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

Jeremy T. Larsen, Tait D. Shanafelt, Jose F. Leis, Betsy Laplant, Tim Call, Adam Pettinger, Curtis Hanson, Charles Erlichman, Thomas Matthew Habermann, Craig Reeder, Daniel Nikcevich, Deborah Bowen, Michael Conte, Justin Boysen, Charla Secreto, Connie Lesnick, Renee Tschumper, Diane F Jelinek, Neil Elliot Kay, Wei D Ding

Research output: Contribution to journalArticle

7 Citations (Scopus)

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.

Original languageEnglish (US)
JournalAmerican Journal of Hematology
DOIs
StateAccepted/In press - 2017

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B-Cell Chronic Lymphocytic Leukemia
Maximum Tolerated Dose
Safety
Febrile Neutropenia
Exanthema
Neutropenia
Thrombocytopenia
Disease-Free Survival
Mouth
Diarrhea
Cell Survival
B-Lymphocytes
Therapeutics
MK 2206
Bendamustine Hydrochloride
Rituximab
Clinical Trials
Survival

ASJC Scopus subject areas

  • Hematology

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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.; Shanafelt, Tait D.; Leis, Jose F.; Laplant, Betsy; Call, Tim; Pettinger, Adam; Hanson, Curtis; Erlichman, Charles; Habermann, Thomas Matthew; Reeder, Craig; Nikcevich, Daniel; Bowen, Deborah; Conte, Michael; Boysen, Justin; Secreto, Charla; Lesnick, Connie; Tschumper, Renee; Jelinek, Diane F; Kay, Neil Elliot; Ding, Wei D.

In: American Journal of Hematology, 2017.

Research output: Contribution to journalArticle

Larsen, JT, Shanafelt, TD, Leis, JF, Laplant, B, Call, T, Pettinger, A, Hanson, C, Erlichman, C, Habermann, TM, Reeder, C, Nikcevich, D, Bowen, D, Conte, M, Boysen, J, Secreto, C, Lesnick, C, Tschumper, R, Jelinek, DF, Kay, NE & Ding, WD 2017, 'Akt inhibitor MK-2206 in combination with bendamustine and rituximab in relapsed or refractory chronic lymphocytic leukemia: Results from the N1087 alliance study', American Journal of Hematology. https://doi.org/10.1002/ajh.24762
Larsen, Jeremy T. ; Shanafelt, Tait D. ; Leis, Jose F. ; Laplant, Betsy ; Call, Tim ; Pettinger, Adam ; Hanson, Curtis ; Erlichman, Charles ; Habermann, Thomas Matthew ; Reeder, Craig ; Nikcevich, Daniel ; Bowen, Deborah ; Conte, Michael ; Boysen, Justin ; Secreto, Charla ; Lesnick, Connie ; Tschumper, Renee ; Jelinek, Diane F ; Kay, Neil Elliot ; Ding, Wei D. / Akt inhibitor MK-2206 in combination with bendamustine and rituximab in relapsed or refractory chronic lymphocytic leukemia : Results from the N1087 alliance study. In: American Journal of Hematology. 2017.
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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.",
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AU - Larsen, Jeremy T.

AU - Shanafelt, Tait D.

AU - Leis, Jose F.

AU - Laplant, Betsy

AU - Call, Tim

AU - Pettinger, Adam

AU - Hanson, Curtis

AU - Erlichman, Charles

AU - Habermann, Thomas Matthew

AU - Reeder, Craig

AU - Nikcevich, Daniel

AU - Bowen, Deborah

AU - Conte, Michael

AU - Boysen, Justin

AU - Secreto, Charla

AU - Lesnick, Connie

AU - Tschumper, Renee

AU - Jelinek, Diane F

AU - Kay, Neil Elliot

AU - Ding, Wei D

PY - 2017

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N2 - 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.

AB - 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.

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