Obatoclax, Fludarabine, and Rituximab in Treating Patients With Previously Treated Chronic Lymphocytic Leukemia

A Phase 1 Study of Obatoclax Mesylate (GX15-070MS) in Combination With Fludarabine-Based Chemoimmunotherapy in Previously Treated Patients With B-Cell Chronic Lymphocytic Leukemia (B-CLL)

Obatoclax may stop the growth of chronic lymphocytic leukemia by blocking blood flow to the cancer and by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as fludarabine, 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 obatoclax together with fludarabine and rituximab may kill more cancer cells. This phase I trial is studying the side effects and best dose of obatoclax when given together with fludarabine and rituximab in treating patients with B-cell chronic lymphocytic leukemia.

Study Overview

• Status: Terminated
• Conditions: Leukemia; B-cell Chronic Lymphocytic Leukemia; Prolymphocytic Leukemia; Refractory Chronic Lymphocytic Leukemia; Stage I Chronic Lymphocytic Leukemia; Stage II Chronic Lymphocytic Leukemia; Stage III Chronic Lymphocytic Leukemia; Stage IV Chronic Lymphocytic Leukemia
• Intervention / Treatment: Drug: fludarabine phosphate; Biological: rituximab; Other: laboratory biomarker analysis; Drug: obatoclax mesylate

Detailed Description

PRIMARY OBJECTIVE:

I. To determine the maximum tolerated dose of obatoclax mesylate in combination with fludarabine phosphate-rituximab (FR) in patients with relapsed chronic lymphocytic leukemia.

SECONDARY OBJECTIVES:

I. To evaluate toxicity of obatoclax mesylate in combination with FR in this patient population.

II. To determine objective response rate and progression-free survival of obatoclax mesylate in combination with FR.

III. To correlate levels of anti-apoptotic Bcl-2 family members with drug response.

IV. To determine whether apoptosis is induced via the mitochondrial pathway in response to obatoclax mesylate and further enhanced by FR.

OUTLINE: This is a dose-escalation study of obatoclax mesylate.

Patients receive obatoclax mesylate IV over 3 hours on days 1 and 3, fludarabine IV over 20-30 minutes on days 1-5, and rituximab IV over 4 hours on day 1 (days 1 and 3 of course 1 only). Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.

Patients undergo peripheral blood collection for correlative studies. Samples are analyzed for expression of pro- and anti-apoptotic Bcl-2 family members by western blot; apoptosis induction by measurement of lymphocyte count, Annexin V staining, and Caspase and PARP cleavage; activated Bax by immunoprecipitation; and Bax promoter polymorphism by PCR amplification and direct sequencing.

After completion of study therapy, patients are followed every 6 months.

• Study Type: Interventional
• Enrollment (Actual): 28
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Dana-Farber Cancer Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Histologically or cytologically confirmed diagnosis of B-cell chronic lymphocytic leukemia (B-CLL) or prolymphocytic leukemia (PLL) arising from CLL
• No de novo PLL
• Malignant B cells must co-express CD5 with CD19 or CD20
• Patients who lack CD23 expression on their leukemia cells may not have t(11;14) or cyclin D1 overexpression, to rule out mantle cell lymphoma
• Must have documented lymphocytosis of > 5,000/uL

• Must require therapy based on any of the following criteria:

  • Massive or progressive splenomegaly and/or lymphadenopathy
  • Anemia (hemoglobin < 11 g/dL) or thrombocytopenia (platelet count < 100,000/uL)
  • Presence of weight loss > 10% over the preceding 6-month period
  • NCI grade 2 or 3 fatigue
  • Fevers > 100.5 F or night sweats for > 2 weeks without evidence of infection
• Progressive lymphocytosis with an increase of > 50% over a 2-month period or an anticipated doubling time of less than 6 months
• Must have received at least one prior therapy for B-CLL
• No known brain metastases
• ECOG performance status (PS) 0-1 or Karnofsky PS 70-100%
• Total bilirubin normal (unless due to Gilbert syndrome or compensated hemolysis)
• Life expectancy > 3 months
• Creatinine normal
• Fertile patients must use effective contraception
• Not pregnant or nursing
• Negative pregnancy test
• Any number of prior therapies allowed
• At least 1 year since prior fludarabine phosphate-rituximab combination therapy
• No concurrent combination antiretroviral therapy for HIV-positive patients
• No chemotherapy or radiotherapy within the past 4 weeks (6 weeks for nitrosoureas or mitomycin C)
• No other concurrent investigational agents
• AST and ALT < 2.5 times upper limit of normal
• Recovered from all prior therapy

Exclusion Criteria:

• History of allergic reactions attributed to compounds of similar chemical or biologic composition to obatoclax mesylate or other agents used in study
• Active Coombs' positive autoimmune hemolytic anemia
• Chronic active hepatitis B patients if not on appropriate antiviral therapy (e.g., lamivudine, adefovir)
• Other neurological disorders or dysfunction or a history of seizure disorder

• Uncontrolled intercurrent illness including, but not limited to, any of the following:

  • Ongoing or active infection
  • Symptomatic congestive heart failure
  • Unstable angina pectoris
  • Cardiac arrhythmia including QTc > 450 msec
  • Psychiatric illness/social situations that would limit compliance with study requirements

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Treatment (obatoclax mesylate, fludarabine, rituximab); Patients receive obatoclax mesylate IV over 3 hours on days 1 and 3, fludarabine IV over 20-30 minutes on days 1-5, and rituximab IV over 4 hours on day 1 (days 1 and 3 of course 1 only). Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Patients undergo peripheral blood collection for correlative studies. Samples are analyzed for expression of pro- and anti-apoptotic Bcl-2 family members by western blot; apoptosis induction by measurement of lymphocyte count, Annexin V staining, and Caspase and PARP cleavage; activated Bax by immunoprecipitation; and Bax promoter polymorphism by PCR amplification and direct sequencing.

Drug: fludarabine phosphate; Given IV; Other Names: 2-F-ara-AMP; Beneflur; Fludara; Biological: rituximab; Given IV; Other Names: Rituxan; Mabthera; IDEC-C2B8; IDEC-C2B8 monoclonal antibody; MOAB IDEC-C2B8; Other: laboratory biomarker analysis; Correlative study; Drug: obatoclax mesylate; Given IV; Other Names: GX15-070MS

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum tolerated dose of obatoclax mesylate	DLT will be defined as any non-hematologic toxicity of grade 3 or greater severity (excluding asymptomatic grade 3 laboratory abnormalities that are not life-threatening and respond to treatment; grade 3 fatigue; grade 3 nausea, vomiting or diarrhea occurring without optimal prophylaxis; or expected grade 3 rituximab infusion reactions). Any grade 4 non-hematological toxicity, as well as any irreversible grade 2 cardiac, renal or neurologic toxicities, will be considered dose-limiting. Grading of non-hematologic toxicities will be according to NCI CTC version 3.0.	28 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Response evaluated using the Revised National Cancer Institute-sponsored Working Group Guidelines	Described using descriptive statistics. Ninety-five percent confidence intervals will be calculated where appropriate.	Up to 2 years

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Jennifer Brown, Dana-Farber Cancer Institute

Study record dates

Study Major Dates

• Study Start: January 1, 2008
• Primary Completion (Actual): July 1, 2013

Study Registration Dates

• First Submitted: February 8, 2008
• First Submitted That Met QC Criteria: February 8, 2008
• First Posted (Estimate): February 11, 2008

Study Record Updates

• Last Update Posted (Estimate): September 30, 2013
• Last Update Submitted That Met QC Criteria: September 27, 2013
• Last Verified: September 1, 2013

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Leukemia, B-Cell; Leukemia; Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia, Lymphoid; Leukemia, Prolymphocytic; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Immunological; Rituximab; Fludarabine; Fludarabine phosphate; Obatoclax
• Other Study ID Numbers: NCI-2009-00254 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); U01CA062490 (U.S. NIH Grant/Contract); 07-100 (Dana-Farber Cancer Institute); CDR0000582311; 7945 (Other Identifier: CTEP)