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

Primary Purpose

B-cell Chronic Lymphocytic Leukemia, Leukemia, Prolymphocytic Leukemia

Status
Terminated
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
obatoclax mesylate
fludarabine phosphate
rituximab
laboratory biomarker analysis
Sponsored by
National Cancer Institute (NCI)
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for B-cell Chronic Lymphocytic Leukemia

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Dana-Farber Cancer Institute

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Treatment (obatoclax mesylate, fludarabine, rituximab)

Arm Description

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.

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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.

Full Information

First Posted
February 8, 2008
Last Updated
September 27, 2013
Sponsor
National Cancer Institute (NCI)
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1. Study Identification

Unique Protocol Identification Number
NCT00612612
Brief Title
Obatoclax, Fludarabine, and Rituximab in Treating Patients With Previously Treated Chronic Lymphocytic Leukemia
Official Title
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)
Study Type
Interventional

2. Study Status

Record Verification Date
September 2013
Overall Recruitment Status
Terminated
Study Start Date
January 2008 (undefined)
Primary Completion Date
July 2013 (Actual)
Study Completion Date
undefined (undefined)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
National Cancer Institute (NCI)

4. Oversight

5. Study Description

Brief Summary
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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
B-cell Chronic Lymphocytic Leukemia, 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

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
28 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Treatment (obatoclax mesylate, fludarabine, rituximab)
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
obatoclax mesylate
Other Intervention Name(s)
GX15-070MS
Intervention Description
Given IV
Intervention Type
Drug
Intervention Name(s)
fludarabine phosphate
Other Intervention Name(s)
2-F-ara-AMP, Beneflur, Fludara
Intervention Description
Given IV
Intervention Type
Biological
Intervention Name(s)
rituximab
Other Intervention Name(s)
IDEC-C2B8, IDEC-C2B8 monoclonal antibody, Mabthera, MOAB IDEC-C2B8, Rituxan
Intervention Description
Given IV
Intervention Type
Other
Intervention Name(s)
laboratory biomarker analysis
Intervention Description
Correlative study
Primary Outcome Measure Information:
Title
Maximum tolerated dose of obatoclax mesylate
Description
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.
Time Frame
28 days
Secondary Outcome Measure Information:
Title
Response evaluated using the Revised National Cancer Institute-sponsored Working Group Guidelines
Description
Described using descriptive statistics. Ninety-five percent confidence intervals will be calculated where appropriate.
Time Frame
Up to 2 years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Jennifer Brown
Organizational Affiliation
Dana-Farber Cancer Institute
Official's Role
Principal Investigator
Facility Information:
Facility Name
Dana-Farber Cancer Institute
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02115
Country
United States

12. IPD Sharing Statement

Learn more about this trial

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

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