Akt, also referred to as Protein Kinase B (PKB), is a serine/threonine kinase and is a key player in numerous cellular pathways including proliferation, transcription, cell migration, and apoptosis.
Jeremy T. Larsen from the Mayo Clinic, Rochester, Minnesota, USA, and colleagues conducted the phase I/II N1087 alliance trial (NCT01369849) aiming to assess the safety and efficacy of MK-2206 (an Akt inhibitor) combined with rituximab and bendamustine (BR) in patients with Relapsed/Refractory (R/R) Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL). The findings of this study were published as an Epub ahead of print on 1st June 2017 in the American Journal of Hematology.
The trial began recruiting patients in November 2011, and patients with CLL/SLL who had R/R symptomatic disease, with an ECOG performance score of ≤2, and adequate end organ function were eligible to participate in the open-label, dose escalation, phase I portion of the study. A standard 3 + 3 design was employed to identify the Maximum Tolerated Dose (MTD) and safety of MK-2206 when combined with BR. MK-2206 was assessed at doses of 90mg, 135mg, and 200mg weekly plus bendamustine (70mg/m2 IV daily 2 days/cycle) and rituximab (cycle 1: 375mg/m2; cycle 2: 500mg/m2) for a maximum of 6 cycles. The MTD was then evaluated in the phase II portion of the study, which had a primary endpoint of Complete Response/Complete Response with Incomplete Marrow Recovery (CR/CRi).
- Overall, 13 pts were eligible
- Median age = 68 years (range, 44–75)
- Median follow-up = 28.7 months (range, 19.1–37.1)
- Most pts had ≥1 adverse prognostic factor: unmutated IGHV (10/11 tested pts), del11q (n=4), ZAP-70+ (8/11 tested pts), CD38+ (8/13 tested pts)
- Median number of prior therapies = 1 (range, 1–2); 9 pts (69%) had received prior purine nucleoside analogue, alkylator, and anti-CD20 based chemoimmunotherapy
- Median number of cycles received = 6 (range, 1–6)
- Phase I:
- 6 pts treated at dose level 1 (90mg), 1 Dose Limiting Toxicity (DLT) of febrile neutropenia and hemolytic anemia reported
- At dose level 2 (135mg), 2 DLTs observed consisting of a grade 3 acneiform rash in 1 patient and febrile neutropenia with dehydration in a second patient
- MTD defined as 90mg weekly
- Phase II:
- Sixty-nine percent (9/13) completed 6 cycles of therapy
- Three pts discontinued early due to AEs: grade 1 neutropenia and grade 3 hemolytic anemia considered as DLT in 1 patient, febrile neutropenia and grade 3 diarrhea considered as a DLT in a second patient, and grade 1 acute allergic reaction of facial edema and grade 3 rash in a third patient
- One patient experienced PD after one cycle and discontinued
- The most common grade 3–4 treatment-related AEs were neutropenia (46%), febrile neutropenia (23%), rash (15%), diarrhea (15%), and thrombocytopenia (15%)
- The most frequent non-hematologic treatment-related AEs of any grade were nausea (54%), diarrhea and rash (39% each), vomiting and hyperglycemia (31% each), oral mucositis (23%), as well as fatigue, fever and sinus bradycardia (15% each)
- In all 13 pts: ORR = 92% (n=12); CR/CRi = 38% (n=5); Complete Clinical Remission (CCR) = 7.7% (n=1); Nodular Partial Remission (nPR) = 7.7% (n=1); PR = 38% (n=5); PD = 7.7% (n=1)
- Of the 12 responders, 6 have since progressed; 8 pts have received subsequent therapy
- Median DoR = not reached (95% CI, 3–NA)
- Median PFS = 16 months (95% CI, 10.4–NA)
- Median treatment free survival = 24.5 months (95% CI, 11.3–NA)
- During the study, 2 deaths were reported
- Median OS = not reached
The authors concluded that their early phase data indicated that the Akt inhibitor MK-2206 combined with BR is “tolerable and active” in patients with R/R CLL/SLL. They did address the fact that their small sample size is a limitation; accrual was stopped early due to the drug-sponsor’s choice to cease developing MK-2206 further. However, the group argue that the Akt inhibitor achieved encouraging efficacy and tolerability results in combination with BR, and recommend that future prospective studies of Akt inhibitors for R/R CLL/SLL should be carried out.
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.