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

Chronic Lymphocytic Leukemia Clinical Trial

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT01369849
• Other study ID #: NCI-2011-02675
• Secondary ID: NCI-2011-02675CD
• Status: Active, not recruiting
• Phase: Phase 1/Phase 2
• First received: June 8, 2011
• Last updated: August 24, 2015
• Start date: September 2011

Study information

• Verified date: June 2015
• Source: National Cancer Institute (NCI)
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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.

Description:

PRIMARY OBJECTIVES:

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)

SECONDARY OBJECTIVES:

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.

TERTIARY OBJECTIVES:

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 15
• Est. primary completion date: February 2014
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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 (?) or lambda (?) 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

Study Design

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Chronic Lymphocytic Leukemia
• Leukemia
• Leukemia, Lymphocytic, Chronic, B-Cell
• Leukemia, Lymphoid
• Lymphoma
• Recurrent Small Lymphocytic Lymphoma
• Refractory Chronic Lymphocytic Leukemia

Intervention

Drug:
• Akt Inhibitor MK2206
Given PO
• Bendamustine Hydrochloride
Given IV

Other:
• Laboratory Biomarker Analysis
Correlative studies

Biological:
• Rituximab
Given IV

Locations

Country	Name	City	State
United States	Essentia Health Saint Joseph's Medical Center	Brainerd	Minnesota
United States	Fairview Ridges Hospital	Burnsville	Minnesota
United States	Adena Regional Medical Center	Chillicothe	Ohio
United States	Columbus CCOP	Columbus	Ohio
United States	Doctors Hospital	Columbus	Ohio
United States	Grant Medical Center	Columbus	Ohio
United States	Mount Carmel Health Center West	Columbus	Ohio
United States	Riverside Methodist Hospital	Columbus	Ohio
United States	Mercy Hospital	Coon Rapids	Minnesota
United States	Grady Memorial Hospital	Delaware	Ohio
United States	Essentia Health Cancer Center	Duluth	Minnesota
United States	Essentia Health Saint Mary's Medical Center	Duluth	Minnesota
United States	Miller-Dwan Hospital	Duluth	Minnesota
United States	Fairview-Southdale Hospital	Edina	Minnesota
United States	Unity Hospital	Fridley	Minnesota
United States	Hutchinson Area Health Care	Hutchinson	Minnesota
United States	Fairfield Medical Center	Lancaster	Ohio
United States	Minnesota Oncology Hematology PA-Maplewood	Maplewood	Minnesota
United States	Saint John's Hospital - Healtheast	Maplewood	Minnesota
United States	Marietta Memorial Hospital	Marietta	Ohio
United States	Abbott-Northwestern Hospital	Minneapolis	Minnesota
United States	Hennepin County Medical Center	Minneapolis	Minnesota
United States	Knox Community Hospital	Mount Vernon	Ohio
United States	Licking Memorial Hospital	Newark	Ohio
United States	Southern Ohio Medical Center	Portsmouth	Ohio
United States	Rapid City Regional Hospital	Rapid City	South Dakota
United States	North Memorial Medical Health Center	Robbinsdale	Minnesota
United States	Mayo Clinic	Rochester	Minnesota
United States	Metro-Minnesota NCI Community Oncology Research Program	Saint Louis Park	Minnesota
United States	Park Nicollet Clinic - Saint Louis Park	Saint Louis Park	Minnesota
United States	Regions Hospital	Saint Paul	Minnesota
United States	United Hospital	Saint Paul	Minnesota
United States	Mayo Clinic in Arizona	Scottsdale	Arizona
United States	Saint Francis Regional Medical Center	Shakopee	Minnesota
United States	Mercy Medical Center-Sioux City	Sioux City	Iowa
United States	Saint Luke's Regional Medical Center	Sioux City	Iowa
United States	Siouxland Regional Cancer Center	Sioux City	Iowa
United States	Springfield Regional Medical Center	Springfield	Ohio
United States	Lakeview Hospital	Stillwater	Minnesota
United States	Ridgeview Medical Center	Waconia	Minnesota
United States	Saint Ann's Hospital	Westerville	Ohio
United States	Rice Memorial Hospital	Willmar	Minnesota
United States	Minnesota Oncology and Hematology PA-Woodbury	Woodbury	Minnesota
United States	Genesis HealthCare System	Zanesville	Ohio

Sponsors (1)

Lead Sponsor	Collaborator
National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	MTD of Akt inhibitor MK2206 defined as the dose level below the lowest dose that induces dose-limiting toxicity in at least one-third of patients graded according to NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 (Phase I)	The number and severity of all adverse events will be tabulated and summarized in this patient population. The grade 3+ adverse events will also be described and summarized in a similar fashion.	Up to 35 days	Yes
Primary	Proportion of complete response defined to be a CR or CRi noted as the objective status (Phase II)	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.	Up to 84 days	No
Secondary	Biomarker analysis (IgVH gene mutation, CD38, CD49d, ZAP-70 and FISH status)	Nonparametric quantitative comparisons by group will be made as appropriate (Fisher's exact, Wilcoxon rank sum, or Kruskal-Wallis test).	Baseline	No
Secondary	Duration of response	The distribution of duration of response will be estimated using the method of Kaplan-Meier.	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, assessed up to 5 years	No
Secondary	Minimal-residual disease	Minimal residual disease will be evaluated after treatment in patients who achieve a clinical response. Minimal residual disease status will be explored in relation to both the quality and duration of response.	Up to 5 years	No
Secondary	Overall response rate, estimated by the total number of complete or partial responses (CR, CRi, CCR, nPR, or PR) divided by the total number of evaluate patients	Exact binomial 95% confidence intervals for the true overall response rate will be calculated.	3 months post-treatment	No
Secondary	Treatment-free survival	The distribution of treatment free survival will be estimated using the method of Kaplan-Meier.	Time from registration to the date of initiation of subsequent therapy or death, assessed up to 5 years	No