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VR-CAP was more effective than R-CHOP in patients with newly diagnosed mantle-cell lymphoma but at the cost of increased hematologic toxicity. (Funded by Janssen Research and Development and Millennium Pharmaceuticals; LYM-3002 ClinicalTrials.gov number, NCT00722137.).

Background Selinexor with dexamethasone has demonstrated activity in patients with heavily pretreated multiple myeloma (MM). In a phase 1b/2 study, the combination of oral selinexor with the proteasome inhibitor (PI) bortezomib, and dexamethasone (SVd) induced high response rates with low rates of peripheral neuropathy, the main dose-limiting toxicity of bortezomib. The aim of this trial was to evaluate the clinical benefit of weekly SVd versus standard bortezomib and dexamethasone (Vd) in patients with previously treated MM.Methods This phase 3, randomised, open label trial was conducted at 123 sites in 21 countries.Patients who were previously treated with one to three lines of therapy, including PIs were randomised (1:1) to selinexor (100 mg once-weekly) plus bortezomib (1•3 mg/m 2 once-weekly) and dexamethasone (20 mg twice-weekly) [SVd] or bortezomib (1•3 mg/m 2 twice-weekly) and dexamethasone (20 mg 4 times per week) [Vd]. Randomisation was done using interactive response technology and stratified by previous PI therapy, lines of treatment, and MM stage. The primary endpoint was progression-free survival (PFS) in the intention-to-treat population.Patients who received at least one dose of study treatment were included in the safety population. This trial is registered at ClinicalTrials.gov, NCT03110562.

We evaluated the safety and biologic activity of the BH3 mimetic protein, navitoclax, combined with rituximab, in comparison to rituximab alone. One hundred and eighteen patients with chronic lymphocytic leukemia (CLL) were randomized to receive eight weekly doses of rituximab (arm A), eight weekly doses of rituximab plus daily navitoclax for 12 weeks (arm B) or eight weekly doses of rituximab plus daily navitoclax until disease progression or unacceptable toxicity (arm C). Investigator-assessed overall response rates (complete [CR] and partial [PR]) were 35% (arm A), 55% (arm B, p = 0.19 vs. A) and 70% (arm C, p = 0.0034 vs. A). Patients with del(17p) or high levels of BCL2 had significantly better clinical responses when treated with navitoclax. Navitoclax in combination with rituximab was well tolerated as initial therapy for patients with CLL, yielded higher response rates than rituximab alone and resulted in prolonged progression-free survival with treatment beyond 12 weeks.

© F e r r a t a S t o r t i F o u n d a t i o nupdated, final analysis was 26 February 2011. All patients provided written informed consent. The study was approved by institutional review boards or independent ethics committees at each participating institution, and was conducted in accordance with the provisions of the Declaration of Helsinki, the International Conference on Harmonisation, and the Guidelines for Good Clinical Practice. Patients (age ≥18 years) with symptomatic relapsed or refractory MM after 1-3 prior therapies who had measurable disease, adequate hematologic, renal and hepatic function, no prior bortezomib treatment, and no grade 2 or higher peripheral neuropathy (PN) were randomized to receive up to eight 21-day cycles of sc or iv bortezomib 1.3 mg/m 2 on Days 1, 4, 8 and 11. Patients with late evolving responses could receive two additional cycles. Patients with less than complete response (CR) and without disease progression at the end of four cycles could additionally receive dexamethasone 20 mg on Days 1, 2, 4, 5, 8, 9, 11 and 12 from cycle 5 onwards. Randomization was stratified by number of prior lines of therapy and International Staging System (ISS) 6 disease stage. Patients were randomized in a 2:1 ratio to sc or iv bortezomib to provide a larger population for the investigational route of administration.The bortezomib sc injection concentration was 2.5 mg/mL (3.5 mg bortezomib reconstituted with 1.4 mL normal 0.9% saline). sc injection sites were the thighs and abdomen, and sites were rotated for successive injections. The iv injection concentration was 1 mg/mL. 5 Response and progression were assessed using a validated computer algorithm applying European Group for Blood and Marrow Transplantation (EBMT) criteria.7 Additional response categories of near-CR 8 and very good partial response (VGPR) 9 were incorporated. Adverse events (AEs) were assessed according to the National Cancer Institute's Common Terminology Criteria for AEs (NCI-CTCAE) version 3.0. After completing treatment, patients were assessed every eight weeks until disease progression and then followed up every 12 weeks for survival and subsequent therapies. Statistical analysisThe primary objective was to demonstrate non-inferiority of sc versus iv bortezomib as measured by ORR after four cycles of treatment. The non-inferiority hypothesis was proven at the initial analysis (P=0.002).5 Additional response end points, including best ORR, and CR/near-CR and VGPR rates, were updated at this analysis for the response-evaluable population using central laboratory M-protein assessment.5 Updated time-to-event end points were analyzed in the intent-to-treat population using the KaplanMeier method. This study is registered with ClinicalTrials.gov (NCT00722566) and EudraCT (2008-000952-28). Results and DiscussionAs previously reported, 5 222 patients were randomized to sc (n=148) or iv (n=74) bortezomib. Baseline demographics and disease characteristics were generally similar between treatment arms.5 Overall, median ag...

We report follow-up results from the randomized, placebo-controlled, phase 3 HELIOS trial of ibrutinib+bendamustine and rituximab (BR) for previously treated chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) without deletion 17p. Overall, 578 patients were randomized 1:1 to either ibrutinib (420 mg daily) or placebo, in combination with 6 cycles of BR, followed by ibrutinib or placebo alone. Median follow-up was 34.8 months (range: 0.1–45.8). Investigator-assessed median progression-free survival (PFS) was not reached for ibrutinib+BR, versus 14.3 months for placebo+BR (hazard ratio [HR] [95% CI], 0.206 [0.159–0.265]; P < 0.0001); 36-month PFS rates were 68.0% versus 13.9%, respectively. The results are consistent with the primary analysis findings (HR = 0.203, as assessed by independent review committee, with 17-month median follow-up). Median overall survival was not reached in either arm; HR (95% CI) for ibrutinib+BR versus placebo: 0.652 (0.454–0.935; P = 0.019). Minimal residual disease (MRD)-negative response rates were 26.3% for ibrutinib+BR and 6.2% for placebo+BR ( P < 0.0001). Incidence of treatment-emergent adverse events (including grades 3–4) were generally consistent with the initial HELIOS report. These long-term data support improved survival outcomes and deepening responses with ibrutinib+BR compared with BR in relapsed CLL/SLL.