Oxaliplatin, Fludarabine, Cytarabine, and Rituximab in Patients With Richter’s Transformation and Leukemias

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Brief Title

Oxaliplatin, Fludarabine, Cytarabine, and Rituximab in Patients With Richter's Transformation and Leukemias

Official Title

A Phase I-II Study of Oxaliplatin, Fludarabine, Cytarabine, and Rituximab in Patients With Richter's Transformation, Prolymphocytic Leukemia, Aggressive, Relapsed or Refractory B-Cell Chronic Lymphocytic Leukemia

Brief Summary

      The goal of this clinical research study is to find the highest tolerable dose of fludarabine
      and cytarabine that can be given in combination with oxaliplatin and rituximab in the
      treatment of chronic lymphocytic leukemia (CLL), prolymphocytic leukemia, or Richter's
      transformation. Once the highest tolerable dose for this drug combination is found, the next
      goal of the study will be to find out if this combination therapy is effective in shrinking
      or slowing the growth of these diseases.
    

Detailed Description

      Cytarabine is designed to insert itself into DNA (the genetic material of cells) and stop the
      DNA from repairing itself.

      Oxaliplatin is designed to kill cancer cells by damaging their DNA.

      Fludarabine is designed to make cancer cells less able to repair damaged DNA. This may
      increase the likelihood of the cells dying.

      Rituximab is designed to attach to lymphoma cells, which may cause them to die.

      During the Phase I portion of the study, researchers will be testing different doses of the
      study drug combination. Oxaliplatin and rituximab will be given at the same dose level.
      However, fludarabine and cytarabine will be given daily for 2 days to the first 3
      participants, daily for 3 days to the next 3 participants, and daily for 4 days to the next 3
      participants. Although the plan is to treat 3, up to 6 participants may be treated in each of
      these groups.

      If participants who receive the fludarabine and cytarabine for 2 or 3 days do not experience
      intolerable side effects, after the second cycle they may receive the next higher dose (an
      additional day of fludarabine and cytarabine) for the following cycles.

      Once the highest tolerated dose of fludarabine and cytarabine given in combination with
      oxaliplatin and rituximab is found, the next group of participants entering the study will
      take part in the Phase II portion of the study. Participants in the Phase II portion will
      receive the study drugs at the highest tolerated dose found in the Phase I portion of the
      study. The goal of this part of the study is to look at how effective the drug combination is
      in treating patients with Richter's syndrome, prolymphocytic leukemia, and aggressive,
      relapsed, or refractory CLL. The same dose levels for all 4 drugs will be used throughout the
      Phase II portion of the study, unless intolerable side effects occur. In that case, the dose
      may be lowered or the treatment may be stopped.

        -  Each cycle will be repeated every 4-6 weeks, depending on your blood counts and your
           medical condition.

        -  You will receive oxaliplatin through a needle in your vein over about 2 hours on Days
           1-4 of every 28-day study "cycle."

        -  You will receive rituximab by vein over about 4-6 hours on Day 3 of the first cycle and
           on Day 1 on every cycle after that.

        -  Starting on Day 2, you will receive fludarabine by vein over about 30 minutes and
           cytarabine by vein over about 2 hours for 2, 3, or 4 days.

        -  On Day 6, you will receive peg-filgrastim subcutaneously (through a needle just under
           your skin) to help increase your white blood cell count.

        -  On the days that you receive the study drugs, you will also be given fluids (such as
           saline) by vein to keep you from becoming dehydrated. If you receive the treatment as an
           outpatient, this means that the visit may take up to 8 hours.

        -  Additional drugs will be given before each dose of rituximab to lower the risk of side
           effects. If side effects do occur, rituximab may have to be stopped until the side
           effects go away, at which point the drug may be restarted. This may make your time in
           the outpatient area longer.

        -  The first study cycle will be given at MD Anderson. Depending on your response, up to 5
           more cycles will be given either at MD Anderson or at home with your regular doctor.

        -  Every 1-2 weeks, blood samples (about 1 teaspoon each) will be drawn for routine tests.

        -  At the end of every cycle, you will have a physical exam and blood (about 1 teaspoon)
           will be drawn to determine whether you should receive another cycle.

        -  You will have a bone marrow biopsy/aspirate at the end of the 3rd and 6th cycles. The
           biopsy at the end of cycle 3 will be used to determine if you are responding to
           treatment and will determine whether you should continue to receive the study drug
           combination.

      You may remain on study for up to 6 cycles. You will be taken off-study early if the disease
      gets worse or intolerable side effects occur.

      Once you are no longer receiving treatment, you will have an end-of-treatment visit. At this
      visit, you will have a physical exam and blood (about 1 teaspoon) will be drawn for routine
      tests.

      If you achieve remission, after your last cycle is complete, you will have blood drawn (about
      2 teaspoons each) every 3 months for routine tests. These tests will continue for as long as
      you are in remission.

      This is an investigational study. Fludarabine, cytarabine, oxaliplatin, and rituximab are all
      FDA approved and commercially available. The use of these drugs together is investigational.
      Up to 102 patients will take part in this multicenter study. Up to 90 will be enrolled at The
      University of Texas (UT) MD Anderson Cancer Center.
    

Study Phase

Phase 1/Phase 2

Study Type

Interventional


Primary Outcome

Maximum Total Tolerated Dose (MTD) of Daily Combination Fludarabine 30 mg/m^2 and Cytarabine 500 mg/m^2 Among 3 Dose Levels (Dose Level 1: 2 Days, Dose Level 2: 3 Days or Dose Level 3: 4 Days)

Secondary Outcome

 Overall Response: Number of Participants With Complete Remission, Nodular Partial Remission, and Partial Remission

Condition

Richter's Transformation

Intervention

Oxaliplatin

Study Arms / Comparison Groups

 OFAR (Phase I)
Description:  Oxaliplatin starting dose 30 mg/m^2/day over 2 hours on days 1-4 before Fludarabine. Fludarabine 30 mg/m^2 daily intravenous (IV) over 30 minutes on days 2-3, 2-4, or 2-5 until maximum tolerated dose reached. Cytarabine 500 mg/m^2 daily IV, 2-hour infusion starting 4 hours after first fludarabine dose started, on days 2-3, 2-4, or 2-5, until maximum tolerated dose (MTD) reached. Rituximab 375 mg/m^2 IV on day 3, course 1 (on day 1, subsequent courses). Pegfilgrastim 6 mg subcutaneously once per chemotherapy cycle, approximately 24 hours after last dose of chemotherapy.

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

92

Start Date

May 2007

Completion Date

February 2012

Primary Completion Date

February 2012

Eligibility Criteria

        Inclusion Criteria:

          -  All patients with histologically or cytologically confirmed Richter's transformation,
             prolymphocytic leukemia, aggressive, or relapsed/refractory B-cell chronic lymphocytic
             leukemia are eligible for this protocol.

          -  Patients must be 18 years of age or older.

          -  Patients must have a performance status of 0-2 (Zubrod scale).

          -  Patients must have adequate renal function (serum creatinine <= 2 mg/dL or creatinine
             clearance > 50 mL/min). Patients with renal dysfunction due to organ infiltration by
             disease may be eligible after discussion with the principal investigator (PI) and
             consideration of appropriate dose adjustments.

          -  Patients must have adequate hepatic function (bilirubin <= 2 mg/dl; aspartate
             aminotransferase (AST or SGOT) and alanine aminotransferase (ALT or SGPT) < 2.5 * the
             upper limit of normal (ULN) for the reference lab unless due to leukemia or congenital
             hemolytic disorder [for bilirubin]). Patients with hepatic dysfunction due to organ
             infiltration by disease may be eligible after discussion with the PI and consideration
             of appropriate dose adjustments.

          -  Female patients of childbearing potential (including those < 1 year post-menopausal)
             and male patients must agree to use contraception.

          -  Patients must sign an informed consent indicating that they are aware of the
             investigational nature of this study.

          -  Patients must have platelet counts > 20,000, unless lower counts are due to disease
             involvement or autoimmune disorders.

        Exclusion Criteria:

          -  Untreated or uncontrolled life-threatening infection.

          -  Oxaliplatin, fludarabine, cytarabine or rituximab intolerance.

          -  Pregnancy or lactation.

          -  Chemotherapy and/or radiation therapy within 4 weeks.

          -  Medical condition, including mental illness or substance abuse, deemed by the
             investigator to be likely to interfere with a patient's ability to sign informed
             consent, cooperate and participate in the study, or interfere with the interpretation
             of the results.
      

Gender

All

Ages

18 Years - N/A

Accepts Healthy Volunteers

No

Contacts

William G. Wierda, M.D., PhD, , 

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT00472849

Organization ID

2006-1026


Responsible Party

Sponsor

Study Sponsor

M.D. Anderson Cancer Center

Collaborators

 Sanofi

Study Sponsor

William G. Wierda, M.D., PhD, Principal Investigator, M.D. Anderson Cancer Center


Verification Date

November 2013