Jean-Pascal H. Machiels

Efficacy and Safety of Pazopanib in Patients With Metastatic Renal Cell Carcinoma

PURPOSE Inactivation of the von Hippel-Lindau gene in clear-cell renal cell carcinomas (RCC) leads to overexpression of hypoxia inducible factor, a transcription factor regulating vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) gene expression. Pazopanib, an angiogenesis inhibitor targeting VEGF receptor, PDGF receptor, and c-KIT, was evaluated in patients with RCC. PATIENTS AND METHODS This phase II study was designed as a randomized discontinuation study but was revised to an open-label study on the recommendation of the data monitoring committee (based on week 12 response rate [RR] of 38% in the first 60 patients). The primary end point was changed from progressive disease rate at 16 weeks postrandomization to RR. Pazopanib 800 mg was administered orally once daily. Pazopanib 800 mg was administered orally once daily. RESULTS The study enrolled 225 patients with metastatic RCC; 155 patients (69%) were treatment naïve, and 70 patients (31%) had received one prior cytokine- or bevacizumab-containing regimen. Overall RR was 35%; median duration of response was 68 weeks. Median progression-free survival (PFS) was 52 weeks. Eastern Cooperative Oncology Group performance status of 0 and time from diagnosis to treatment of more than 1 year were correlated with prolonged PFS. Pazopanib was generally well tolerated. The most common adverse events were diarrhea, fatigue, and hair depigmentation. The most common laboratory abnormalities were elevated AST and ALT. CONCLUSION Pazopanib demonstrated durable activity in patients with advanced RCC and was generally well tolerated in this population. These findings support the further development of pazopanib in advanced RCC.

Phase II Study of Sunitinib in Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck: GORTEC 2006-01

PURPOSE To assess the efficacy and toxicity of sunitinib monotherapy in palliative squamous cell carcinoma of the head and neck (SCCHN). PATIENTS AND METHODS Thirty-eight patients with SCCHN having evidence of progressive disease (PD) were treated with sunitinib 37.5 mg/d given continuously until PD or unacceptable toxicity. The primary end point was the rate of disease control, defined as stable disease (SD) or partial response (PR) at 6 to 8 weeks after treatment initiation (two-stage design, Simon). Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) was performed in a subset of patients before and 6 to 8 weeks after treatment. The volume transfer constant of the contrast agent (K(trans)) was used to measure changes in the microcirculation blood flow and endothelial permeability of the tumor. Results A PR was observed in one patient, SD in 18, and PD in 19 (Response Evaluation Criteria in Solid Tumors [RECIST]), resulting in a disease control rate of 50%. Among the 18 patients with SD, there were five unconfirmed PRs and six additional minor responses. A significant decrease in K(trans) was seen in three of the four patients who received DCE-MRI monitoring. Grade 5 head and neck bleeds occurred in four patients. Local complications, including the appearance or worsening of tumor skin ulceration or tumor fistula, were recorded in 15 patients. CONCLUSION Sunitinib demonstrated modest activity in palliative SSCHN. The severity of some of the complications highlights the importance of improved patient selection for future studies with sunitinib in head and neck cancer. Sunitinib should not be used outside clinical trials in SSCHN.

Cetuximab, docetaxel, and cisplatin (TPEx) as first-line treatment in patients with recurrent or metastatic (R/M) squamous cell carcinoma of the head and neck (SCCHN): Final results of phase II trial GORTEC 2008-03.

5567 Background: Cetuximab in combination with platinum and 5FU has become a standard in first-line treatment of patients (pts) with R/M SCCHN. Cetuximab and taxane combinations have shown promising activity. This multicenter phase II study evaluates the efficacy and safety of cetuximab, docetaxel and cisplatin combination (TPEx) as first-line treatment in pts with R/M SCCHN. METHODS Pts were required to have WHO PS 0-1, no prior systemic therapy for R/M SCCHN, cumulative dose of cisplatin less than 300 mg/m² and no prior anti-EGFR therapy. Pts received docetaxel 75 mg/m² day 1, cisplatin 75 mg/m² day 1 and cetuximab (400 mg/m² on day 1 of cycle 1 then 250 mg/m² weekly), repeated every 21 days x 4 cycles then followed by cetuximab 500 mg/m² every 2 weeks as maintenance therapy until disease progression or unacceptable toxicity. G-CSF support with lenograstim 150 microgr./m²/day was delivered after each cycle of chemotherapy. Response was assessed every 6 weeks, according to RECIST. The primary endpoint was objective response rate (ORR) at 12 weeks. Secondary endpoints were safety, best overall response, progression-free survival, overall survival and biomarkers. A Simon two-stage design was used with OR in more than 9/30 pts needed before continuing accrual to the final 54 pts. RESULTS 51 pts have been enrolled to date and 33 pts could be evaluated for primary endpoint: all male, median age 55 years (48-68), 50% metastatic.ORR at 12 weeks was 48.5%. Partial response, stable disease and progression were respectively found in 16 pts (PR 48.5%), 15 pts (SD 45.5%) and 2 pts (PD 6%). There were 18 pts (54.5%) with PR as best response. Treatment related toxicities included G4 neutropenia (n=3). Grade 3 events were skin rash (n=5), hypersensitivity (n=3), mucositis (n=1), fatigue (n=1) and febrile neutropenia (n=1). Alopecia was common. No death was related to study treatment. CONCLUSIONS Preliminary efficacy analysis based on response rate demonstrates that TPEx regimen has encouraging activity as first-line treatment in pts with R/M SCCHN. Toxicity is manageable with G-CSF support. Trial accrual continues up to 54 pts.

Phase II study of dual phosphoinositol‐3‐kinase (PI3K) and mammalian target of rapamycin (mTOR) inhibitor BEZ235 in patients with locally advanced or metastatic transitional cell carcinoma

To assess, in a multicentre phase II trial, the safety and efficacy of BEZ235, an oral pan‐class I phosphoinositol‐3‐kinase (PI3K) and mammalian target of rapamycin (mTOR) complex1/2 inhibitor, in locally advanced or metastatic transitional cell carcinoma (TCC) after failure of platinum‐based therapy.

The use of chemotherapy regimens carrying a moderate or high risk of febrile neutropenia and the corresponding management of febrile neutropenia : an expert survey in breast cancer and non-Hodgkin's lymphoma

BackgroundThe use of chemotherapy regimens with moderate or high risk of febrile neutropenia (defined as having a FN incidence of 10% or more) and the respective incidence and clinical management of FN in breast cancer and NHL has not been studied in Belgium. The existence of a medical need for G-CSF primary and secondary prophylaxis with these regimens was investigated in a real-life setting.MethodsNine oncologists and six hematologists from different Belgian general hospitals and university centers were surveyed to collect expert opinion and real-life data (year 2007) on the use of chemotherapy regimens with moderate or high risk of febrile neutropenia and the clinical management of FN in patients aged <65 years with breast cancer or NHL. Data were retrospectively obtained, over a 6-month observation period.ResultsThe most frequently used regimens in breast cancer patients (n = 161) were FEC (45%), FEC-T (37%) and docetaxel alone (6%). In NHL patients (n = 39), R-CHOP-21 (33%) and R-ACVBP-14 (15%) were mainly used. Without G-CSF primary prophylaxis (PP), FN occurred in 31% of breast cancer patients, and 13% had PSN. After G-CSF secondary prophylaxis (SP), 4% experienced further FN events. Only 1 breast cancer patient received PP, and did not experience a severe neutropenic event. Overall, 30% of chemotherapy cycles observed in breast cancer patients were protected by PP/SP. In 10 NHL patients receiving PP, 2 (20%) developed FN, whereas 13 (45%) of the 29 patients without PP developed FN and 3 (10%) PSN. Overall, 55% of chemotherapy cycles observed in NHL patients were protected by PP/SP. Impaired chemotherapy delivery (timing and/or dose) was reported in 40% (breast cancer) and 38% (NHL) of patients developing FN. Based on oncologist expert opinion, hospitalization rates for FN (average length of stay) without and with PP were, respectively, 48% (4.2 days) and 19% (1.5 days). Similar rates were obtained from hematologists.ConclusionsDespite the studied chemotherapy regimens being known to be associated with a moderate or high risk of FN, upfront G-CSF prophylaxis was rarely used. The observed incidence of severe neutropenic events without G-CSF prophylaxis was higher than generally reported in the literature. The impact on medical resources used is sizeable.

A multicenter, randomized phase II study of rilotumumab (R) (AMG 102) or placebo (Pbo) plus mitoxantrone (M) and prednisone (P) in patients (pts) with previously treated castrate-resistant prostate cancer (CRPC).

115 Background: R is an investigational, fully human monoclonal antibody to hepatocyte growth factor (HGF) that prevents HGF binding to the c-Met receptor. We conducted a 3-arm, double-blind, randomized phase 2 study to examine the safety and estimate the efficacy of adding R to MP in CRPC pts. METHODS Eligible pts (≥ 18 years) had progressive CRPC, prior taxane-based chemotherapy, and ECOG PS ≤ 1. The primary endpoint was overall survival (OS). Secondary endpoints included progression-free survival (PFS), PSA response, pharmacokinetics (PK), and safety. Pts were randomized 1:1:1 to R (15 mg/kg IV Q3W) + MP (12 mg/m2 IV Q3W, 5 mg BID orally) [Arm A]; R (7.5 mg/kg IV Q3W) + MP [Arm B]; or Pbo + MP [Arm C] for up to 12 cycles. RESULTS 142 pts (Arms A/B/C: 45/48/49 pts) were enrolled between March 10, 2009 and December 2, 2009. Median age: 67/67/69 yrs; ECOG PS 1: 69/71/61%; progression during prior taxane therapy: 51/54/47%. Most common reason for discontinuation was disease progression (60/58/69%). Efficacy is shown in the table. R + MP showed no statistically significant difference in OS. Adverse events (AE) with ≥ 5% difference in Arms A + B vs C included peripheral edema, 24/8%; nausea, 44/35%; mucosal inflammation, 8/0%; rash, 8/0%; arthralgia, 16/8%; neutropenia, 16/8%. Grade 5 AE: cardiac arrest, pulmonary embolism, septic shock (1 each in Arm B). R showed linear PK with mean (SD) steady state Cmin of 251 (100) and 127 (35) μg/mL and Cmax of 609 (126) and 297 (75) μg/mL in Arms A and B. R did not affect PK of M. CONCLUSIONS R + MP was well tolerated with no unexpected toxicities. R + MP showed no significant improvements in OS, PFS, and PSA response. [Table: see text].

Abiraterone acetate post-docetaxel for metastatic castration-resistant prostate cancer in the Belgian compassionate use program

BACKGROUND Abiraterone acetate (AA) is licensed for treating metastatic castration-resistant prostate cancer (mCRPC). Real-world data on oncological outcome after AA are scarce. The current study assesses efficacy and safety of AA in mCRPC patients previously treated with docetaxel who started treatment during the Belgian compassionate use program (January 2011-July 2012). PATIENTS AND METHODS Records from 368 patients with mCRPC from 23 different Belgian hospitals who started AA 1000mg per day with 10mg prednisone or equivalent were retrospectively reviewed (September 2013-December 2014). Prostate-specific antigen (PSA) response (decrease≥50%), time to PSA progression (increase>50% over PSA nadir in case of PSA response/>25% in absence of PSA response), time to radiographic progression (on bone scans or for soft tissue lesions using Response Evaluation Criteria In Solid Tumors 1.1), overall survival and adverse event rate (Common Terminology Criteria for Adverse Events v4.03) were analyzed. Kaplan-Meier statistics were applied. RESULTS Overall, 92 patients (25%) had an Eastern Cooperative Oncology Group performance status≥2. Median age was 73 years, median PSA was 103ng/dl. PSA response was observed in 131 patients (37.4%). Median time to PSA and radiographic progression was 4.1 months (95% CI: 3.6-4.6) and 5.8 months (5.3-6.4), respectively. Median overall survival was 15.1 months (13.6-16.6). Most common grade 3 to 4 adverse events were anemia (13.9%), hypokalemia (7.3%), fatigue (6.8%), and pain (6.3%). Median duration of AA treatment was 5.3 months (interquartile range: 2.8-10.3). The main study limitation is its retrospective design. CONCLUSIONS These real-world data on post-docetaxel AA efficacy are in line with the COU-AA-301 trial. Importantly, incidence of severe anemia and hypokalemia is up to 50% higher than reported in previous studies.

Randomized Phase II Study of Cabazitaxel Versus Methotrexate in Patients With Recurrent and/or Metastatic Squamous Cell Carcinoma of the Head and Neck Previously Treated With Platinum-Based Therapy

Lessons Learned Cabazitaxel has activity in squamous cell carcinoma of the head and neck (SCCHN) and taxane-resistant cell lines. For the first time, cabazitaxel was investigated in incurable patients with recurrent SCCHN. Patients were randomly assigned to cabazitaxel every 3 weeks or weekly methotrexate. This phase II study did not meet its primary endpoint. Cabazitaxel has low activity in SCCHN. The toxicity profile in this population also was not favorable owing to the high rate of febrile neutropenia observed (17%). Background. Cabazitaxel is a second-generation taxane that improves the survival of patients with metastatic castrate-resistant prostate cancer following docetaxel therapy. Cabazitaxel has activity in squamous cell carcinoma of the head and neck (SCCHN) and taxane-resistant cell lines. In this randomized phase II trial, we investigated cabazitaxel in patients with recurrent SCCHN. Methods. Patients with incurable SCCHN with progression after platinum-based therapy were randomly assigned to cabazitaxel every 3 weeks (cycle 1, 20 mg/m2, increased to 25 mg/m2 for subsequent cycles in the absence of nonhematological adverse events [AEs] greater than grade 2 and hematological AEs greater than grade 3) or methotrexate (40 mg/m2/week). The patients were stratified according to their performance status and previous platinum-based chemotherapy for palliation versus curative intent. The primary endpoint was the progression-free survival rate (PFSR) at 18 weeks. Results. Of the 101 patients, 53 and 48, with a median age of 58.0 years (range, 41–80), were randomly assigned to cabazitaxel or methotrexate, respectively. The PFSR at 18 weeks was 13.2% (95% confidence interval [CI], 5%–25%) for cabazitaxel and 8.3% (95% CI, 2%–20%) for methotrexate. The median progression-free survival was 1.9 months in both arms. The median overall survival was 5.0 and 3.6 months for cabazitaxel and methotrexate, respectively. More patients experienced serious adverse events with cabazitaxel than with methotrexate (54% vs. 36%). The most common drug-related grade 3–4 AE in the cabazitaxel arm was febrile neutropenia (17.3%). Conclusion. This study did not meet its primary endpoint. Cabazitaxel has low activity in recurrent SCCHN.

Study protocol for THINK: a multinational open-label phase I study to assess the safety and clinical activity of multiple administrations of NKR-2 in patients with different metastatic tumour types

Introduction NKR-2 are autologous T cells genetically modified to express a chimeric antigen receptor (CAR) comprising a fusion of the natural killer group 2D (NKG2D) receptor with the CD3ζ signalling domain, which associates with the adaptor molecule DNAX-activating protein of 10 kDa (DAP10) to provide co-stimulatory signal upon ligand binding. NKG2D binds eight different ligands expressed on the cell surface of many tumour cells and which are normally absent on non-neoplastic cells. In preclinical studies, NKR-2 demonstrated long-term antitumour activity towards a breadth of tumour indications, with maximum efficacy observed after multiple NKR-2 administrations. Importantly, NKR-2 targeted tumour cells and tumour neovasculature and the local tumour immunosuppressive microenvironment and this mechanism of action of NKR-2 was established in the absence of preconditioning. Methods and analysis This open-label phase I study will assess the safety and clinical activity of NKR-2 treatment administered three times, with a 2-week interval between each administration in different tumour types. The study will contain two consecutive segments: a dose escalation phase followed by an expansion phase. The dose escalation study involves two arms, one in solid tumours (five specific indications) and one in haematological tumours (two specific indications) and will include three dose levels in each arm: 3×108, 1×109 and 3×109 NKR-2 per injection. On the identification of the recommended dose in the first segment, based on dose-limiting toxicity occurrences, the study will expand to seven different cohorts examining the seven different tumour types separately. Clinical responses will be determined according to standard Response Evaluation Criteria In Solid Tumors (RECIST) criteria for solid tumours or international working group response criteria in haematological tumours. Ethics approval and dissemination Ethical approval has been obtained at all sites. Written informed consent will be taken from all participants. The results of this study will be disseminated through presentation at international scientific conferences and reported in peer-reviewed scientific journals. Trial registration number NCT03018405, EudraCT 2016-003312-12; Pre-result.

Which Factors Predict Overall Survival in Patients With Metastatic Castration-Resistant Prostate Cancer Treated With Abiraterone Acetate Post-Docetaxel?

Background Abiraterone acetate (AA) increases overall survival (OS) in patients with metastatic castration‐resistant prostate cancer (mCRPC) previously treated with docetaxel. However, survival time varies substantially between individuals. Our goal was to identify prognostic factors that better estimate OS. Materials and Methods This is a retrospective multicentric analysis of 368 patients with mCRPC starting AA with prednisone after docetaxel. Cox proportional hazards statistics were applied. A multivariate model was constructed based on significant univariate predictors by using a manual stepwise forward and backward selection strategy. Model performance was determined by using receiver operating characteristic (ROC) curves. Results Univariate analysis identified 20 significant OS predictors. A multivariate model was constructed, based on 220 patients, incorporating 5 independent risk factors for decreased OS at the time of AA initiation: hemoglobin < 12 g/dL (hazard ratio [HR] 2.02), > 10 metastases (HR 1.80), ECOG performance status ≥ 2 (HR 1.88), radiographic progression (HR 1.50), and time since diagnosis < 90 months (HR 1.66, all P < .05). Patients were stratified into 3 groups: good (0‐2 risk factors, median OS 22.6 months), intermediate (3 risk factors, median OS 13.9 months), and poor prognosis (4‐5 risk factors, median OS 6.2 months). The area under the ROC curve based on the event “death by the time of median OS (13.3 months)” was 0.736 (95% confidence interval 0.670‐0.803). Conclusion We identified 5 readily available risk factors independently associated with decreased OS. The resulting model may be used for patient counseling in daily clinical practice, as well as patient stratification in clinical trials. Micro‐Abstract Individual patients’ survival varies greatly in metastatic castration‐resistant prostate cancer. Retrospective analysis of 368 patients treated with docetaxel and starting abiraterone acetate revealed 5 adverse prognostic factors: hemoglobin < 12 g/dL, > 10 metastases, ECOG performance status ≥ 2, radiographic progression, and time since diagnosis < 90 months. A prognostic model stratifies patients into 3 groups with different estimated survival, which can aid in patient counseling.