Akt Inhibitor MK2206, Bendamustine Hydrochloride, and Rituximab in Treating Patients With Relapsed Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma
|Chronic Lymphocytic Leukemia Recurrent Small Lymphocytic Lymphoma Refractory Chronic Lymphocytic Leukemia||Drug: Akt Inhibitor MK2206 Drug: Bendamustine Hydrochloride Other: Laboratory Biomarker Analysis Biological: Rituximab||Phase 1 Phase 2|
|Study Design:||Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
|Official Title:||Phase I/II Study of the Combination of Bendamustine, Rituximab and MK-2206 in the Treatment of Relapsed Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma|
- Number of Phase I Participants With Dose-Limiting Toxicity Events (Phase I) [ Time Frame: Up to 35 days ]The Maximum Tolerated Dose (MTD) is defined as the dose level below the lowest dose that induces dose-limiting toxicity (DLT) in at least one-third of patients graded according to NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Dose-limiting toxicities include non-hematologic events graded 3 or higher and deemed at least possibly related to treatment. A total of 6 patients treated at the MTD will be sufficient to identify common toxicities at the MTD.The number of patients reporting a dose-limiting event are reported.
- Proportion of Complete Response Defined to be a CR or CRi Noted as the Objective Status (Phase II) [ Time Frame: From registration to response, up to 84 days ]
A Complete Response (CR) is defined by the NCI Working Group criteria and requires all of the following for a period of at least 2 months:
- Absence of lymphadenopathy (e.g. lymph nodes >1.5 cm) by physical examination.
- No hepatomegaly or splenomegaly by physical examination.
- Absence of constitutional symptoms.
- Neutrophils ≥1500/ul.
- Platelets >100,000/ul (untransfused).
- Hemoglobin >11.0 gm/dl (untransfused)
- Peripheral blood lymphocytes <4000/uL
Patients who fulfill all criteria for a CR but who have a persistent anemia, thrombocytopenia, or neutropenia related to drug toxicity rather than residual CLL will be classified as CR with incomplete marrow recovery (CRi).
The proportion of successes will be estimated by the number of successes divided by the total number of evaluable patients. Confidence intervals for the true success proportion will be calculated according to the approach of Duffy and Santner.
- Biomarker Analysis (IgVH Gene Mutation) [ Time Frame: Baseline ]IgVH gene mutationwill be evaluated pre-treatment. This factors will be summarized and used to help characterize the types of patients accrued to this trial.
- Biomarker Analysis (CD38, CD49d, and ZAP-70) [ Time Frame: Baseline ]CD38, CD49d, and ZAP-70 status will be evaluated pre-treatment. These factors will be summarized and used to help characterize the types of patients accrued to this trial.
- Fluorescent in Situ Hybridization (FISH) Biomarker Analysis [ Time Frame: Baseline ]Fluorescent in situ hybridization (FISH) is a molecular cytogenetic technique that uses fluorescent probes that bind to only those parts of the chromosome with a high degree of sequence complementarity. It was developed by biomedical researchers in the early 1980s and is used to detect and localize the presence or absence of specific DNA sequences on chromosomes. In this disease group, there are recognized patterns of DNA sequences that play a role in prognostic outcomes. Patterns named 11q-, 13q-, Trisomy 12 may lead to different responses to treatments. Here we report the number of patients with each FISH prognosis evaluated pre-treatment. These factors will be summarized and used to help characterize the types of patients accrued to this trial.
- Duration of Response [ Time Frame: Median follow-up of 39 months and maximum follow-up of 54 months ]Duration of response is defined for all evaluable patients who have achieved a clinical response as the date at which the patient's objective status is first noted to be a CR, CRi, CCR, nPR, or PR to the earliest date progression is documented. The distribution of duration of response will be estimated using the method of Kaplan-Meier.
- Minimal-residual Disease [ Time Frame: Cycle 6 assessment (maximum of 231 days post-registration) ]Minimal residual disease (MRD) will be evaluated after treatment in patients who achieve a complete clinical response. Flow cytometry will be used to detect approximately 1 CLL cell per 10,000 leukocytes following induction. A score of positive means CLL cells were found and a negative score means no CLL cells were found. The number of patients with an MRD negative score are reported here.
- Overall Response Rate [ Time Frame: 3 months post-treatment ]The Overall response rate is estimated by the total number of complete or partial responses (CR, CRi, CCR, nPR, or PR) divided by the total number of evaluate patients. Complete and partial responses were scored using the NCI Working Group criteria. A Complete Response (CR, CRi, and CCR) is characterized by an absence of lymphadenopathy, heptomegaly and splenomegaly with or without normalized blood counts and bone marrow assessment . A PR is defined as having >50% decrease in lymphocyte count and reduction in sum of the products of measured nodes and an improvement in blood counts. Exact binomial 95% confidence intervals for the true overall response rate will be calculated.
- Treatment-free Survival [ Time Frame: Time from registration to the date of initiation of subsequent therapy or death, median follow-up time is 37 months ]Treatment free survival is defined to be the time from registration to the date of initation of subsequent therapy or death. The distribution of treatment free survival will be estimated using the method of Kaplan-Meier.
|Study Start Date:||September 2011|
|Study Completion Date:||February 2014|
|Primary Completion Date:||February 2014 (Final data collection date for primary outcome measure)|
Experimental: Treatment (Akt inhibitor MK2206, bendamustine, rituximab)
Patients receive Akt inhibitor MK2206 PO on days 1, 8, 15, and 22 (days 1, 8, 15, 22, and 29 of course 1); rituximab IV on day 1 (day 8 of course 1); and bendamustine hydrochloride IV over 30-60 minutes on days 1-2 (days 8-9 of course 1). Treatment repeats every 28 days (35 days for course 1 and 84 days for course 6) for 6 courses in the absence of disease progression or unacceptable toxicity.
Drug: Akt Inhibitor MK2206
Other Name: MK2206Drug: Bendamustine Hydrochloride
Other Names:Other: Laboratory Biomarker Analysis
Correlative studiesBiological: Rituximab
I. To assess the safety and maximum tolerated dose (MTD) of MK-2206 (Akt inhibitor MK2206) in combination therapy with bendamustine (bendamustine hydrochloride)-rituximab in relapsed chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) patients. (Phase I) II. To assess the rate of complete response (CR) of MK-2206 in combination with bendamustine-rituximab in relapsed CLL or SLL patients. (Phase II)
I. To assess clinical efficacy of MK-2206 in combination with bendamustine-rituximab as demonstrated by analysis of overall response rate (CR, complete response with incomplete bone marrow recovery [CRi], clinical complete response [CCR], near partial response [nPR] and partial response [PR]), duration of response, and treatment free survival.
II. To assess the toxicity profile of MK-2206 in combination with bendamustine-rituximab.
I. Evaluation of whether the established CLL prognostic factors (cluster of differentiation [CD]38, CD49d, immunoglobulin heavy chain variable [IGHV], fluorescence in situ hybridization [FISH] and zeta-chain-associated protein kinase 70 [ZAP-70]) predict responses to the combination therapy of MK2206, with bendamustine-rituximab.
II. Minimal residual disease will be evaluated after treatment in patients who achieve a clinical response; minimal residual disease (MRD) status will be explored in relation to both the quality and duration of response.
III. Evaluation of the effects of the addition of MK-2206 to bendamustine-rituximab on B cell receptor initiated, phosphoinositide 3-kinase (PI3K)/Akt downstream signal pathways, apoptosis analysis and leukemic cell activation status, as well as multiple cytokine profiles and key gene expression analysis with focus on leukemic cells.
IV. Evaluation of marrow stromal cells (MSC)-CLL biology including the effects of the addition of MK-2206 to bendamustine-rituximab on CLL marrow stromal cell (MSC) proliferation, migration and cytokine production, as well as the adhesion capacity between MSC and leukemic cells.
OUTLINE: This is a phase I, dose-escalation study of Akt inhibitor MK2206 followed by a phase II study.
Patients receive Akt inhibitor MK2206 orally (PO) on days 1, 8, 15, and 22 (days 1, 8, 15, 22, and 29 of course 1); rituximab intravenously (IV) on day 1 (day 8 of course 1); and bendamustine hydrochloride IV over 30-60 minutes on days 1-2 (days 8-9 of course 1). Treatment repeats every 28 days (35 days for course 1 and 84 days for course 6) for 6 courses in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up every 3 months for 2 years and then every 6 or 12 months for 3 years.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01369849
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|Principal Investigator:||Wei Ding||Alliance for Clinical Trials in Oncology|