Cladribine With Simultaneous or Delayed Rituximab to Treat Hairy Cell Leukemia

This study is currently recruiting participants.
Verified December 2013 by National Institutes of Health Clinical Center (CC)
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )
ClinicalTrials.gov Identifier:
NCT00923013
First received: June 17, 2009
Last updated: March 14, 2014
Last verified: December 2013
  Purpose

Background:

Hairy cell leukemia (HCL) is highly responsive to but not curable by cladribine (CdA). HCL responds to rituximab, which is not yet standard therapy for HCL.

Patients with the CD25-negative variant (HCLv) respond poorly to initial cladribine but do respond to rituximab in anecdotal reports.

Deoxycytidine kinase phosphorylates cladribine to CdATP, which incorporates into DNA, leading to DNA strand breaks and inhibition of DNA synthesis. Rituximab is an anti-CD20 monoclonal antibody which induces apoptosis and either complement or antibody dependent cytotoxicity (ADCC or CDC).

Patients in complete remission (CR) to cladribine have minimal residual disease (MRD) by immunohistochemistry of the bone marrow biopsy (BMBx IHC), a risk for early relapse. Tests for HCL MRD in blood or marrow include flow cytometry (FACS) or PCR using consensus primers. The most sensitive HCL MRD test is real-time quantitative PCR using sequence-specific primers (RQ-PCR).

In studies with limited follow-up, MRD detected by tests other than RQ-PCR can be eliminated by rituximab after cladribine in greater than 90 percent of patients, but MRD rates after cladribine alone are unknown. Simultaneous cladribine and rituximab might be superior or inferior to delaying rituximab until detection of MRD.

Only 4 HCL-specific trials are listed on Cancer.gov: a phase II trial of cladribine followed 4 weeks later by 8 weekly doses of rituximab, and phase I-II trials of recombinant immunotoxins targeting CD22 (BL22, HA22) and CD25 (LMB-2).

Objectives:

Primary:

To determine if HCL MRD differs at 6 months after cladribine with or without rituximab administered concurrently with cladribine.

Secondary:

  • To compare cladribine plus rituximab vs cladribine alone in terms of 1) initial MRD-free survival and disease-free survival, and 2) response to delayed rituximab for relapse, to determine if early rituximab compromises later response.
  • To determine if MRD levels and tumor markers (soluble CD25 and CD22) after cladribine and/or rituximab correlate with response and clinical endpoints.
  • To determine, using MRD and tumor marker data, when BMBx can be avoided.
  • To compare response and MRD after the 1st and 2nd courses of cladribine.
  • To evaluate the effects of cladribine and rituximab on normal T- and B-cells.
  • To enhance the study of HCL biology by cloning, sequencing and characterizing monoclonal immunoglobulin rearrangements.

Eligibility:

HCL with 0-1 prior courses of cladribine and treatment indicated.

Design:

Cladribine 0.15 mg/Kg/day times 5 doses each by 2hr i.v. infusion (days 1-5)

Rituximab 375 mg/m2/week times 8 weeks, randomized half to begin day 1, then repeat for all patients with blood-MRD relapse at least 6 months after cladribine. Also may repeat for those with blood-MRD relapse at least 6 months after delayed rituximab.

MRD tests used for the primary objective will be limited to BMBx IHC, blood FACS or blood consensus PCR, all CLIA certified. Blood MRD relapse is defined as FACS positivity or low blood counts (ANC less than 1500/microl, Plt less than 100,000/microl, or Hgb less than 11).

Stratification: 68 patients with 0 and 62 with 1 prior course of cladribine.

Statistics: 80% power to discriminate rates of MRD of 5 vs 25%, or 10 vs 35%

Non-randomized arm: 20 with HCLv will begin rituximab with cladribine.

Accrual Ceiling: 152 patients (130 HCL, 2 extra HCL if needed, and 20 HCLv.)


Condition Intervention Phase
Hairy Cell Leukemia
Drug: Cladribine
Drug: Rituximab
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Randomized Trial of Cladribine (CdA) With Simultaneous or Delayed Rituximab to Eliminate Hairy Cell Leukemia Minimal Residual Disease

Resource links provided by NLM:


Further study details as provided by National Institutes of Health Clinical Center (CC):

Primary Outcome Measures:
  • To determine if hairy cell leukemia (HCL) minimal residual disease (MRD) differs at 6 months after cladribine with or without rituximab administered concurrently with cladribine.

Secondary Outcome Measures:
  • To compare cladribine plus rituximab vs. cladribine alone in terms of 1) initial MRD-free survival and disease-free survival, and 2) response to delayed rituximab for relapse, to determine if early rituximab compromises later response.

Estimated Enrollment: 152
Study Start Date: October 2008
Estimated Study Completion Date: December 2015
Estimated Primary Completion Date: December 2015 (Final data collection date for primary outcome measure)
Intervention Details:
    Drug: Cladribine
    N/A
    Drug: Rituximab
    N/A
  Hide Detailed Description

Detailed Description:

Background:

Hairy cell leukemia (HCL) is highly responsive to but not curable by cladribine (CdA). HCL responds to rituximab, which is not yet standard therapy for HCL.

Patients with the CD25-negative variant (HCLv) respond poorly to initial cladribine but do respond to rituximab in anecdotal reports.

Purine analogs cladribine and pentostatin have similar efficacy for HCL, both inhibiting DNA synthesis selectively in HCL cells. Cladribine is effective after just 1 cycle. Rituximab is an anti-CD20 monoclonal antibody which induces apoptosis and either complement or antibody dependent cytotoxicity (ADCC or CDC).

Patients in complete remission (CR) to cladribine have minimal residual disease (MRD) by immunohistochemistry of the bone marrow biopsy (BMBx IHC), a risk for early relapse. Tests for HCL MRD in blood or marrow include flow cytometry (FACS) or PCR using consensus primers. The most sensitive HCL MRD test is real-time quantitative PCR using sequence-specific primers (RQ-PCR).

In studies with limited follow-up, MRD detected by tests other than RQ-PCR can be eliminated by rituximab after cladribine in > 90% of patients, but MRD rates after purine analog alone are unknown. Simultaneous cladribine and rituximab might be superior or inferior to delaying rituximab until detection of MRD.

Only 4 HCL-specific trials are listed on Cancer.gov: a phase II trial of cladribine followed 4 weeks later by 8 weekly doses of rituximab, and phase I-II trials of recombinant immunotoxins targeting CD22 (BL22, HA22) and CD25 (LMB-2).

Objectives:

Primary:

To determine if HCL MRD differs at 6 months after cladribine with or without rituximab administered concurrently with cladribine.

Secondary:

  • To compare cladribine plus rituximab vs cladribine alone in terms of 1) initial MRD-free survival and disease-free survival, and 2) response to delayed rituximab for relapse, to determine if early rituximab compromises later response.
  • To determine if MRD levels and tumor markers (soluble CD25 and CD22) after cladribine and/or rituximab correlate with response and clinical endpoints.
  • To determine, using MRD and tumor marker data, when BMBx can be avoided.
  • To compare response and MRD after the 1st and 2nd courses of cladribine.
  • To evaluate the effects of cladribine and rituximab on normal T- and B-cells.
  • To enhance the study of HCL biology by cloning, sequencing and characterizing monoclonal immunoglobulin rearrangements.

Eligibility:

HCL with 0-1 prior courses of cladribine or pentostatin and treatment indicated.

Design:

Cladribine 0.15 mg/Kg/day times 5 doses each by 2hr i.v. infusion (days 1-5)

Rituximab 375 mg/m2/week times 8 weeks, randomized half to begin day 1, then repeat for all patients with blood-MRD relapse at least 6 months after cladribine. Also may repeat for those with blood-MRD relapse at least 6 months after delayed rituximab.

MRD tests used for the primary objective will be limited to BMBx IHC, blood FACS or blood consensus PCR, all CLIA certified. Blood MRD relapse is defined as FACS positivity or low blood counts (ANC less than 1500/microl, Plt less than 100,000/microl, or Hgb less than 11).

Stratification: 68 HCL patients with 0 and 62 with 1 prior course of purine analog

Statistics: 80% power to discriminate rates of MRD of 5 vs 25%, or 10 vs 35%

Non-randomized arm: 20 with HCLv will begin rituximab with cladribine.

Accrual Ceiling: 152 patients (130 HCL, 2 extra HCL if needed, and 20 HCLv.)

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria
  • INCLUSION CRITERIA:

Evidence of HCL by flow cytometry, reviewed by the Laboratory of Pathology, NCI, including positivity for CD19, CD22, CD20, and CD11c.

BMBx consistent with HCL, reviewed by Laboratory of Pathology, NCI. BMBx may be negative in HCLv in patients with increasing peripheral blood HCLv cells and spleen size.

Treatment indicated based on demonstration of at least one of the following no more than 4 weeks from the time of enrollment, and no less than 6 months after prior purine analog and no less than 4 weeks after other prior treatment, if applicable.

  • Neutropenia (ANC less than 1000 cells/microl).
  • Anemia (Hgb less than 10g/dL).
  • Thrombocytopenia (Plt less than 100,000/microl).
  • Absolute lymphocyte count (ALC) of greater than 5,000 cells/microL
  • Symptomatic splenomegaly.
  • Enlarging lymph nodes greater than 2cm.
  • Repeated infections requiring oral or i.v. antibiotics.

No prior purine analog therapy except up to 1 prior course of cladribine.

No prior rituximab unless HCLv patient.

ECOG performance status (70) of 0-3.

Patients must be able to understand and give informed consent.

Women of child-bearing age and all men must use birth control of any type until at least 12 months after the last dose of therapy.

Creatinine less than or equal to 1.5 or creatinine clearance greater than or equal to 60 ml/ml.

Bilirubin less than or equal to 2 unless consistent with Gilbert s (total/direct greater than 5), ALT and AST less than or equal to 2.5 times upper limits of normal.

No other therapy (i.e. chemotherapy, interferon) for 4 weeks prior to study entry, or cladribine for 6 months prior to study entry.

Age at least 18

Men and women of reproductive potential must agree to use an acceptable method of birth control during treatment and for twelve months after completion of treatment.

Subject has provided written informed consent

EXCLUSION CRITERIA:

Presence of active untreated infection

Uncontrolled coronary disease or NYHA class III-IV heart disease.

Known infection with HIV, hepatitis B or C.

Patients with documented history of no response to cladribine, and without 50% improvement in platelets, hemoglobin or granulocytes. This exclusion does not apply to HCLv. These patients are eligible regardless of prior response to CDA.

Pregnant or lactating women.

Presence of active 2nd malignancy requiring treatment. 2nd malignancies with low activity which do not require treatment (i.e. low grade prostate cancer, basal cell or squamous cell skin cancer) do not constitute exclusions.

Inability to comply with study and/or follow-up procedures.

Presence of CNS disease

At the Investigator s discretion, receipt of a live vaccine within 4 weeks prior to randomization. Efficacy and/or safety of immunization during periods of B-cell depletion have not been adequately studied. It is recommended that a patient s vaccination record and possible requirements be reviewed. Per the investigator s discretion, the patient may have any required vaccination/booster administered at least 4 weeks prior to the initiation of study treatment. Review of the patient s immunization status for the following vaccinations is recommended: tetanus; diphtheria; influenza; pneumococcal polysaccharide; Varicella; measles, mumps and rubella (MMR); and hepatitis B. Patients who are considered to be at high risk for hepatitis B virus (HBV) infection and for whom the investigator has determined that immunization is indicated should complete the entire HBV vaccine series at least 4 weeks prior to participation in the study.

  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00923013

Contacts
Contact: Elizabeth J Maestri, R.N. (301) 402-5633 maestrie@mail.nih.gov
Contact: Robert J Kreitman, M.D. (301) 648-7375 kreitmar@mail.nih.gov

Locations
United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike Recruiting
Bethesda, Maryland, United States, 20892
Contact: For more information at the NIH Clinical Center contact National Cancer Institute Referral Office    (888) NCI-1937      
Sponsors and Collaborators
Investigators
Principal Investigator: Robert J Kreitman, M.D. National Cancer Institute (NCI)
  More Information

Additional Information:
Publications:
Responsible Party: National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )
ClinicalTrials.gov Identifier: NCT00923013     History of Changes
Obsolete Identifiers: NCT00781235
Other Study ID Numbers: 090005, 09-C-0005
Study First Received: June 17, 2009
Last Updated: March 14, 2014
Health Authority: United States: Federal Government

Keywords provided by National Institutes of Health Clinical Center (CC):
Hairy Cell Leukemia
Cladribine
Rituximab
Minimal Residual Disease
Leukemia

Additional relevant MeSH terms:
Leukemia
Leukemia, Hairy Cell
Neoplasm, Residual
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Neoplastic Processes
Pathologic Processes
Rituximab
Cladribine
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents

ClinicalTrials.gov processed this record on April 16, 2014