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Rituximab + Bendamustine at 70 mg/m\^2 for initial tolerability study (closed)

Rituximab + Bendamustine at 90 mg/m\^2 for initial tolerability study (closed)

Rituximab + Bendamustine (at the tolerated dose)

After initial tolerability studies are completed. Non-randomize up to 4 total participants to Bendamustine and/or Pentostatin with Rituximab

28 participants to pentostatin 4 mg/m\^2 days 1 and 15 of each cycle.

Rituximab 375 mg/m\^2 on day 1, 15 for 6 x 28-day cycles

1-4 participants to bendamustine 90 mg/m\^2/day, days 1 and 2 each cycle

Bendamustine

Treatment of infusion-related symptoms with acetaminophen is recommended.

Treatment of infusion-related symptoms with diphenhydramine is recommended.

Epinephrine should be available for immediate use in the event of a hypersensitivity reaction to Rituximab.

Antihistamines should be available for immediate use in the event of a hypersensitivity reaction to Rituximab.

Antihistamines

Corticosteroids should be available for immediate use in the event of a hypersensitivity reaction to Rituximab.

Corticosteroids

Additional treatment with bronchodilators may be indicated.

Bronchodilators

Additional treatment with intravenous (IV) saline may be indicated.

Intravenous (IV) Saline

Robert J Kreitman, M.D.

Background:

* Researchers are attempting to develop new treatments for hairy cell leukemia (HCL) that has not responded well to or has recurred after standard HCL therapies. One nonstandard treatment for HCL is rituximab, an antibody that binds to the cancer cells and helps the immune system destroy them. By combining rituximab with other anti-cancer drugs, researchers hope to determine whether the combined drugs are successful in treating HCL.
* Pentostatin and bendamustine are two anti-cancer drugs that have been used to treat different kinds of blood and immune system cancers. Bendamustine is approved to treat other kinds of leukemia and lymphoma, but it has not been used to treat HCL. Pentostatin has been used for more than 20 years to treat HCL, but it has not been combined with rituximab in official clinical trials.

Objectives:

* To determine whether rituximab with either pentostatin or bendamustine is a more effective treatment for HCL than rituximab alone.
* To determine whether pentostatin or bendamustine is a more effective treatment for HCL when combined with rituximab.

Eligibility:

- Individuals at least 18 years of age who have been diagnosed with hairy cell leukemia that has not responded well to or has relapsed after standard HCL therapies.

Design:

* The study will last for four treatment cycles of 28 days each.
* Prior to the study, participants will be screened with a full medical history and physical exam, bone marrow biopsy (if one has not been performed in the last 6 months), computed tomography (CT) or ultrasound scan, tumor measurements, and other tests as required by the researchers. Participants will provide blood and urine samples at this time as well.
* Rituximab with bendamustine: Participants will receive rituximab on Days 1 and 15 of each cycle and bendamustine on Days 1 and 2 of each cycle, for a total of four cycles.
* Rituximab with pentostatin: Participants will receive rituximab on Days 1 and 15 of each cycle and pentostatin on rituximab on Days 1 and 15 of each cycle, for a total of four cycles.
* Participants will have regular tests during the treatment cycles, including bone marrow biopsies and CT or ultrasound scans. Participants will also provide regular blood and urine samples to assess the results of treatment.

Background:

* Hairy cell leukemia (HCL) is highly responsive to purine analogs cladribine and pentostatin, without evidence of cure. Neither is standard after 2 courses, due to cumulative marrow and T-cell toxicity and declining remission rates and durations. Once resistant, patients after multiple relapses can die of disease-related cytopenias.
* Rituximab alone in 51 patients from 5 trials who had cytopenias and at least 1 prior purine analog resulted in 10 complete + 10 partial remissions (complete response (CR) + partial response (PR) = overall response rate (ORR 39%).
* Rituximab with cladribine gives high CR rates in 1st or 2nd line but is not standard.
* While cladribine use is more common for 1st and 2nd line, pentostatin is often used for subsequent treatment because of \< 100% cross-resistance.
* Retrospective published data for pentostatin plus rituximab in HCL include 7 of 7 responses with 6 (86%) CRs, and there are no prospective data.
* Recombinant immunotoxins targeting cluster of Differentiation 25 (CD25) (LMB-2) and cluster of differentiation-22 (CD22) (CAT-3888 (BL22) and R490A (HA22) are highly active in purine analog resistant HCL. Palliative pentostatin-rituximab is often used off-protocol for patients with immunogenicity needing more therapy.
* Bendamustine is approved for early treatment of chronic lymphocytic leukemia (CLL) and is effective with rituximab for relapsed/refractory CLL. Its use in HCL is unreported.
* CRs with minimal residual disease (MRD) by immunohistochemistry (IHC) of bone marrow biopsy (BMBx IHC), can relapse early. Tests for HCL MRD in blood or marrow include flow cytometry (fluorescence-activated cell sorting (FACS) or polymerase chain reaction (PCR) using consensus primers. The most sensitive MRD test in HCL is real-time quantitative PCR using sequence-specific primers (real-time quantitative polymerase chain reaction (RQ-PCR).
* Of 5 HCL-specific trials listed on Cancer.gov, 2 are phase II trials of cladribine + rituximab in 1st and 2nd line (1 randomized at National Institutes of Health (NIH), 1 non-randomized at MDA), and 3 NIH phase I-II trials of recombinant immunotoxins BL22, HA22 and LMB-2.

Objectives:

-Primary:

--To determine if pentostatin + rituximab and bendamustine + rituximab are each associated with adequate response rates (ORR=PR+CR) in patients with relapsed HCL, and, if so, to select which combination is likely to be superior.

Eligibility:

* HCL needing therapy, either greater than or equal to 2 prior courses of purine analog, 1 course purine analog plus greater than or equal to 1 course rituximab if \< 1 year response to the 1 course purine analog, diagnosis of HCL variant (HCLv), or unmutated immunoglobulin heavy variable 4-34 (IGHV4-34+) expressing HCL/HCLv.
* Prior treatment, ineligibility for, or patient refusal of recombinant immunotoxin.

Design:

* Rituximab 375 mg/m\^2 on day 1, 15 for 6 x 28-day cycles (all 72 patients).
* Initial tolerability study: 12 patients receive rituximab + bendamustine (nonrandom), including 6 at 70 mg/m\^2 and 6 at 90 mg/m\^2 of bendamustine.
* Randomize: 1) 28 patients to bendamustine 90 mg/m\^2/day, days 1 and 2 each cycle 2) 28 patients to pentostatin 4 mg/m\^2 days 1 and 15 of each cycle.
* Non-randomized: up to 4 patients to receive either bendamustine 90 mg/m\^2P2P/day, days 1 and 2 each cycle or pentostatin 4 mg/m\^2P2P days 1 and 15 of each cycle.
* Statistics: If \> 14/28 respond, can conclude with 90% power that response \> 40% in that arm. \>80% probability of selecting the better arm if true response probability is approximately 40-50% on the inferior arm and \>15% higher on the superior arm.
* Stratify to equalize the % of patients/arm refractory to last course of purine analog.
* Accrual Ceiling: 72 evaluable participants

Randomized Phase II Trial of Rituximab With Either Pentostatin or Bendamustine for Multiply Relapsed or Refractory Hairy Cell Leukemia

All individual participant data (IPD) recorded in the medical record will be shared with intramural investigators upon request.

Here is the number of participants with serious and/or non-serious adverse events assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.

Number of participants receiving pentostatin + rituximab and bendamustine + rituximab who achieve a CR +PR measured by the following response criteria. Complete remission is all of the following for at least 4 weeks: absolute neutrophil count ≥ 1500/mm\^3, platelets ≥ 100,000/mm\^3, hemoglobin ≥ 11g/dl, spleen non-palpable below the costal margin, or not below costal margin on computed tomography, and circulating hairy cell leukemia (HCL) cells either non-visible on Wright stain or \< 1% by flow cytometry. Partial response is all of the following for at least 4 weeks: neutrophils ≥ 1,500/µL or 50% improvement over baseline, platelets ≥100,000/µL or 50% improvement over baseline, hemoglobin ≥ 11.0 g/dL or 50% improvement over baseline, ≥ 50% decrease in circulating malignant HCL count from the pretreatment baseline, ≥ 50% reduction in sum of products of perpendicular diameters or decrease to ≤ 2 cm in evaluable (\> 2cm) lymphadenopathy.

Compare the 2 regimens - pentostatin + rituximab and bendamustine + rituximab in crossover when used after failure of the 1st regimen.

Response rate between participants who received rituximab plus either pentostatin or bendamustine measured by the following response criteria. Complete remission is all of the following for at least 4 weeks: absolute neutrophil count ≥ 1500/mm\^3, platelets ≥ 100,000/mm\^3, hemoglobin ≥ 11g/dl, spleen non-palpable below the costal margin, or not below costal margin on computed tomography, and circulating hairy cell leukemia (HCL) cells either non-visible on Wright stain or \< 1% by flow cytometry. Partial response is all of the following for at least 4 weeks: neutrophils ≥ 1,500/µL or 50% improvement over baseline, platelets ≥100,000/µL or 50% improvement over baseline, hemoglobin ≥ 11.0 g/dL or 50% improvement over baseline, ≥ 50% decrease in circulating malignant HCL count from the pretreatment baseline, ≥ 50% reduction in sum of products of perpendicular diameters. Progressive disease is appearance of new evaluable lymph nodes \>2cm. Stable disease is none of the above

The mechanism of thrombocytopenia after purine analog plus rituximab.

HCL biology was determined by cloning, sequencing and characterizing monoclonal immunoglobulin rearrangements, and other genes.

Determine if MRD levels and tumor markers (soluble cluster of Differentiation 25 (CD25) and cluster of differentiation-22 (CD22), and real-time quantitative reverse transcriptase polymerase chain reaction (RQ-PCR) correlate with response and clinical endpoints, and if bone marrow magnetic resonance imaging (MRI) signal correlates with bone marrow biopsy (BMBx) results, and whether these tests could in some cases possibly replace BMBx.

MRD-free survival is defined by the Response criteria.

Disease-free survival is the time from start of treatment to documented evidence of disease progression measured by the following response criteria. Progressive disease ≥50% increase in sum of products of perpendicular diameters of evaluable (\> 2cm) lymphadenopathy or appearance of new evaluable lymph nodes \>2cm.

OS is the time between the first day of treatment to the day of death.

Toxicity was assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.

Cluster of differentiation 4 (CD4+) T-cells assessed by analysis.

National Cancer Institute (NCI)

Principal Investigator

Treatment Assignment Code 5 (TAC 5) Rituximab + Bendamustine at 70 mg/m\^2 for initial tolerability study (closed) Rituximab 375 mg/m\^2 on day 1, 15 for 6 x 28-day cycles 6 participants to bendamustine 70 mg/m\^2/day, days 1 and 2 each cycle Acetaminophen: Treatment of infusion-related symptoms with acetaminophen is recommended.

Diphenhydramine: Treatment of infusion-related symptoms with diphenhydramine is recommended.

Epinephrine: Epinephrine should be available for immediate use in the event of a hypersensitivity reaction to Rituximab.

Antihistamines: Antihistamines should be available for immediate use in the event of a hypersensitivity reaction to Rituximab.

Corticosteroids: Corticosteroids should be available for immediate use in the event of a hypersensitivity reaction to Rituximab.

Bronchodilators: Additional treatment with bronchodilators may be indicated. Intravenous (IV) Saline: Additional treatment with intravenous (IV) saline may be indicated.

Non-Randomized to 70 mg/m2 Bendamustine-Rituximab

Treatment Assignment Code 5 (TAC 5) Rituximab + Bendamustine at 90 mg/m\^2 for initial tolerability study (closed) Rituximab 375 mg/m\^2 on day 1, 15 for 6 x 28-day cycles Bendamustine: 6 participants to bendamustine 90 mg/m\^2/day, days 1 and 2 each cycle Acetaminophen: Treatment of infusion-related symptoms with acetaminophen is recommended.

Diphenhydramine: Treatment of infusion-related symptoms with diphenhydramine is recommended.

Epinephrine: Epinephrine should be available for immediate use in the event of a hypersensitivity reaction to Rituximab.

Antihistamines: Antihistamines should be available for immediate use in the event of a hypersensitivity reaction to Rituximab.

Corticosteroids: Corticosteroids should be available for immediate use in the event of a hypersensitivity reaction to Rituximab.

Bronchodilators: Additional treatment with bronchodilators may be indicated. Intravenous (IV) Saline: Additional treatment with intravenous (IV) saline may be indicated

Non-randomized to 90 mg/m^2 Bendamustine-Rituximab

Treatment Assignment Code 5 (TAC 5) Rituximab + Bendamustine at 90 mg/m\^2 Rituximab: 28 participants Rituximab 375 mg/m\^2 on day 1, 15 for 6 x 28-day cycles Bendamustine:28 participants to bendamustine 90 mg/m\^2/day, days 1 and 2 each cycle, days 1 and 2 each cycle Acetaminophen: Treatment of infusion-related symptoms with acetaminophen is recommended.

Diphenhydramine: Treatment of infusion-related symptoms with diphenhydramine is recommended.

Epinephrine: Epinephrine should be available for immediate use in the event of a hypersensitivity reaction to Rituximab.

Antihistamines: Antihistamines should be available for immediate use in the event of a hypersensitivity reaction to Rituximab.

Corticosteroids: Corticosteroids should be available for immediate use in the event of a hypersensitivity reaction to Rituximab.

Bronchodilators: Additional treatment with bronchodilators may be indicated. Intravenous (IV) Saline: Additional treatment with intravenous (IV) saline may be indicated.

Randomized to 90 mg/m^2 Bendamustine-Rituximab

Treatment Assignment Code 2 (TAC 2) Rituximab + Pentostatin

Pentostatin: 28 participants to pentostatin 4 mg/m\^2 days 1 and 15 of each cycle.

Rituximab: Rituximab 375 mg/m\^2 on day 1, 15 for 6 x 28-day cycles

Acetaminophen: Treatment of infusion-related symptoms with acetaminophen is recommended.

Diphenhydramine: Treatment of infusion-related symptoms with diphenhydramine is recommended.

Epinephrine: Epinephrine should be available for immediate use in the event of a hypersensitivity reaction to Rituximab.

Antihistamines: Antihistamines should be available for immediate use in the event of a hypersensitivity reaction to Rituximab.

Corticosteroids: Corticosteroids should be available for immediate use in the event of a hypersensitivity reaction to Rituximab.

Bronchodilators: Additional treatment with bronchodilators may be indicated.

Intravenous (IV) Saline: Additional treatment with intravenous (IV) saline may be indicated.

Randomized to Pentostatin-Rituximab

Treatment Assignment Code 5 (TAC 5) Rituximab + Bendamustine at 90 mg/m\^2 or Rituxan + Pentostatin After initial tolerability studies are completed. Non-randomize up to 4 total participants to Bendamustine and/or Pentostatin with Rituximab Rituximab 375 mg/m\^2 on day 1, 15 for 6 x 28-day cycles Bendamustine: 1-4 participants to bendamustine 90 mg/m\^2/day, days 1 and 2 each cycle Pentostatin 1-4 participants to pentostatin 4 mg/m\^2 days 1 and 15 of each cycle.

Acetaminophen: Treatment of infusion-related symptoms with acetaminophen is recommended.

Diphenhydramine: Treatment of infusion-related symptoms with diphenhydramine is recommended.

Epinephrine: Epinephrine should be available for immediate use in the event of a hypersensitivity reaction to Rituximab.

Antihistamines: Antihistamines should be available for immediate use in the event of a hypersensitivity reaction to Rituximab.

Corticosteroids: Corticosteroids should be available for immediate use in the event of a hypersensitivity reaction to Rituximab.

Bronchodilators: Additional treatment with bronchodilators may be indicated. Intravenous (IV) Saline: Additional treatment with intravenous (IV) saline may be indicated.

Non-randomized to Bendamustine 90mg/m^2 or Pentostatin 4mg/m^2 With Rituximab

Total

Age, Categorical

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

Dr. Robert J. Kreitman

Complete Remission

Partial Response

Treatment Assignment Code 5 (TAC 5) Rituximab + Bendamustine at 90 mg/m\^2 or Rituxan + Pentostatin After initial tolerability studies are completed. Non-randomize up to 4 total participants to Bendamustine and/or Pentostatin with Rituximab Rituximab 375 mg/m\^2 on day 1, 15 for 6 x 28-day cycles Bendamustine: 1-4 participants to bendamustine 90 mg/m\^2/day, days 1 and 2 each cycle Pentostatin 1-4 participants to pentostatin 4 mg/m\^2 days 1 and 15 of each cycle.

Acetaminophen: Treatment of infusion-related symptoms with acetaminophen is recommended.

Diphenhydramine: Treatment of infusion-related symptoms with diphenhydramine is recommended.

Epinephrine: Epinephrine should be available for immediate use in the event of a hypersensitivity reaction to Rituximab.

Antihistamines: Antihistamines should be available for immediate use in the event of a hypersensitivity reaction to Rituximab.

Corticosteroids: Corticosteroids should be available for immediate use in the event of a hypersensitivity reaction to Rituximab.

Bronchodilators: Additional treatment with bronchodilators may be indicated. Intravenous (IV) Saline: Additional treatment with intravenous (IV) saline may be indicated

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Randomized Phase II Trial of Rituximab With Either Pentostatin or Bendamustine for Multiply Relapsed or Refractory Hairy Cell Leukemia	NCT01059786	Hairy Cell Leuk...	Pentostatin Rituximab Bendamustine Acetaminophen Diphenhydramine Epinephrine Antihistamines Corticosteroids Bronchodilators Intravenous (IV...	18 Years -	National Institutes of Health Clinical Center (CC)
Randomized Phase II Trial of Rituximab With Either Pentostatin or Bendamustine for Multiply Relapsed or Refractory Hairy Cell Leukemia	NCT01059786	Hairy Cell Leuk...	Pentostatin Rituximab Bendamustine Acetaminophen Diphenhydramine Epinephrine Antihistamines Corticosteroids Bronchodilators Intravenous (IV...	18 Years -	National Institutes of Health Clinical Center (CC)

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