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

Phase 2

Active, not recruiting

Conditions: Hairy Cell Leukemia

Interventions: Drug: Rituximab
Drug: Pentostatin
Drug: Bendamustine
Drug: Acetaminophen
Drug: Diphenhydramine
Drug: Epinephrine
Drug: Antihistamines
Drug: Corticosteroids
Drug: Bronchodilators
Other: Intravenous (IV) Saline

Registration Number: NCT01059786

Lead Sponsor: National Cancer Institute (NCI)

Brief Summary: 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.

Detailed Description: 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

Recruitment & Eligibility

Status: ACTIVE_NOT_RECRUITING

Sex: All

Target Recruitment: 69

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Non-randomized to Bendamustine 90mg/m^2 or Pentostatin 4mg/m^2 with Rituximab	Diphenhydramine	After initial tolerability studies are completed. Non-randomize up to 4 total participants to Bendamustine and/or Pentostatin with Rituximab
Non-randomized to Bendamustine 90mg/m^2 or Pentostatin 4mg/m^2 with Rituximab	Bronchodilators	After initial tolerability studies are completed. Non-randomize up to 4 total participants to Bendamustine and/or Pentostatin with Rituximab
Arm 1 - Non-Randomized to 70 mg/m^2 Bendamustine-Rituximab	Acetaminophen	Rituximab + Bendamustine at 70 mg/m\^2 for initial tolerability study (closed)
Arm 1 - Non-Randomized to 70 mg/m^2 Bendamustine-Rituximab	Bronchodilators	Rituximab + Bendamustine at 70 mg/m\^2 for initial tolerability study (closed)
Arm 2 - Non-randomized to 90 mg/m^2 Bendamustine-Rituximab	Rituximab	Rituximab + Bendamustine at 90 mg/m\^2 for initial tolerability study (closed)
Arm 2 - Non-randomized to 90 mg/m^2 Bendamustine-Rituximab	Bendamustine	Rituximab + Bendamustine at 90 mg/m\^2 for initial tolerability study (closed)
Arm 2 - Non-randomized to 90 mg/m^2 Bendamustine-Rituximab	Antihistamines	Rituximab + Bendamustine at 90 mg/m\^2 for initial tolerability study (closed)
Arm 2 - Non-randomized to 90 mg/m^2 Bendamustine-Rituximab	Bronchodilators	Rituximab + Bendamustine at 90 mg/m\^2 for initial tolerability study (closed)
Arm 2 - Non-randomized to 90 mg/m^2 Bendamustine-Rituximab	Intravenous (IV) Saline	Rituximab + Bendamustine at 90 mg/m\^2 for initial tolerability study (closed)
Arm 3 - Randomized to 90 mg/m^2 Bendamustine-Rituximab	Bendamustine	Rituximab + Bendamustine (at the tolerated dose)
Arm 3 - Randomized to 90 mg/m^2 Bendamustine-Rituximab	Corticosteroids	Rituximab + Bendamustine (at the tolerated dose)
Arm 3 - Randomized to 90 mg/m^2 Bendamustine-Rituximab	Intravenous (IV) Saline	Rituximab + Bendamustine (at the tolerated dose)
Arm 3 - Randomized to 90 mg/m^2 Bendamustine-Rituximab	Antihistamines	Rituximab + Bendamustine (at the tolerated dose)
Arm 1 - Non-Randomized to 70 mg/m^2 Bendamustine-Rituximab	Corticosteroids	Rituximab + Bendamustine at 70 mg/m\^2 for initial tolerability study (closed)
Arm 2 - Non-randomized to 90 mg/m^2 Bendamustine-Rituximab	Diphenhydramine	Rituximab + Bendamustine at 90 mg/m\^2 for initial tolerability study (closed)
Arm 2 - Non-randomized to 90 mg/m^2 Bendamustine-Rituximab	Corticosteroids	Rituximab + Bendamustine at 90 mg/m\^2 for initial tolerability study (closed)
Arm 1 - Non-Randomized to 70 mg/m^2 Bendamustine-Rituximab	Antihistamines	Rituximab + Bendamustine at 70 mg/m\^2 for initial tolerability study (closed)
Arm 2 - Non-randomized to 90 mg/m^2 Bendamustine-Rituximab	Acetaminophen	Rituximab + Bendamustine at 90 mg/m\^2 for initial tolerability study (closed)
Arm 3 - Randomized to 90 mg/m^2 Bendamustine-Rituximab	Bronchodilators	Rituximab + Bendamustine (at the tolerated dose)
Arm 1 - Non-Randomized to 70 mg/m^2 Bendamustine-Rituximab	Intravenous (IV) Saline	Rituximab + Bendamustine at 70 mg/m\^2 for initial tolerability study (closed)
Non-randomized to Bendamustine 90mg/m^2 or Pentostatin 4mg/m^2 with Rituximab	Rituximab	After initial tolerability studies are completed. Non-randomize up to 4 total participants to Bendamustine and/or Pentostatin with Rituximab
Arm 4 - Randomized to Pentostatin-Rituximab	Bronchodilators	Rituximab + Pentostatin
Arm 4 - Randomized to Pentostatin-Rituximab	Antihistamines	Rituximab + Pentostatin
Arm 4 - Randomized to Pentostatin-Rituximab	Corticosteroids	Rituximab + Pentostatin
Arm 4 - Randomized to Pentostatin-Rituximab	Intravenous (IV) Saline	Rituximab + Pentostatin
Non-randomized to Bendamustine 90mg/m^2 or Pentostatin 4mg/m^2 with Rituximab	Corticosteroids	After initial tolerability studies are completed. Non-randomize up to 4 total participants to Bendamustine and/or Pentostatin with Rituximab
Non-randomized to Bendamustine 90mg/m^2 or Pentostatin 4mg/m^2 with Rituximab	Intravenous (IV) Saline	After initial tolerability studies are completed. Non-randomize up to 4 total participants to Bendamustine and/or Pentostatin with Rituximab
Non-randomized to Bendamustine 90mg/m^2 or Pentostatin 4mg/m^2 with Rituximab	Antihistamines	After initial tolerability studies are completed. Non-randomize up to 4 total participants to Bendamustine and/or Pentostatin with Rituximab
Arm 1 - Non-Randomized to 70 mg/m^2 Bendamustine-Rituximab	Bendamustine	Rituximab + Bendamustine at 70 mg/m\^2 for initial tolerability study (closed)
Arm 1 - Non-Randomized to 70 mg/m^2 Bendamustine-Rituximab	Rituximab	Rituximab + Bendamustine at 70 mg/m\^2 for initial tolerability study (closed)
Arm 1 - Non-Randomized to 70 mg/m^2 Bendamustine-Rituximab	Epinephrine	Rituximab + Bendamustine at 70 mg/m\^2 for initial tolerability study (closed)
Arm 1 - Non-Randomized to 70 mg/m^2 Bendamustine-Rituximab	Diphenhydramine	Rituximab + Bendamustine at 70 mg/m\^2 for initial tolerability study (closed)
Arm 2 - Non-randomized to 90 mg/m^2 Bendamustine-Rituximab	Epinephrine	Rituximab + Bendamustine at 90 mg/m\^2 for initial tolerability study (closed)
Arm 3 - Randomized to 90 mg/m^2 Bendamustine-Rituximab	Rituximab	Rituximab + Bendamustine (at the tolerated dose)
Arm 3 - Randomized to 90 mg/m^2 Bendamustine-Rituximab	Acetaminophen	Rituximab + Bendamustine (at the tolerated dose)
Arm 3 - Randomized to 90 mg/m^2 Bendamustine-Rituximab	Diphenhydramine	Rituximab + Bendamustine (at the tolerated dose)
Arm 3 - Randomized to 90 mg/m^2 Bendamustine-Rituximab	Epinephrine	Rituximab + Bendamustine (at the tolerated dose)
Arm 4 - Randomized to Pentostatin-Rituximab	Pentostatin	Rituximab + Pentostatin
Arm 4 - Randomized to Pentostatin-Rituximab	Acetaminophen	Rituximab + Pentostatin
Arm 4 - Randomized to Pentostatin-Rituximab	Rituximab	Rituximab + Pentostatin
Arm 4 - Randomized to Pentostatin-Rituximab	Diphenhydramine	Rituximab + Pentostatin
Arm 4 - Randomized to Pentostatin-Rituximab	Epinephrine	Rituximab + Pentostatin
Non-randomized to Bendamustine 90mg/m^2 or Pentostatin 4mg/m^2 with Rituximab	Pentostatin	After initial tolerability studies are completed. Non-randomize up to 4 total participants to Bendamustine and/or Pentostatin with Rituximab
Non-randomized to Bendamustine 90mg/m^2 or Pentostatin 4mg/m^2 with Rituximab	Bendamustine	After initial tolerability studies are completed. Non-randomize up to 4 total participants to Bendamustine and/or Pentostatin with Rituximab
Non-randomized to Bendamustine 90mg/m^2 or Pentostatin 4mg/m^2 with Rituximab	Acetaminophen	After initial tolerability studies are completed. Non-randomize up to 4 total participants to Bendamustine and/or Pentostatin with Rituximab
Non-randomized to Bendamustine 90mg/m^2 or Pentostatin 4mg/m^2 with Rituximab	Epinephrine	After initial tolerability studies are completed. Non-randomize up to 4 total participants to Bendamustine and/or Pentostatin with Rituximab

Primary Outcome Measures

Name	Time	Method
Number of Participants Receiving Pentostatin + Rituximab and Bendamustine + Rituximab Who Achieve a Complete Remission (CR) + Partial Response (PR)	At end of treatment, approximately 6 months	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.

Secondary Outcome Measures

Name	Time	Method
Response Rate	4 years	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
Hairy Cell Leukemia (HCL) Biology	4 years	HCL biology was determined by cloning, sequencing and characterizing monoclonal immunoglobulin rearrangements, and other genes.
Pentostatin + Rituximab and Bendamustine + Rituximab in Crossover When Used After Failure of the 1st Regimen	4 years	Compare the 2 regimens - pentostatin + rituximab and bendamustine + rituximab in crossover when used after failure of the 1st regimen.
Mechanism of Thrombocytopenia	4 years	The mechanism of thrombocytopenia after purine analog plus rituximab.
Disease-free Survival (DFS)	time from start of treatment to documented evidence of disease progression	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.
Cluster of Differentiation 4 (CD4+) T-cells	4 years	Cluster of differentiation 4 (CD4+) T-cells assessed by analysis.
Measurable Residual Disease (MRD)-Free Survival	4 years	MRD-free survival is defined by the Response criteria.
Correlation of Measurable Residual Disease (MRD) Levels and Tumor Markers With Response	4 years	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.
Overall Survival	time between the first day of treatment to the day of death	OS is the time between the first day of treatment to the day of death.
Toxicity	4 years	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.