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Background: BYON3521 is a novel c-MET targeting antibody-drug conjugate (ADC) with a cleavable linker-duocarmycin (vc-seco-DUBA) payload that causes irreversible alkylation of DNA in tumor cells. BYON3521 has demonstrated potent and selective killing of c-MET expressing tumor cells in preclinical models, even at low c-MET expression levels. In addition, in vitro studies showed that the active toxin can passively permeate the cell membrane and kill neighboring, c-MET negative cells as a bystander effect. Methods: Patients with previously treated progressive locally advanced or metastatic solid tumors, c-MET positive membrane staining by immunohistochemistry and/or MET-amplified by dual in situ hybridization and/or known activating MET-mutation (excluding exon14m), ECOG performance status 0-1 and adequate organ function are eligible for the dose-escalation part of this first-in-human trial (ClinicalTrials.gov identifier: NCT05323045). An adaptive approach using the Continual Reassessment Method of Neuenschwander (N-CRM model) is used to evaluate the safety of BYON3521 and to determine the maximum tolerated dose (MTD) and recommended dose for expansion (RDE). BYON3521 is administered intravenously every three weeks until tumor progression or unacceptable toxicity. Results: Up to 01 January 2023, 8 patients (1F, 7M, median age 61 yrs) were enrolled. Tumor types were: 4 colorectal cancer, 1 NSCLC, 1 renal cell carcinoma, 1 esophageal cancer and 1 pancreatic cancer. One patient received 0.8 mg/kg, three patients each 1.6 and 3.2 mg/kg and one patient received 4.8 mg/kg. So far, no grade 3 or 4 related adverse events and no dose-limiting toxicities (DLTs) occurred. Most commonly observed related AEs were decreased appetite/weight, fatigue, abdominal pain, back pain, vomiting and chills. Typical ADC associated AEs as keratitis and pneumonitis have not been observed so far. Stable disease was the best response observed in 2 patients at a dose of 3.2 mg/kg. Human PK was in line with predicted preclinical in vivo PK. Conclusions: To date, BYON3521 is well-tolerated with no DLTs at the investigated dose levels. Patient enrollment is ongoing and updated safety, efficacy and pharmacokinetic data will be presented. After the dose-escalation phase the trial will continue with expanded cohorts of patients with specific c-MET expressing cancer types. Citation Format: N. Kotecki, C.M.L. van Herpen, C. Curigliano, M. Hendriks, T C. Vermaas, L. Corrigan, C. Belli, C. Jungels, I.M.E. Desar, N.P. Koper, J.H.M. Schellens, U. Banerji. First in human dose-escalation trial with the c-MET targeting antibody-drug conjugate BYON3521 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT185.

IntroductionCaring for a significant other during cancer treatment can be demanding. Little is known about the well-being of informal caregivers of patients with colon cancer. This study aims to examine informal caregiver well-being during adjuvant chemotherapy for colon cancer.Material and methodsThis exploratory longitudinal, prospective study measured the course of informal caregiver burden (Self-Perceived Pressure of Informal Care), distress (Hospital Anxiety and Depression Scale), health-related quality of life (RAND-36), marital satisfaction (Maudsley Marital Questionnaire), social support (Social Support List – Discrepancies), fatigue (Abbreviated Fatigue Questionnaire), and self-esteem (Caregiver Reaction Assessment) before (T0), during (T1), and after (T2) patients’ treatment.ResultsBaseline data of 60 out of 76 eligible dyads (79%) were analyzed. Mean levels of informal caregiver burden and distress improved significantly over time, as did their health-related quality of life and perceived social support. At baseline, 30% and 26.7% of informal caregivers reported moderate-to-high levels of burden and clinically relevant levels of distress, respectively, which changed to 20% and 18.8% at T2. Informal caregiver burden and distress at baseline were the strongest predictors of informal caregiver burden and distress during and following patients’ treatment, respectively.ConclusionWhen informal caregivers and patients experience problems before start of adjuvant chemotherapy, problems seem to improve over time. Approximately 20% of informal caregivers remain burdened and distressed after patients’ end of treatment. Paying attention to baseline distress and burden seems indicated, as these were strong predictors of informal caregivers’ well-being during and after treatment.

Item does not contain fulltext Whole-body hyperthermia (WBH) might be beneficial for patients with metastasized solid malignancies when combined with systemic therapy. This review identified and summarized the phase I/II studies (n = 13/14) conducted using this combination of therapies. Most of the phase II studies used radiant heating methods in a thermal dose of 41.8 degrees C (1 h). All studies used classic chemotherapy. Great inter-study heterogeneity was observed regarding treatment regimes, included patients and reported response rates (12-89%). Ovarian cancer, colorectal adenocarcinoma, lung cancer and sarcoma have been studied most. Most reported toxicity (grade 3/4) was myelosuppression. Treatment related mortality was present (4 patients) in three out 14 phase II studies (350 evaluable patients, over 966 cycles of WBH with chemotherapy). Absence of phase III trials makes the additive value of WBH highly speculative. As modern oncology offers many less invasive treatments options, it is unlikely WBH will ever find its way in routine clinical care.

Introduction: Estrogen receptor (ER) expression largely determines the therapy choice for patients diagnosed with metastatic breast cancer (MBC). Given potential conversion of ER-status, the current golden standard for ER assessment is by immunohistochemistry (IHC) on metastatic tissue. Since a biopsy is cumbersome and sometimes not feasible, ER-status assessments by means of [18F]-fluorestradiol (FES)-PET or circulating tumor cells (CTCs) might be potential alternatives. We hypothesize that FES-PET or CTCs can determine ER status in patients with MBC, in a more efficient and patient friendly way than IHC. Methods: In the Dutch multicenter IMPACT-MBC trial (NCT01832051) patients with non-rapidly progressive MBC at first presentation, regardless of subtype, underwent extensive molecular imaging (including FES-PET, 89Zr-trastuzumab-PET and serial [18F]-fluorodeoxyglucose (FDG)-PET), a metastasis biopsy and blood sampling to obtain a whole body molecular profile of their disease. ER-status on the metastasis biopsy was evaluated by IHC and considered positive if ≥10% of the tumor cells showed ER expression. The FES-PET was considered positive when the maximum standardized uptake value (SUVmax) of at least one lesion was ≥ 1.5. Reverse transcription polymerase chain reaction was used to quantify the ESR1 expression in CTCs. ER-positivity was defined as an ESR1 mRNA ΔCq level ≥ -7.86, corrected for background healthy donor blood signal, only in samples with ≥5 CTCs/7.5ml and a sufficient mRNA signal of reference and epithelial genes. Sensitivity, specificity, positive and negative predictive values were calculated (PPV and NPV). Results: From 178 patients of 201 evaluable patients both metastasis IHC and FES-PET could be assessed. 129 of these 178 patients had an IHC ER positive metastasis (72%) and 133 patients had a positive FES-PET (75%). The PPV and NPV for IHC by FES-PET were 91% and 82%, respectively. From 54 of the 178 patients, blood samples contained sufficient CTCs for ESR1 analysis, allowing combined assessment of IHC, FES-PET and CTCs. ER positive CTCs were present in 45 patients (83%). Table 1 Metastasis ER positive (n=42)Metastasis ER negative (n=12)Sensitivity(%)PPV(%)Specificity(%)NPV(%)FES-PET positive4159889 CTC ER positive3879084 FES-PET and CTC positive3849090 FES-PET negative17 5888CTC ER negative45 4256FES-PET and CTC negative14 3380 Conclusion: In newly diagnosed patients with MBC, ER-status in metastatic lesions could be predicted by means of non-invasive FES-PET scan or CTCs. Prediction was most optimal with FES-PET compared to CTCs, and combining FES-PET with CTCs did not essentially improve this. Furthermore, CTCs were not detectable in most of these patients with non-rapidly progressive MBC, limiting their applicability for the present purpose. However, as CTC assessment is most patient friendly, CTCs might be considered as first step in determining MBC ER-status. If ER positive CTCs are detected, ER positive disease is very likely; if no- or ER negative CTCs are detected, MBC ER-status needs to be further assessed by means of tissue confirmation or FES-PET. Funding: Dutch Cancer Society grant RUG 2012-5565, project EMCR 16-8196 Citation Format: Eisses B, Angus L, van der Vegt B, Sieuwerts AM, Kraan J, Martens JW, Glaudemans AW, Brouwers AH, Hoekstra OS, Oyen W, Emmering J, Gerritse S, Menke-van der Houven van Oordt CW, Boon E, van Herpen CM, Jager A, Sleijfer S, de Vries EG, Schröder CP. Non-invasive estrogen receptor assessment by [18F]-fluorestradiol(FES)-PET or circulating tumor cells predicts receptor status in patients with metastatic breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr PD4-09.

Background: TKIs are a long-term treatment for GIST, and may have an impact on caregivers. Material and Methods: For this cross-sectional study, patients and caregivers were both included when patients had been treated with TKIs for at least six months. Caregivers completed questionnaires including demographics, distress (Hospital Anxiety and Depression scale), burden (Self-Perceived Pressure from Informal Care) general health (RAND-36), comorbidity (Self-administered Comorbidity Questionnaire), social support (Social Support List - Discrepancies) and marital satisfaction (Maudsley Marital Questionnaire). Patients completed similar questionnaires, without 'burden'. We conducted analyses to explore differences between caregivers with low/moderate versus high levels of burden and low versus high levels of distress. Results: Sixty-one out of seventy-one eligible couples (84%) were included in the analysis. The median age of the caregivers was 60 years; 66% were female and 78% were the patients' spouse. The median age of the patients was 66 years; 43% were female. Caregivers experienced high levels of burden and distress in 10% and 23%, respectively. Caregivers with high levels of burden perceived significantly lower mental health, less vitality, lower general health and high levels of distress. Significantly higher levels of burden were found in non-spouses, caregivers of patients with more treatment-related side-effects, caregivers who spent more hours caring, and those caring for more than one person. For distress, caregivers with high levels of distress perceived significantly more burden, lower social functioning, more role physical and emotional problems, lower mental health, less vitality and lower general health. Furthermore, high levels of distress were found in caregivers of more dependent patients and those caring for more than one person. Conclusions: Caregivers of the patients with GIST treated with TKI are managing well. There is a small, vulnerable group of caregivers with high levels of burden and/or distress, show more health-related problems, both physical and mental, and require adequate support.

In the past decade, a growing body of literature has reported promising results for prostate-specific membrane antigen (PSMA)-targeted radionuclide imaging and therapy in prostate cancer. First clinical studies evaluating the efficacy of [177Lu]Lu-PSMA radioligand therapy (PSMA-RLT) demonstrated favorable results in prostate cancer patients. [177Lu]Lu-PSMA is generally well tolerated due to its limited side effects. While PSMA is highly overexpressed in prostate cancer cells, varying degrees of PSMA expression have been reported in other malignancies as well, particularly in the tumor-associated neovasculature. Hence, it is anticipated that PSMA-RLT could be explored for other solid cancers. Here, we describe the current knowledge of PSMA expression in other solid cancers and define a perspective towards broader clinical implementation of PSMA-RLT. This review focuses specifically on salivary gland cancer, glioblastoma, thyroid cancer, renal cell carcinoma, hepatocellular carcinoma, lung cancer, and breast cancer. An overview of the (pre)clinical data on PSMA immunohistochemistry and PSMA PET/CT imaging is provided and summarized. Furthermore, the first clinical reports of non-prostate cancer patients treated with PSMA-RLT are described. Supplementary Information The online version contains supplementary material available at 10.1007/s00259-021-05433-w.

Contains fulltext : 225075.pdf (Publisher’s version ) (Open Access) BACKGROUND: Salivary duct carcinoma (SDC) is an aggressive subtype of salivary gland cancer. Approximately half of SDC patients will develop recurrences or metastases. Therapeutic palliative therapy is therefore often needed. The majority of SDC tumors expresses the androgen receptor (AR) and one-third expresses human epidermal growth factor receptor 2 (HER2), both are potential therapeutic targets. The aim of this paper is to systematically review and summarize the evidence on systemic palliative therapy for SDC and to provide treatment recommendations. MATERIALS AND METHODS: Electronic libraries were systematically searched with a broad search strategy to identify studies where SDC patients received systemic therapy. Due to the rarity of SDC no restrictions were placed on study designs. RESULTS: The search resulted in 2014 articles of which 153 were full-text analyzed. Forty-five studies were included in the analysis, which included in total 256 SDC patients receiving systemic therapy. Two phase 2 trials primarily including SDC patients were identified. The majority of the studies were case series or case reports, resulting in an overall low quality of available evidence. Based on studies including ≥ 5 SDC patients, objective responses to HER2 targeting agents were observed in 60-70%, to AR pathway agents in 18-53% and to chemotherapy in 10-50%. CONCLUSION: For AR or HER2 positive SDC, agents targeting these pathways are the cornerstone for palliative treatment. Regarding chemotherapy, the combination of carboplatin combined with a taxane is best studied. Regarding other targeted agents and immunotherapy evidence is anecdotal, limiting formulation of treatment recommendations for these antineoplastic agents.

Purpose One-third of patients with RAS wild-type mCRC do not benefit from anti-EGFR monoclonal antibodies. This might be a result of variable pharmacokinetics and insufficient tumor targeting. We evaluated cetuximab tumor accumulation on [89Zr]Zr-cetuximab PET/CT as a potential predictive biomarker and determinant for an escalating dosing strategy. Patients and methods PET/CT imaging of [89Zr]Zr-cetuximab (37 MBq/10 mg) after a therapeutic pre-dose (500 mg/m2 ≤ 2 h) cetuximab was performed at the start of treatment. Patients without visual tumor uptake underwent dose escalation and a subsequent [89Zr]Zr-cetuximab PET/CT. Treatment benefit was defined as stable disease or response on CT scan evaluation after 8 weeks. Results Visual tumor uptake on [89Zr]Zr-cetuximab PET/CT was observed in 66% of 35 patients. There was no relationship between PET positivity and treatment benefit (52% versus 80% for PET-negative, P = 0.16), progression-free survival (3.6 versus 5.7 months, P = 0.15), or overall survival (7.1 versus 9.4 months, P = 0.29). However, in 67% of PET-negative patients, cetuximab dose escalation (750–1250 mg/m2) was applied, potentially influencing outcome in this group. None of the second [89Zr]Zr-cetuximab PET/CT was positive. Eighty percent of patients without visual tumor uptake had treatment benefit, making [89Zr]Zr-cetuximab PET/CT unsuitable as a predictive biomarker. Tumor SUVpeak did not correlate to changes in tumor size on CT (P = 0.23), treatment benefit, nor progression-free survival. Cetuximab pharmacokinetics were not related to treatment benefit. BRAF mutations, right-sidedness, and low sEGFR were correlated with intrinsic resistance to cetuximab. Conclusion Tumor uptake on [89Zr]Zr-cetuximab PET/CT failed to predict treatment benefit in patients with RAS wild-type mCRC receiving cetuximab monotherapy. BRAF mutations, right-sidedness, and low sEGFR correlated with intrinsic resistance to cetuximab.

Contains fulltext : 226010.pdf (Publisher’s version ) (Open Access) Locally advanced head and neck squamous cell carcinoma (LAHNSCC) treatment consists of radiotherapy (RT) alone or cisplatin-based concomitant chemoradiotherapy (CCRT). CCRT is accompanied by substantially more toxicity than RT alone. A previous retrospective cohort study found that LAHNSCC patients with tumors negative for nuclear expression of the signal transducer and activator of transcription 3 (STAT3) protein might not benefit from the addition of cisplatin to radiotherapy (RT) treatment. We set out to validate these results in a new cohort. We found that in patients with both STAT3 positive and negative tumors, disease-free survival (DFS) and overall survival (OS) did not differ significantly between treatment with cisplatin-based concomitant chemoradiotherapy (CCRT) and radiotherapy alone. Therefore, our validation study does not confirm that STAT3 is a potential biomarker to predict the effectiveness of the addition of cisplatin to RT in LAHNSCC patients.

Purpose Everolimus treatment is seriously hampered by its toxicity profile. As a relationship between everolimus exposure and effectiveness and toxicity has been established, early and ongoing concentration measurement can be key to individualize the dose and optimize treatment outcomes. Dried blood spot (DBS) facilitates sampling at a patients’ home and thereby eases dose individualization. The aim of this study is to determine the agreement and predictive performance of DBS compared to whole blood (WB) to measure everolimus concentrations in cancer patients. Methods Paired DBS and WB samples were collected in 22 cancer patients treated with everolimus and analyzed using UPLC-MS/MS. Bland-Altman and Passing-Bablok analysis were used to determine method agreement. Limits of clinical relevance were set at a difference of ± 25%, as this would lead to a different dosing advice. Using DBS concentration and Passing-Bablok regression analysis, WB concentrations were predicted. Results Samples of 20 patients were suitable for analysis. Bland-Altman analysis showed a mean ratio of everolimus WB to DBS concentrations of 0.90, with 95% of data points within limits of clinical relevance. Passing-Bablok regression of DBS compared to WB revealed no constant bias (intercept 0.02; 95% CI 0.93–1.35) and a small proportional bias (slope 0.89; 95% CI 0.76–0.99). Predicted concentrations showed low bias and imprecision and 90% of samples had an absolute percentage prediction error of

Background: SYD985 is a HER2-targeting antibody-drug conjugate (ADC) based on trastuzumab and a cleavable linker-duocarmycin (vc-seco-DUBA) payload. Following proteolytic cleavage the synthetic duocarmycin prodrug is activated, binds to the minor groove of DNA, and subsequently causes irreversible DNA-alkylation. SYD985 has demonstrated unprecedented anti-tumor activity in preclinical breast cancer models with high (HER2 3+) or moderate/low expression of HER2 (HER2 2+ and HER2 1+). Clinical data of patients with HER2-positive and HER2-negative breast cancer treated with SYD985 in an ongoing first-in-human phase I trial (NCT02277717) in patients with locally advanced or metastatic solid tumors are presented. Trial design: Main inclusion criteria are ECOG performance status 0-1, left ventricular ejection fraction ≥ 55%, and adequate organ function. Patients are treated with SYD985 every three weeks until tumor progression or unacceptable toxicity. Thirty nine patients, including 26 breast cancer patients, were enrolled in the dose-escalation part and treated with doses varying from 0.3 mg/kg to 2.4 mg/kg SYD985. Patients enrolling in the first expanded cohort will be treated with 1.2 mg/kg SYD985. In this cohort a total of 48 patients with HER2-positive breast cancer (IHC 3+ or ISH positive) will be enrolled from May 2016 onwards. HER2 status was determined locally in the dose-escalation part but will be done centrally in the expanded cohort part of the trial. Tumor evaluation (RECIST 1.1) is performed every 6 weeks. Results: Enrolled breast cancer patients were heavily pretreated with a median of 7 systemic therapies. All patients with HER2-positive breast cancer were previously treated with trastuzumab and ado-trastuzumab emtansine (T-DM1). As of 16 May 2016, tumor evaluation data were available for 19 of the 26 enrolled breast cancer patients. In total, 8 partial responses were observed of which 6 were confirmed by a second CT-scan. The number of cycles administered ranged from 1 to 11. Ten of the 26 patients are still on treatment. Best overall response HER2 statusN EvaluablePRSDPDORR All dosesORR Doses ≥1.2 mg/kgHER2-positive (all T-DM1 pretreated)1458136%42%HER2-negative (IHC 1+/2+ and ISH neg)531160%75%Overall1989242%50% One dose-limiting toxicity occurred at 2.4 mg/kg SYD985, i.e. pneumonitis (grade 5). Overall, SYD985 is well tolerated up to doses of 1.8 mg/kg every 3 weeks. The most frequently reported drug-related AEs were conjunctivitis, stomatitis, fatigue, and decreased appetite. The majority of drug-related AEs were of mild or moderate intensity. Conclusion: SYD985 shows promising efficacy in both HER2-positive and HER2-negative metastatic breast cancer patients with an acceptable safety profile. SYD985 may offer a new targeted treatment option for patients who have become refractory to the available HER2-targeting therapies, and potentially for breast cancer patients who are not indicated for HER2-targeting therapies. Updated data, including additional results of up to 48 HER2-positive breast cancer patients, will be presented during the meeting. Citation Format: Aftimos PG, van Herpen CM, Mommers EC, Koper NP, Goedings P, Oesterholt M, Awada A, Desar IM, Lim J, Dean E, Rolfo C, Macpherson I, Banerji U. SYD985, a novel anti-HER2 ADC, shows promising activity in patients with HER2-positive and HER2-negative metastatic breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P6-12-02.

Background: Due to rapid technical advances, steeply declining sequencing costs, and the ever-increasing number of targeted therapies, it can be expected that extensive tumor sequencing such as whole-exome and whole-genome sequencing will soon be applied in standard care. Clinicians will thus be confronted with increasingly complex genetic information and multiple test-platforms to choose from. General medical training, meanwhile, can hardly keep up with the pace of innovation. Consequently, there is a rapidly growing gap between clinical knowledge and genetic potential in cancer care. Multidisciplinary Molecular Tumor Boards (MTBs) have been suggested as a means to address this disparity, but shared experiences are scarce in literature and no quality requirements or guidelines have been published to date.Methods: Based on literature review, a survey among hospitals in The Netherlands, and our own experience with the establishment of a nationally operating MTB, this article evaluates current knowledge and unmet needs and lays out a strategy for successful MTB implementation.Results: Having access to an MTB can improve and increase the application of genetics-guided cancer care. In our survey, however, Conclusions: This article acknowledges a leading role for MTBs to govern (extensive) tumor sequencing into daily practice and proposes three basic necessities for successful MTB implementation: (i) global harmonization in cancer sequencing practices and procedures, (ii) minimal member and operational requirements, and (iii) an appropriate unsolicited findings policy. Meeting these prerequisites would not only optimize MTB functioning but also improve general interpretation and application of genomics-guided cancer care.

Aim Salivary duct carcinoma (SDC), an aggressive subtype of salivary gland cancer, is androgen receptor (AR)–positive in 67–96% of cases. In patients with locally recurrent and metastatic (R/M) AR-positive SDC, androgen deprivation therapy (ADT) has an overall response rate of 18–64.7%. In this study, we describe the efficacy of adjuvant ADT in patients with poor-risk (stage 4a) AR-positive SDC. Methods This is a retrospective cohort study in which patients with stage 4a AR-positive SDC were offered adjuvant ADT, i.e. bicalutamide, luteinizing hormone-releasing hormone (LHRH) analogue or a combination of these after tumour resection. In the control group, data were collected on patients with stage 4a SDC who underwent a tumour resection but did not receive adjuvant ADT. Results Twenty-two AR-positive SDC patients were treated with adjuvant ADT for a median duration of 12 months. The control group consisted of 111 SDC patients. After a median follow-up of 20 months in the ADT-treated patients and 26 months in the control group, the 3-year disease-free survival (DFS) was estimated as 48.2% (95% confidence interval [CI] 14.0–82.4%) and 27.7% (95% CI 18.5–36.9%) (P = 0.037). Multivariable Cox regression analysis showed a hazard ratio of 0.138 (95% CI 0.025–0.751, P = 0.022) for DFS and 0.064 (95% CI 0.005–0.764, P = 0.030) for overall survival (OS) in favour of the ADT-treated patients. Conclusion Poor-risk, AR-positive SDC patients who received adjuvant ADT have a significantly longer DFS compared with patients in the control group, who did not receive adjuvant ADT. For OS, this was just below and above the significance level, in case there was or was no correction for confounders.

One-third of patients with RAS wild-type mCRC do not benefit from anti-EGFR monoclonal antibodies. This might be a result of variable pharmacokinetics and insufficient tumor targeting. We evaluated cetuximab tumor accumulation on [PET/CT imaging of [Visual tumor uptake on [Tumor uptake on [

Background Recently 3D organoid cell cultures have been established for a variety of human cancers. Salivary gland cancer (SGC) is a rare cancer with 22 different subtypes and few treatment options. Our aim is to generate a large repertoire of patient-derived SGC organoids with different phenotypes, which will facilitate pre-clinical and pharmacological studies. Methods Fresh tissues of resected primary tumours and/or metastases of SGC patients were collected. Tissues were minced and digested with collagenase type 2 and TrypLE to generate single cells. After washing, the cells were seeded in growth factor reduced Matrigel. Organoid medium, containing Rho kinase inhibitor Y27632, was refreshed twice a week. Viable organoids were characterized by immunohistochemistry and by DNA/RNA sequencing. Moreover, the organoids were used to evaluate various treatments that are or may be relevant for the treatment of SGC. Results Between 2016 and 2018 we obtained tissue of 17 SGC patients, of which 16 contained sufficient material for processing: 10 salivary duct carcinoma (SDC), 3 adenoid cystic carcinoma (ACC), 2 muco-epidermoid carcinoma (MEC) and 1 parotid adenocarcinoma not otherwise specified (NOS). For 5 tumors (2 SDC, 2 ACC, 1 adenocarcinoma NOS) viable organoids were established, which could be passaged at least three times. Organoids cultures derived from the other tumours stopped growing after the first passage. Viable organoids showed resemblance with the original primary tumour, based on morphology, protein expression, and growth pattern. Various drugs were tested at a single dose, and showed reduced organoid cell growth compared to untreated controls. Moreover, a dose-response relationship was established for an ALK-positive MEC organoid that was treated with crizotinib. Finally, epithelial-mesenchymal transition was shown in SDC organoids of a primary tumour and a lymph node metastasis of the same patient. Conclusions We are the first that have successfully developed and characterized long-term organoid cultures for ACC and SDC. These organoid cell lines will facilitate pre-clinical and pharmacological studies. Other SGC organoid cultures do not grow infinitely, but do provide an in vitro model to study different treatments during initial growth. Legal entity responsible for the study Radboud University Medical Center. Funding Dutch Salivary Gland Cancer Patient Platform. Disclosure All authors have declared no conflicts of interest.

Background Large-scale genetic tumor profiling can identify increasing numbers of potentially actionable molecular variants for which approved anti-cancer drugs are available. In daily practice, however, when patients with such variants are treated with drugs outside of their approved label, successes and failures are not systematically collected or shared. Methods We initiated the Drug Rediscovery Protocol (DRUP), an innovative and adaptive precision oncology trial aimed at identifying signals of activity in cohorts of patients with defined tumor types and molecular variants, treated with anti-cancer drugs outside their approved label. Eligible patients have exhausted (or declined) standard therapies and have malignancies with potentially actionable variants for which no approved anti-cancer drugs are available. Results Here, we show an overall clinical benefit rate (defined as complete or partial response, or stable disease ≥16 weeks) of 34% in the first 215 treated patients. This comprised 136 patients who received targeted therapies, and 79 patients who received immunotherapy. Overall median clinical benefit duration was nine months (95% CI 8 – 11 months), including 26 patients with ongoing clinical benefit at data cutoff. The potential of DRUP was illustrated by the identification of a successful cohort of patients with microsatellite instable tumors receiving nivolumab, and a cohort of colorectal cancer patients with relatively low mutational load with limited clinical benefit from immunotherapy. Conclusions The DRUP hereby facilitates defined use of approved drugs beyond their label in (rare) cancer subgroups, identifies early signals of activity in these subgroups, accelerates clinical translation of new insights, and creates a publicly available knowledge-base for future decision making. Legal entity responsible for the study Netherlands Cancer Institute. Funding Hartwig Medical Foundation, Dutch Cancer Society, Barcode for Life, Roche, Novartis, MSD, GSK, Pfizer, AstraZeneca, BMS. Disclosure E.E. Voest: Research grant / Funding (self), Legally responsible for all contracts: All pharma. C. van Herpen: Advisory / Consultancy: Bayer; Advisory / Consultancy, Research grant / Funding (self): Bristol-Myers Squibb; Advisory / Consultancy, Research grant / Funding (self): Ipsen; Advisory / Consultancy, Research grant / Funding (self): MSD; Advisory / Consultancy: Regeneron; Research grant / Funding (self): AstraZeneca; Research grant / Funding (self): Merck; Research grant / Funding (self): Novartis; Research grant / Funding (self): Sanofi. M. Chalabi: Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Netherlands Cancer Institute. E.F. Smit: Honoraria (institution), Research grant / Funding (institution): AstraZeneca; Honoraria (institution), Research grant / Funding (institution): Bristol-Myers Squibb; Honoraria (institution): Bayer; Honoraria (institution), Advisory / Consultancy: Eli Lilly; Honoraria (institution), Research grant / Funding (institution): MSD; Honoraria (institution), Research grant / Funding (institution): Merck; Honoraria (institution): Novartis ; Honoraria (institution): Pfizer; Honoraria (institution): Takeda; Honoraria (institution): Regeneron; Honoraria (institution), Research grant / Funding (institution): Roche Genentech; Honoraria (institution): Seattle Genetics. N. Mehra: Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb; Advisory / Consultancy: Bayer; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche; Advisory / Consultancy, Travel / Accommodation / Expenses: MSD; Advisory / Consultancy, Research grant / Funding (institution): Janssen-Cilag; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Astellas; Advisory / Consultancy, Research grant / Funding (institution): Sanofi. E. Cuppen: Honoraria (institution), Advisory / Consultancy: Illumina; Honoraria (self), Advisory / Consultancy: InteRNA Technologies; Full / Part-time employment, Officer / Board of Directors: Hartwig Medical Foundation. H.M.W. Verheul: Honoraria (institution), Advisory / Consultancy: Glycostem; Honoraria (institution), Advisory / Consultancy: Lava Therapeutics. H. Gelderblom: Research grant / Funding (institution): Five Prime; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Deciphera; Research grant / Funding (institution): Eli Lilly; Research grant / Funding (institution): Roche; Research grant / Funding (institution): Eisai; Research grant / Funding (institution): Debio; Research grant / Funding (institution): Boehringer Ingelheim; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Amgen; Research grant / Funding (institution): Teva. All other authors have declared no conflicts of interest.

Background Systemic anti-cancer treatment is hampered by drug resistance (DR). However, little is known about the pharmacokinetic consequences of genetic changes in tumor cells. We hypothesize that somatic point mutations, small indels, copy number variations (sCNV) and/or structural variations in genes encoding drug transporters are drivers of DR mechanisms in tumor cells. We therefore performed an explorative analysis to quantify somatic aberrations that could reflect DR mechanisms and, in parallel, identify their stressors. Methods We interrogated whole-genome sequencing (WGS) data from a Dutch pan-cancer cohort of metastatic cancer patients (N = 3149 at ∼118x and matched peripheral blood at∼38x read depth), of which more than half had failed previous systemic treatment. Somatic aberrations (germline filtered) were analyzed in drug transporters (N = 51), present on the Drug Metabolizing Enzymes and Transporters (DMET™ plus) panel (v.32). Enrichment of somatic DR variants was estimated by assessing nonsynonymous/synonymous mutation ratio deviations (dN/dS) and sCNV were detected with GISTIC2. Results In total, 5137 somatic variants (2645 in treatment-naive and 2484 in pretreated patients) in drug transporter genes were observed in 1651 patients (52.4%) of whom 55.1% were systemically pretreated. Three genes (ABCB4, ABCC5, SLCO1B1) showed dN/dS enrichment (p = 0.0142 - 0.0364). sCNVs (N = 7656; 5849 deep gene-level gains and 1807 deletions) were observed in 1906 patients (60.5%). Interestingly, we identified 20 somatic DR-related variants in 12 patients (58.3% pretreated), not present in the matching germline samples, that were identical to SNP variants on DMET™ plus. Conclusions In the largest metastatic pan-cancer WGS cohort worldwide, we characterized the pharmacogenomic drug transporter landscape in tumor cells. Potentially, the incidence of somatic variants in pharmacogenes accounts for acquired DR in pretreated patients and/or intrinsic DR. We will extend our study with analyses of prior treatments and germline variations, in order to assess the clinical consequences of the variations and improve clinical decision-making. Clinical trial identification NCT01855477. Legal entity responsible for the study The authors. Funding This publication and the underlying study have been made possible partly on the basis of the data that Hartwig Medical Foundation and the Center of Personalised Cancer Treatment (CPCT) have made available to the study. Disclosure C. van Herpen: Advisory/Consultancy: Bayer; Advisory/Consultancy, Research grant/Funding (institution): Bristol-Myers Squibb; Advisory / Consultancy, Research grant / Funding (institution): Ipsen; Advisory / Consultancy, Research grant / Funding (institution): MSD; Advisory / Consultancy: Regeneron; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Sanofi. R.H.J. Mathijssen: Research grant / Funding (institution), Travel / Accommodation / Expenses: Astellas; Research grant / Funding (institution), Travel / Accommodation / Expenses: Pfizer; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Boehringer; Research grant / Funding (institution): Cristal Therapeutics; Honoraria (self), Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Pamgene; Research grant / Funding (institution): Roche; Research grant / Funding (institution): Sanofi; Honoraria (self): Servier. All other authors have declared no conflicts of interest.

Contains fulltext : 136260.pdf (Publisher’s version ) (Closed access) Malignant ascites and pleural effusion are challenging clinical problems, with a major impact on quality of life. We conducted a randomized phase II trial to assess the palliative value of cediranib, an oral vascular endothelial growth factor tyrosine kinase inhibitor (VEGF TKI). After a baseline paracentesis or thoracentesis (on day 0), patients with symptomatic malignant ascites and/or pleural effusion were randomized between immediate treatment with cediranib (Immediate Cediranib) or delayed treatment with cediranib (Delayed Cediranib) on day 29, or after a new puncture was needed. The primary objective of the study was the puncture-free survival, defined as the time from study start (day 1) to the first need for paracentesis or thoracentesis, or time to death, whichever event occurred first. Twelve patients were enrolled. The median puncture-free survival was 45 days (range 10-368) in the Immediate Cediranib patients and 7 days (range 4-13) in the Delayed Cediranib patients (P = 0.011). The change in puncture-free interval (the puncture-free survival after study start minus the puncture-free interval before study start) increased with a median of 31 days in the Immediate Cediranib patients and shortened with a median of 3 days in the Delayed Cediranib patients (P = 0.015). The most common adverse events were fatigue and anorexia. In conclusion, cediranib increased the puncture-free survival and puncture-free interval with an acceptable toxicity profile. This is the first study in which an oral VEGFR TKI showed beneficial palliative effects in patients with malignant effusions.

SummaryAim: Early treatment response of head and neck cancer to radiotherapy concomitant with cetuximab was monitored by repetitive PET imaging with the proliferation tracer 18F-FLT. Patients, methods: Five head and neck cancer patients, treated with radiotherapy and concomitant cetuximab following cetuximab induction, received four 18F-FLT PET-CT scans before and during treatment. Changes in SUVpeak, SUVmean and CT- and PET-segmented gross tumour volumes were evaluated, as were correlations with immu- nohistochemical staining for Epidermal Growth Factor Receptor (EGFR) and Ki-67 (proliferation marker) in pre-treatment tumour biopsies. Results: 18F-FLT PET measured tumor responses to the induction dose of ce- tuximab varied from 43% SUVpeak decrease to 47% increase. After start of radiotherapy 18F-FLT PET parameters decreased significantly in all patients. No associations were found between PET parameters and EGFR or Ki-67 expression levels. Conclusion: Proliferation of head and neck carcinomas shows a varying response to cetuximab induction, but consistently decreases after addition of radiotherapy.

Item does not contain fulltext Background:The vascular endothelial growth factor receptor (VEGFR) pathway plays a pivotal role in solid malignancies and is probably involved in chemotherapy resistance. Pazopanib, inhibitor of, among other receptors, VEGFR1-3, has activity as single agent and is attractive to enhance anti-tumour activity of chemotherapy. We conducted a dose-finding and pharmacokinetic (PK)/pharmacodynamics study of pazopanib combined with two different schedules of ifosfamide.Methods:In a 3+3+3 design, patients with advanced solid tumours received escalating doses of oral pazopanib combined with ifosfamide either given 3 days continuously or given 3-h bolus infusion daily for 3 days (9 g m(-2) per cycle, every 3 weeks). Pharmacokinetic data of ifosfamide and pazopanib were obtained. Plasma levels of placental-derived growth factor (PlGF), vascular endothelial growth factor-A (VEGF-A), soluble VEGFR2 (sVEGFR2) and circulating endothelial cells were monitored as biomarkers.Results:Sixty-one patients were included. Pazopanib with continuous ifosfamide infusion appeared to be safe up to 1000 mg per day, while combination with bolus infusion ifosfamide turned out to be too toxic based on a variety of adverse events. Ifosfamide-dependent decline in pazopanib exposure was observed. Increases in PlGF and VEGF-A with concurrent decline in sVEGFR2 levels, consistent with pazopanib-mediated VEGFR2 inhibition, were observed after addition of ifosfamide.Conclusion:Continuous as opposed to bolus infusion ifosfamide can safely be combined with pazopanib. Ifosfamide co-administration results in lower exposure to pazopanib, not hindering biological effects of pazopanib. Recommended dose of pazopanib for further studies combined with 3 days continuous ifosfamide (9 g m(-2) per cycle, every 3 weeks) is 800 mg daily.

Background Metastatic cancer is one of the major causes of death and is associated with poor treatment efficiency. A better understanding of the characteristics of late stage cancer is required to help tailor personalised treatment, reduce overtreatment and improve outcomes. Methods Here we describe the largest pan-cancer study of metastatic solid tumor genomes, including 2,520 whole genome-sequenced tumor-normal pairs, analyzed at a median depth of 106x and 38x respectively, and surveying over 70 million somatic variants. Results Metastatic lesions were found to be very diverse, with mutation characteristics reflecting those of the primary tumor types, although with high rates of whole genome duplication events (56%). Metastatic lesions are relatively homogeneous with the vast majority (96%) of driver mutations being clonal and up to 80% of tumor suppressor genes bi-allelically inactivated through different mutational mechanisms. For 62% of all patients, genetic variants that may be associated with outcome of approved or experimental therapies were detected. These actionable events were distributed over the various mutation types (single and multiple nucleotide variants, insertions and deletions, copy number alterations and structural variants) underlining the importance of comprehensive genomic tumor profiling for cancer precision medicine for advanced cancer treatment. Conclusions Whole genome sequencing on fresh biopsies of metastatic cancer is feasible and identifies not only new insights in genome biology but also new opportunities for patients with both approved and experimental agents. We have created the largest data base of whole genome sequenced metastatic cancer patients which continues to facilitate new precision medicine studies. Legal entity responsible for the study The authors. Funding Hartwig Medical Foundation, Barcode for Life, Dutch Cancer Society. Disclosure E. Cuppen: Honoraria (self), Advisory / Consultancy: InteRNA technologies BV; Honoraria (institution), Advisory / Consultancy: Illumina; Full / Part-time employment, Officer / Board of Directors: Hartwig Medical Foundation. M.P. Lolkema: Advisory / Consultancy: Incyte; Advisory / Consultancy: Amgen; Advisory / Consultancy: Janssen Cilag BV; Advisory / Consultancy: Bayer; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Sanofi Aventis Netherlands BV. P. Roepman: Honoraria (institution), Advisory / Consultancy: Illumina. V.C.G. Tjan-Heijnen: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: E. Lilly; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Novartis; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Pfizer; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: AstraZeneca. C. van Herpen: Advisory / Consultancy: Bayer; Advisory / Consultancy: BMS; Advisory / Consultancy: Ipsen ; Advisory / Consultancy: MSD; Advisory / Consultancy: Regeneron; Research grant / Funding (self): AstraZeneca; Research grant / Funding (self): BMS ; Research grant / Funding (self): MSD; Research grant / Funding (self): Merck; Research grant / Funding (self): Ipen; Research grant / Funding (self): Novartis ; Research grant / Funding (self): Sanofi . E.F. Smit: Honoraria (institution): AstraZeneca ; Honoraria (institution): BMC; Honoraria (institution): Bayer; Honoraria (institution): Eli Lilly ; Honoraria (institution): MSD; Honoraria (institution): Merck ; Honoraria (institution): Novartis; Honoraria (institution): Pfizer; Honoraria (institution): Takeda; Honoraria (institution): Regeneron; Honoraria (institution): Roche ; Honoraria (institution): Seattle Genetrics; Advisory / Consultancy: Eli Lilly ; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): BMS; Research grant / Funding (institution): Merck; Research grant / Funding (institution): MSD; Research grant / Funding (institution): Roche. All other authors have declared no conflicts of interest.

The large-scale genetic profiling of tumours can identify potentially actionable molecular variants for which approved anticancer drugs are available1–3. However, when patients with such variants are treated with drugs outside of their approved label, successes and failures of targeted therapy are not systematically collected or shared. We therefore initiated the Drug Rediscovery protocol, an adaptive, precision-oncology trial that aims to identify signals of activity in cohorts of patients, with defined tumour types and molecular variants, who are being treated with anticancer drugs outside of their approved label. To be eligible for the trial, patients have to have exhausted or declined standard therapies, and have malignancies with potentially actionable variants for which no approved anticancer drugs are available. Here we show an overall rate of clinical benefit—defined as complete or partial response, or as stable disease beyond 16 weeks—of 34% in 215 treated patients, comprising 136 patients who received targeted therapies and 79 patients who received immunotherapy. The overall median duration of clinical benefit was 9 months (95% confidence interval of 8–11 months), including 26 patients who were experiencing ongoing clinical benefit at data cut-off. The potential of the Drug Rediscovery protocol is illustrated by the identification of a successful cohort of patients with microsatellite instable tumours who received nivolumab (clinical benefit rate of 63%), and a cohort of patients with colorectal cancer with relatively low mutational load who experienced only limited clinical benefit from immunotherapy. The Drug Rediscovery protocol facilitates the defined use of approved drugs beyond their labels in rare subgroups of cancer, identifies early signals of activity in these subgroups, accelerates the clinical translation of new insights into the use of anticancer drugs outside of their approved label, and creates a publicly available repository of knowledge for future decision-making. Clinical benefit was observed in 34% of a cohort of 215 patients with cancer who received treatment with anticancer drugs outside of their approved label, in the Drug Rediscovery protocol trial.

Item does not contain fulltext Hypertension is an important side effect of sunitinib treatment. In a retrospective study in 255 patients, single-nucleotide polymorphisms (SNPs) in vascular endothelial growth factor A (VEGFA), vascular endothelial growth factor receptor (VEGFR)-2, endothelin-1 (ET-1), and endothelium-derived nitric oxide synthase (eNOS) were multivariately tested against hypertension grades and changes in systolic blood pressure (SBP), diastolic BP (DBP), and mean arterial BP (MAP). Next, the association between hypertension and survival in patients with metastatic renal cell cancer (mRCC) was studied. Greater elevations in SBP and MAP were associated with the presence of a haplotype in VEGFA (P = 0.014 and P = 0.036, respectively). The tendency to develop grade 3 hypertension was associated with this haplotype and also with a SNP in eNOS (P = 0.031 and P = 0.045, respectively). In mRCC patients, sunitinib-induced hypertension was found to confer a survival benefit, with the mean overall survival being prolonged by 7.2 months (P = 0.035 and P = 0.026 for SBP and DBP elevations, respectively). Genetic polymorphisms in VEGFA and eNOS independently predict rise in BP and/or development of severe hypertension in sunitinib-treated patients. Grade 3 hypertension was found to be an independent factor for overall survival in patients with mRCC.

Contains fulltext : 97671.pdf (Publisher’s version ) (Closed access) AIM: Cytoreductive nephrectomy is considered beneficial in patients with metastasised kidney cancer but only a minority of these patients undergo cytoreductive surgery. Factors associated with nephrectomy and the independent effect of nephrectomy on survival were evaluated in this study. METHODS: Patients were selected from the population-based cancer registry and detailed data were retrieved from clinical files. Factors associated with nephrectomy were evaluated by logistic regression analyses. Cox proportional hazard regression analysis was performed to evaluate factors associated with survival; a propensity score reflecting the probability of being treated surgically was included in order to adjust for confounding by indication. RESULTS: 37.5% of 328 patients diagnosed with metastatic kidney cancer between 1999 and 2005 underwent nephrectomy. Patients with a low performance score, high age, >/=2 comorbid conditions, >/=2 metastases, low or high BMI, weight loss, elevated lactate dehydrogenase, elevated alkaline phosphatase, female gender and liver or bone metastases were less likely to be treated surgically. Three year survival was 25% and 4% for patients with and without nephrectomy, respectively (p

Item does not contain fulltext AIM: To ensure safety and optimise efficacy, careful patient selection for participation in oncologic phase I trials is warranted. Therefore, we did a validation study on existing phase I prognostic scores, and subsequently aimed to make an even more simple prognostic score. PATIENTS AND METHODS: We retrospectively analysed characteristics and clinical outcome of 122 patients who participated in eight different phase I studies in our centre. A literature search was performed for existing prognostic scores which were validated in our dataset. Additionally, a simple prognostic score able to predict overall survival (OS), progression free survival (PFS), 90-d mortality and duration of participation was developed. RESULTS: In our population the median OS was 31 (range 4-241) weeks, median PFS was 10 (range 3-119) weeks. Thirteen patients (11%) died within 90-d and median participation duration was 11 (range 1-119) weeks. Two out of five existing prognostic scores could be validated in this dataset for OS. Based on multivariate analyses a new, objective and simple score, consisting of LDH, sodium and haemoglobin, was tested. High score (2-3 points) compared to low score (0-1) significantly predicted OS (HR 1.878, p = 0.003), PFS (HR 1.156, p = 0.038), participation duration (HR 1.858, p = 0.004) and 90-d mortality (OR 4.200, p = 0.022). CONCLUSION: We propose a new prognostic model, using LDH, sodium and haemoglobin, helpful to predict OS, PFS, participation duration and 90-d mortality. Larger multicentre studies are needed to validate this score.

Contains fulltext : 107957.pdf (Publisher’s version ) (Open Access) OBJECTIVE: To assess the early vascular effects of sunitinib in patients with renal cell carcinoma (RCC) with diffusion-weighted magnetic resonance imaging (DWI), dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) and T2* perfusion MRI. PATIENTS AND METHODS: In 10 patients with abdominal RCC lesions, DWI, DCE-MRI and T2* perfusion MRI measurements at 3 Tesla were performed at baseline, 3 and 10 days after start of sunitinib. VEGF-A plasma levels were measured on days 0, 3 and 10. RESULTS: DWI showed a significant increase in the apparent diffusion coefficient (x10(-6) s/mm(2)) from baseline (mean 1158, range 814-2003) to day 3 (mean 1306, range 1008-2097, P = 0.015) followed by a decrease to baseline levels at day 10 (mean 1132, range 719-2005, P = 0.001). No significant changes were found in mean DCE-MRI parameters. T2* perfusion MRI showed a significant decrease in relative tumor blood volume (rBV) and relative tumor blood flow (rBF) at day 3 (rBV P = 0.037, rBF P = 0.018) and day 10 (rBV P = 0.006, rBF P = 0.009). VEGF-A plasma levels significantly increased after 10 days, but did not correlate with MRI parameters. CONCLUSIONS: Sunitinib induces antiangiogenic effects as measured by DWI and T2*-perfusion MRI, 3 and 10 days after the start of the initial treatment. DCE-MRI did not show significant changes. In the near future, early functional MRI-based evaluation can play an important role in tailoring treatment to the individual patient with RCC. Further investigation is warranted.

Contains fulltext : 87630.pdf (Publisher’s version ) (Closed access) BACKGROUND: The combination of sorafenib (vascular endothelial growth factor receptor 2 inhibitor) and sirolimus (mammalian target of rapamycin inhibitor) might work synergistically. METHODS: A phase I dose-escalation study with sorafenib twice a day (b.i.d.) and sirolimus once daily (q.d.) was performed to determine the recommended dose of the combination in patients with solid tumours. Secondary objectives were to determine the safety profile and maximum tolerated dose (MTD), and to evaluate the pharmacokinetics (PK) of the combination. RESULTS: Dose-limiting toxicities were transaminitis and cutaneous toxicity. The most frequently reported adverse events were elevated transaminases, hypophosphatemia, fatigue, anorexia, diarrhoea, nausea, rash and palmar-plantar erythrodysaesthesia. Sirolimus did not change the PK of sorafenib; in contrast, sorafenib reduced the AUC(0-96) and C(max) of sirolimus. No objective responses were observed; eight patients showed stable disease for a median of 16.3 weeks (range 8-24). The MTD of the combination was sorafenib 200 mg b.i.d. with sirolimus 1 mg q.d. CONCLUSION: The combination of sorafenib and sirolimus showed enhanced toxicity, which could not be explained by the PK of both drugs. The relative low doses at the MTD, in combination with the PK results, do not warrant further development of this combination.

BACKGROUND: This Phase Ib dose-escalating study investigated safety, maximum tolerated dose (MTD), dose-limiting toxicity (DLT), pharmacokinetics (PK) and clinical antitumour activity of tosedostat (CHR-2797), an orally bioavailable aminopeptidase inhibitor, in combination with paclitaxel. METHODS: A total of 22 patients received paclitaxel (135-175 mg m(-2)) intravenously, administered once every three weeks for up to six cycles, with oral tosedostat (90-240 mg) daily. RESULTS: One DLT (grade 3 dyspnoea) was observed in one patient with tosedostat 180 mg combined with paclitaxel 175 mg m(-2). A high number of paclitaxel infusion reactions was noted during the second administration (59%) and this prompted interruption of tosedostat dosing for 5 days around every second and subsequent paclitaxel infusion. No formal MTD was determined because of the high frequency of paclitaxel infusion reactions that may have been influenced by tosedostat. Most frequently observed drug-related adverse events were alopecia, fatigue (95% each), peripheral sensory neuropathy (59%), paclitaxel hypersensitivity (59%) and rash (55%). One patient died because of eosinophilic myocarditis, possibly related to study medication. There was no PK interaction between tosedostat and paclitaxel. In all, 3 patients had a partial response and 12 patients had stable disease lasting >3 months. CONCLUSION: The combination of tosedostat with paclitaxel was well tolerated except for the high incidence of paclitaxel-related infusion reactions. British Journal of Cancer (2010) 103, 1362-1368. doi: 10.1038/sj.bjc.6605917 www.bjcancer.com Published online 28 September 2010 (C) 2010 Cancer Research UK

Contains fulltext : 80474.pdf (Publisher’s version ) (Closed access) The development of targeted therapies is a major breakthrough in the treatment of cancer. By evoking necrosis and cavitation, evaluation based on tumour size alone, as is done in the RECIST criteria, is no longer an adequate method. New molecular and functional imaging techniques are developed. This review focuses on the use of new imaging modalities for the evaluation of treatment response of pathway based targeted therapies. First, the basic principles of functional and molecular imaging modalities are briefly discussed. Thereafter, their clinical application in targeted therapies is correlated to the underlying biological mechanism. In this way, the best method for response evaluation for a new agent can be identified.

Contains fulltext : 57819.pdf (Publisher’s version ) (Closed access) PURPOSE: To determine the safety profile and activity of the combination of docetaxel, cisplatin and 5-fluorouracil (5-FU) in chemotherapy-naive patients with squamous cell carcinoma of the head and neck (SCCHN). PATIENTS AND METHODS: Patients with locally advanced unresectable SCCHN were treated with docetaxel and cisplatin both as a 1-h infusion on day 1 followed by a continuous infusion of 5-FU for 5 days. Cycles were planned every 3 weeks up to four cycles, whereafter the patients were treated with locoregional radiotherapy. Two dose levels were studied. Doses in level I were 75 mg/m(2) of docetaxel, 75 mg/m(2) of cisplatin and 750 mg/m(2)/day of 5-FU; in level II the cisplatin dose was escalated to 100 mg/m(2). Following chemotherapy, all patients were to receive curative radiotherapy according to the standards in the different institutions. RESULTS: Twenty-five patients were treated at dose level I with 86 cycles (median four; range one to four), and 23 at dose level II with 84 cycles (median four; range two to four). The median relative dose intensity was 0.99 (range 0.86-1.04) at level I and 0.94 (range 0.79-1.02) at level II. The response rate in the intention-to-treat population was 64% [95% confidence interval (CI) 42.5% to 82%] in level I and 78.3% (95% CI 56.3% to 92.5%) in level II; all were partial responses. The maximum tolerated dose was reached at level II with renal toxicity, nausea, stomatitis and thrombocytopenia as principal dose-limiting toxicities. The median survival of the 48 patients was 18.5 months. The survival at 12, 18, 24 and 30 months was 69, 54, 41 and 31%, respectively. CONCLUSIONS: The combination of docetaxel, cisplatin and 5-FU associated with prophylactic ciprofloxacin is feasible and active in patients with SCCHN. Dose level I is recommended for phase III testing.

Item does not contain fulltext Metastatic renal cell carcinoma has a poor prognosis. The value of immunotherapy with IFN-alpha and IL-2 both as single agent or as the combination is extensively investigated. The optimal dose and schedule is not known. In various studies response rates vary between 10 and 40%. The duration of response is variable. For a partial response a median duration between 10 and 12 months is given. Complete responses are sometimes long-lasting (a couple of years). The toxicity is drug, dose and schedule dependent. On the basis of a number of prognostic factors, such as performance score, time between the initial diagnosis and the treatment of metastases and the number of metastatic sites, patients can be divided in different prognostic groups. Patients who are classified in the good or intermediate prognostic group may have an improvement of their survival after immunotherapy and therefore they are candidates for immunotherapy.

Contains fulltext : 127680.pdf (Publisher’s version ) (Closed access) A patient with neurofibromatosis type 2 (bilateral vestibular schwannomas) was treated with bevacizumab (anti-vascular endothelial growth factor [VEFG] monoclonal antibody). The left-sided tumor showed intense uptake on pretreatment In-bevacizumab scintigraphy, indicating VEGF production in the tumor, and no uptake 4 weeks later, demonstrating effective binding of nonradiolabeled bevacizumab to the VEGF produced in the tumor. The right-sided tumor showed no tracer uptake at any time point. Significant tumor volume reduction (assessed with MRI) and hearing improvement were observed on the left side. In-bevacizumab scintigraphy may be a promising upfront patient selection tool to identify patients who may benefit from expensive bevacizumab treatment. 01 maart 2014