Trial Outcomes & Findings for Akt Inhibitor MK2206, Bendamustine Hydrochloride, and Rituximab in Treating Patients With Relapsed Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma (NCT NCT01369849)

Last Updated: 2017-09-15

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE1/PHASE2

Target enrollment

15 participants

Primary outcome timeframe

Up to 35 days

Results posted on

2017-09-15

Participant Flow

Participant milestones

Participant milestones
Measure	Phase I: Dose Level 1 Patients receive: Cycle 1: 1. Akt inhibitor MK2206 PO 90 mg on days 1, 8, 15, and 22 (days 1, 8, 15, 22) 2. Rituximab IV 375 mg/m\^2 on day 8. 3. Bendamustine IV 70 mg/m\^2 on day 8 and 9. Cycles 2-6: 1. Akt inhibitor MK2206 PO on days 1, 8, 15, and 22 (days 1, 8, 15, 22, and 29) 2. Rituximab IV 500 mg/m\^2 on day 1. 3. Bendamustine IV 70 mg/m\^2 on day 1 and 2.	Phase I: Dose Level 2 Patients receive: Cycle 1: 1. Akt inhibitor MK2206 PO 135 mg on days 1, 8, 15, and 22 (days 1, 8, 15, 22) 2. Rituximab IV 375 mg/m\^2 on day 8. 3. Bendamustine IV 70 mg/m\^2 on day 8 and 9. Cycles 2-6: 1. Akt inhibitor MK2206 PO on days 1, 8, 15, and 22 (days 1, 8, 15, 22, and 29) 2. Rituximab IV 500 mg/m\^2 on day 1. 3. Bendamustine IV 70 mg/m\^2 on day 1 and 2.	Phase II Patients receive: Cycle 1: 1. Akt inhibitor MK2206 PO 90 mg on days 1, 8, 15, and 22 (days 1, 8, 15, 22) 2. Rituximab IV 375 mg/m\^2 on day 8. 3. Bendamustine IV 70 mg/m\^2 on day 8 and 9. Cycles 2-6: 1. Akt inhibitor MK2206 PO 90 mg on days 1, 8, 15, and 22 (days 1, 8, 15, 22, and 29) 2. Rituximab IV 500 mg/m\^2 on day 1. 3. Bendamustine IV 70 mg/m\^2 on day 1 and 2.
Overall Study STARTED	6	4	5
Overall Study COMPLETED	6	3	4
Overall Study NOT COMPLETED	0	1	1

Reasons for withdrawal

Reasons for withdrawal
Measure	Phase I: Dose Level 1 Patients receive: Cycle 1: 1. Akt inhibitor MK2206 PO 90 mg on days 1, 8, 15, and 22 (days 1, 8, 15, 22) 2. Rituximab IV 375 mg/m\^2 on day 8. 3. Bendamustine IV 70 mg/m\^2 on day 8 and 9. Cycles 2-6: 1. Akt inhibitor MK2206 PO on days 1, 8, 15, and 22 (days 1, 8, 15, 22, and 29) 2. Rituximab IV 500 mg/m\^2 on day 1. 3. Bendamustine IV 70 mg/m\^2 on day 1 and 2.	Phase I: Dose Level 2 Patients receive: Cycle 1: 1. Akt inhibitor MK2206 PO 135 mg on days 1, 8, 15, and 22 (days 1, 8, 15, 22) 2. Rituximab IV 375 mg/m\^2 on day 8. 3. Bendamustine IV 70 mg/m\^2 on day 8 and 9. Cycles 2-6: 1. Akt inhibitor MK2206 PO on days 1, 8, 15, and 22 (days 1, 8, 15, 22, and 29) 2. Rituximab IV 500 mg/m\^2 on day 1. 3. Bendamustine IV 70 mg/m\^2 on day 1 and 2.	Phase II Patients receive: Cycle 1: 1. Akt inhibitor MK2206 PO 90 mg on days 1, 8, 15, and 22 (days 1, 8, 15, 22) 2. Rituximab IV 375 mg/m\^2 on day 8. 3. Bendamustine IV 70 mg/m\^2 on day 8 and 9. Cycles 2-6: 1. Akt inhibitor MK2206 PO 90 mg on days 1, 8, 15, and 22 (days 1, 8, 15, 22, and 29) 2. Rituximab IV 500 mg/m\^2 on day 1. 3. Bendamustine IV 70 mg/m\^2 on day 1 and 2.
Overall Study Ineligible prior to treatment	0	0	1
Overall Study Ineligible after receiving treatment	0	1	0

Baseline Characteristics

Akt Inhibitor MK2206, Bendamustine Hydrochloride, and Rituximab in Treating Patients With Relapsed Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Phase I: Dose Level 1 n=6 Participants Patients receive: Cycle 1: 1. Akt inhibitor MK2206 PO 90 mg on days 1, 8, 15, and 22 (days 1, 8, 15, 22) 2. Rituximab IV 375 mg/m\^2 on day 8. 3. Bendamustine IV 70 mg/m\^2 on day 8 and 9. Cycles 2-6: 1. Akt inhibitor MK2206 PO on days 1, 8, 15, and 22 (days 1, 8, 15, 22, and 29) 2. Rituximab IV 500 mg/m\^2 on day 1. 3. Bendamustine IV 70 mg/m\^2 on day 1 and 2.	Phase I: Dose Level 2 n=4 Participants Patients receive: Cycle 1: 1. Akt inhibitor MK2206 PO 135 mg on days 1, 8, 15, and 22 (days 1, 8, 15, 22) 2. Rituximab IV 375 mg/m\^2 on day 8. 3. Bendamustine IV 70 mg/m\^2 on day 8 and 9. Cycles 2-6: 1. Akt inhibitor MK2206 PO on days 1, 8, 15, and 22 (days 1, 8, 15, 22, and 29) 2. Rituximab IV 500 mg/m\^2 on day 1. 3. Bendamustine IV 70 mg/m\^2 on day 1 and 2.	Phase II n=4 Participants Patients receive: Cycle 1: 1. Akt inhibitor MK2206 PO 90 mg on days 1, 8, 15, and 22 (days 1, 8, 15, 22) 2. Rituximab IV 375 mg/m\^2 on day 8. 3. Bendamustine IV 70 mg/m\^2 on day 8 and 9. Cycles 2-6: 1. Akt inhibitor MK2206 PO 90 mg on days 1, 8, 15, and 22 (days 1, 8, 15, 22, and 29) 2. Rituximab IV 500 mg/m\^2 on day 1. 3. Bendamustine IV 70 mg/m\^2 on day 1 and 2.	Total n=14 Participants Total of all reporting groups
Age, Continuous	67.5 years n=5 Participants	66.5 years n=7 Participants	65 years n=5 Participants	67 years n=4 Participants
Sex: Female, Male Female	1 Participants n=5 Participants	1 Participants n=7 Participants	0 Participants n=5 Participants	2 Participants n=4 Participants
Sex: Female, Male Male	5 Participants n=5 Participants	3 Participants n=7 Participants	4 Participants n=5 Participants	12 Participants n=4 Participants
Region of Enrollment United States	6 participants n=5 Participants	4 participants n=7 Participants	4 participants n=5 Participants	14 participants n=4 Participants

PRIMARY outcome

Timeframe: Up to 35 days

Population: Only the patients registered to the Phase I portion of this study were analyzed for this endpoint. One of the 4 patients accrued to dose level 2 was not eligible for this endpoint. Therefore, 6 patients at Dose Level 1 and 3 patients at Dose Level 2 are included in this endpoint.

Outcome measures

Outcome measures
Measure	Phase I: Dose Level 1 n=6 Participants Patients receive: Cycle 1: 1. Akt inhibitor MK2206 PO 90 mg on days 1, 8, 15, and 22 (days 1, 8, 15, 22) 2. Rituximab IV 375 mg/m\^2 on day 8. 3. Bendamustine IV 70 mg/m\^2 on day 8 and 9. Cycles 2-6: 1. Akt inhibitor MK2206 PO on days 1, 8, 15, and 22 (days 1, 8, 15, 22, and 29) 2. Rituximab IV 500 mg/m\^2 on day 1. 3. Bendamustine IV 70 mg/m\^2 on day 1 and 2.	Phase I: Dose Level 2 n=3 Participants Patients receive: Cycle 1: 1. Akt inhibitor MK2206 PO 135 mg on days 1, 8, 15, and 22 (days 1, 8, 15, 22) 2. Rituximab IV 375 mg/m\^2 on day 8. 3. Bendamustine IV 70 mg/m\^2 on day 8 and 9. Cycles 2-6: 1. Akt inhibitor MK2206 PO on days 1, 8, 15, and 22 (days 1, 8, 15, 22, and 29) 2. Rituximab IV 500 mg/m\^2 on day 1. 3. Bendamustine IV 70 mg/m\^2 on day 1 and 2.	Phase II Patients receive: Cycle 1: 1. Akt inhibitor MK2206 PO 90 mg on days 1, 8, 15, and 22 (days 1, 8, 15, 22) 2. Rituximab IV 375 mg/m\^2 on day 8. 3. Bendamustine IV 70 mg/m\^2 on day 8 and 9. Cycles 2-6: 1. Akt inhibitor MK2206 PO 90 mg on days 1, 8, 15, and 22 (days 1, 8, 15, 22, and 29) 2. Rituximab IV 500 mg/m\^2 on day 1. 3. Bendamustine IV 70 mg/m\^2 on day 1 and 2.
Number of Phase I Participants With Dose-Limiting Toxicity Events (Phase I)	1 Patients reporting Dose-Limiting Events	2 Patients reporting Dose-Limiting Events	—

PRIMARY outcome

Timeframe: From registration to response, up to 84 days

Population: All eligible patients treated at Dose Level 1 were included in the Phase II primary endpoint. All 6 patients from Phase I, Dose level 1 and 4 of the 5 patients registered to the Phase II portion of the study were eligible for this endpoint.

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.

Outcome measures

Outcome measures
Measure	Phase I: Dose Level 1 n=10 Participants Patients receive: Cycle 1: 1. Akt inhibitor MK2206 PO 90 mg on days 1, 8, 15, and 22 (days 1, 8, 15, 22) 2. Rituximab IV 375 mg/m\^2 on day 8. 3. Bendamustine IV 70 mg/m\^2 on day 8 and 9. Cycles 2-6: 1. Akt inhibitor MK2206 PO on days 1, 8, 15, and 22 (days 1, 8, 15, 22, and 29) 2. Rituximab IV 500 mg/m\^2 on day 1. 3. Bendamustine IV 70 mg/m\^2 on day 1 and 2.	Phase I: Dose Level 2 Patients receive: Cycle 1: 1. Akt inhibitor MK2206 PO 135 mg on days 1, 8, 15, and 22 (days 1, 8, 15, 22) 2. Rituximab IV 375 mg/m\^2 on day 8. 3. Bendamustine IV 70 mg/m\^2 on day 8 and 9. Cycles 2-6: 1. Akt inhibitor MK2206 PO on days 1, 8, 15, and 22 (days 1, 8, 15, 22, and 29) 2. Rituximab IV 500 mg/m\^2 on day 1. 3. Bendamustine IV 70 mg/m\^2 on day 1 and 2.	Phase II Patients receive: Cycle 1: 1. Akt inhibitor MK2206 PO 90 mg on days 1, 8, 15, and 22 (days 1, 8, 15, 22) 2. Rituximab IV 375 mg/m\^2 on day 8. 3. Bendamustine IV 70 mg/m\^2 on day 8 and 9. Cycles 2-6: 1. Akt inhibitor MK2206 PO 90 mg on days 1, 8, 15, and 22 (days 1, 8, 15, 22, and 29) 2. Rituximab IV 500 mg/m\^2 on day 1. 3. Bendamustine IV 70 mg/m\^2 on day 1 and 2.
Proportion of Complete Response Defined to be a CR or CRi Noted as the Objective Status (Phase II)	50 percentage of participants Interval 19.0 to 81.0	—	—

SECONDARY outcome

Timeframe: Baseline

Population: All patients that started treatment and had baseline biomarkers completed were included in this analysis. One of the 4 patients accrued to dose level 2 was not eligible for this endpoint. Therefore, 6 patients at Dose Level 1 and 3 patients at Dose Level 2 and 4 patients accrued to the Phase II portion of the study are included in this endpoint.

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.

Outcome measures

Outcome measures
Measure	Phase I: Dose Level 1 n=6 Participants Patients receive: Cycle 1: 1. Akt inhibitor MK2206 PO 90 mg on days 1, 8, 15, and 22 (days 1, 8, 15, 22) 2. Rituximab IV 375 mg/m\^2 on day 8. 3. Bendamustine IV 70 mg/m\^2 on day 8 and 9. Cycles 2-6: 1. Akt inhibitor MK2206 PO on days 1, 8, 15, and 22 (days 1, 8, 15, 22, and 29) 2. Rituximab IV 500 mg/m\^2 on day 1. 3. Bendamustine IV 70 mg/m\^2 on day 1 and 2.	Phase I: Dose Level 2 n=3 Participants Patients receive: Cycle 1: 1. Akt inhibitor MK2206 PO 135 mg on days 1, 8, 15, and 22 (days 1, 8, 15, 22) 2. Rituximab IV 375 mg/m\^2 on day 8. 3. Bendamustine IV 70 mg/m\^2 on day 8 and 9. Cycles 2-6: 1. Akt inhibitor MK2206 PO on days 1, 8, 15, and 22 (days 1, 8, 15, 22, and 29) 2. Rituximab IV 500 mg/m\^2 on day 1. 3. Bendamustine IV 70 mg/m\^2 on day 1 and 2.	Phase II n=4 Participants Patients receive: Cycle 1: 1. Akt inhibitor MK2206 PO 90 mg on days 1, 8, 15, and 22 (days 1, 8, 15, 22) 2. Rituximab IV 375 mg/m\^2 on day 8. 3. Bendamustine IV 70 mg/m\^2 on day 8 and 9. Cycles 2-6: 1. Akt inhibitor MK2206 PO 90 mg on days 1, 8, 15, and 22 (days 1, 8, 15, 22, and 29) 2. Rituximab IV 500 mg/m\^2 on day 1. 3. Bendamustine IV 70 mg/m\^2 on day 1 and 2.
Biomarker Analysis (IgVH Gene Mutation) Mutated	0 Participants	0 Participants	1 Participants
Biomarker Analysis (IgVH Gene Mutation) Unmutated	5 Participants	3 Participants	1 Participants
Biomarker Analysis (IgVH Gene Mutation) Not Done	1 Participants	0 Participants	2 Participants

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Phase I: Dose Level 1 n=6 Participants Patients receive: Cycle 1: 1. Akt inhibitor MK2206 PO 90 mg on days 1, 8, 15, and 22 (days 1, 8, 15, 22) 2. Rituximab IV 375 mg/m\^2 on day 8. 3. Bendamustine IV 70 mg/m\^2 on day 8 and 9. Cycles 2-6: 1. Akt inhibitor MK2206 PO on days 1, 8, 15, and 22 (days 1, 8, 15, 22, and 29) 2. Rituximab IV 500 mg/m\^2 on day 1. 3. Bendamustine IV 70 mg/m\^2 on day 1 and 2.	Phase I: Dose Level 2 n=3 Participants Patients receive: Cycle 1: 1. Akt inhibitor MK2206 PO 135 mg on days 1, 8, 15, and 22 (days 1, 8, 15, 22) 2. Rituximab IV 375 mg/m\^2 on day 8. 3. Bendamustine IV 70 mg/m\^2 on day 8 and 9. Cycles 2-6: 1. Akt inhibitor MK2206 PO on days 1, 8, 15, and 22 (days 1, 8, 15, 22, and 29) 2. Rituximab IV 500 mg/m\^2 on day 1. 3. Bendamustine IV 70 mg/m\^2 on day 1 and 2.	Phase II n=4 Participants Patients receive: Cycle 1: 1. Akt inhibitor MK2206 PO 90 mg on days 1, 8, 15, and 22 (days 1, 8, 15, 22) 2. Rituximab IV 375 mg/m\^2 on day 8. 3. Bendamustine IV 70 mg/m\^2 on day 8 and 9. Cycles 2-6: 1. Akt inhibitor MK2206 PO 90 mg on days 1, 8, 15, and 22 (days 1, 8, 15, 22, and 29) 2. Rituximab IV 500 mg/m\^2 on day 1. 3. Bendamustine IV 70 mg/m\^2 on day 1 and 2.
Biomarker Analysis (CD38, CD49d, and ZAP-70) CD49d · Not Done	4 Participants	0 Participants	1 Participants
Biomarker Analysis (CD38, CD49d, and ZAP-70) ZAP-70 · Positive	6 Participants	1 Participants	1 Participants
Biomarker Analysis (CD38, CD49d, and ZAP-70) ZAP-70 · Negative	0 Participants	2 Participants	1 Participants
Biomarker Analysis (CD38, CD49d, and ZAP-70) ZAP-70 · Not Done	0 Participants	0 Participants	2 Participants
Biomarker Analysis (CD38, CD49d, and ZAP-70) CD38 · Positive	4 Participants	1 Participants	1 Participants
Biomarker Analysis (CD38, CD49d, and ZAP-70) CD38 · Negative	2 Participants	2 Participants	3 Participants
Biomarker Analysis (CD38, CD49d, and ZAP-70) CD38 · Not Done	0 Participants	0 Participants	0 Participants
Biomarker Analysis (CD38, CD49d, and ZAP-70) CD49d · Positive	1 Participants	0 Participants	3 Participants
Biomarker Analysis (CD38, CD49d, and ZAP-70) CD49d · Negative	1 Participants	3 Participants	0 Participants

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Phase I: Dose Level 1 n=6 Participants Patients receive: Cycle 1: 1. Akt inhibitor MK2206 PO 90 mg on days 1, 8, 15, and 22 (days 1, 8, 15, 22) 2. Rituximab IV 375 mg/m\^2 on day 8. 3. Bendamustine IV 70 mg/m\^2 on day 8 and 9. Cycles 2-6: 1. Akt inhibitor MK2206 PO on days 1, 8, 15, and 22 (days 1, 8, 15, 22, and 29) 2. Rituximab IV 500 mg/m\^2 on day 1. 3. Bendamustine IV 70 mg/m\^2 on day 1 and 2.	Phase I: Dose Level 2 n=3 Participants Patients receive: Cycle 1: 1. Akt inhibitor MK2206 PO 135 mg on days 1, 8, 15, and 22 (days 1, 8, 15, 22) 2. Rituximab IV 375 mg/m\^2 on day 8. 3. Bendamustine IV 70 mg/m\^2 on day 8 and 9. Cycles 2-6: 1. Akt inhibitor MK2206 PO on days 1, 8, 15, and 22 (days 1, 8, 15, 22, and 29) 2. Rituximab IV 500 mg/m\^2 on day 1. 3. Bendamustine IV 70 mg/m\^2 on day 1 and 2.	Phase II n=4 Participants Patients receive: Cycle 1: 1. Akt inhibitor MK2206 PO 90 mg on days 1, 8, 15, and 22 (days 1, 8, 15, 22) 2. Rituximab IV 375 mg/m\^2 on day 8. 3. Bendamustine IV 70 mg/m\^2 on day 8 and 9. Cycles 2-6: 1. Akt inhibitor MK2206 PO 90 mg on days 1, 8, 15, and 22 (days 1, 8, 15, 22, and 29) 2. Rituximab IV 500 mg/m\^2 on day 1. 3. Bendamustine IV 70 mg/m\^2 on day 1 and 2.
Fluorescent in Situ Hybridization (FISH) Biomarker Analysis 13q-	2 Participants	0 Participants	1 Participants
Fluorescent in Situ Hybridization (FISH) Biomarker Analysis 11q-	1 Participants	3 Participants	0 Participants
Fluorescent in Situ Hybridization (FISH) Biomarker Analysis Trisomy 12	1 Participants	0 Participants	1 Participants
Fluorescent in Situ Hybridization (FISH) Biomarker Analysis Other	0 Participants	0 Participants	2 Participants
Fluorescent in Situ Hybridization (FISH) Biomarker Analysis Normal	2 Participants	0 Participants	0 Participants

SECONDARY outcome

Timeframe: Median follow-up of 39 months and maximum follow-up of 54 months

Population: 12 patients achieved a response and were included in this analysis.

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.

Outcome measures

Outcome measures
Measure	Phase I: Dose Level 1 n=12 Participants Patients receive: Cycle 1: 1. Akt inhibitor MK2206 PO 90 mg on days 1, 8, 15, and 22 (days 1, 8, 15, 22) 2. Rituximab IV 375 mg/m\^2 on day 8. 3. Bendamustine IV 70 mg/m\^2 on day 8 and 9. Cycles 2-6: 1. Akt inhibitor MK2206 PO on days 1, 8, 15, and 22 (days 1, 8, 15, 22, and 29) 2. Rituximab IV 500 mg/m\^2 on day 1. 3. Bendamustine IV 70 mg/m\^2 on day 1 and 2.	Phase I: Dose Level 2 Patients receive: Cycle 1: 1. Akt inhibitor MK2206 PO 135 mg on days 1, 8, 15, and 22 (days 1, 8, 15, 22) 2. Rituximab IV 375 mg/m\^2 on day 8. 3. Bendamustine IV 70 mg/m\^2 on day 8 and 9. Cycles 2-6: 1. Akt inhibitor MK2206 PO on days 1, 8, 15, and 22 (days 1, 8, 15, 22, and 29) 2. Rituximab IV 500 mg/m\^2 on day 1. 3. Bendamustine IV 70 mg/m\^2 on day 1 and 2.	Phase II Patients receive: Cycle 1: 1. Akt inhibitor MK2206 PO 90 mg on days 1, 8, 15, and 22 (days 1, 8, 15, 22) 2. Rituximab IV 375 mg/m\^2 on day 8. 3. Bendamustine IV 70 mg/m\^2 on day 8 and 9. Cycles 2-6: 1. Akt inhibitor MK2206 PO 90 mg on days 1, 8, 15, and 22 (days 1, 8, 15, 22, and 29) 2. Rituximab IV 500 mg/m\^2 on day 1. 3. Bendamustine IV 70 mg/m\^2 on day 1 and 2.
Duration of Response	NA months Interval 3.0 to Too few events have occurred to provide a median and upper-level confidence interval.	—	—

SECONDARY outcome

Timeframe: Cycle 6 assessment (maximum of 231 days post-registration)

Population: 5 patients achieved a complete response and were analyzed for MRD

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.

Outcome measures

Outcome measures
Measure	Phase I: Dose Level 1 n=5 Participants Patients receive: Cycle 1: 1. Akt inhibitor MK2206 PO 90 mg on days 1, 8, 15, and 22 (days 1, 8, 15, 22) 2. Rituximab IV 375 mg/m\^2 on day 8. 3. Bendamustine IV 70 mg/m\^2 on day 8 and 9. Cycles 2-6: 1. Akt inhibitor MK2206 PO on days 1, 8, 15, and 22 (days 1, 8, 15, 22, and 29) 2. Rituximab IV 500 mg/m\^2 on day 1. 3. Bendamustine IV 70 mg/m\^2 on day 1 and 2.	Phase I: Dose Level 2 Patients receive: Cycle 1: 1. Akt inhibitor MK2206 PO 135 mg on days 1, 8, 15, and 22 (days 1, 8, 15, 22) 2. Rituximab IV 375 mg/m\^2 on day 8. 3. Bendamustine IV 70 mg/m\^2 on day 8 and 9. Cycles 2-6: 1. Akt inhibitor MK2206 PO on days 1, 8, 15, and 22 (days 1, 8, 15, 22, and 29) 2. Rituximab IV 500 mg/m\^2 on day 1. 3. Bendamustine IV 70 mg/m\^2 on day 1 and 2.	Phase II Patients receive: Cycle 1: 1. Akt inhibitor MK2206 PO 90 mg on days 1, 8, 15, and 22 (days 1, 8, 15, 22) 2. Rituximab IV 375 mg/m\^2 on day 8. 3. Bendamustine IV 70 mg/m\^2 on day 8 and 9. Cycles 2-6: 1. Akt inhibitor MK2206 PO 90 mg on days 1, 8, 15, and 22 (days 1, 8, 15, 22, and 29) 2. Rituximab IV 500 mg/m\^2 on day 1. 3. Bendamustine IV 70 mg/m\^2 on day 1 and 2.
Minimal-residual Disease	2 Participants	—	—

SECONDARY outcome

Timeframe: 3 months post-treatment

Population: All patients that were treated and evaluable for response were included together in this endpoint.

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.

Outcome measures

Outcome measures
Measure	Phase I: Dose Level 1 n=13 Participants Patients receive: Cycle 1: 1. Akt inhibitor MK2206 PO 90 mg on days 1, 8, 15, and 22 (days 1, 8, 15, 22) 2. Rituximab IV 375 mg/m\^2 on day 8. 3. Bendamustine IV 70 mg/m\^2 on day 8 and 9. Cycles 2-6: 1. Akt inhibitor MK2206 PO on days 1, 8, 15, and 22 (days 1, 8, 15, 22, and 29) 2. Rituximab IV 500 mg/m\^2 on day 1. 3. Bendamustine IV 70 mg/m\^2 on day 1 and 2.	Phase I: Dose Level 2 Patients receive: Cycle 1: 1. Akt inhibitor MK2206 PO 135 mg on days 1, 8, 15, and 22 (days 1, 8, 15, 22) 2. Rituximab IV 375 mg/m\^2 on day 8. 3. Bendamustine IV 70 mg/m\^2 on day 8 and 9. Cycles 2-6: 1. Akt inhibitor MK2206 PO on days 1, 8, 15, and 22 (days 1, 8, 15, 22, and 29) 2. Rituximab IV 500 mg/m\^2 on day 1. 3. Bendamustine IV 70 mg/m\^2 on day 1 and 2.	Phase II Patients receive: Cycle 1: 1. Akt inhibitor MK2206 PO 90 mg on days 1, 8, 15, and 22 (days 1, 8, 15, 22) 2. Rituximab IV 375 mg/m\^2 on day 8. 3. Bendamustine IV 70 mg/m\^2 on day 8 and 9. Cycles 2-6: 1. Akt inhibitor MK2206 PO 90 mg on days 1, 8, 15, and 22 (days 1, 8, 15, 22, and 29) 2. Rituximab IV 500 mg/m\^2 on day 1. 3. Bendamustine IV 70 mg/m\^2 on day 1 and 2.
Overall Response Rate	0.92 proportion of patients Interval 0.64 to 0.998	—	—

SECONDARY outcome

Timeframe: Time from registration to the date of initiation of subsequent therapy or death, median follow-up time is 37 months

Population: All patients that were treated and evaluable were included in this endpoint.

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.

Outcome measures

Outcome measures
Measure	Phase I: Dose Level 1 n=13 Participants Patients receive: Cycle 1: 1. Akt inhibitor MK2206 PO 90 mg on days 1, 8, 15, and 22 (days 1, 8, 15, 22) 2. Rituximab IV 375 mg/m\^2 on day 8. 3. Bendamustine IV 70 mg/m\^2 on day 8 and 9. Cycles 2-6: 1. Akt inhibitor MK2206 PO on days 1, 8, 15, and 22 (days 1, 8, 15, 22, and 29) 2. Rituximab IV 500 mg/m\^2 on day 1. 3. Bendamustine IV 70 mg/m\^2 on day 1 and 2.	Phase I: Dose Level 2 Patients receive: Cycle 1: 1. Akt inhibitor MK2206 PO 135 mg on days 1, 8, 15, and 22 (days 1, 8, 15, 22) 2. Rituximab IV 375 mg/m\^2 on day 8. 3. Bendamustine IV 70 mg/m\^2 on day 8 and 9. Cycles 2-6: 1. Akt inhibitor MK2206 PO on days 1, 8, 15, and 22 (days 1, 8, 15, 22, and 29) 2. Rituximab IV 500 mg/m\^2 on day 1. 3. Bendamustine IV 70 mg/m\^2 on day 1 and 2.	Phase II Patients receive: Cycle 1: 1. Akt inhibitor MK2206 PO 90 mg on days 1, 8, 15, and 22 (days 1, 8, 15, 22) 2. Rituximab IV 375 mg/m\^2 on day 8. 3. Bendamustine IV 70 mg/m\^2 on day 8 and 9. Cycles 2-6: 1. Akt inhibitor MK2206 PO 90 mg on days 1, 8, 15, and 22 (days 1, 8, 15, 22, and 29) 2. Rituximab IV 500 mg/m\^2 on day 1. 3. Bendamustine IV 70 mg/m\^2 on day 1 and 2.
Treatment-free Survival	24.5 months Interval 11.3 to 50.6	—	—

Adverse Events

Phase I: Dose Level 1

Serious events: 2 serious events

Other events: 6 other events

Deaths: 0 deaths

Phase I: Dose Level 2

Serious events: 1 serious events

Other events: 4 other events

Deaths: 0 deaths

Phase II

Serious events: 2 serious events

Other events: 4 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Phase I: Dose Level 1 n=6 participants at risk Patients receive: Cycle 1: 1. Akt inhibitor MK2206 PO 90 mg on days 1, 8, 15, and 22 (days 1, 8, 15, 22) 2. Rituximab IV 375 mg/m\^2 on day 8. 3. Bendamustine IV 70 mg/m\^2 on day 8 and 9. Cycles 2-6: 1. Akt inhibitor MK2206 PO on days 1, 8, 15, and 22 (days 1, 8, 15, 22, and 29) 2. Rituximab IV 500 mg/m\^2 on day 1. 3. Bendamustine IV 70 mg/m\^2 on day 1 and 2.	Phase I: Dose Level 2 n=4 participants at risk Patients receive: Cycle 1: 1. Akt inhibitor MK2206 PO 135 mg on days 1, 8, 15, and 22 (days 1, 8, 15, 22) 2. Rituximab IV 375 mg/m\^2 on day 8. 3. Bendamustine IV 70 mg/m\^2 on day 8 and 9. Cycles 2-6: 1. Akt inhibitor MK2206 PO on days 1, 8, 15, and 22 (days 1, 8, 15, 22, and 29) 2. Rituximab IV 500 mg/m\^2 on day 1. 3. Bendamustine IV 70 mg/m\^2 on day 1 and 2.	Phase II n=4 participants at risk Patients receive: Cycle 1: 1. Akt inhibitor MK2206 PO 90 mg on days 1, 8, 15, and 22 (days 1, 8, 15, 22) 2. Rituximab IV 375 mg/m\^2 on day 8. 3. Bendamustine IV 70 mg/m\^2 on day 8 and 9. Cycles 2-6: 1. Akt inhibitor MK2206 PO 90 mg on days 1, 8, 15, and 22 (days 1, 8, 15, 22, and 29) 2. Rituximab IV 500 mg/m\^2 on day 1. 3. Bendamustine IV 70 mg/m\^2 on day 1 and 2.
Blood and lymphatic system disorders Anemia	16.7% 1/6 • Number of events 1 Adverse Events assessments took place at the end of each cycle during treatment. For each event, we are reporting the number of patients that reported the event. The total number of events reported will be defined as the total number of cycles in which the event was reported, not necessarily the number of independent events.	0.00% 0/4 Adverse Events assessments took place at the end of each cycle during treatment. For each event, we are reporting the number of patients that reported the event. The total number of events reported will be defined as the total number of cycles in which the event was reported, not necessarily the number of independent events.	0.00% 0/4 Adverse Events assessments took place at the end of each cycle during treatment. For each event, we are reporting the number of patients that reported the event. The total number of events reported will be defined as the total number of cycles in which the event was reported, not necessarily the number of independent events.
Blood and lymphatic system disorders Febrile neutropenia	16.7% 1/6 • Number of events 1 Adverse Events assessments took place at the end of each cycle during treatment. For each event, we are reporting the number of patients that reported the event. The total number of events reported will be defined as the total number of cycles in which the event was reported, not necessarily the number of independent events.	25.0% 1/4 • Number of events 1 Adverse Events assessments took place at the end of each cycle during treatment. For each event, we are reporting the number of patients that reported the event. The total number of events reported will be defined as the total number of cycles in which the event was reported, not necessarily the number of independent events.	25.0% 1/4 • Number of events 1 Adverse Events assessments took place at the end of each cycle during treatment. For each event, we are reporting the number of patients that reported the event. The total number of events reported will be defined as the total number of cycles in which the event was reported, not necessarily the number of independent events.
Blood and lymphatic system disorders Hemolysis	16.7% 1/6 • Number of events 1 Adverse Events assessments took place at the end of each cycle during treatment. For each event, we are reporting the number of patients that reported the event. The total number of events reported will be defined as the total number of cycles in which the event was reported, not necessarily the number of independent events.	0.00% 0/4 Adverse Events assessments took place at the end of each cycle during treatment. For each event, we are reporting the number of patients that reported the event. The total number of events reported will be defined as the total number of cycles in which the event was reported, not necessarily the number of independent events.	0.00% 0/4 Adverse Events assessments took place at the end of each cycle during treatment. For each event, we are reporting the number of patients that reported the event. The total number of events reported will be defined as the total number of cycles in which the event was reported, not necessarily the number of independent events.
Gastrointestinal disorders Diarrhea	0.00% 0/6 Adverse Events assessments took place at the end of each cycle during treatment. For each event, we are reporting the number of patients that reported the event. The total number of events reported will be defined as the total number of cycles in which the event was reported, not necessarily the number of independent events.	25.0% 1/4 • Number of events 1 Adverse Events assessments took place at the end of each cycle during treatment. For each event, we are reporting the number of patients that reported the event. The total number of events reported will be defined as the total number of cycles in which the event was reported, not necessarily the number of independent events.	0.00% 0/4 Adverse Events assessments took place at the end of each cycle during treatment. For each event, we are reporting the number of patients that reported the event. The total number of events reported will be defined as the total number of cycles in which the event was reported, not necessarily the number of independent events.
Gastrointestinal disorders Small intestinal obstruction	16.7% 1/6 • Number of events 1 Adverse Events assessments took place at the end of each cycle during treatment. For each event, we are reporting the number of patients that reported the event. The total number of events reported will be defined as the total number of cycles in which the event was reported, not necessarily the number of independent events.	0.00% 0/4 Adverse Events assessments took place at the end of each cycle during treatment. For each event, we are reporting the number of patients that reported the event. The total number of events reported will be defined as the total number of cycles in which the event was reported, not necessarily the number of independent events.	0.00% 0/4 Adverse Events assessments took place at the end of each cycle during treatment. For each event, we are reporting the number of patients that reported the event. The total number of events reported will be defined as the total number of cycles in which the event was reported, not necessarily the number of independent events.
Infections and infestations Sinusitis	0.00% 0/6 Adverse Events assessments took place at the end of each cycle during treatment. For each event, we are reporting the number of patients that reported the event. The total number of events reported will be defined as the total number of cycles in which the event was reported, not necessarily the number of independent events.	0.00% 0/4 Adverse Events assessments took place at the end of each cycle during treatment. For each event, we are reporting the number of patients that reported the event. The total number of events reported will be defined as the total number of cycles in which the event was reported, not necessarily the number of independent events.	25.0% 1/4 • Number of events 1 Adverse Events assessments took place at the end of each cycle during treatment. For each event, we are reporting the number of patients that reported the event. The total number of events reported will be defined as the total number of cycles in which the event was reported, not necessarily the number of independent events.
Investigations Neutrophil count decreased	16.7% 1/6 • Number of events 1 Adverse Events assessments took place at the end of each cycle during treatment. For each event, we are reporting the number of patients that reported the event. The total number of events reported will be defined as the total number of cycles in which the event was reported, not necessarily the number of independent events.	25.0% 1/4 • Number of events 1 Adverse Events assessments took place at the end of each cycle during treatment. For each event, we are reporting the number of patients that reported the event. The total number of events reported will be defined as the total number of cycles in which the event was reported, not necessarily the number of independent events.	0.00% 0/4 Adverse Events assessments took place at the end of each cycle during treatment. For each event, we are reporting the number of patients that reported the event. The total number of events reported will be defined as the total number of cycles in which the event was reported, not necessarily the number of independent events.
Investigations Platelet count decreased	16.7% 1/6 • Number of events 1 Adverse Events assessments took place at the end of each cycle during treatment. For each event, we are reporting the number of patients that reported the event. The total number of events reported will be defined as the total number of cycles in which the event was reported, not necessarily the number of independent events.	0.00% 0/4 Adverse Events assessments took place at the end of each cycle during treatment. For each event, we are reporting the number of patients that reported the event. The total number of events reported will be defined as the total number of cycles in which the event was reported, not necessarily the number of independent events.	0.00% 0/4 Adverse Events assessments took place at the end of each cycle during treatment. For each event, we are reporting the number of patients that reported the event. The total number of events reported will be defined as the total number of cycles in which the event was reported, not necessarily the number of independent events.
Metabolism and nutrition disorders Tumor lysis syndrome	0.00% 0/6 Adverse Events assessments took place at the end of each cycle during treatment. For each event, we are reporting the number of patients that reported the event. The total number of events reported will be defined as the total number of cycles in which the event was reported, not necessarily the number of independent events.	0.00% 0/4 Adverse Events assessments took place at the end of each cycle during treatment. For each event, we are reporting the number of patients that reported the event. The total number of events reported will be defined as the total number of cycles in which the event was reported, not necessarily the number of independent events.	25.0% 1/4 • Number of events 1 Adverse Events assessments took place at the end of each cycle during treatment. For each event, we are reporting the number of patients that reported the event. The total number of events reported will be defined as the total number of cycles in which the event was reported, not necessarily the number of independent events.
Renal and urinary disorders Renal and urinary disorders - Other, specify	0.00% 0/6 Adverse Events assessments took place at the end of each cycle during treatment. For each event, we are reporting the number of patients that reported the event. The total number of events reported will be defined as the total number of cycles in which the event was reported, not necessarily the number of independent events.	0.00% 0/4 Adverse Events assessments took place at the end of each cycle during treatment. For each event, we are reporting the number of patients that reported the event. The total number of events reported will be defined as the total number of cycles in which the event was reported, not necessarily the number of independent events.	25.0% 1/4 • Number of events 1 Adverse Events assessments took place at the end of each cycle during treatment. For each event, we are reporting the number of patients that reported the event. The total number of events reported will be defined as the total number of cycles in which the event was reported, not necessarily the number of independent events.
Surgical and medical procedures Surgical and medical procedures - Other, specify	16.7% 1/6 • Number of events 1 Adverse Events assessments took place at the end of each cycle during treatment. For each event, we are reporting the number of patients that reported the event. The total number of events reported will be defined as the total number of cycles in which the event was reported, not necessarily the number of independent events.	0.00% 0/4 Adverse Events assessments took place at the end of each cycle during treatment. For each event, we are reporting the number of patients that reported the event. The total number of events reported will be defined as the total number of cycles in which the event was reported, not necessarily the number of independent events.	0.00% 0/4 Adverse Events assessments took place at the end of each cycle during treatment. For each event, we are reporting the number of patients that reported the event. The total number of events reported will be defined as the total number of cycles in which the event was reported, not necessarily the number of independent events.

Other adverse events

Additional Information

Wei Ding, MBBS, PhD

Mayo Clinic

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Restriction type: LTE60