Dataset Information

Akt inhibitor MK-2206 in combination with bendamustine and rituximab in relapsed or refractory chronic lymphocytic leukemia: Results from the N1087 alliance study.

ABSTRACT: Akt is a downstream target of B cell receptor signaling and is a central regulator of CLL cell survival. We aim to investigate the safety and efficacy of the Akt inhibitor MK-2206 in combination with bendamustine and rituximab (BR) in relapsed and/or refractory CLL in a phase I/II study. A standard phase I design was used with cohorts of three plus three patients to determine the maximum tolerated dose (MTD) of MK-2206 in combination with BR in relapsed CLL. Single-agent MK-2206 (weekly dosed) was administered one-week in advance before BR on cycle 1 and subsequently was given with BR at the same time for cycle 2-6. Phase II employed the MTD of MK-2206 with BR to evaluate safety and efficacy of this study combination. Thirteen relapsed/refractory CLL were treated for maximal 6-cycle of therapy. The maximum tolerated dose of MK-2206 was 90 mg by mouth once weekly. The most common grade 3/4 adverse events were neutropenia (46%), febrile neutropenia (23%), rash (15%), diarrhea (15%), and thrombocytopenia (15%). Overall response rate was 92% with a median progression free survival and treatment free survival of 16 and 24 months, respectively. Five patients (38%) achieved complete remission or complete remission with incomplete count recovery, two of whom were MRD negative. The efficacy and tolerability of this combination indicates that Akt inhibition combined with chemoimmunotherapy is a promising novel treatment combination in CLL and deserves further prospective clinical trial.

SUBMITTER: Larsen JT

PROVIDER: S-EPMC5507724 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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Akt inhibitor MK-2206 in combination with bendamustine and rituximab in relapsed or refractory chronic lymphocytic leukemia: Results from the N1087 alliance study.

Larsen Jeremy T JT Shanafelt Tait D TD Leis Jose F JF LaPlant Betsy B Call Tim T Pettinger Adam A Hanson Curtis C Erlichman Charles C Habermann Thomas Matthew TM Reeder Craig C Nikcevich Daniel D Bowen Deborah D Conte Michael M Boysen Justin J Secreto Charla C Lesnick Connie C Tschumper Renee R Jelinek Diane D Kay Neil E NE Ding Wei W

American journal of hematology 20170601 8

Akt is a downstream target of B cell receptor signaling and is a central regulator of CLL cell survival. We aim to investigate the safety and efficacy of the Akt inhibitor MK-2206 in combination with bendamustine and rituximab (BR) in relapsed and/or refractory CLL in a phase I/II study. A standard phase I design was used with cohorts of three plus three patients to determine the maximum tolerated dose (MTD) of MK-2206 in combination with BR in relapsed CLL. Single-agent MK-2206 (weekly dosed) w ...[more]

PMID: 28402581

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Project description:Bendamustine plus rituximab is a standard of care for the management of patients with relapsed or refractory chronic lymphocytic leukaemia. New therapies are needed to improve clinically relevant outcomes in these patients. We assessed the efficacy and safety of adding idelalisib, a first-in-class targeted phosphoinositide-3-kinase ? inhibitor, to bendamustine plus rituximab in this population.For this international, multicentre, double-blind, placebo-controlled trial, adult patients (?18 years) with relapsed or refractory chronic lymphocytic leukaemia requiring treatment who had measurable lymphadenopathy by CT or MRI and disease progression within 36 months since their last previous therapy were enrolled. Patients were randomly assigned (1:1) by a central interactive web response system to receive bendamustine plus rituximab for a maximum of six cycles (bendamustine: 70 mg/m2 intravenously on days 1 and 2 for six 28-day cycles; rituximab: 375 mg/m2 on day 1 of cycle 1, and 500 mg/m2 on day 1 of cycles 2-6) in addition to either twice-daily oral idelalisib (150 mg) or placebo until disease progression or intolerable study drug-related toxicity. Randomisation was stratified by high-risk features (IGHV, del[17p], or TP53 mutation) and refractory versus relapsed disease. The primary endpoint was progression-free survival assessed by an independent review committee in the intention-to-treat population. This trial is ongoing and is registered with ClinicalTrials.gov, number NCT01569295.Between June 26, 2012, and Aug 21, 2014, 416 patients were enrolled and randomly assigned to the idelalisib (n=207) and placebo (n=209) groups. At a median follow-up of 14 months (IQR 7-18), median progression-free survival was 20·8 months (95% CI 16·6-26·4) in the idelalisib group and 11·1 months (8·9-11·1) in the placebo group (hazard ratio [HR] 0·33, 95% CI 0·25-0·44; p<0·0001). The most frequent grade 3 or worse adverse events in the idelalisib group were neutropenia (124 [60%] of 207 patients) and febrile neutropenia (48 [23%]), whereas in the placebo group they were neutropenia (99 [47%] of 209) and thrombocytopenia (27 [13%]). An increased risk of infection was reported in the idelalisib group compared with the placebo group (grade ?3 infections and infestations: 80 [39%] of 207 vs 52 [25%] of 209). Serious adverse events, including febrile neutropenia, pneumonia, and pyrexia, were more common in the idelalisib group (140 [68%] of 207 patients) than in the placebo group (92 [44%] of 209). Treatment-emergent adverse events leading to death occurred in 23 (11%) patients in the idelalisib group and 15 (7%) in the placebo group, including six deaths from infections in the idelalisib group and three from infections in the placebo group.Idelalisib in combination with bendamustine plus rituximab improved progression-free survival compared with bendamustine plus rituximab alone in patients with relapsed or refractory chronic lymphocytic leukaemia. However, careful attention needs to be paid to management of serious adverse events and infections associated with this regimen during treatment selection.Gilead Sciences Inc.

Dataset Information

Akt inhibitor MK-2206 in combination with bendamustine and rituximab in relapsed or refractory chronic lymphocytic leukemia: Results from the N1087 alliance study.

Publications

Akt inhibitor MK-2206 in combination with bendamustine and rituximab in relapsed or refractory chronic lymphocytic leukemia: Results from the N1087 alliance study.

Similar Datasets

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