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

This study has been terminated.
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT00612612
First received: February 8, 2008
Last updated: September 27, 2013
Last verified: September 2013
  Purpose

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.


Condition Intervention Phase
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
Drug: obatoclax mesylate
Drug: fludarabine phosphate
Biological: rituximab
Other: laboratory biomarker analysis
Phase 1

Study Type: Interventional
Study Design: Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
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)

Resource links provided by NLM:


Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • Maximum tolerated dose of obatoclax mesylate [ Time Frame: 28 days ] [ Designated as safety issue: Yes ]
    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 [ Time Frame: Up to 2 years ] [ Designated as safety issue: No ]
    Described using descriptive statistics. Ninety-five percent confidence intervals will be calculated where appropriate.


Enrollment: 28
Study Start Date: January 2008
Primary Completion Date: July 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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: obatoclax mesylate
Given IV
Other Name: GX15-070MS
Drug: fludarabine phosphate
Given IV
Other Names:
  • 2-F-ara-AMP
  • Beneflur
  • Fludara
Biological: rituximab
Given IV
Other Names:
  • IDEC-C2B8
  • IDEC-C2B8 monoclonal antibody
  • Mabthera
  • MOAB IDEC-C2B8
  • Rituxan
Other: laboratory biomarker analysis
Correlative study

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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00612612

Locations
United States, Massachusetts
Dana-Farber Cancer Institute
Boston, Massachusetts, United States, 02115
Sponsors and Collaborators
Investigators
Principal Investigator: Jennifer Brown Dana-Farber Cancer Institute
  More Information

No publications provided

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT00612612     History of Changes
Obsolete Identifiers: NCT00574938
Other Study ID Numbers: NCI-2009-00254, NCI-2009-00254, CDR0000582311, 07-100, 07-100, 7945, U01CA062490
Study First Received: February 8, 2008
Last Updated: September 27, 2013
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Leukemia
Leukemia, Lymphocytic, Chronic, B-Cell
Leukemia, Lymphoid
Leukemia, Prolymphocytic
Neoplasms by Histologic Type
Neoplasms
Leukemia, B-Cell
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Antibodies, Monoclonal
Fludarabine phosphate
Rituximab
Fludarabine
Vidarabine
Immunologic Factors
Physiological Effects of Drugs
Pharmacologic Actions
Antineoplastic Agents
Therapeutic Uses
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Immunosuppressive Agents
Antiviral Agents
Anti-Infective Agents
Antirheumatic Agents

ClinicalTrials.gov processed this record on August 01, 2014