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

Sponsor
National Cancer Institute (NCI) (NIH)
Overall Status
Completed
CT.gov ID
NCT01369849
Collaborator
(none)
15
44
1
29
0.3
0

Study Details

Study Description

Brief Summary

This phase I/II trial studies the side effects and best dose of v-akt murine thymoma viral oncogene homolog 1 (Akt) inhibitor MK2206 when given together with bendamustine hydrochloride and rituximab and to see how well they work in treating patients with refractory chronic lymphocytic leukemia or small lymphocytic lymphoma. Akt inhibitor MK2206 may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as bendamustine hydrochloride, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as rituximab, can block cancer growth in different ways. Some block the ability of cancer cells to grow and spread. Others find cancer cells and help kill them or carry cancer-killing substances to them. Giving Akt inhibitor MK2206 with bendamustine hydrochloride and rituximab may be an effective treatment for relapsed chronic lymphocytic leukemia or small lymphocytic lymphoma.

Condition or Disease Intervention/Treatment Phase
  • Drug: Akt Inhibitor MK2206
  • Drug: Bendamustine Hydrochloride
  • Other: Laboratory Biomarker Analysis
  • Biological: Rituximab
Phase 1/Phase 2

Detailed Description

PRIMARY OBJECTIVES:
  1. 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)
  2. To assess the rate of complete response (CR) of MK-2206 in combination with bendamustine-rituximab in relapsed CLL or SLL patients. (Phase II)
SECONDARY OBJECTIVES:
  1. 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.

  2. To assess the toxicity profile of MK-2206 in combination with bendamustine-rituximab.

TERTIARY OBJECTIVES:
  1. 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.

  2. 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.

  3. 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.

  4. 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.

Study Design

Study Type:
Interventional
Actual Enrollment :
15 participants
Allocation:
N/A
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
Study Start Date :
Sep 1, 2011
Actual Primary Completion Date :
Feb 1, 2014
Actual Study Completion Date :
Feb 1, 2014

Arms and Interventions

Arm Intervention/Treatment
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
Given PO
Other Names:
  • MK2206
  • Drug: Bendamustine Hydrochloride
    Given IV
    Other Names:
  • Bendamustin Hydrochloride
  • Cytostasan Hydrochloride
  • Ribomustin
  • SyB L-0501
  • Treanda
  • Other: Laboratory Biomarker Analysis
    Correlative studies

    Biological: Rituximab
    Given IV
    Other Names:
  • BI 695500
  • C2B8 Monoclonal Antibody
  • Chimeric Anti-CD20 Antibody
  • IDEC-102
  • IDEC-C2B8
  • IDEC-C2B8 Monoclonal Antibody
  • MabThera
  • Monoclonal Antibody IDEC-C2B8
  • PF-05280586
  • Rituxan
  • Rituximab Biosimilar BI 695500
  • Rituximab Biosimilar PF-05280586
  • Rituximab Biosimilar RTXM83
  • RTXM83
  • Outcome Measures

    Primary Outcome Measures

    1. Number of Phase I Participants With Dose-Limiting Toxicity Events (Phase I) [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.

    2. Proportion of Complete Response Defined to be a CR or CRi Noted as the Objective Status (Phase II) [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.

    Secondary Outcome Measures

    1. Biomarker Analysis (IgVH Gene Mutation) [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.

    2. Biomarker Analysis (CD38, CD49d, and ZAP-70) [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.

    3. Fluorescent in Situ Hybridization (FISH) Biomarker Analysis [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.

    4. Duration of Response [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.

    5. Minimal-residual Disease [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.

    6. Overall Response Rate [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.

    7. Treatment-free Survival [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.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:
    • Diagnosis of chronic lymphocytic leukemia (CLL) according to the National Cancer Institute (NCI) criteria or small lymphocytic lymphoma (SLL) according to the World
    Health Organization (WHO) criteria; this includes previous documentation of:
    • Biopsy-proven SLL or

    • Diagnosis of CLL according to NCI working group criteria as evidenced by all of the following:

    • Peripheral blood B-cell count of > 5 x 10^9/L consisting of small to moderate size lymphocytes

    • Immunophenotyping consistent with CLL defined as:

    • The predominant population of lymphocytes share both B-cell antigens (CD19, CD20 [typically dim expression], or CD23) as well as CD5 in the absence of other pan-T-cell markers (CD3,CD2, etc.)

    • Clonality as evidenced by kappa (Κ) or lambda (λ) light chain expression (typically dim immunoglobulin expression) or other genetic method (e.g., immunoglobulin heavy chain variable [IGHV] analysis)

    • NOTE: splenomegaly, hepatomegaly, or lymphadenopathy are not required for the diagnosis of CLL

    • Before diagnosing CLL or SLL, mantle cell lymphoma must be excluded by demonstrating a negative fluorescence in situ hybridization (FISH) analysis for t (11;14) (IgH/CCND1) on peripheral blood or tissue biopsy, or negative immunohistochemical stains for cyclin D1 on involved tissue biopsy

    • Demonstrated progression after one or two prior lines of CLL therapy; note: rituximab monotherapy does not count as a prior line of therapy

    • Progressive disease with any one of the following characteristics based on standard criteria for treatment as defined by the NCI-Working Group (WG) 1996

    • Symptomatic CLL characterized by any one of the following:

    • Weight loss >= 10% within the previous 6 months

    • Extreme fatigue attributed to CLL

    • Fevers > 100.5° Fahrenheit (F) for 2 weeks without evidence of infection

    • Drenching night sweats without evidence of infection

    • Evidence of progressive bone marrow failure with hemoglobin < 11 g/dL or platelet count < 100 x 10^9/L

    • Massive or rapidly progressive splenomegaly (> 6 cm below left costal margin)

    • Massive (> 10 cm) or rapidly progressive lymphadenopathy

    • Life expectancy >= 12 months

    • Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1, or 2

    • Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) unless due to Gilbert's disease; if total bilirubin is > 1.5 x ULN, a direct bilirubin should be performed and must be < 1.5 mg/dL for Gilbert's to be diagnosed

    • Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) =< 2.5 ULN

    • Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 2.5 times ULN

    • Creatinine =< 1.5 times ULN OR creatinine clearance >= 60 mL/min/1.73 m^2 for patients with creatinine levels > 1.5 x ULN

    • A non-transfused platelet count >= 30 x 10^9/L

    • Neutrophil count (absolute neutrophil count [ANC]) >= 1 x 10^9/L

    • Hemoglobin (Hgb) >= 8 g/dL

    • Note: cytopenias due to bone marrow failure are common in patients with relapsed CLL requiring treatment; accordingly, normal bone marrow function is NOT required for participation

    • Negative pregnancy test done =< 7 days prior to registration, for women of childbearing potential only

    • Ability to complete patient diaries and questionnaire(s) by themselves or with assistance

    • Provide informed written consent

    • Willing to return to North Central Cancer Treatment Group (NCCTG) enrolling institution for follow-up

    • Willing to provide blood samples for correlative research purposes

    • Willing to provide bone marrow aspirate (body fluid) for correlative research purposes

    • MAYO ROCHESTER ONLY: willing to provide bone marrow core biopsy tissue for correlative research purposes

    • Willing to provide bone marrow biopsy for central pathology review (all patients)

    • Able to swallow whole tablets; NOTE: nasogastric or gastrostomy (G) tube administration is not allowed; tablets must not be crushed or chewed

    Exclusion Criteria:
    • Prior treatment with bendamustine

    • Prior treatment with any experimental Akt inhibitors

    • More than 2 previous purine nucleoside based-therapy (i.e. fludarabine, pentostatin, or cladribine)

    • More than 2 previous alkylating agent based-therapy (i.e. cyclophosphamide, chlorambucil)

    • More than 3 total prior lines of therapy for CLL

    • Primary refractory disease as defined by progression while receiving or within 6 months of completion of a chemoimmunotherapy regimen such as fludarabine, cyclophosphamide and rituximab (FCR) or pentostatin, cyclophosphamide and rituximab (PCR)

    • PHASE II ONLY: FISH abnormality of 17P deletions; (note: patients with 17P deletions will be included in Phase I but will be excluded in Phase II unless enough activity is found in the Phase I)

    • Pregnant women

    • Nursing women

    • Men or women of childbearing potential who are unwilling to employ adequate contraception

    • Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens; including but not limited to the following:

    • New York Heart Association class III or IV heart disease

    • Recent myocardial infarction (< 1 month)

    • Uncontrolled infection

    • Known infection with the human immunodeficiency virus (HIV/acquired immune deficiency syndrome [AIDS]) and/or patients taking highly active antiretroviral therapy (HAART) as further severe immunosuppression with this regimen may occur

    • Infection with known chronic, active hepatitis C

    • Positive serology for hepatitis B (HB) defined as a positive test for hepatitis B surface antigen (HBsAg); in addition, if negative for HBsAg but hepatitis B core antibody (HBcAb) positive (regardless of hepatitis B surface antibody [HBsAb] status), a HB deoxyribonucleic acid (DNA) test will be performed and if positive the subject will be excluded

    • Uncontrolled diabetes defined as hemoglobin A1c (HbA1c) >= 8 or fasting blood glucose >= 140 mg/dL

    • Any of the following:

    • History of significant ventricular arrhythmia in the last 5 years including: ventricular tachycardia or ventricular fibrillation

    • Corrected QT (QTc) prolongation on baseline electrocardiogram (ECG) (defined as a QTc interval > 450 msec for males and QTc interval > 470 msec for females)

    • Currently using a medication known to cause prolonged QTc which cannot be discontinued; note: other medications with possible risk of prolonged QTc are allowed but should be used with caution; patients using these medications should be monitored accordingly

    • Ventricular arrhythmia on baseline ECG (ventricular tachycardia or ventricular fibrillation >= 3 beats in a row)

    • Second or third degree heart block

    • Receiving any other investigational agent concurrently which would be considered as a treatment for the primary neoplasm

    • Other active primary malignancy requiring treatment or which limits survival to < 24 months

    • Any major surgery =< 28 days prior to registration

    • Any radiation therapy =< 4 weeks prior to registration

    • Current use of corticosteroids; EXCEPTION: low doses of steroids (< 10 mg of prednisone or equivalent dose of other steroid) used for treatment of non-hematologic medical conditions; NOTE: previous use of corticosteroids is allowed

    • Active hemolytic anemia requiring immunosuppressive therapy or other pharmacologic treatment; NOTE: patients who have a positive Coombs test but no evidence of hemolysis are NOT excluded from participation

    • Receiving any medications or substances that are strong or moderate inhibitors of cytochrome P450 3A4 (CYP450 3A4); use of the following strong or moderate inhibitors are prohibited =< 7 days prior to registration:

    • Strong inhibitors of CYP3A4

    • Indinavir

    • Nelfinavir

    • Ritonavir

    • Clarithromycin

    • Itraconazole

    • Ketoconazole

    • Nefazodone

    • Saquinavir

    • Telithromycin

    • Moderate inhibitors of CYP3A4

    • Aprepitant

    • Erythromycin

    • Fluconazole

    • Grapefruit juice

    • Verapamil

    • Diltiazem

    • Receiving any medications or substances that are inducers of CYP450 3A4; use of the following inducers is prohibited =< 12 days prior to registration

    • Inducers of CYP3A4

    • Efavirenz

    • Nevirapine

    • Carbamazepine

    • Modafinil

    • Phenobarbital

    • Phenytoin

    • Pioglitazone

    • Rifabutin

    • Rifampin

    • St. John's wort

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Mayo Clinic in Arizona Scottsdale Arizona United States 85259
    2 Siouxland Regional Cancer Center Sioux City Iowa United States 51101
    3 Mercy Medical Center-Sioux City Sioux City Iowa United States 51104
    4 Saint Luke's Regional Medical Center Sioux City Iowa United States 51104
    5 Essentia Health Saint Joseph's Medical Center Brainerd Minnesota United States 56401
    6 Fairview Ridges Hospital Burnsville Minnesota United States 55337
    7 Mercy Hospital Coon Rapids Minnesota United States 55433
    8 Essentia Health Cancer Center Duluth Minnesota United States 55805
    9 Essentia Health Saint Mary's Medical Center Duluth Minnesota United States 55805
    10 Miller-Dwan Hospital Duluth Minnesota United States 55805
    11 Fairview-Southdale Hospital Edina Minnesota United States 55435
    12 Unity Hospital Fridley Minnesota United States 55432
    13 Hutchinson Area Health Care Hutchinson Minnesota United States 55350
    14 Minnesota Oncology Hematology PA-Maplewood Maplewood Minnesota United States 55109
    15 Saint John's Hospital - Healtheast Maplewood Minnesota United States 55109
    16 Abbott-Northwestern Hospital Minneapolis Minnesota United States 55407
    17 Hennepin County Medical Center Minneapolis Minnesota United States 55415
    18 North Memorial Medical Health Center Robbinsdale Minnesota United States 55422
    19 Mayo Clinic Rochester Minnesota United States 55905
    20 Metro-Minnesota NCI Community Oncology Research Program Saint Louis Park Minnesota United States 55416
    21 Park Nicollet Clinic - Saint Louis Park Saint Louis Park Minnesota United States 55416
    22 Regions Hospital Saint Paul Minnesota United States 55101
    23 United Hospital Saint Paul Minnesota United States 55102
    24 Saint Francis Regional Medical Center Shakopee Minnesota United States 55379
    25 Lakeview Hospital Stillwater Minnesota United States 55082
    26 Ridgeview Medical Center Waconia Minnesota United States 55387
    27 Rice Memorial Hospital Willmar Minnesota United States 56201
    28 Minnesota Oncology and Hematology PA-Woodbury Woodbury Minnesota United States 55125
    29 Adena Regional Medical Center Chillicothe Ohio United States 45601
    30 Riverside Methodist Hospital Columbus Ohio United States 43214
    31 Columbus CCOP Columbus Ohio United States 43215
    32 Grant Medical Center Columbus Ohio United States 43215
    33 Mount Carmel Health Center West Columbus Ohio United States 43222
    34 Doctors Hospital Columbus Ohio United States 43228
    35 Grady Memorial Hospital Delaware Ohio United States 43015
    36 Fairfield Medical Center Lancaster Ohio United States 43130
    37 Marietta Memorial Hospital Marietta Ohio United States 45750
    38 Knox Community Hospital Mount Vernon Ohio United States 43050
    39 Licking Memorial Hospital Newark Ohio United States 43055
    40 Southern Ohio Medical Center Portsmouth Ohio United States 45662
    41 Springfield Regional Medical Center Springfield Ohio United States 45505
    42 Saint Ann's Hospital Westerville Ohio United States 43081
    43 Genesis HealthCare System Zanesville Ohio United States 43701
    44 Rapid City Regional Hospital Rapid City South Dakota United States 57701

    Sponsors and Collaborators

    • National Cancer Institute (NCI)

    Investigators

    • Principal Investigator: Wei Ding, Alliance for Clinical Trials in Oncology

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    National Cancer Institute (NCI)
    ClinicalTrials.gov Identifier:
    NCT01369849
    Other Study ID Numbers:
    • NCI-2011-02675
    • NCI-2011-02675
    • CDR0000701372
    • NCCTG-N1087
    • N1087
    • N1087
    • U10CA180821
    • U10CA025224
    First Posted:
    Jun 9, 2011
    Last Update Posted:
    Sep 15, 2017
    Last Verified:
    Aug 1, 2017

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail
    Arm/Group Title Phase I: Dose Level 1 Phase I: Dose Level 2 Phase II
    Arm/Group Description Patients receive: Cycle 1: Akt inhibitor MK2206 PO 90 mg on days 1, 8, 15, and 22 (days 1, 8, 15, 22) Rituximab IV 375 mg/m^2 on day 8. Bendamustine IV 70 mg/m^2 on day 8 and 9. Cycles 2-6: Akt inhibitor MK2206 PO on days 1, 8, 15, and 22 (days 1, 8, 15, 22, and 29) Rituximab IV 500 mg/m^2 on day 1. Bendamustine IV 70 mg/m^2 on day 1 and 2. Patients receive: Cycle 1: Akt inhibitor MK2206 PO 135 mg on days 1, 8, 15, and 22 (days 1, 8, 15, 22) Rituximab IV 375 mg/m^2 on day 8. Bendamustine IV 70 mg/m^2 on day 8 and 9. Cycles 2-6: Akt inhibitor MK2206 PO on days 1, 8, 15, and 22 (days 1, 8, 15, 22, and 29) Rituximab IV 500 mg/m^2 on day 1. Bendamustine IV 70 mg/m^2 on day 1 and 2. Patients receive: Cycle 1: Akt inhibitor MK2206 PO 90 mg on days 1, 8, 15, and 22 (days 1, 8, 15, 22) Rituximab IV 375 mg/m^2 on day 8. Bendamustine IV 70 mg/m^2 on day 8 and 9. Cycles 2-6: Akt inhibitor MK2206 PO 90 mg on days 1, 8, 15, and 22 (days 1, 8, 15, 22, and 29) Rituximab IV 500 mg/m^2 on day 1. Bendamustine IV 70 mg/m^2 on day 1 and 2.
    Period Title: Overall Study
    STARTED 6 4 5
    COMPLETED 6 3 4
    NOT COMPLETED 0 1 1

    Baseline Characteristics

    Arm/Group Title Phase I: Dose Level 1 Phase I: Dose Level 2 Phase II Total
    Arm/Group Description Patients receive: Cycle 1: Akt inhibitor MK2206 PO 90 mg on days 1, 8, 15, and 22 (days 1, 8, 15, 22) Rituximab IV 375 mg/m^2 on day 8. Bendamustine IV 70 mg/m^2 on day 8 and 9. Cycles 2-6: Akt inhibitor MK2206 PO on days 1, 8, 15, and 22 (days 1, 8, 15, 22, and 29) Rituximab IV 500 mg/m^2 on day 1. Bendamustine IV 70 mg/m^2 on day 1 and 2. Patients receive: Cycle 1: Akt inhibitor MK2206 PO 135 mg on days 1, 8, 15, and 22 (days 1, 8, 15, 22) Rituximab IV 375 mg/m^2 on day 8. Bendamustine IV 70 mg/m^2 on day 8 and 9. Cycles 2-6: Akt inhibitor MK2206 PO on days 1, 8, 15, and 22 (days 1, 8, 15, 22, and 29) Rituximab IV 500 mg/m^2 on day 1. Bendamustine IV 70 mg/m^2 on day 1 and 2. Patients receive: Cycle 1: Akt inhibitor MK2206 PO 90 mg on days 1, 8, 15, and 22 (days 1, 8, 15, 22) Rituximab IV 375 mg/m^2 on day 8. Bendamustine IV 70 mg/m^2 on day 8 and 9. Cycles 2-6: Akt inhibitor MK2206 PO 90 mg on days 1, 8, 15, and 22 (days 1, 8, 15, 22, and 29) Rituximab IV 500 mg/m^2 on day 1. Bendamustine IV 70 mg/m^2 on day 1 and 2. Total of all reporting groups
    Overall Participants 6 4 4 14
    Age (years) [Median (Full Range) ]
    Median (Full Range) [years]
    67.5
    66.5
    65
    67
    Sex: Female, Male (Count of Participants)
    Female
    1
    16.7%
    1
    25%
    0
    0%
    2
    14.3%
    Male
    5
    83.3%
    3
    75%
    4
    100%
    12
    85.7%
    Region of Enrollment (participants) [Number]
    United States
    6
    100%
    4
    100%
    4
    100%
    14
    100%

    Outcome Measures

    1. Primary Outcome
    Title Number of Phase I Participants With Dose-Limiting Toxicity Events (Phase I)
    Description 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.
    Time Frame Up to 35 days

    Outcome Measure Data

    Analysis Population Description
    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.
    Arm/Group Title Phase I: Dose Level 1 Phase I: Dose Level 2 Phase II
    Arm/Group Description Patients receive: Cycle 1: Akt inhibitor MK2206 PO 90 mg on days 1, 8, 15, and 22 (days 1, 8, 15, 22) Rituximab IV 375 mg/m^2 on day 8. Bendamustine IV 70 mg/m^2 on day 8 and 9. Cycles 2-6: Akt inhibitor MK2206 PO on days 1, 8, 15, and 22 (days 1, 8, 15, 22, and 29) Rituximab IV 500 mg/m^2 on day 1. Bendamustine IV 70 mg/m^2 on day 1 and 2. Patients receive: Cycle 1: Akt inhibitor MK2206 PO 135 mg on days 1, 8, 15, and 22 (days 1, 8, 15, 22) Rituximab IV 375 mg/m^2 on day 8. Bendamustine IV 70 mg/m^2 on day 8 and 9. Cycles 2-6: Akt inhibitor MK2206 PO on days 1, 8, 15, and 22 (days 1, 8, 15, 22, and 29) Rituximab IV 500 mg/m^2 on day 1. Bendamustine IV 70 mg/m^2 on day 1 and 2. Patients receive: Cycle 1: Akt inhibitor MK2206 PO 90 mg on days 1, 8, 15, and 22 (days 1, 8, 15, 22) Rituximab IV 375 mg/m^2 on day 8. Bendamustine IV 70 mg/m^2 on day 8 and 9. Cycles 2-6: Akt inhibitor MK2206 PO 90 mg on days 1, 8, 15, and 22 (days 1, 8, 15, 22, and 29) Rituximab IV 500 mg/m^2 on day 1. Bendamustine IV 70 mg/m^2 on day 1 and 2.
    Measure Participants 6 3 0
    Number [Patients reporting Dose-Limiting Events]
    1
    2
    2. Primary Outcome
    Title Proportion of Complete Response Defined to be a CR or CRi Noted as the Objective Status (Phase II)
    Description 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.
    Time Frame From registration to response, up to 84 days

    Outcome Measure Data

    Analysis Population Description
    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.
    Arm/Group Title Dose Level 1
    Arm/Group Description Patients receive: Cycle 1: Akt inhibitor MK2206 PO 90 mg on days 1, 8, 15, and 22 (days 1, 8, 15, 22) Rituximab IV 375 mg/m^2 on day 8. Bendamustine IV 70 mg/m^2 on day 8 and 9. Cycles 2-6: Akt inhibitor MK2206 PO on days 1, 8, 15, and 22 (days 1, 8, 15, 22, and 29) Rituximab IV 500 mg/m^2 on day 1. Bendamustine IV 70 mg/m^2 on day 1 and 2.
    Measure Participants 10
    Number (95% Confidence Interval) [percentage of participants]
    50
    833.3%
    3. Secondary Outcome
    Title Biomarker Analysis (IgVH Gene Mutation)
    Description 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.
    Time Frame Baseline

    Outcome Measure Data

    Analysis Population Description
    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.
    Arm/Group Title Phase I: Dose Level 1 Phase I: Dose Level 2 Phase II
    Arm/Group Description Patients receive: Cycle 1: Akt inhibitor MK2206 PO 90 mg on days 1, 8, 15, and 22 (days 1, 8, 15, 22) Rituximab IV 375 mg/m^2 on day 8. Bendamustine IV 70 mg/m^2 on day 8 and 9. Cycles 2-6: Akt inhibitor MK2206 PO on days 1, 8, 15, and 22 (days 1, 8, 15, 22, and 29) Rituximab IV 500 mg/m^2 on day 1. Bendamustine IV 70 mg/m^2 on day 1 and 2. Patients receive: Cycle 1: Akt inhibitor MK2206 PO 135 mg on days 1, 8, 15, and 22 (days 1, 8, 15, 22) Rituximab IV 375 mg/m^2 on day 8. Bendamustine IV 70 mg/m^2 on day 8 and 9. Cycles 2-6: Akt inhibitor MK2206 PO on days 1, 8, 15, and 22 (days 1, 8, 15, 22, and 29) Rituximab IV 500 mg/m^2 on day 1. Bendamustine IV 70 mg/m^2 on day 1 and 2. Patients receive: Cycle 1: Akt inhibitor MK2206 PO 90 mg on days 1, 8, 15, and 22 (days 1, 8, 15, 22) Rituximab IV 375 mg/m^2 on day 8. Bendamustine IV 70 mg/m^2 on day 8 and 9. Cycles 2-6: Akt inhibitor MK2206 PO 90 mg on days 1, 8, 15, and 22 (days 1, 8, 15, 22, and 29) Rituximab IV 500 mg/m^2 on day 1. Bendamustine IV 70 mg/m^2 on day 1 and 2.
    Measure Participants 6 3 4
    Mutated
    0
    0%
    0
    0%
    1
    25%
    Unmutated
    5
    83.3%
    3
    75%
    1
    25%
    Not Done
    1
    16.7%
    0
    0%
    2
    50%
    4. Secondary Outcome
    Title Biomarker Analysis (CD38, CD49d, and ZAP-70)
    Description 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.
    Time Frame Baseline

    Outcome Measure Data

    Analysis Population Description
    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.
    Arm/Group Title Phase I: Dose Level 1 Phase I: Dose Level 2 Phase II
    Arm/Group Description Patients receive: Cycle 1: Akt inhibitor MK2206 PO 90 mg on days 1, 8, 15, and 22 (days 1, 8, 15, 22) Rituximab IV 375 mg/m^2 on day 8. Bendamustine IV 70 mg/m^2 on day 8 and 9. Cycles 2-6: Akt inhibitor MK2206 PO on days 1, 8, 15, and 22 (days 1, 8, 15, 22, and 29) Rituximab IV 500 mg/m^2 on day 1. Bendamustine IV 70 mg/m^2 on day 1 and 2. Patients receive: Cycle 1: Akt inhibitor MK2206 PO 135 mg on days 1, 8, 15, and 22 (days 1, 8, 15, 22) Rituximab IV 375 mg/m^2 on day 8. Bendamustine IV 70 mg/m^2 on day 8 and 9. Cycles 2-6: Akt inhibitor MK2206 PO on days 1, 8, 15, and 22 (days 1, 8, 15, 22, and 29) Rituximab IV 500 mg/m^2 on day 1. Bendamustine IV 70 mg/m^2 on day 1 and 2. Patients receive: Cycle 1: Akt inhibitor MK2206 PO 90 mg on days 1, 8, 15, and 22 (days 1, 8, 15, 22) Rituximab IV 375 mg/m^2 on day 8. Bendamustine IV 70 mg/m^2 on day 8 and 9. Cycles 2-6: Akt inhibitor MK2206 PO 90 mg on days 1, 8, 15, and 22 (days 1, 8, 15, 22, and 29) Rituximab IV 500 mg/m^2 on day 1. Bendamustine IV 70 mg/m^2 on day 1 and 2.
    Measure Participants 6 3 4
    Positive
    4
    66.7%
    1
    25%
    1
    25%
    Negative
    2
    33.3%
    2
    50%
    3
    75%
    Not Done
    0
    0%
    0
    0%
    0
    0%
    Positive
    1
    16.7%
    0
    0%
    3
    75%
    Negative
    1
    16.7%
    3
    75%
    0
    0%
    Not Done
    4
    66.7%
    0
    0%
    1
    25%
    Positive
    6
    100%
    1
    25%
    1
    25%
    Negative
    0
    0%
    2
    50%
    1
    25%
    Not Done
    0
    0%
    0
    0%
    2
    50%
    5. Secondary Outcome
    Title Fluorescent in Situ Hybridization (FISH) Biomarker Analysis
    Description 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.
    Time Frame Baseline

    Outcome Measure Data

    Analysis Population Description
    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.
    Arm/Group Title Phase I: Dose Level 1 Phase I: Dose Level 2 Phase II
    Arm/Group Description Patients receive: Cycle 1: Akt inhibitor MK2206 PO 90 mg on days 1, 8, 15, and 22 (days 1, 8, 15, 22) Rituximab IV 375 mg/m^2 on day 8. Bendamustine IV 70 mg/m^2 on day 8 and 9. Cycles 2-6: Akt inhibitor MK2206 PO on days 1, 8, 15, and 22 (days 1, 8, 15, 22, and 29) Rituximab IV 500 mg/m^2 on day 1. Bendamustine IV 70 mg/m^2 on day 1 and 2. Patients receive: Cycle 1: Akt inhibitor MK2206 PO 135 mg on days 1, 8, 15, and 22 (days 1, 8, 15, 22) Rituximab IV 375 mg/m^2 on day 8. Bendamustine IV 70 mg/m^2 on day 8 and 9. Cycles 2-6: Akt inhibitor MK2206 PO on days 1, 8, 15, and 22 (days 1, 8, 15, 22, and 29) Rituximab IV 500 mg/m^2 on day 1. Bendamustine IV 70 mg/m^2 on day 1 and 2. Patients receive: Cycle 1: Akt inhibitor MK2206 PO 90 mg on days 1, 8, 15, and 22 (days 1, 8, 15, 22) Rituximab IV 375 mg/m^2 on day 8. Bendamustine IV 70 mg/m^2 on day 8 and 9. Cycles 2-6: Akt inhibitor MK2206 PO 90 mg on days 1, 8, 15, and 22 (days 1, 8, 15, 22, and 29) Rituximab IV 500 mg/m^2 on day 1. Bendamustine IV 70 mg/m^2 on day 1 and 2.
    Measure Participants 6 3 4
    11q-
    1
    16.7%
    3
    75%
    0
    0%
    Trisomy 12
    1
    16.7%
    0
    0%
    1
    25%
    13q-
    2
    33.3%
    0
    0%
    1
    25%
    Other
    0
    0%
    0
    0%
    2
    50%
    Normal
    2
    33.3%
    0
    0%
    0
    0%
    6. Secondary Outcome
    Title Duration of Response
    Description 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.
    Time Frame Median follow-up of 39 months and maximum follow-up of 54 months

    Outcome Measure Data

    Analysis Population Description
    12 patients achieved a response and were included in this analysis.
    Arm/Group Title All Patients
    Arm/Group Description Patients receive: Cycle 1: Akt inhibitor MK2206 PO (90 or 135 mg) on days 1, 8, 15, and 22 (days 1, 8, 15, 22) Rituximab IV 375 mg/m^2 on day 8. Bendamustine IV 70 mg/m^2 on day 8 and 9. Cycles 2-6: Akt inhibitor MK2206 PO on days 1, 8, 15, and 22 (days 1, 8, 15, 22, and 29) Rituximab IV 500 mg/m^2 on day 1. Bendamustine IV 70 mg/m^2 on day 1 and 2.
    Measure Participants 12
    Median (95% Confidence Interval) [months]
    NA
    7. Secondary Outcome
    Title Minimal-residual Disease
    Description 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.
    Time Frame Cycle 6 assessment (maximum of 231 days post-registration)

    Outcome Measure Data

    Analysis Population Description
    5 patients achieved a complete response and were analyzed for MRD
    Arm/Group Title All Patients
    Arm/Group Description Patients receive: Cycle 1: Akt inhibitor MK2206 PO (90 or 135 mg) on days 1, 8, 15, and 22 (days 1, 8, 15, 22) Rituximab IV 375 mg/m^2 on day 8. Bendamustine IV 70 mg/m^2 on day 8 and 9. Cycles 2-6: Akt inhibitor MK2206 PO on days 1, 8, 15, and 22 (days 1, 8, 15, 22, and 29) Rituximab IV 500 mg/m^2 on day 1. Bendamustine IV 70 mg/m^2 on day 1 and 2.
    Measure Participants 5
    Count of Participants [Participants]
    2
    33.3%
    8. Secondary Outcome
    Title Overall Response Rate
    Description 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.
    Time Frame 3 months post-treatment

    Outcome Measure Data

    Analysis Population Description
    All patients that were treated and evaluable for response were included together in this endpoint.
    Arm/Group Title All Patients
    Arm/Group Description Patients receive: Cycle 1: Akt inhibitor MK2206 PO (90 or 135 mg) on days 1, 8, 15, and 22 (days 1, 8, 15, 22) Rituximab IV 375 mg/m^2 on day 8. Bendamustine IV 70 mg/m^2 on day 8 and 9. Cycles 2-6: Akt inhibitor MK2206 PO on days 1, 8, 15, and 22 (days 1, 8, 15, 22, and 29) Rituximab IV 500 mg/m^2 on day 1. Bendamustine IV 70 mg/m^2 on day 1 and 2.
    Measure Participants 13
    Number (95% Confidence Interval) [proportion of patients]
    0.92
    9. Secondary Outcome
    Title Treatment-free Survival
    Description 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.
    Time Frame Time from registration to the date of initiation of subsequent therapy or death, median follow-up time is 37 months

    Outcome Measure Data

    Analysis Population Description
    All patients that were treated and evaluable were included in this endpoint.
    Arm/Group Title All Patients
    Arm/Group Description Patients receive: Cycle 1: Akt inhibitor MK2206 PO (90 or 135 mg) on days 1, 8, 15, and 22 (days 1, 8, 15, 22) Rituximab IV 375 mg/m^2 on day 8. Bendamustine IV 70 mg/m^2 on day 8 and 9. Cycles 2-6: Akt inhibitor MK2206 PO on days 1, 8, 15, and 22 (days 1, 8, 15, 22, and 29) Rituximab IV 500 mg/m^2 on day 1. Bendamustine IV 70 mg/m^2 on day 1 and 2.
    Measure Participants 13
    Median (95% Confidence Interval) [months]
    24.5

    Adverse Events

    Time Frame
    Adverse Event Reporting Description 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.
    Arm/Group Title Phase I: Dose Level 1 Phase I: Dose Level 2 Phase II
    Arm/Group Description Patients receive: Cycle 1: Akt inhibitor MK2206 PO 90 mg on days 1, 8, 15, and 22 (days 1, 8, 15, 22) Rituximab IV 375 mg/m^2 on day 8. Bendamustine IV 70 mg/m^2 on day 8 and 9. Cycles 2-6: Akt inhibitor MK2206 PO on days 1, 8, 15, and 22 (days 1, 8, 15, 22, and 29) Rituximab IV 500 mg/m^2 on day 1. Bendamustine IV 70 mg/m^2 on day 1 and 2. Patients receive: Cycle 1: Akt inhibitor MK2206 PO 135 mg on days 1, 8, 15, and 22 (days 1, 8, 15, 22) Rituximab IV 375 mg/m^2 on day 8. Bendamustine IV 70 mg/m^2 on day 8 and 9. Cycles 2-6: Akt inhibitor MK2206 PO on days 1, 8, 15, and 22 (days 1, 8, 15, 22, and 29) Rituximab IV 500 mg/m^2 on day 1. Bendamustine IV 70 mg/m^2 on day 1 and 2. Patients receive: Cycle 1: Akt inhibitor MK2206 PO 90 mg on days 1, 8, 15, and 22 (days 1, 8, 15, 22) Rituximab IV 375 mg/m^2 on day 8. Bendamustine IV 70 mg/m^2 on day 8 and 9. Cycles 2-6: Akt inhibitor MK2206 PO 90 mg on days 1, 8, 15, and 22 (days 1, 8, 15, 22, and 29) Rituximab IV 500 mg/m^2 on day 1. Bendamustine IV 70 mg/m^2 on day 1 and 2.
    All Cause Mortality
    Phase I: Dose Level 1 Phase I: Dose Level 2 Phase II
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total / (NaN) / (NaN) / (NaN)
    Serious Adverse Events
    Phase I: Dose Level 1 Phase I: Dose Level 2 Phase II
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 2/6 (33.3%) 1/4 (25%) 2/4 (50%)
    Blood and lymphatic system disorders
    Anemia 1/6 (16.7%) 1 0/4 (0%) 0 0/4 (0%) 0
    Febrile neutropenia 1/6 (16.7%) 1 1/4 (25%) 1 1/4 (25%) 1
    Hemolysis 1/6 (16.7%) 1 0/4 (0%) 0 0/4 (0%) 0
    Gastrointestinal disorders
    Diarrhea 0/6 (0%) 0 1/4 (25%) 1 0/4 (0%) 0
    Small intestinal obstruction 1/6 (16.7%) 1 0/4 (0%) 0 0/4 (0%) 0
    Infections and infestations
    Sinusitis 0/6 (0%) 0 0/4 (0%) 0 1/4 (25%) 1
    Investigations
    Neutrophil count decreased 1/6 (16.7%) 1 1/4 (25%) 1 0/4 (0%) 0
    Platelet count decreased 1/6 (16.7%) 1 0/4 (0%) 0 0/4 (0%) 0
    Metabolism and nutrition disorders
    Tumor lysis syndrome 0/6 (0%) 0 0/4 (0%) 0 1/4 (25%) 1
    Renal and urinary disorders
    Renal and urinary disorders - Other, specify 0/6 (0%) 0 0/4 (0%) 0 1/4 (25%) 1
    Surgical and medical procedures
    Surgical and medical procedures - Other, specify 1/6 (16.7%) 1 0/4 (0%) 0 0/4 (0%) 0
    Other (Not Including Serious) Adverse Events
    Phase I: Dose Level 1 Phase I: Dose Level 2 Phase II
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 6/6 (100%) 4/4 (100%) 4/4 (100%)
    Blood and lymphatic system disorders
    Anemia 4/6 (66.7%) 16 4/4 (100%) 21 3/4 (75%) 19
    Cardiac disorders
    Atrioventricular block complete 0/6 (0%) 0 0/4 (0%) 0 1/4 (25%) 1
    Cardiac disorders - Other, specify 1/6 (16.7%) 1 0/4 (0%) 0 0/4 (0%) 0
    Sinus bradycardia 1/6 (16.7%) 5 0/4 (0%) 0 2/4 (50%) 9
    Gastrointestinal disorders
    Abdominal pain 0/6 (0%) 0 1/4 (25%) 2 0/4 (0%) 0
    Diarrhea 2/6 (33.3%) 2 3/4 (75%) 5 1/4 (25%) 3
    Dyspepsia 0/6 (0%) 0 0/4 (0%) 0 1/4 (25%) 1
    Mucositis oral 1/6 (16.7%) 2 1/4 (25%) 1 1/4 (25%) 1
    Nausea 3/6 (50%) 6 3/4 (75%) 8 2/4 (50%) 6
    Vomiting 1/6 (16.7%) 2 2/4 (50%) 3 2/4 (50%) 4
    General disorders
    Chills 0/6 (0%) 0 1/4 (25%) 1 1/4 (25%) 1
    Fatigue 2/6 (33.3%) 3 1/4 (25%) 2 0/4 (0%) 0
    Fever 0/6 (0%) 0 0/4 (0%) 0 2/4 (50%) 2
    Injury, poisoning and procedural complications
    Hip fracture 0/6 (0%) 0 1/4 (25%) 1 0/4 (0%) 0
    Investigations
    Alkaline phosphatase increased 1/6 (16.7%) 1 0/4 (0%) 0 0/4 (0%) 0
    Blood bilirubin increased 1/6 (16.7%) 1 0/4 (0%) 0 0/4 (0%) 0
    Creatinine increased 0/6 (0%) 0 0/4 (0%) 0 1/4 (25%) 1
    Lymphocyte count decreased 1/6 (16.7%) 2 0/4 (0%) 0 2/4 (50%) 8
    Neutrophil count decreased 2/6 (33.3%) 2 3/4 (75%) 9 4/4 (100%) 10
    Platelet count decreased 2/6 (33.3%) 16 4/4 (100%) 19 4/4 (100%) 26
    White blood cell decreased 1/6 (16.7%) 1 3/4 (75%) 4 3/4 (75%) 6
    Metabolism and nutrition disorders
    Dehydration 0/6 (0%) 0 1/4 (25%) 2 0/4 (0%) 0
    Hyperglycemia 5/6 (83.3%) 15 1/4 (25%) 7 3/4 (75%) 21
    Hyperkalemia 0/6 (0%) 0 0/4 (0%) 0 1/4 (25%) 1
    Hypocalcemia 0/6 (0%) 0 1/4 (25%) 1 0/4 (0%) 0
    Hypokalemia 0/6 (0%) 0 1/4 (25%) 1 0/4 (0%) 0
    Skin and subcutaneous tissue disorders
    Rash acneiform 3/6 (50%) 9 3/4 (75%) 7 3/4 (75%) 4
    Surgical and medical procedures
    Surgical and medical procedures - Other, specify 0/6 (0%) 0 0/4 (0%) 0 1/4 (25%) 1
    Vascular disorders
    Hypotension 0/6 (0%) 0 1/4 (25%) 1 0/4 (0%) 0

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.

    Results Point of Contact

    Name/Title Wei Ding, MBBS, PhD
    Organization Mayo Clinic
    Phone
    Email ding.wei@mayo.edu
    Responsible Party:
    National Cancer Institute (NCI)
    ClinicalTrials.gov Identifier:
    NCT01369849
    Other Study ID Numbers:
    • NCI-2011-02675
    • NCI-2011-02675
    • CDR0000701372
    • NCCTG-N1087
    • N1087
    • N1087
    • U10CA180821
    • U10CA025224
    First Posted:
    Jun 9, 2011
    Last Update Posted:
    Sep 15, 2017
    Last Verified:
    Aug 1, 2017