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

Hairy Cell Leukemia Clinical Trial

Official title:

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT01059786
• Other study ID #: 100025
• Secondary ID: 10-C-0025
• Status: Active, not recruiting
• Phase: Phase 2
• Start date: July 1, 2010
• Est. completion date: December 31, 2025

Study information

• Verified date: April 2024
• Source: National Institutes of Health Clinical Center (CC)
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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 information / eligibility

• Status: Active, not recruiting
• Enrollment: 69
• Est. completion date: December 31, 2025
• Est. primary completion date: December 15, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

• INCLUSION CRITERIA:

• Evidence of Hairy Cell Leukemia (HCL) by flow cytometry of blood or a solid (lymph node) mass, confirmed by the Laboratory of Pathology, National Cancer Institute (NCI), including positivity for cluster of Differentiation 19 (CD19), cluster of differentiation-22 (CD22), cluster of differentiate 20 (CD20), and Integrin, alpha X (CD11c). Patients with flow cytometry consistent with hairy cell leukemia-variant (HCLv) are eligible, including those with cluster of Differentiation 25 (CD25) and/or cluster of differentiation 103 (CD103) negative disease.

• bone marrow biopsy (BMBx) or bone marrow aspiration (BMA) consistent with HCL, confirmed by National Institutes of Health (NIH) Laboratory of Pathology, NCI, or the Department of Laboratory Medicine, Clinical Center, NIH, unless the diagnosis can be confirmed from a solid (lymph node) mass.

• 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 cladribine and no less than 4 weeks after other prior treatment, if applicable.

• Neutropenia (Absolute neutrophil count (ANC) less than 1000 cells/microl).

• Anemia (Hemoglobin (Hgb) less than 10g/dL).

• Thrombocytopenia (Platelet (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 intravenous (i.v.) antibiotics.

• Increasing lytic bone lesions

Patients who have eligible blood counts within 4 weeks from enrollment will not be considered ineligible if subsequent blood counts prior to enrollment fluctuate and become ineligible up until the time of enrollment.

• One of the following:

• At least 2 prior courses of purine analog

• 1 prior course of purine analog plus greater than or equal to1 course of rituximab if the response to the course of purine analog lasted less than 1 year.

• Diagnosis of HCL variant (HCLv)

• Unmutated (>98% homology to germline) immunoglobulin heavy variable 4-34 (IGHV4-34+) expressing hairy cell leukemia (HCL)/HCLv

• Eastern Cooperative Oncology Group (ECOG) performance status (102) of 0-3

• Patients must be able to understand and give informed consent.

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

• Bilirubin less than or equal to 2 unless consistent with Gilbert's (total/direct greater than 5), alanine transaminase (ALT) and aspartate aminotransferase (AST) less than or equal to 3 x 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, unless progressive disease more than 2 months after cladribine is documented.

• 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.

• Patients must be willing to co-enroll in the investigators companion protocol 10-C-0066 titled Collection of Human Samples to Study Hairy Cell and other Leukemias, and to Develop Recombinant Immunotoxins for Cancer Treatment.

EXCLUSION CRITERIA:

• Presence of active untreated infection

• Uncontrolled coronary disease or New York Heart Association (NYHA) class III-IV heart disease.

• Known infection with human immunodeficiency virus (HIV), hepatitis B or C.

• 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 central nervous system (CNS) disease

• Patients with history of non-response to both pentostatin plus rituximab and to bendamustine plus rituximab.

• 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 patients vaccination record and possible requirements be reviewed. 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.

Related Conditions & MeSH terms

• Hairy Cell Leukemia
• Leukemia
• Leukemia, Hairy Cell

Intervention

Drug:
• 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
• Bendamustine
1-4 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.

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

Locations

Country	Name	City	State
United States	National Institutes of Health Clinical Center	Bethesda	Maryland

Sponsors (1)

Lead Sponsor	Collaborator
National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

References & Publications (3)

Bouroncle BA. Thirty-five years in the progress of hairy cell leukemia. Leuk Lymphoma. 1994;14 Suppl 1:1-12. — View Citation

Jemal A, Siegel R, Ward E, Murray T, Xu J, Thun MJ. Cancer statistics, 2007. CA Cancer J Clin. 2007 Jan-Feb;57(1):43-66. doi: 10.3322/canjclin.57.1.43. — View Citation

Kreitman RJ, Cheson BD. Malignancy: Current Clinical Practice: Treatment of Hairy Cell Leukemia at the Close of the 20th Century. Hematology. 1999;4(4):283-303. doi: 10.1080/10245332.1999.11746452. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Number of Participants With Serious and/or Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0)	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.	Date treatment consent signed to date off study, approximately 103 months and 19 days; 133 months and 11 days; 111 months and 15 days; 102 months and 25 days; 44 months and 14 days; and 19 months and 2 days for each group respectively.
Primary	Number of Participants Receiving Pentostatin + Rituximab and Bendamustine + Rituximab Who Achieve a Complete Remission (CR) + Partial Response (PR)	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.	At end of treatment, approximately 6 months
Secondary	Pentostatin + Rituximab and Bendamustine + Rituximab in Crossover When Used After Failure of the 1st Regimen	Compare the 2 regimens - pentostatin + rituximab and bendamustine + rituximab in crossover when used after failure of the 1st regimen.	4 years
Secondary	Response Rate	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	4 years
Secondary	Mechanism of Thrombocytopenia	The mechanism of thrombocytopenia after purine analog plus rituximab.	4 years
Secondary	Hairy Cell Leukemia (HCL) Biology	HCL biology was determined by cloning, sequencing and characterizing monoclonal immunoglobulin rearrangements, and other genes.	4 years
Secondary	Correlation of Measurable Residual Disease (MRD) Levels and Tumor Markers With Response	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.	4 years
Secondary	Measurable Residual Disease (MRD)-Free Survival	MRD-free survival is defined by the Response criteria.	4 years
Secondary	Disease-free Survival (DFS)	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.	time from start of treatment to documented evidence of disease progression
Secondary	Overall Survival	OS is the time between the first day of treatment to the day of death.	time between the first day of treatment to the day of death
Secondary	Toxicity	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.	4 years
Secondary	Cluster of Differentiation 4 (CD4+) T-cells	Cluster of differentiation 4 (CD4+) T-cells assessed by analysis.	4 years

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