A Phase 2 Study of Coltuximab Ravtansine (SAR3419) Monotherapy in Patients with Relapsed or Refractory Acute Lymphoblastic Leukemia (ALL)

International audienceBackground Long-term disease-free survival in adult patients with acute lymphoblastic leukemia (ALL) remains unsatisfactory, and treatment options are limited for those patients who relapse or fail to respond following initial therapy. We conducted a dose-escalation/expansion phase 2, multicenter, single-arm study to determine the optimal dose of coltuximab ravtansine (SAR3419), an anti-CD19 antibody-drug conjugate, in this setting. Patients and Methods The dose-escalation part of the study determined the selected dose of coltuximab ravtansine for evaluation of efficacy and safety in the dose-expansion phase. Patients received coltuximab ravtansine induction therapy (up to 8 weekly doses); responding patients were eligible for maintenance therapy (biweekly administrations for up to 24 weeks). Three dose levels of coltuximab ravtansine were examined: 55, 70, and 90 mg/m2. The primary endpoint was objective response rate (ORR). Secondary endpoints included duration of response (DOR) and safety. Results A total of 36 patients were treated: 19 during dose escalation; 17 during dose expansion. One dose-limiting toxicity was observed at 90 mg/m2 (grade 3 peripheral motor neuropathy), and therefore 70 mg/m2 was selected for the dose-expansion phase. Five patients discontinued therapy due to adverse events (AEs). The most common AEs were pyrexia, diarrhea, and nausea. Of 17 evaluable patients treated at the selected dose, 4 responded (estimated ORR using Bayesian methodology: 25.47% [80% confidence interval: 14.18-39.6%]); DOR was 1.94 (range: 1-5.6) months. Based on these results, the study was prematurely discontinued. Conclusions Coltuximab ravtansine is well tolerated but is associated with a low clinical response rate in patients with relapsed/refractory AL

A Phase II Study of Coltuximab Ravtansine (SAR3419) Monotherapy in Patients With Relapsed or Refractory Acute Lymphoblastic Leukemia.

BackgroundLong-term disease-free survival in adult patients with acute lymphoblastic leukemia (ALL) remains unsatisfactory, and the treatment options are limited for those patients with relapse or a failure to respond after initial therapy. We conducted a dose-escalation/expansion phase II, multicenter, single-arm study to determine the optimal dose of coltuximab ravtansine (SAR3419), an anti-CD19 antibody-drug conjugate, in this setting.Patients and methodsThe dose-escalation part of the study determined the selected dose of coltuximab ravtansine for the evaluation of efficacy and safety in the dose-expansion phase. Patients received coltuximab ravtansine induction therapy (≤ 8 weekly doses). The responding patients were eligible for maintenance therapy (biweekly administration for ≤ 24 weeks). Three dose levels of coltuximab ravtansine were examined: 55, 70, and 90 mg/m(2). The primary endpoint was the objective response rate (ORR). The secondary endpoints included the duration of response (DOR) and safety.ResultsA total of 36 patients were treated: 19 during dose escalation and 17 during dose expansion. One dose-limiting toxicity was observed at 90 mg/m(2) (grade 3 peripheral motor neuropathy); therefore, 70 mg/m(2) was selected for the dose-expansion phase. Five patients discontinued therapy because of adverse events (AEs). The most common AEs were pyrexia, diarrhea, and nausea. Of the 17 evaluable patients treated at the selected dose, 4 had a disease response (estimated ORR using the Bayesian method: 25.5% (80% confidence interval, 14.2%-39.6%). The DOR was 1.9 months (range, 1-5.6 months). Because of these results, the study was prematurely discontinued.ConclusionColtuximab ravtansine was well tolerated but was associated with a low clinical response rate in patients with relapsed or refractory ALL

A phase II, single-arm, multicentre study of coltuximab ravtansine (SAR3419) and rituximab in patients with relapsed or refractory diffuse large B-cell lymphoma

International audienceIn this phase II, multicentre, single-arm study, 52 patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) received the anti-CD19 antibody–drug conjugate coltuximab ravtansine (55 mg/m2) and rituximab (375 mg/m2) weekly for 4 weeks, then every 2 weeks for 8 weeks. The primary endpoint was objective response rate (ORR) by International Working Group Criteria. The primary objective was to reject the null hypothesis of an ORR of ≤40%. Among 45 evaluable patients, the ORR was 31·1% (80% confidence interval [CI]: 22·0–41·6%) and the primary objective was not met. The ORR appeared higher in patients with relapsed disease (58·3% [80% CI: 36·2–78·1%]) versus those refractory to their last (42·9% [80% CI: 17·0–72·1%]) or first-line therapy (15·4% [80% CI: 6·9–28·4%]). Median progression-free survival, overall survival and duration of response were 3·9 [80% CI: 3·22–3·98], 9·0 [80% CI: 6·47–13·67] and 8·6 (range: 0–18) months, respectively. The pharmacokinetics of both drugs were unaffected by co-administration. Common adverse events included gastrointestinal disorders (52%) and asthenia (25%). No patients discontinued due to adverse events. In conclusion, coltuximab ravtansine with rituximab was well tolerated and yielded clinical responses in a subset of patients with relapsed/refractory DLBC

A dose-escalation study of SAR3419, an anti-CD19 antibody maytansinoid conjugate, administered by intravenous infusion once weekly in patients with relapsed/refractory B-cell non-Hodgkin lymphoma

International audiencePURPOSE: To determine recommended dose, dose-limiting toxicity, safety profile, pharmacokinetics, preliminary antitumor activity, and exploratory pharmacodynamics of SAR3419, an antibody-drug conjugate targeting CD19, administered alone by intravenous infusion weekly (qw), in a dose-escalation phase I study in patients with refractory/relapsed (R/R) non-Hodgkin lymphoma (NHL). EXPERIMENTAL DESIGN: Patients with R/R CD19(+) B-NHL were treated with escalating doses of SAR3419 repeated qw for eight to 12 doses. On the basis of clinical evidence of late or cumulative toxicities, the study protocol was amended to test an "optimized" administration schedule consisting of four qw doses followed by four biweekly (q2w) doses (qw/q2w) at the recommended dose with the intent of reducing drug accumulation. RESULTS: Forty-four patients were treated on seven dose levels ranging from 5 to 70 mg/m(2). SAR3419 recommended dose was determined as 55 mg/m(2) qw. Twenty-five patients received the qw/q2w schedule at 55 mg/m(2), which showed an improved safety profile compared with the qw schedule. Antilymphoma activity was observed with both schedules in around 30% of patients with either indolent or aggressive diseases. SAR3419 displayed a long terminal half-life (approximately 7 days) and a low clearance (approximately 0.6 L/d), with no dose effect. The qw/q2w schedule allowed limiting accumulation with a decrease in SAR3419 plasma trough and average concentrations by around 1.4-fold compared with the qw schedule. CONCLUSION: While administered weekly, SAR3419 is well tolerated and active. The qw/q2w schedule that shows an improved safety profile and preserves antilymphoma activity is selected for clinical phase II studies

Aflibercept versus placebo in combination with docetaxel and prednisone for treatment of men with metastatic castration-resistant prostate cancer (VENICE): a phase 3, double-blind randomised trial.

BACKGROUND: Docetaxel plus prednisone is standard first-line chemotherapy for men with metastatic castrate-resistant prostate cancer. Aflibercept is a recombinant human fusion protein that binds A and B isoforms of VEGF and placental growth factor, thereby inhibiting angiogenesis. We assessed whether the addition of aflibercept to docetaxel and prednisone would improve overall survival in men with metastatic castrate-resistant prostate cancer compared with the addition of placebo to docetaxel and prednisone. METHODS: VENICE was a phase 3, multicentre, randomised double-blind placebo-controlled parallel group study done in 31 countries (187 sites). Men with metastatic castrate-resistant prostate cancer, adequate organ function, and no prior chemotherapy were treated with docetaxel (75 mg/m(2) intravenously every 3 weeks) and oral prednisone (5 mg twice daily) and randomly allocated (1:1) to receive aflibercept (6 mg/kg) or placebo, intravenously, every 3 weeks. Treatment allocation was done centrally via an interactive voice response system, using a computer-generated sequence with a permuted-block size of four and stratified according Eastern Co-operative Group performance status (0-1 vs 2). Patients, investigators, and other individuals responsible for study conduct and data analysis were masked to treatment assignment. Aflibercept or placebo vials were supplied in identical boxes. The primary endpoint was overall survival using intention-to-treat analysis. This is the primary analysis of the completed trial. The study is registered with ClinicalTrials.gov, number NCT00519285 FINDINGS: Between Aug 17, 2007, and Feb 11, 2010, 1224 men were randomly allocated to treatment: 612 to each group. At final analysis, median follow-up was 35 months (IQR 29-41) and 873 men had died. Median overall survival was 22·1 months (95·6% CI 20·3-24·1) in the aflibercept group and 21·2 months (19·6-23·8) in the placebo group (stratified hazard ratio 0·94, 95·6% CI 0·82-1·08; p=0·38). We recorded a higher incidence of grade 3-4 gastrointestinal disorders (182 [30%] vs 48 [8·0%]), haemorrhagic events (32 [5·2%] vs ten [1·7%]), hypertension (81 [13%] vs 20 [3·3%]), fatigue (97 [16%] vs 46 [7·7%]), infections (123 [20%] vs 60 [10%]) and treatment-related fatal adverse events (21 [3·4%] vs nine [1·5%]) in the aflibercept group than in the placebo group. INTERPRETATION: Aflibercept in combination with docetaxel and prednisone given as first-line chemotherapy for men with metastatic castrate-resistant prostate cancer resulted in no improvement in overall survival and added toxicity compared with placebo. Docetaxel plus prednisone remains the standard treatment for such men who need first-line chemotherap