Antineoplastic Agents ,Breast Neoplasms ,Pyridinium Compounds ,Kaplan-Meier Estimate ,Deoxycytidine ,Cyclic N-Oxides ,Capecitabine ,chemistry.chemical_compound ,Breast cancer ,Internal medicine ,Humans ,Medicine ,Dinaciclib ,education ,Aged ,Proportional Hazards Models ,Aged, 80 and over ,education.field_of_study ,business.industry ,Indolizines ,Cancer ,Middle Aged ,Bridged Bicyclo Compounds, Heterocyclic ,medicine.disease ,Metastatic breast cancer ,Tolerability ,chemistry ,Anesthesia ,Female ,Fluorouracil ,business ,Febrile neutropenia ,medicine.drug - Abstract
Introduction Effective therapies after failure of treatment with anthracyclines and taxanes are needed for patients with metastatic breast cancer. Dinaciclib (MK-7965, formerly SCH727965), a small-molecule cyclin-dependent kinase inhibitor, has demonstrated antitumor activity in phase I studies with solid-tumor patients. This phase II trial was designed to assess the efficacy and safety of dinaciclib compared with that of capecitabine in women with previously treated advanced breast cancer. Patients and Methods Patients were randomized to receive either dinaciclib at 50 mg/m 2 , administered as a 2-hour infusion every 21 days, or 1250 mg/m 2 capecitabine, administered orally twice daily in 21-day cycles. Results An unplanned interim analysis showed that the time to disease progression was inferior with dinaciclib treatment compared with capecitabine treatment; therefore, the trial was stopped after 30 patients were randomized. Dinaciclib treatment demonstrated antitumor activity in 2 of 7 patients with estrogen receptor–positive and human epidermal growth factor receptor 2–negative metastatic breast cancer (1 confirmed and 1 unconfirmed partial response), as well as acceptable safety and tolerability. Grade 3 or 4 treatment-related adverse events were common and included neutropenia, leukopenia, increase in aspartate aminotransferase, and febrile neutropenia. Population pharmacokinetic model–predicted mean dinaciclib exposure (area under the concentration-time curve extrapolated to infinity [AUC [I] ]) at 50 mg/m 2 was similar to that observed in a previous phase I trial, and no drug accumulation was observed after multiple-dose administration. Conclusion Although dinaciclib monotherapy demonstrated some antitumor activity and was generally tolerated, efficacy was not superior to capecitabine. Future studies may be considered to evaluate dinaciclib in select patient populations with metastatic breast cancer and in combination with other agents.
- Published
- 2014
19. Phase II study evaluating the efficacy, safety, and pharmacodynamic correlative study of dual antiangiogenic inhibition using bevacizumab in combination with sorafenib in patients with advanced malignant melanoma
- Author
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Alain C. Mita, Muralidhar Beeram, J. Rodon, Daniel Benjamin, Kamalesh Kumar Sankhala, Anthony W. Tolcher, Norma S. Ketchum, Laeeq Malik, John J. Wright, Joel E. Michalek, Devalingam Mahalingam, and John Sarantopoulos
- Subjects
Male ,Niacinamide ,Oncology ,Sorafenib ,Cancer Research ,medicine.medical_specialty ,Bevacizumab ,Phases of clinical research ,Angiogenesis Inhibitors ,Antibodies, Monoclonal, Humanized ,Toxicology ,Severity of Illness Index ,chemistry.chemical_compound ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,Pharmacology (medical) ,Melanoma ,Protein Kinase Inhibitors ,Neoplasm Staging ,Pharmacology ,Proteinuria ,Vascular Endothelial Growth Factors ,business.industry ,Phenylurea Compounds ,Middle Aged ,medicine.disease ,Vascular endothelial growth factor ,Kinetics ,Receptors, Vascular Endothelial Growth Factor ,Tolerability ,chemistry ,Tumor progression ,Early Termination of Clinical Trials ,Hypertension ,Disease Progression ,Feasibility Studies ,Female ,Hand-Foot Syndrome ,Drug Monitoring ,medicine.symptom ,business ,Biomarkers ,medicine.drug - Abstract
Melanomas are vascular tumors with a high incidence of BRAF mutations driving tumor proliferation. Complete inhibition of vascular endothelial growth factor (VEGF) signaling has potential for enhanced antitumor efficacy.Patients with advanced melanoma and adequate organ function were eligible. Sorafenib was given orally at 200 mg BiD for 5 days every week; bevacizumab was administered 5 mg/kg intravenously every 14 days. The primary objective was to determine clinical biological activity. The secondary objectives were safety, tolerability, and time to progression (TTP). Pharmacodynamic analysis included serum VEGF and soluble VEGF receptor-1 and VEGF receptor-2 performed at baseline, C1D15 and C2D1. The study was terminated during the first stage of a Simon two-stage design, after 14 of planned 21 subjects were enrolled.Of the 14 patients who received treatment, no objective tumor responses were observed. Stable disease (SD) ≥16 weeks was observed in 57 % patients, including three patients with SD lasting ≥1 year. Median TTP was 32 weeks. The most frequently reported drug-related adverse events (AEs) were hand-foot syndrome (57.1 %), fatigue (57.1 %), hypertension (64.3 %), and proteinuria (35.7). Grade 3/4 drug-related AEs were hypertension (14.2 %), hand-foot syndrome, proteinuria, and thrombocytopenia (7 % each). Patients with low VEGF (300 pg/ml) experienced longer TTP than those with high VEGF [median 50 vs. 15 weeks, p = 0.02). A similar pattern was seen for VEGFR1 and VEGFR2, although it did not reach statistical significance.Combined VEGF/VEGFR blockade using bevacizumab with sorafenib shows clinical activity. The linkage between VEGF levels and time to tumor progression needs further exploration.
- Published
- 2014
20. Case Report: Prolonged Disease Stability in Giant Cell Tumor of the Bone in the Cervical Spine Treated with Denosumab
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Madhuri Sudan, William E. Mendanha, Kumar Sankhala, Susan V. Bukata, Sant P. Chawla, Imran S. Syed, Neal Shiv Chawla, and Suzan P Arasheben
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medicine.medical_specialty ,Stromal cell ,Ifosfamide ,business.industry ,Disease ,medicine.disease ,Surgery ,Clinical trial ,03 medical and health sciences ,Regimen ,0302 clinical medicine ,Denosumab ,Giant cell ,030220 oncology & carcinogenesis ,medicine ,030212 general & internal medicine ,business ,Giant-cell tumor of bone ,medicine.drug - Abstract
We present a case of locally recurring giant cell tumor (GCT) of the bone in the cervical spine of a 12-year-old girl. After three surgeries with two resulting in negative margins, adjuvant chemotherapy with Doxorubicin and Ifosfamide, and two local recurrences of the GCT of the bone within the cervical spine, she was started on a Denosumab clinical trial at the age of 13 years. The patient’s pain and neurologic symptoms decreased significantly within a few weeks and disappeared after 5 months. She has been receiving monthly Denosumab for over five years, totaling 68 doses to date, and will continue this regimen for the forseeable future. GCT of the bone is rarely seen in adolescents or in the cervical spine and effective treatment options are limited. Denosumab is an excellent treatment for non-resectable and recurrent GCT of the bone, it only eliminates giant cells, leaving the stromal cells to reactivate the GCT of the bone after a period of halting Denosumab. While this patient has maintained tumor stability over five years, the effects of receiving life-long Denosumab supplementation are currently unknown. This case demonstrates the efficacy of Denosumab in stabilizing the progression of giant cell tumor of bone but also highlights the need for further investigation into cumulative dose-related side effects and long term treatment planning as patients currently have no other treatment options once stability is achieved.
- Published
- 2016
21. Safety, Pharmacokinetics, and Activity of GRN1005, a Novel Conjugate of Angiopep-2, a Peptide Facilitating Brain Penetration, and Paclitaxel, in Patients with Advanced Solid Tumors
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Nashat Y. Gabrail, Danielle Bouchard, Kelly Elian, Kamalesh Kumar Sankhala, Alain C. Mita, Stacy L. Moulder, John Sarantopoulos, Andrew Brenner, Carrie Smith, Chandtip Chandhasin, and Razelle Kurzrock
- Subjects
Adult ,Male ,Cancer Research ,medicine.medical_specialty ,Neutropenia ,Paclitaxel ,Metabolic Clearance Rate ,Pharmacology ,Gastroenterology ,Drug Administration Schedule ,Cohort Studies ,Young Adult ,chemistry.chemical_compound ,Pharmacokinetics ,Neoplasms ,Internal medicine ,medicine ,Humans ,Dosing ,Infusions, Intravenous ,Fatigue ,Aged ,Aged, 80 and over ,Taxane ,Dose-Response Relationship, Drug ,biology ,business.industry ,Brain ,Alopecia ,Middle Aged ,medicine.disease ,Antineoplastic Agents, Phytogenic ,Treatment Outcome ,Oncology ,chemistry ,Tolerability ,Area Under Curve ,Toxicity ,biology.protein ,Female ,Antibody ,Peptides ,business ,Ovarian cancer - Abstract
GRN1005 is a novel peptide–drug conjugate composed of paclitaxel covalently linked to a peptide, angiopep-2, that targets the low-density lipoprotein receptor-related protein 1. This first-in-human study evaluated the safety, tolerability, pharmacokinetics, and efficacy of GRN1005 in patients with advanced solid tumors. Patients in sequential cohorts (one patient per cohort until grade 2 toxicity, then 3 + 3 design) received intravenous GRN1005 at escalating doses between 30 and 700 mg/m2 once in every 21 days. In the maximum tolerated dose (MTD) expansion group, patients were required to have brain metastases. Fifty-six patients received GRN1005, including 41 with brain metastases (median number of prior therapies = 4). MTD was 650 mg/m2; the main dose-limiting toxicity was myelosuppression. Sixteen of 20 patients dosed at the MTD had brain metastases. Pharmacokinetics was dose linear and the mean terminal-phase elimination half-life was 3.6 hours. No evidence of accumulation was observed after repeat dosing. No anti-GRN1005 antibodies were detected. Five of the 20 patients (25%) dosed at 650 mg/m2 (MTD), three of whom had previous taxane therapy, achieved an overall partial response (breast, n = 2; non–small cell lung cancer, n = 2; and ovarian cancer, n = 1); responses in all five patients were also accompanied by shrinkage of brain lesions (−17% to −50%). In addition, six patients (11%; doses 30–700 mg/m2) experienced stable disease that lasted 4 months or more. GRN1005 was well tolerated and showed activity in heavily pretreated patients with advanced solid tumors, including those who had brain metastases and/or failed prior taxane therapy. Mol Cancer Ther; 11(2); 308–16. ©2011 AACR.
- Published
- 2012
22. Heat Shock Proteins: A Potential Anticancer Target
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Monica M. Mita, Kamalesh Kumar Sankhala, Chris H. Takimoto, and Alain C. Mita
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Pharmacology ,Cell signaling ,Stromal cell ,Angiogenesis ,Clinical Biochemistry ,Antineoplastic Agents ,Apoptosis ,Biology ,Geldanamycin ,Hsp90 ,Hsp90 inhibitor ,Cell biology ,chemistry.chemical_compound ,chemistry ,Neoplasms ,Heat shock protein ,Drug Discovery ,biology.protein ,Animals ,Humans ,Molecular Medicine ,Neoplasm Invasiveness ,HSP90 Heat-Shock Proteins - Abstract
Heat shock proteins (Hsp) are highly conserved proteins and their expression is dependent on the level of various cellular stresses. Hsp work as a molecular chaperon for several cellular proteins and have cytoprotective roles. Their function is essential for normal cell viability and growth. Hsp90 interacts with proteins mediating cell signaling involved in essential processes such as proliferation, cell cycle control, angiogenesis and apoptosis. The naturally occurring Hsp90 inhibitor geldanamycin (GA) was the first to demonstrate anticancer activity but its significant toxicity profile in pre-clinical models precluded its clinical development. Subsequent, several Hsp90 inhibitors have been developed and underwent clinical development with favorable safety profiles. Several initial clinical studies have shown promising anticancer activity of Hsp90 inhibitors mainly in breast cancer, non small cell lung carcinoma (NSCLC), gastrointestinal stromal tumors (GIST) and various hematological malignancies. The universal involvement of Hsp90 in multiple oncogenic processes makes Hsp90 inhibitors ideal compounds to be explored as a single agent or in combination with other anticancer therapies.
- Published
- 2011
23. The emerging role of mammalian target of rapamycin inhibitors in the treatment of sarcomas
- Author
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Alain C. Mita, Monica M. Mita, Sushma Vemulapalli, Yesid Alvarado, and Kamalesh Kumar Sankhala
- Subjects
Cancer Research ,Protein degradation ,Ridaforolimus ,chemistry.chemical_compound ,medicine ,Animals ,Humans ,Pharmacology (medical) ,Molecular Targeted Therapy ,PI3K/AKT/mTOR pathway ,Sirolimus ,Antibiotics, Antineoplastic ,business.industry ,Cell growth ,TOR Serine-Threonine Kinases ,RPTOR ,Sarcoma ,medicine.disease ,Temsirolimus ,Oncology ,chemistry ,Cancer research ,Signal transduction ,business ,Signal Transduction ,medicine.drug - Abstract
The mammalian target of rapamycin (mTOR) is a protein kinase that functions as a key regulator of cell growth, proliferation and differentiation, cell-cycle progression, angiogenesis, protein degradation, and apoptosis. Following activation by a number of oncogenic signals such as growth factors, energy and nutrients, mTOR stimulates several downstream effectors including the 40S ribosomal protein S6 kinase (p70s6k) and the eukaryotic initiation factor 4 E binding protein-1 (4 EBP-1), as well as a complex network of regulatory loops. Activation of the mTOR pathway plays a critical role in the development of many tumor types, including renal cell and breast carcinomas, neuroendocrine tumors, and sarcomas. Bone and soft tissue sarcomas are rare, heterogeneous tumors that are curable by local treatments if diagnosed at early stages; however advanced or metastatic sarcomas are rarely curable and very few drugs are efficacious in this setting. Several disruptions in phosphatidylinositol-3 kinase (PI3K)-Akt-mTOR signaling are associated with malignant transformation or progression in various sarcoma sub-types. The PI3K-Akt-mTOR pathway is therefore an exciting target for therapy of sarcomas, and its blockade represents an opportunity to improve outcomes in this poor-prognosis disease. Early studies with mTOR inhibitors have demonstrated promising antitumor activity in patients with metastatic sarcoma who have failed standard treatments. This article discusses the mTOR signaling pathway and summarizes the clinical experience with mTOR inhibitors in patients with advanced or metastatic sarcoma.
- Published
- 2011
24. Phase I and Pharmacokinetic Study of CT-322 (BMS-844203), a Targeted Adnectin Inhibitor of VEGFR-2 Based on a Domain of Human Fibronectin
- Author
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Bruce A. Silver, Cheryl Eaton, Amita Patnaik, Christopher Sweeney, Kyri Papadopoulos, Kamalesh Kumar Sankhala, Eric Furfine, Alain C. Mita, Jochem Gokemeijer, Anthony W. Tolcher, Monica M. Mita, Lisa Iacono, and Elena G. Chiorean
- Subjects
Adult ,Male ,Cancer Research ,Maximum Tolerated Dose ,Nausea ,Antineoplastic Agents ,Pharmacology ,Pharmacokinetics ,Neoplasms ,medicine ,Humans ,Molecular Targeted Therapy ,Aged ,Proteinuria ,biology ,business.industry ,Immunogenicity ,Cancer ,Middle Aged ,medicine.disease ,Vascular Endothelial Growth Factor Receptor-2 ,Peptide Fragments ,Fibronectins ,Oncology ,Pharmacodynamics ,Antibody Formation ,Vomiting ,biology.protein ,Female ,medicine.symptom ,Antibody ,business - Abstract
Purpose: To determine the maximum tolerated dose (MTD), safety, pharmacokinetics, pharmacodynamics, immunogenicity, and preliminary antitumor activity of CT-322 (BMS-844203), a VEGFR-2 inhibitor and the first human fibronectin domain–based targeted biologic (Adnectin) to enter clinical studies. Experimental Design: Patients with advanced solid malignancies were treated with escalating doses of CT-322 intravenously (i.v.) weekly (qw), or biweekly (q2w). Plasma samples were assayed for CT-322 concentrations, plasma VEGF-A concentrations, and antidrug antibodies. Results: Thirty-nine patients completed 105 cycles of 0.1 to 3.0 mg/kg CT-322 i.v. either qw or q2w. The most common treatment-emergent grade 1/2 toxicities were fatigue, nausea, proteinuria, vomiting, anorexia, and hypertension. Grade 3/4 toxicities were rare. Reversible proteinuria, retinal artery, and vein thrombosis, left ventricular dysfunction, and reversible posterior leukoencephalopathy syndrome were dose limiting at 3.0 mg/kg. The MTD was 2 mg/kg qw or q2w. CT-322 plasma concentrations increased dose proportionally. Plasma VEGF-A levels increased with dose and plateaued at 2 mg/kg qw. Anti–CT-322 antibodies developed without effects on pharmacokinetics, VEGF-A levels, or safety. Minor decreases in tumor measurements occurred in 4 of 34 evaluable patients and 24 patients had stable disease. Conclusions: CT-322 can be safely administered at 2 mg/kg i.v. qw or q2w and exhibits promising antitumor activity in patients with advanced solid tumors. The absence of severe toxicities at the MTD, demonstration of plasma drug concentrations active in preclinical models, and clinical pharmacodynamic evidence of VEGFR-2 inhibition warrant further development of CT-322 and suggest strong potential for Adnectin-based targeted biologics. Cancer Res; 17(2); 363–71. ©2011 AACR. Clin Cancer Res; 17(2); 363–71. ©2011 AACR.
- Published
- 2011
25. Efficacy and safety of lurbinectedin (PM1183) in Ewing sarcoma: Final results from a phase 2 study
- Author
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Pilar Lardelli, Sant P. Chawla, Ravin Ratan, Vivek Subbiah, Valentina Boni, Thierry Gil, Carmen Kahatt, Arturo Soto-Matos, Kamalesh Kumar Sankhala, Enrique Sanz Garcia, Victor M. Villalobos, Mariano Siguero, and Stefano Ferrari
- Subjects
0301 basic medicine ,Cancer Research ,business.industry ,Lurbinectedin ,Phases of clinical research ,medicine.disease ,Anticancer drug ,03 medical and health sciences ,chemistry.chemical_compound ,030104 developmental biology ,0302 clinical medicine ,Oncology ,chemistry ,Transcription (biology) ,030220 oncology & carcinogenesis ,Cancer research ,Medicine ,Sarcoma ,business ,DNA - Abstract
11519Background: Patients (pts) with relapsed Ewing sarcoma (ES) have a poor outcome. New therapeutic agents are needed. L is a new anticancer drug that blocks transcription and induces DNA double-...
- Published
- 2018
26. Clinical experience with combination chemo-/immunotherapy using trabectedin and nivolumab for advanced soft tissue sarcoma
- Author
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Joshua R. Ravicz, Bryan Leong, Nathan Stumpf, Sant P. Chawla, William W. Tseng, Susan Arasheben, Erlinda M. Gordon, Seiya Liu, Kamalesh Kumar Sankhala, Grace Kang, and Seth Kim
- Subjects
0301 basic medicine ,Cancer Research ,business.industry ,animal diseases ,Immune checkpoint inhibitors ,Soft tissue sarcoma ,Cancer ,chemical and pharmacologic phenomena ,biochemical phenomena, metabolism, and nutrition ,medicine.disease ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Immune system ,Oncology ,030220 oncology & carcinogenesis ,Cancer research ,bacteria ,Medicine ,Nivolumab ,business ,Chemo immunotherapy ,Trabectedin ,medicine.drug - Abstract
e23568Background: Immune checkpoint inhibitors revive pre-existing immune responses that are suppressed in cancer. To restore tumor surveillance that is lost in cancer patients, a tumoricidal agent...
- Published
- 2018
27. Mutational analysis and safety/efficacy in a phase 2 multi-center investigation of ABI-009 (nab-rapamycin) in patients with advanced malignant perivascular epithelioid cell tumors (PEComa)
- Author
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Neil Desai, Andrew J. Wagner, Kristen N. Ganjoo, Richard F. Riedel, Brian A. Van Tine, Erlinda M. Gordon, Berta Grigorian, Rashmi Chugh, Jason L. Hornick, Lee D. Cranmer, Mark A. Dickson, Kamalesh Kumar Sankhala, David J. Kwiatkowski, Vinod Ravi, and Seth M. Pollack
- Subjects
Cancer Research ,Pathology ,medicine.medical_specialty ,business.industry ,Mesenchymal stem cell ,Perivascular Epithelioid Cell Tumors ,Mutational analysis ,Oncology ,Nab-Rapamycin ,Blood vessel walls ,medicine ,In patient ,business ,Epithelioid cell - Abstract
TPS11589Background: PEComas are rare mesenchymal tumors with a female predominance, composed of epithelioid cells that show a focal association with blood vessel walls and usually express both mela...
- Published
- 2018
28. A randomized Bayesian phase 1 design combining an MPS-1 inhibitor with paclitaxel: A strategy to improve determination of the incremental toxicity of a novel compound over a known backbone therapy
- Author
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Vivek Subbiah, Ingmar Bruns, Ron H.J. Mathijssen, Jennifer R. Diamond, Martijn P. Lolkema, Jaap Verweij, Martin Gutierrez, Oliver Boix, Prabhu Rajagopalan, Joseph Paul Eder, Jian Mei, Kamalesh Kumar Sankhala, Patricia LoRusso, Florence Atrafi, Anthony W. Tolcher, and Sant P. Chawla
- Subjects
Cancer Research ,Chemotherapy ,chemistry.chemical_compound ,Oncology ,Paclitaxel ,chemistry ,business.industry ,medicine.medical_treatment ,Toxicity ,Medicine ,Pharmacology ,business - Abstract
2537Background: Here we present a study combining BAY1217389 (BAY), a potent MPS-1 kinase inhibitor with a backbone chemotherapy paclitaxel. Since we expected overlapping toxicities we sought to im...
- Published
- 2018
29. Cancer immunotherapy using trabectedin and nivolumab in advanced soft tissue sarcoma: A retrospective analysis
- Author
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William W. Tseng, Grace Kang, Kamalesh Kumar Sankhala, Seth Kim, Bryan Leong, Sant P. Chawla, Joshua R. Ravicz, Suzan P Arasheben, Nathan Stumpf, and Erlinda M. Gordon
- Subjects
0301 basic medicine ,Oncology ,Leiomyosarcoma ,Cancer Research ,medicine.medical_specialty ,Myxoid liposarcoma ,business.industry ,Soft tissue sarcoma ,Cancer ,medicine.disease ,Synovial sarcoma ,Undifferentiated Pleomorphic Sarcoma ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,030220 oncology & carcinogenesis ,Internal medicine ,Medicine ,Nivolumab ,business ,Trabectedin ,medicine.drug - Abstract
40 Background: To restore innate tumor surveillance that is lost in cancer patients, a tumoricidal agent may have synergistic activity with an immune checkpoint inhibitor. Herein, we report on a retrospective analysis of our clinical experience using trabectedin, an alkylating agent, and nivolumab, a PD-1 inhibitor in advanced soft tissue sarcoma. Methods: Twenty previously treated STS patients received trabectedin (1.5 mg/m2 continuous intravenous infusion, CIV, for 24 hours) every 3 weeks, and nivolumab (3 mg/kg IV over 30 minutes) every 2 weeks. Safety/toxicity was analyzed using the NIH/NCI CTCAE v.4.03. Tumor responses were assessed by RECIST v1.1 and immune-related response criteria (irRECIST). Results: Histologic subtypes in 20 patients include undifferentiated pleomorphic sarcoma (UPS; n = 7), leiomyosarcoma (n = 5), synovial sarcoma (n = 2), myxoid liposarcoma (n = 4) and chondrosarcoma (n = 2). All patients had metastatic disease and a median of 4 lines of prior chemotherapy. Safety analysis (n = 20): Grade 3 treatment emergent adverse events include anemia (n = 2), fatigue (n = 1), decreased platelet count (n = 1), decreased granulocyte count (n = 1) and increased creatine kinase (n = 1). Efficacy analysis (n = 17): Seventeen patients were followed for at least 6 months and their results are reported here. There were 4 partial responses (UPS = 1, myxoid liposarcoma = 1, chondrosarcoma = 1, leiomyosarcoma = 1), 7 stable disease, and 6 progressive disease, with best overall response rate of 23.5%, median progression free survival (PFS) of > 11.6 months (range: 2.3- > 16.9 months), median overall survival (OS) of > 14.2 months (4.5- > 24.0 months), 6 month PFS rate of 64.7%, and 6 month OS rate of 94.1%. In a Phase 3 study, the median PFS was 4.2 months using trabectedin alone (Demetri et al., 2015). Conclusions: Taken together, the data suggest that paired administration of trabectedin and nivolumab is safe, and that this chemo-/immuno-therapy approach has synergistic activity.
- Published
- 2018
30. Targeting Sarcomas: Novel Biological Agents and Future Perspectives
- Author
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Alain C. Mita, Kevin R. Kelly, Ronan T. Swords, Francis J. Giles, Kamalesh Kumar Sankhala, Monica M. Mita, and Devalingam Mahalingam
- Subjects
Adult ,Pathology ,medicine.medical_specialty ,Stromal cell ,Angiogenesis ,Clinical Biochemistry ,Antineoplastic Agents ,Bone Neoplasms ,Soft Tissue Neoplasms ,Receptor tyrosine kinase ,Drug Delivery Systems ,Drug Discovery ,medicine ,Animals ,Humans ,Child ,PI3K/AKT/mTOR pathway ,Pharmacology ,Biological Products ,Clinical Trials as Topic ,biology ,Oncogene ,Retinoblastoma ,Mesenchymal stem cell ,Sarcoma ,medicine.disease ,biology.protein ,Cancer research ,Molecular Medicine - Abstract
Sarcomas are a group of heterogeneous tumors that arise from mesenchymal tissue and account for approximately 1% of all adult solid malignancies diagnosed, although its incidence approaches 20% in pediatric cancers. Characterization of molecular abnormalities in patients with sarcomas, in particular the up-regulation of the receptor tyrosine kinase and the PI3K-AKT-mTOR pathway, loss or deletions of retinoblastoma (Rb) and p53 gene, increased VEGF expression and angiogenesis, dysregulation of apoptosis through Bcl-2 overexpression, along with oncogene mutations and activations, such as c-KIT in Gastrointestinal stromal tumors (GISTs), makes treatment with novel biological therapies a promising option. This review focuses on the molecular heterogeneity of soft tissue and bone sarcomas, novel biological therapies currently in clinical trials to target the various molecular pathways, and the potential biological agents in pre-clinical and early clinical development.
- Published
- 2009
31. Potential of mTOR inhibitors as therapeutic agents in hematological malignancies
- Author
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Kamalesh Kumar Sankhala and Francis J. Giles
- Subjects
Everolimus ,business.industry ,TOR Serine-Threonine Kinases ,medicine.medical_treatment ,Antineoplastic Agents ,Hematology ,Pharmacology ,medicine.disease ,Temsirolimus ,Targeted therapy ,Leukemia ,Drug development ,Hematologic Neoplasms ,medicine ,Cancer research ,Animals ,Humans ,Signal transduction ,business ,Protein Kinase Inhibitors ,Protein kinase B ,PI3K/AKT/mTOR pathway ,Signal Transduction ,medicine.drug - Abstract
Despite significant advances in the treatment of hematological malignancies over the last decade, morbidity and mortality from these disorders remain high. New discoveries in the pathogenesis of these malignancies have led to better understanding of these diseases and new thinking in drug development. mTOR is a downstream effector of the PI3K/Akt (protein kinase B) signaling pathway that mediates cell survival and proliferation and is known to be deregulated in many cancers. Preclinical activity of mTOR inhibitors has been very promising in various hematological malignancies. Rapamycin analogs with relatively favorable pharmaceutical properties, including temsirolimus (CCI-779), everolimus (RAD001) and deforolimus (AP23573), are under clinical evaluations in patients with hematologic malignancies. They have shown encouraging results thus far and a favorable toxicity profile. Their utility, mainly as cytostatic agents, needs to be further explored in combination with pre-existing chemotherapeutic agents for various hematological malignancies.
- Published
- 2009
32. The emerging safety profile of mTOR inhibitors, a novel class of anticancer agents
- Author
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Kevin R. Kelly, Devalingam Mahalingam, Alain C. Mita, Kamalesh Kumar Sankhala, Monica Mita, and Francis J. Giles
- Subjects
Graft Rejection ,Mucositis ,Cancer Research ,Pulmonary toxicity ,Antineoplastic Agents ,Pharmacology ,Drug Hypersensitivity ,Th2 Cells ,Neoplasms ,medicine ,Animals ,Humans ,Pharmacology (medical) ,PI3K/AKT/mTOR pathway ,Pneumonitis ,Sirolimus ,business.industry ,TOR Serine-Threonine Kinases ,Cancer ,Organ Transplantation ,Pneumonia ,Th1 Cells ,Prognosis ,medicine.disease ,Treatment Outcome ,Oncology ,Immunology ,Toxicity ,business ,Protein Kinases ,medicine.drug - Abstract
Mammalian target of rapamycin (mTOR) has emerged as an important target for cancer therapy. Rapamycin has a distinct, well-documented toxicity profile and most of the toxicity data has been reported in patients with organ transplantation. Newer mTOR inhibitors have slightly different pharmacokinetic properties, yet they present toxicity profiles similar to rapamycin. Most of these toxicities are mild to moderate in severity and can be managed clinically by dose modification and supportive measures. Mucositis and pneumonitis are the most commonly reported toxicities, but they rarely lead to treatment discontinuation. Pathogenesis of pneumonitis is uncertain, but various hypotheses have been suggested, including cell-mediated immune response to the drug.
- Published
- 2009
33. Deforolimus (AP23573) a novel mTOR inhibitor in clinical development
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Alain C. Mita, Issam Abdel-Karim, Francis J. Giles, Monica M. Mita, and Kamalesh Kumar Sankhala
- Subjects
Drug ,media_common.quotation_subject ,Pharmacology ,Neoplasms ,Animals ,Humans ,Medicine ,Pharmacology (medical) ,Everolimus ,Protein Kinase Inhibitors ,PI3K/AKT/mTOR pathway ,media_common ,Sirolimus ,Clinical Trials as Topic ,business.industry ,TOR Serine-Threonine Kinases ,General Medicine ,Prodrug ,medicine.disease ,Discovery and development of mTOR inhibitors ,Temsirolimus ,Clinical trial ,sense organs ,Sarcoma ,business ,Protein Kinases ,Signal Transduction ,medicine.drug - Abstract
mTOR was determined to be a promising anticancer target and several drug inhibitors of mTOR are currently in clinical development. Rapamycin (RAP) was the first mTOR inhibitor discovered. However, RAP has poor aqueous solubility and chemical stability and therefore its utilization at doses susceptible to produce an effect as an anticancer agent is limited. This represented the main rationale for developing new RAP analogs. The RAP analogs currently in clinical development as anticancer agents include temsirolimus (CCI-779), everolimus (RAD-001), and deforolimus (AP23573). These agents have demonstrated antiproliferative activity against a diverse range of malignancies in preclinical studies, and clinical evaluations have been very encouraging thus far. Deforolimus (AP23573), a non-RAP prodrug, has been tested in Phase I and II clinical trials and shows promising results in several tumor types including sarcoma. A Phase III study in patients with sarcoma is currently ongoing. The preclinical and clinical studies with deforolimus will be presented.
- Published
- 2008
34. Long-term treatment of giant cell tumors of bone (GCTB) with denosumab: a two institutions 8-year experience
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Imran S. Syed, Prarthana Parthasarathy, Anna Paioli, Piero Picci, Neal Shiv Chawla, Justin Daneshrad, Sant P. Chawla, William E. Mendanha, Emanuela Palmerini, Stefano Ferrari, Emanuela Marchesi, Kamalesh Kumar Sankhala, Madhuri Sudan, Martina Piccinni Leopardi, Neal Shiv Chawla, Madhuri Sudan, Imran Syed, Sant P. Chawla, Stefano Ferrari, Piero Picci, Emanuela Marchesi, Martina Piccinni Leopardi, Kamalesh Kumar Sankhala, Prarthana Parthasarathy, William Esteves Mendanha, Anna Paioli, Justin Daneshrad, and Emanuela Palmerini
- Subjects
0301 basic medicine ,Cancer Research ,Pathology ,medicine.medical_specialty ,Long term treatment ,business.industry ,Giant cell tumours ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Denosumab ,Oncology ,030220 oncology & carcinogenesis ,medicine ,Giant Cell Tumors ,business ,giant cell tumors of bone, Denosumab ,medicine.drug - Abstract
11021Background: Giant cell tumours of bone (GCTB’s) are RANK-ligand (RANK-L) positive, aggressive and progressive osteolytic tumors. Denosumab, a RANK-L inhibitor, was FDA-approved for adults and ...
- Published
- 2016
35. Abstract CT060: STARTRK-2: A global phase 2, open-label, basket study of entrectinib in patients with locally advanced or metastatic solid tumors harboring TRK, ROS1, or ALK gene fusions
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Collin M. Blakely, Cheng E. Chee, Zachary Hornby, Marwan Fakih, Alexander Drilon, Pratik S. Multani, Byoung Chul Cho, Jonathan Polikoff, Stephen V. Liu, Edna Chow Maneval, Robert C. Doebele, David Luo, Lisa Schechet, and Kamalesh Kumar Sankhala
- Subjects
0301 basic medicine ,Oncology ,Cancer Research ,medicine.medical_specialty ,Pathology ,Performance status ,Crizotinib ,business.industry ,Cancer ,Entrectinib ,medicine.disease ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Response Evaluation Criteria in Solid Tumors ,030220 oncology & carcinogenesis ,Internal medicine ,medicine ,ROS1 ,Anaplastic lymphoma kinase ,business ,Lung cancer ,medicine.drug - Abstract
Background: Entrectinib is a potent, CNS-penetrant, oral inhibitor of the tyrosine kinases TRKA/B/C (encoded by the genes NTRK1/2/3, respectively), ROS1, and ALK with IC50s < 2 nM (biochemical kinase assay). Two Phase 1 studies ALKA-372-001 and STARTRK-1 have enrolled more than 130 patients with advanced or metastatic solid tumors harboring TRKA/B/C, ROS1, or ALK molecular alterations, with or without CNS disease. Previously, we reported an objective response rate of 79% in 24 tyrosine kinase inhibitor-naïve patients with TRK, ROS1, or ALK gene fusions who were treated at doses that achieved therapeutic exposures consistent with the Recommended Phase 2 Dose (RP2D) (Drilon et al, AACR 2016). Entrectinib was well tolerated, with predominantly Grades 1 or 2 adverse events that were reversible with dose modification. Responses were observed in NSCLC, colorectal cancer, mammary analog secretory carcinoma, melanoma, and renal cell carcinoma, as early as 4 weeks after starting treatment and lasting as long as > 2 years. Notably, a complete CNS response was achieved in a patient with SQSTM1-NTRK1-rearranged lung cancer. Methods: STARTRK (Studies of Tumor Alterations Responsive to Targeting Receptor Kinases)-2 is a potentially registration-enabling Phase 2 basket study of entrectinib for the treatment of patients with advanced solid tumors that harbor a TRK, ROS1, or ALK gene fusion. In order to determine enrollment eligibility and assignment to a specific tumor type basket, patients are screened for gene fusions either locally, including by ctDNA, or centrally at Ignyta’s CLIA/CAP diagnostic laboratory using next generation sequencing. The study’s eligibility criteria were designed to maximize enrollment of these rare patients by allowing CNS disease, Eastern Cooperative Oncology Group (ECOG) performance status 2, and any prior line of therapy, with the exception of TRK, ROS1, or ALK inhibitors. Patients with ALK- or ROS1-rearranged NSCLC who had previously been treated with crizotinib and experienced CNS-only progression are also eligible. In addition, a “non-evaluable” basket allows enrollment of patients confirmed to have gene fusions who do not meet all the inclusion or exclusion criteria. Entrectinib is administered orally on a continuous daily dosing regimen, at a dose of 600 mg once-daily in repeated 4-week cycles. Safety is assessed by monitoring of adverse events, laboratory tests, and clinic visits. Tumor assessments (computed tomography (CT) or magnetic resonance imaging (MRI)) of the chest, abdomen, pelvis (depending on tumor type), plus bone and/or brain as applicable, are performed at the end of Cycle 1 and every 8 weeks thereafter. All CT and MRI scans are read by a central independent imaging laboratory using the Response Evaluation Criteria In Solid Tumors (RECIST) v1.1 and the Response Assessment in Neuro-Oncology Criteria (RANO) or RANO - Brain Metastases (RANO-BM), as applicable, for patients with primary or secondary CNS disease, respectively. Blood and tissue are collected at the time of progression for biomarker analyses for potential mechanisms of resistance to entrectinib. Patients remain on study treatment until documented radiographic progression as assessed by blinded independent central review (BICR), development of unacceptable toxicity, or withdrawal of consent. Citation Format: Alexander Drilon, Kamalesh Kumar Sankhala, Stephen V. Liu, Byoung Chul Cho, Collin Blakely, Cheng E. Chee, Marwan Fakih, Jonathan Polikoff, Zachary Hornby, Lisa Schechet, David Luo, Edna Chow Maneval, Pratik S. Multani, Robert C. Doebele. STARTRK-2: A global phase 2, open-label, basket study of entrectinib in patients with locally advanced or metastatic solid tumors harboring TRK, ROS1, or ALK gene fusions [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT060. doi:10.1158/1538-7445.AM2017-CT060
- Published
- 2017
36. Administration of aldoxorubicin and 14 days continuous infusion of ifosfamide/mesna in metastatic or locally advanced sarcomas
- Author
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Shanta Chawla, Nancy Wu, Erlinda M. Gordon, Katherine K. Kim, Victoria S. Chua-Alcala, Doris Quon, Frederick C. Eilber, Sant P. Chawla, Scott Wieland, Daniel J. Levitt, and Kamalesh Kumar Sankhala
- Subjects
Cancer Research ,business.industry ,Continuous infusion ,Locally advanced ,Aldoxorubicin ,03 medical and health sciences ,0302 clinical medicine ,Oncology ,IFOSFAMIDE/MESNA ,Anesthesia ,Cardiac toxicity ,Medicine ,Doxorubicin ,030212 general & internal medicine ,business ,030217 neurology & neurosurgery ,medicine.drug - Abstract
11051 Background: Aldoxorubicin (A) has demonstrated superior anti-tumor efficacy and lack of cumulative cardiac toxicity in multiple studies. A is doxorubicin (D) with a linker which rapidly binds in vivo to albumin after iv. We studied the combination of A administered on Day 1 with continuous infusion (CI) of ifosfamide/Mesna (I-M) days 1-14, as first line therapy or second line therapy in patients with soft tissue sarcomas (STS) to evaluate efficacy and toxicity. Methods: 27 patients have entered the study at 250 mg/m2 ( 185 mg/m2 D equiv) administered on Day 1. I-M (1 g/m2 of each per day) was given up to 14 days as a CI via an out-patient portable pump. Chemotherapy cycles were repeated at 28 day interval. I-M was limited to a maximum of 6 cycles to avoid cumulative marrow toxicity, but A was continued per investigator decision in responding or SD patients for clinical benefit. Subjects were followed for tumor response (RECIST 1.1) by CT scans and echocardiogram/ECG for cardiac toxicity every 8 weeks along with standard labs. Enrollment continues up to 50 patients. Results: Demographics: Leiomyosarc. = 20%, liposarc. = 20%, synovial sarc. = 20%, rhabdosarc. = 8%, others = 32%. Caucasian, 11% Asian, 4% Black; 67% no prior tx, 26% 1 prior tx, 7% > 1 prior tx; Median cum. A = 1000 mg/m2 (740 mg/m2 D eq.; 185-4070 mg/m2 D eq.); I = 6.9 g/m2 (2.1-12.6 g/m2). Best response: 42% PR, 58% SD. Median PFS not reached. 10 subjects with either PR or SD had surgery to remove accesible tumors. Range of tumor necrosis = 70 to > 95%. Grade 3/4 AEs: neutropenia = 78%, febrile neutropenia = 9%, thrombocytopenia = 22%, anemia = 65%, nausea = 4%. Related SAEs = 4 (febrile neutropenia (2), pyrexia, stomatitis). No tx related deaths. No clinically significant cardiac AEs, no decrease in LVEF > 20% Conclusions: A can be administered for prolonged periods and safely with CI ifosfamide/mesna and achieves high ORR and SD with substantial tumor necrosis. Clinical trial information: NCT02235701.
- Published
- 2017
37. A phase I/II dose escalation and expansion study of cabiralizumab (cabira; FPA-008), an anti-CSF1R antibody, in tenosynovial giant cell tumor (TGCT, diffuse pigmented villonodular synovitis D-PVNS)
- Author
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Helen Collins, Philippe A. Cassier, Kamalesh Kumar Sankhala, Andrew Bassim Hassan, Charlie Zhang, Vinod Ravi, Hans Gelderblom, Neil Sankar, Tae Min Kim, Kristen N. Ganjoo, Antoine Italiano, Robert Sikorski, Jean-Yves Blay, Ibrahim Qazi, Piotr Rutkowski, and Ellyn Shocron
- Subjects
0301 basic medicine ,Macrophage colony-stimulating factor ,Cancer Research ,Pathology ,medicine.medical_specialty ,biology ,medicine.drug_class ,business.industry ,Nodule (medicine) ,Inflammation ,medicine.disease ,Monoclonal antibody ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Oncology ,Pigmented villonodular synovitis ,030220 oncology & carcinogenesis ,Synovitis ,medicine ,biology.protein ,medicine.symptom ,Antibody ,Receptor ,business - Abstract
11078 Background: TGCTis a proliferative, neoplastic joint disease that presents as single nodule (local) or multiple nodules (diffuse D-TGCT). Localized overexpression of colony stimulating factor 1 (CSF1) leads to recruitment of cells expressing the CSF1 receptor (CSF1R), formation of a tumor and inflammation of joints and tendons. Cabira is a monoclonal antibody that inhibits the interaction of the CSF1 and IL-34 ligands with their shared receptor CSF1R. Methods: This Ph 1/2 study is evaluating the safety and efficacy of cabira monotherapy administered IV Q 2wk for 6 mo in patients (pts) with D-TGCT. Eligible pts have inoperable D-TGCT or tumor for which resection would cause unacceptable morbidity. Response is evaluated by MRI, pt reported outcomes, and Ogilvie-Harris (O-H) score (which combines pain, synovitis, range of motion and functional capacity on a scale of 0-12). Results: As of 15 Dec 2016, 22 pts received ≥ 1 dose of cabira at 1, 2 or 4mg/kg. Dose-related exposure increase and significant reduction in target peripheral monocytes were observed. No dose limiting toxicity was identified. 4 mg/kg was chosen for Ph2 based on efficacy, tolerability, and PK. AEs ≥ Gr 2 ( > 10%) were CK elevation 46%, rash and other skin disorders 36%, fatigue 23%, and periorbital/peripheral/face edema 18% each. Gr 3 AEs in ≥ 2 pt were CK elevation (n = 8) and periorbital edema (n = 2). Four drug-related SAEs were reported in 3 pts; hypertension, fever, CRP elevation, and myocarditis. AEs of CK elevation were asymptomatic, improved to < 2X ULN after protocol mandated drug discontinuation and are a known on-target effect of CSF1R inhibition. An amendment was made during Phase 2 to allow dosing with higher CK levels Activity at 4 mg/kg was: 1PR and 1 CK discontinuation in 3 pts in Ph1; 4 PRs in 7 evaluable pts with 6 additional ongoing in Ph2. Positive functional status improvements by O-H score were noted in objective responders (from 2 to 7). Conclusions: The initial demonstration of objective and functional activity supports further development of cabiralizumab in pts with D-TGCT. Updated data from the ongoing Ph2 will be presented. NCT02471716 . Clinical trial information: NCT02471716.
- Published
- 2017
38. Acute lymphoblastic leukemia presenting with avascular necrosis of the elbow
- Author
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Francis J. Giles, Swaminathan Padmanabhan, Ronan T. Swords, Kevin R. Kelly, Kamalesh Kumar Sankhala, Devalingam Mahalingam, and Aoife Kilcoyne
- Subjects
Cancer Research ,Pathology ,medicine.medical_specialty ,medicine.anatomical_structure ,Oncology ,business.industry ,Lymphoblastic Leukemia ,Elbow ,medicine ,Avascular necrosis ,Hematology ,medicine.disease ,business - Published
- 2009
39. Trabectedin for advanced soft-tissue sarcoma: A single-center experience of over 10 years
- Author
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Babak Aryanfar, Sant P. Chawla, Katherine K. Kim, William W. Tseng, Susan Arasheben, Prarthana Parthasarathy, William E. Mendanha, Neal Shiv Chawla, Bryan Leong, Imran S. Syed, Kamalesh Kumar Sankhala, Madhuri Sudan, Erlinda M. Gordon, Rishi Nanda, and Justin Daneshrad
- Subjects
0301 basic medicine ,Double strand ,Cancer Research ,business.industry ,Soft tissue sarcoma ,DNA replication ,Single Center ,medicine.disease ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Oncology ,Apoptosis ,030220 oncology & carcinogenesis ,medicine ,Cancer research ,business ,Trabectedin ,medicine.drug - Abstract
11052Background: Trabectedin (T) is an anti-tumor agent used in the treatment of advanced soft-tissue sarcomas (STS). It interferes with DNA replication, causing double strand breaks and apoptosis,...
- Published
- 2016
40. A phase 1B/ phase 2A study of TRC105 (Endoglin Antibody) in combination with pazopanib (P) in patients (pts) with advanced soft tissue sarcoma (STS)
- Author
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Robert M. Conry, Steven I. Robinson, Robert G. Maki, Patrick McKay Boland, Charles P. Theuer, Steven Attia, Ronald L. Shazer, Karen J. Fritchie, Ben K. Seon, Kamalesh Kumar Sankhala, Delia Alvarez, Richard F. Riedel, Minal A. Barve, and Bonne J. Adams
- Subjects
0301 basic medicine ,Cancer Research ,Pazopanib ,03 medical and health sciences ,0302 clinical medicine ,otorhinolaryngologic diseases ,medicine ,In patient ,Vegfr tki ,Receptor ,biology ,business.industry ,Soft tissue sarcoma ,Endoglin ,medicine.disease ,respiratory tract diseases ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,Immunology ,cardiovascular system ,Cancer research ,biology.protein ,Antibody ,business ,medicine.drug - Abstract
11016Background: P, a VEGFR TKI, is approved for advanced STS based on median PFS (mPFS) in the absence of CR. Endoglin is a receptor expressed on tumor vessels that is overexpressed in certain STS...
- Published
- 2016
41. A phase 1/2 study of continuous infusion ifosfamide/mesna + aldoxorubicin in sarcoma patients
- Author
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Neal Shiv Chawla, Kelli Sung, Daniel J. Levitt, Sant P. Chawla, Kamalesh Kumar Sankhala, Shanta Chawla, Scott Wieland, Victoria S. Chua, and Erlinda M. Gordon
- Subjects
0301 basic medicine ,Cancer Research ,medicine.medical_specialty ,Ifosfamide ,Continuous infusion ,business.industry ,Urology ,Soft tissue ,Aldoxorubicin ,medicine.disease ,03 medical and health sciences ,Regimen ,030104 developmental biology ,0302 clinical medicine ,Oncology ,IFOSFAMIDE/MESNA ,030220 oncology & carcinogenesis ,medicine ,Doxorubicin ,Sarcoma ,business ,medicine.drug - Abstract
e22547Background: Ifosfamide (I)+ doxorubicin (D) is considered the most active treatment regimen for soft tissue sarcomas (STS). I is given as a 4-5 day infusion with D administered on Day 1 of ea...
- Published
- 2016
42. Phase 1b study of aldoxorubicin + gemcitabine in metastatic solid tumors
- Author
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Monica M. Mita, Kelli Sung, Jasgit C. Sachdev, Victoria S. Chua, Daniel J. Levitt, Shanta Chawla, Scott Wieland, Sant P. Chawla, Alain C. Mita, Kamalesh Kumar Sankhala, Erkut Borazanci, and Brenda Laabs
- Subjects
Cardiac function curve ,Cancer Research ,Lung ,business.industry ,Albumin ,Aldoxorubicin ,Pharmacology ,Prodrug ,Gemcitabine ,chemistry.chemical_compound ,medicine.anatomical_structure ,Oncology ,Paclitaxel ,chemistry ,medicine ,Doxorubicin ,business ,medicine.drug - Abstract
2523Background: Aldoxorubicin (A) is a novel prodrug of doxorubicin (D) that binds covalently to albumin, accumulates in tumors and releases D under acidic conditions. It has demonstrated significant efficacy against soft tissue sarcomas in a phase 2b study versus D. Gemcitabine (G), when combined with various chemotherapies (albumin/paclitaxel nanoparticles, liposomal D) has demonstrated efficacy in patients with pancreatic, ovarian and lung cancers. It was hypothesized that A+G might possess synergistic activity against solid tumors. This study was designed to identifiy the major toxicities of this combination and establish its MTD. Methods: Adults who had relapsed or not responded to prior chemotherapies were eligible. Initial cohorts were (i) A 170 mg/m2+ G 900 mg/m2 ); (ii) A 250 mg/m2 + G 900 mg/m2; and (iii) A 200 mg/m2 + G 750 mg/m2. A was administered on Day 1 and G on Days 1 and 8 of each 21 day cycle. Safety was monitored continuously, cardiac function was assessed every 2 months by echocardiog...
- Published
- 2016
43. Phase II study of the mammalian target of rapamycin inhibitor ridaforolimus in patients with advanced bone and soft tissue sarcomas
- Author
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John W. Loewy, George D. Demetri, Lori Berk, Laurence H. Baker, Victor M. Rivera, Arthur P. Staddon, Gina Z. D'Amato, Tim Clackson, Monica M. Mita, Kamalesh Kumar Sankhala, Frank G. Haluska, Scott M. Schuetze, Jean-Yves Blay, Anthony W. Tolcher, Sant P. Chawla, International Institute of Clinical Studies, Pennsylvania Oncology Hematology Associates, Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Léon Bérard [Lyon], Department of Cancer Biology, Dana-Farber Cancer Institute [Boston], Centre de Recherche en Cancérologie de Lyon ( CRCL ), Université Claude Bernard Lyon 1 ( UCBL ), and Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS )
- Subjects
Male ,Vascular Endothelial Growth Factor A ,Oncology ,Cancer Research ,Pathology ,MESH : Aged ,Phases of clinical research ,Kaplan-Meier Estimate ,[ SDV.CAN ] Life Sciences [q-bio]/Cancer ,chemistry.chemical_compound ,0302 clinical medicine ,MESH : Tumor Markers, Biological ,Clinical endpoint ,Medicine ,MESH : Female ,Infusions, Intravenous ,MESH: Treatment Outcome ,MESH: Aged ,0303 health sciences ,education.field_of_study ,MESH: Middle Aged ,TOR Serine-Threonine Kinases ,Soft tissue ,Sarcoma ,MESH : Infusions, Intravenous ,Middle Aged ,MESH : Adult ,MESH: Bone Neoplasms ,3. Good health ,MESH : Antineoplastic Agents ,Treatment Outcome ,030220 oncology & carcinogenesis ,MESH : Vascular Endothelial Growth Factor A ,MESH : TOR Serine-Threonine Kinases ,MESH : Disease-Free Survival ,Female ,Adult ,medicine.medical_specialty ,MESH : Male ,MESH : Sex Factors ,Population ,MESH : Drug Administration Schedule ,Antineoplastic Agents ,Bone Neoplasms ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,MESH : Treatment Outcome ,Bone Sarcoma ,MESH: Drug Administration Schedule ,MESH : Sarcoma ,Disease-Free Survival ,Drug Administration Schedule ,Ridaforolimus ,MESH : Kaplan-Meier Estimate ,03 medical and health sciences ,Sex Factors ,MESH: Sex Factors ,Internal medicine ,Biomarkers, Tumor ,Humans ,MESH : Middle Aged ,education ,MESH: Infusions, Intravenous ,MESH: TOR Serine-Threonine Kinases ,MESH: Kaplan-Meier Estimate ,Aged ,030304 developmental biology ,MESH : Bone Neoplasms ,Sirolimus ,MESH: Humans ,Errata ,Akt/PKB signaling pathway ,business.industry ,MESH : Sirolimus ,MESH: Vascular Endothelial Growth Factor A ,MESH : Humans ,MESH: Adult ,MESH: Male ,Clinical trial ,chemistry ,MESH: Sarcoma ,MESH: Tumor Markers, Biological ,MESH: Disease-Free Survival ,MESH: Antineoplastic Agents ,MESH: Sirolimus ,business ,MESH: Female - Abstract
Purpose Ridaforolimus is an inhibitor of mammalian target of rapamycin, an integral component of the phosphatidyl 3-kinase/AKT signaling pathway, with early evidence of activity in sarcomas. This multicenter, open-label, single-arm, phase II trial was conducted to assess the antitumor activity of ridaforolimus in patients with distinct subtypes of advanced sarcomas. Patients and Methods Patients with metastatic or unresectable soft tissue or bone sarcomas received ridaforolimus 12.5 mg administered as a 30-minute intravenous infusion once daily for 5 days every 2 weeks. The primary end point was clinical benefit response (CBR) rate (complete response or partial response [PR] or stable disease ≥ 16 weeks). Safety, progression-free survival (PFS), overall survival (OS), time to progression, and duration of response were also evaluated. Results A total of 212 patients were treated in four separate histologic cohorts. In this heavily pretreated population, 61 patients (28.8%) achieved CBR. Median PFS was 15.3 weeks; median OS was 40 weeks. Response Evaluation Criteria in Solid Tumors (RECIST) confirmed response rate was 1.9%, with four patients achieving confirmed PR (two with osteosarcoma, one with spindle cell sarcoma, and one with malignant fibrous histiocytoma). Archival tumor protein markers analyzed were not correlated with CBR. Related adverse events were generally mild or moderate and consisted primarily of stomatitis, mucosal inflammation, mouth ulceration, rash, and fatigue. Conclusion Single-agent ridaforolimus in patients with advanced and pretreated sarcomas led to PFS results that compare favorably with historical metrics. A phase III trial based on these data will further define ridaforolimus activity in sarcomas.
- Published
- 2012
44. First-Line Aldoxorubicin vs Doxorubicin in Metastatic or Locally Advanced Unresectable Soft-Tissue Sarcoma
- Author
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Kristen N. Ganjoo, Kamalesh Kumar Sankhala, Scott Wieland, Sant P. Chawla, Guzel Mukhametshina, Leonid Vasylyev, Zsuzsanna Papai, Daniel J. Levitt, Kenneth Khamly, Rajnish Nagarkar, and Alexander Fedenko
- Subjects
Adult ,Male ,Cancer Research ,medicine.medical_specialty ,Aldoxorubicin ,Drug Administration Schedule ,law.invention ,Young Adult ,Randomized controlled trial ,law ,medicine ,Humans ,Prodrugs ,Doxorubicin ,Progression-free survival ,Neoplasm Metastasis ,Infusions, Intravenous ,Aged ,Antibiotics, Antineoplastic ,business.industry ,Soft tissue sarcoma ,Hydrazones ,Sarcoma ,Middle Aged ,medicine.disease ,Chemotherapy regimen ,Surgery ,Clinical trial ,Treatment Outcome ,Oncology ,Female ,Radiology ,Epidemiologic Methods ,business ,medicine.drug - Abstract
Standard therapy for advanced soft-tissue sarcoma has not changed substantially in decades, and patient prognosis remains poor. Aldoxorubicin, a novel albumin-binding prodrug of doxorubicin, showed clinical activity against advanced soft-tissue sarcoma in phase 1 studies.To evaluate efficacy and safety of aldoxorubicin vs doxorubicin in patients with advanced soft-tissue sarcoma.International, multicenter, phase 2b, open-label, randomized study at general community practices, private practices, or institutional practices. Between August 2012 and December 2013, 140 patients with previously untreated locally advanced, unresectable, or metastatic soft-tissue sarcoma were screened.Randomization (2:1) to aldoxorubicin 350 mg/m2 (dose equivalent to doxorubicin 260 mg/m2) or doxorubicin 75 mg/m2, administered once every 3 weeks for up to 6 cycles.Primary end point was progression-free survival. Secondary end points were 6-month progression-free survival, overall survival, tumor response rate, and safety. All efficacy end points were evaluated by independent and local review.A total of 126 patients were randomized, and 123 received aldoxorubicin (n = 83) or doxorubicin (n = 40). Median (range) patient age was 54.0 (21-77 years); 42 (34%) had leiomyosarcoma. By independent review, median progression-free survival was significantly improved (5.6 [95% CI, 3.0-8.1] vs 2.7 [95% CI, 1.6-4.3] months; P = .02) with aldoxorubicin compared with doxorubicin, as was the rate of 6-month progression-free survival (46% and 23%; P = .02). Median overall survival was 15.8 (95% CI, 13.0 to not available) months with aldoxorubicin and 14.3 (95% CI, 8.6-20.6) months with doxorubicin (P = .21). Overall tumor response rate (by Response Evaluation Criteria in Solid Tumors, version 1.1) by independent review was higher with aldoxorubicin than with doxorubicin (25% [20 patients, all partial response] vs 0%). Grade 3 or 4 neutropenia was more frequent with aldoxorubicin than with doxorubicin (24 [29%] vs 5 [12%]), but not grade 3 or 4 febrile neutropenia (12 [14%] vs 7 [18%]). No acute cardiotoxic effects were observed with either treatment, although left ventricular ejection fraction less than 50% occurred in 3 of 40 patients receiving doxorubicin.Single-agent aldoxorubicin therapy showed superior efficacy over doxorubicin by prolonging progression-free survival and improving rates of 6-month progression-free survival and tumor response. Aldoxorubicin therapy exhibited manageable adverse effects, without unexpected events, and without evidence of acute cardiotoxicity. Further investigation of aldoxorubicin therapy in advanced soft-tissue sarcoma is warranted.clinicaltrials.gov Identifier: NCT01514188.
- Published
- 2015
45. Phase 1 study of AMG 386, a selective angiopoietin 1/2-neutralizing peptibody, in combination with chemotherapy in adults with advanced solid tumors
- Author
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Erik Rasmussen, Leslie Wood, Manuel Valdivieso, Patricia LoRusso, Yu Nien Sun, Chris H. Takimoto, Alain C. Mita, Ngocdiep T. Le, Michael Bass, Z. Don Zhong, Monica M. Mita, John Sarantopoulos, Anthony W. Tolcher, and Kamalesh Kumar Sankhala
- Subjects
Oncology ,Adult ,Male ,Cancer Research ,medicine.medical_specialty ,medicine.medical_treatment ,Recombinant Fusion Proteins ,Pharmacology ,Drug Administration Schedule ,Angiopoietin-2 ,chemistry.chemical_compound ,Internal medicine ,Neoplasms ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Angiopoietin-1 ,Humans ,Cisplatin ,Chemotherapy ,Bladder cancer ,business.industry ,Drugs, Investigational ,Middle Aged ,medicine.disease ,Gemcitabine ,Carboplatin ,Recombinant Proteins ,Tolerability ,chemistry ,Docetaxel ,Female ,business ,Progressive disease ,medicine.drug - Abstract
Purpose: To evaluate the safety, pharmacokinetics, and antitumor activity of AMG 386, an investigational selective angiopoietin 1/2-neutralizing peptibody, in combination with FOLFOX-4 (F), carboplatin/paclitaxel (C/P), or docetaxel (D), in adult patients with advanced solid tumors. Experimental Design: Three cohorts of patients (F, n = 6; C/P, n = 8; D, n = 12) received one full cycle of chemotherapy alone during the pretreatment phase, followed by administration of AMG 386 10 mg/kg i.v. weekly in combination with chemotherapy until disease progression or intolerance. Safety and tolerability, tumor response, pharmacokinetic profiles, and biomarkers were assessed. Results: Twenty-six patients were enrolled; 22 received treatment with AMG 386. No dose-limiting toxicities or grade 3 or 4 adverse events related to AMG 386 were reported. The most common adverse events were diarrhea and hypomagnesemia (n = 3 each). One patient developed grade 2 hypertension and one had grade 1 subconjunctival eye hemorrhage. No neutralizing antibodies to AMG 386 were detected. There were no pharmacokinetic interactions between AMG 386 and F, C/P, or D. One patient receiving AMG 386 plus C/P for bladder cancer refractory to gemcitabine/cisplatin had a complete response at week 8. The remaining best tumor responses were partial response (n = 3, one from each cohort), stable disease ≥8 weeks (n = 13), and progressive disease (n = 1). Conclusions: Weekly administration of AMG 386 in combination with three common chemotherapy regimens was well tolerated in patients with advanced solid tumors. No pharmacokinetic interactions between AMG 386 and any of the tested chemotherapy regimens were noted. Promising antitumor activity was observed with all three treatment combinations. Clin Cancer Res; 16(11); 3044–56. ©2010 AACR.
- Published
- 2010
46. Prevention of chemotherapy induced nausea and vomiting: a focus on aprepitant
- Author
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John Sarantopoulos, Devesh M. Pandya, Kamalesh Kumar Sankhala, Francis J. Giles, Sant P. Chawla, and Scott A. Soefje
- Subjects
medicine.medical_specialty ,Side effect ,Nausea ,Vomiting ,medicine.medical_treatment ,Morpholines ,Antineoplastic Agents ,Toxicology ,Neurokinin-1 Receptor Antagonists ,medicine ,Animals ,Humans ,Intensive care medicine ,Aprepitant ,Pharmacology ,Chemotherapy ,Clinical Trials as Topic ,business.industry ,General Medicine ,Drug interaction ,humanities ,Anesthesia ,Antiemetics ,medicine.symptom ,business ,medicine.drug ,Chemotherapy-induced nausea and vomiting - Abstract
Nausea and vomiting is one of the most feared side effects of chemotherapy; however, in the past 20 years, a better understanding of the pathophysiology of chemotherapy-induced nausea and vomiting (CINV) has led to the introduction of newer antiemetics, which have improved the management of this side effect.This article reviews the prevention of CINV and the role of aprepitant, the first of the newest class of antiemetics, the neurokinin-1 inhibitors. A brief description of the pathophysiology of CINV and the background on the prevention of CINV using the 5-HT(3) antagonists is outlined. The pharmacology, pharmacokinetics, drug interactions and various clinical studies with aprepitant are reviewed.The literature about aprepitant is reviewed focusing on the role of aprepitant in the management of CINV in relationship to other commonly used antiemetics. The literature was searched regarding aprepitant and its pharmacological characteristics, pharmacokinetics, drug interactions and various clinical studies.Aprepitant has a significant role in the management of CINV, as it allows the majority of patients to complete their chemotherapies without significant morbidity. Its use in a variety of clinical settings in cancer patients needs to be further explored.
- Published
- 2009
47. Targeting the mTOR pathway using deforolimus in cancer therapy
- Author
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Alain C. Mita, Devalingam Mahalingam, Kamalesh Kumar Sankhala, Francis J. Giles, and Monica M. Mita
- Subjects
Cancer Research ,Tumor suppressor gene ,medicine.medical_treatment ,Antineoplastic Agents ,Protein degradation ,mTORC2 ,Neoplasms ,Medicine ,PTEN ,Animals ,Humans ,Protein kinase B ,PI3K/AKT/mTOR pathway ,Sirolimus ,Clinical Trials as Topic ,biology ,business.industry ,Growth factor ,TOR Serine-Threonine Kinases ,RPTOR ,General Medicine ,Cell biology ,Oncology ,biology.protein ,business ,Protein Kinases ,Signal Transduction - Abstract
The mammalian target of rapamycin (mTOR) is an intracellular protein with a key role in cellular protein synthesis and energy balance that influences many aspects of cell growth and proliferation, including differentiation, cell-cycle progression, angiogenesis, protein degradation and apoptosis. mTOR can be activated by numerous oncogenic signals, such as growth factor activation through the EGF, IGF and VEGF receptors, mutation and silencing of the PTEN tumor suppressor gene, activating mutations in the PI3K catalytic subunit, Akt amplification and the Ras–Raf–MEK pathway. Once activated, the cellular functions of mTOR are achieved through its downstream targets, 4E-BP1 and p70S6K1. The mTOR pathway can be further regulated through a negative feedback loop, which may lead to resistance to specific inhibitors of mTOR. This review will outline the mTOR signaling pathway, which is often activated in cancers and account for tumor proliferation and growth, highlight the rationale in targeting mTOR with a focus on the preclinical and clinical development of one of these inhibitors, deforolimus (AP23573, MK-8669), and discuss potential benefit and barriers to these agents being introduced in the clinic.
- Published
- 2009
48. Future options for imatinib mesilate-resistant tumors
- Author
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Kyriakos P Papadopoulos and Kamalesh Kumar Sankhala
- Subjects
medicine.drug_class ,Gastrointestinal Stromal Tumors ,Antineoplastic Agents ,Drug resistance ,Pharmacology ,Tyrosine-kinase inhibitor ,Piperazines ,hemic and lymphatic diseases ,Medicine ,Animals ,Humans ,Pharmacology (medical) ,neoplasms ,Protein Kinase Inhibitors ,PI3K/AKT/mTOR pathway ,biology ,business.industry ,Sunitinib ,Imatinib ,General Medicine ,Imatinib mesylate ,Pyrimidines ,Drug Resistance, Neoplasm ,Benzamides ,Cancer research ,biology.protein ,Imatinib Mesylate ,business ,Tyrosine kinase ,Platelet-derived growth factor receptor ,medicine.drug - Abstract
The outcome of patients with gastrointestinal stromal tumors has been dramatically improved by therapy with imatinib mesilate (imatinib mesylate), a KIT and platelet-derived growth factor (PDGFR) tyrosine kinase inhibitor. Unfortunately, the majority of patients eventually experience disease progression due to drug resistance. Recent elucidation of the mechanisms of resistance to imatinib, particularly the acquisition of secondary mutations of the KIT and PDGF receptors, has provided significant insight and potential for the development of novel therapies. This review discusses the efficacy of sunitinib, which is approved for the treatment of patients with imatinib-resistant tumors, and highlights a number of emerging second-generation receptor tyrosine kinase inhibitors that show therapeutic potential in imatinib-resistant patients. Also considered are several promising agents targeting pathways downstream of the constitutionally activated KIT and PDGF receptors. Strategies to overcome imatinib resistance by optimizing combination therapy and selecting specific kinase inhibitors based on the secondary mutations identified in tumors of individual patients are presented.
- Published
- 2007
49. Phase 2 study of gemcitabine, docetaxel, and doxorubicin in patients with advanced, unresectable, and/or metastatic sarcoma who have failed prior therapies
- Author
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Neal Shiv Chawla, Doris Quon, Andrew Eugene Hendifar, William E. Mendanha, Xiao Zhang, Victoria S. Chua, Kamalesh Kumar Sankhala, Sant P. Chawla, and Lita Fernandez
- Subjects
Oncology ,Cancer Research ,medicine.medical_specialty ,Chemotherapy ,business.industry ,medicine.medical_treatment ,Soft tissue ,Phases of clinical research ,Gemcitabine ,Docetaxel ,Internal medicine ,medicine ,Doxorubicin ,In patient ,Metastatic sarcoma ,business ,medicine.drug - Abstract
10573 Background: Gemcitabine and docetaxel chemotherapy protocols have proven efficacy in the treatment of metastatic soft tissue sarcomas. Doxorubicin is also a commonly used treatment both as a ...
- Published
- 2015
50. A phase Ib dose-escalation study of TRC105 (anti-endoglin antibody) in combination with pazopanib in patients with advanced soft tissue sarcoma (STS)
- Author
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Steven Attia, Robert M. Conry, Charles P. Theuer, Steven I. Robinson, Bonne J. Adams, Ben K. Seon, Delia Alvarez, Richard F. Riedel, Robert G. Maki, and Kamalesh Kumar Sankhala
- Subjects
Leiomyosarcoma ,Cancer Research ,Pathology ,medicine.medical_specialty ,business.industry ,Epithelioid sarcoma ,Soft tissue sarcoma ,Endoglin ,medicine.disease ,Synovial sarcoma ,Pazopanib ,Oncology ,otorhinolaryngologic diseases ,Cancer research ,Medicine ,Angiosarcoma ,business ,Epithelioid hemangioendothelioma ,medicine.drug - Abstract
10514 Background: The VEGFR inhibitor pazopanib is approved for the treatment of advanced STS. Resistance to pazopanib is a challenge in the treatment of STS, and endoglin (CD105) activation may be an important resistance mechanism. Endoglin is an angiogenic receptor expressed on proliferating tumor vessels, which is upregulated following VEGF inhibition and expressed on certain STS subtypes, including angiosarcoma. A phase Ib study of TRC105, an anti-endoglin antibody, in combination with pazopanib was performed in patients (pts) with advanced STS. Methods: Heavily-pretreated STS pts with leiomyosarcoma (11); angiosarcoma (2); synovial sarcoma (2); epithelioid sarcoma (1); myxofibrosarcoma (1); epithelioid hemangioendothelioma (1); and unclassifiable high grade sarcoma (2), ECOG PS 0-1, were treated with infusional TRC105 weekly in two cohorts (8mg/kg and 10mg/kg). TRC105 was initiated following a 2 to 4 week lead-in period of pazopanib starting at 800 mg PO daily. Results: Twenty pts (median age = 57; M...
- Published
- 2015
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