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Clinical Trials (PDQ®)

Moxetumomab Pasudotox for Advanced Hairy Cell Leukemia

Basic Trial Information
Trial Description
     Summary
     Further Trial Information
     Eligibility Criteria
Trial Contact Information

Basic Trial Information

PhaseTypeStatusAgeSponsorProtocol IDs
Phase IIITreatmentActive18 and overNCI130106
13-C-0106, NCT01829711

Trial Description

Summary

Background:

  • Moxetumomab pasudotox is an experimental non-chemotherapy cancer treatment drug. It targets CD22, a molecule on the surface of essentially all hairy cell leukemia cells. Moxetumomab pasudotox binds to CD22, goes into the cell, and releases a toxin which kills the cell. In a phase I trial it had activity in relapsed/refractory hairy cell leukemia with safety profile supporting further clinical study (http://ncbi.nlm.nih.gov/pubmed/22355053). This is a phase III multicenter trial designed to confirm these results.

Objectives:

  • To see how effective moxetumomab pasudotox is at destroying hairy cell leukemia tumor cells and producing lasting complete remissions.

Eligibility:

  • Individuals at least 18 years of age who have hairy cell leukemia that has not responded to or relapsed at least twice after standard therapy.

Design:

  • Participants will be screened with a physical exam and medical history. Blood and urine samples will be collected. Imaging studies and heart and lung function tests will also be performed.
  • Participants will have 28-day cycles of treatment. They will receive the study drug on days 1, 3, and 5 of every cycle. Each dose will take about 30 minutes.
  • Treatment will be monitored with frequent blood and urine tests and imaging studies.
  • The study will focus on the results from the first 6 months of treatment. However, participants will continue to take the study drug for as long as it is effective and the side effects are not severe.
  • After stopping the study drug, participants will have frequent follow-up visits to monitor the outcome of the treatment.

Further Study Information

Background:

  • Hairy cell leukemia is an indolent B-cell leukemia comprising 2% of all leukemias, or approximately 900 of the 44,000 new cases of leukemia/year in the US
  • Over the last two decades, immunotoxin research has accumulated to support a role for CD22-targeted therapy in the treatment of HCL.
  • Moxetumomab pasudotox is a recombinant immunotoxin containing an Fv fragment of an anti-CD22 monoclonal antibody and truncated Pseudomonas exotoxin.
  • Moxetumomab pasudotox has demonstrated a high complete remission (CR) rate in patients with chemoresistant hairy cell leukemia (HCL) and has shown activity in pediatric acute lymphoblastic leukemia as well.
  • Modification of the structure of moxetumomab pasudotox has greatly improved binding and cytotoxicity toward CD22 expressing malignant cells compared to the precursor molecule. Preclinical and clinical studies have demonstrated that this increase in binding affinity results in improved antitumor activity and tolerability
  • 114 patients have been treated with moxetumomab pasudotox, including 48 with HCL. Moxetumomab pasudotox was generally well tolerated in HCL patients with no MTD defined and some patients treated for over a year.
  • Currently there are no approved agents with significant efficacy for HCL patients after failure of standard therapy

Objectives:

  • The primary objective of this study is to determine the rate of durable complete response (CR) in multiply relapsed HCL with moxetumomab pasudotox. To meet the primary endpoint, patients will need to meet standard criteria for CR by analysis of blood, bone marrow and imaging, and maintain a hematologic remission (HR), namely the blood counts needed for CR, for > 180 days.
  • Secondary objectives include determining the overall response rate (ORR), progressionfree survival (PFS), time to treatment failure (TTF), duration of responses (CR and PR), confirming safety, and pharmacokinetics.

Eligibility:

  • Histologically confirmed, immunotoxin-na(SqrRoot) ve hairy cell leukemia with a need for therapy based on at least one of the following criteria:

neutrophils < 1000/mm(3)

platelets < 100,000/mm(3)

hemoglobin < 10 g/dL)

symptomatic splenomegaly.

  • Have had at least 2 prior purine analogs, or at least 1 course of purine analog, or 1 of either rituximab or BRAF inhibitor.
  • Age greater than or equal to 18 years

Design:

  • This is a multicenter, single-arm study of moxetumomab pasudotox in patients with relapsed/refractory hairy cell leukemia.
  • 77 patients will be enrolled to receive 40 mcg/kg moxetumomab pasudotox IV on days 1, 3 and 5 of each 28 day cycle until the subject progresses, toxicity occurs, the subject begins alternate therapy, or 2 cycles beyond CR (for subjects who have no assessable minimal residual disease). If less than or equal to 2 of the first 25 patients do not achieve durable CR, no additional patients will be accrued.
  • The primary endpoint is to determine the durable complete response (CR) rate of moxetumomab pasudotox with a minimum duration of > 180 days. A durable CR will be defined as one in which hematologic remission (HR), namely the blood counts required for CR, are maintained for > 180 days from the time CR was first confirmed by tests of marrow, imaging and blood. Recurrent sustained (nontransient) cytopenias, particularly during the first 6 months of CR, will prompt a repeat bone marrow study to confirm relapse. The durable CR rate and its 95% CI will be constructed using the exact probability method (Clopper-Pearson exact interval) in the Intent-to-Treat population. With 77 patients enrolled, there will be 90% power to detect a difference between 28% and 13% (expected CR rate from best alternative non-chemotherapy treatment, rituximab) durable CR rates using 2- sided significance level of 0.05.

The overall IRB accrual ceiling is currently set at 80 to allow for a small number of patients that cannot be assessed for response.

Eligibility Criteria

  • INCLUSION CRITERIA:
  • Patients must have histologically confirmed hairy cell leukemia or hairy cell leukemia variant .with a need for therapy based on at least one of the following criteria:

neutrophils less than 1000/mm(3)

platelets less than 100,000/mm(3)

hemoglobin less than 10 g/dL)

symptomatic splenomegaly.

  • Patients must be Pseudomonas-immunotoxin na(SqrRoot) ve
  • Patients must have had at least 2 prior purine analogs, or at least 1 course of purine analog and 1 of either rituximub or BRAF inhibitor.
  • Men or women age greater than or equal to 18 years. Because this disease does not generally occur in children, children are excluded from this study, but will be eligible for future pediatric trials in other indications.
  • ECOG performance status less than or equal to 2.
  • The effects of moxetumomab pasudotox on the developing human fetus are unknown. For this reason, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation, and 4 months after completion of moxetumomab pasudotox administration. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately.
  • Patients must have adequate organ function as defined below:
  • total bilirubin less than or equal to 1.5 mg/dL, unless consistent with Gilbert s (ratio between total and direct bilirubin greater than 5)
  • AST and ALT less than or equal to 3 times upper limit of normal (ULN)
  • alkaline phosphatase less than or equal to 2.5 ULN
  • serum creatinine less than or equal to 1.5 mg/dL or creatinine clearance greater than or equal to 60 mL/min as estimated by the Cockcroft-Gault equation
  • Prothrombin time/INR or partial thromboplastin time less 2.5 ULN, fibrinogen greater than or equal to 0.5 LLN; if on warfarin, INR less than 3.5, if on any other anticoagulation, PT less than 2.5 times baseline
  • Ability to understand and the willingness to sign a written informed consent document.
  • Life expectancy greater than or equal to 6 months

EXCLUSION CRITERIA

  • Patients who have had chemotherapy, immunotherapy or radiotherapy within 4 weeks prior to entering the study.
  • Patients who are receiving any other investigational agents.
  • Patients with known brain metastases should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events.
  • Patients with clinically significant ophthalmologic findings during screening
  • Pregnant or breastfeeding females. The effects of moxetumomab pasudotox on the developing fetus are unknown. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with moxetumomab pasudotox breastfeeding should be discontinued if the mother is treated with moxetumomab pasudotox
  • Positive for Hepatitis B surface antigen unless the patient is on Lamivudine or Entecavir and Hepatitis B Viral DNA load is less than 2000 IU/mL.
  • Lymph nodes greater than 4cm or prior splenectomy
  • Active second malignancy requiring treatment other than minor resection of indolent cancers like basal cell and squamous skin cancers
  • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, malaria infection or psychiatric illness/social situations that would limit compliance with study requirements.
  • HIV-positive patients unless taking appropriate anti-HIV medications with a CD4 count of greater than 200. Otherwise, there may be increased risk of lethal infections when temporarily suppressing normal B-cells.
  • History of allogeneic bone marrow transplant.
  • Patients with history of both thromboembolism and known congenital hypercoagulable conditions.
  • Uncontrolled pulmonary infection, pulmonary edema.
  • Oxygen saturation at rest less than 88% measured by pulse oximetry or PaO (2) less than or equal to 55 mm Hg.
  • Serum albumin less than 2 g/dL.
  • Radioimmunotherapy within 2 years prior to enrollment in study.
  • ANC less than 1000/mm(3), or platelet count less than 50,000/mm(3), if these cytopenias are not judged by the investigator to be due to underlying disease (ie, potentially reversible with antineoplastic therapy). A patient will not be excluded because of pancytopenia greater than or equal to Grade 3, or erythropoietin dependence, if it is due to disease, based on the results of bone marrow studies.
  • Patients with less than 50% of predicted forced expiratory volume (FEV1) or less than 50% of predicted diffusing capacity for carbon monoxide (DLCO), corrected for hemoglobin concentration and alveolar volume. Note: Patients with no prior history of pulmonary illness are not required to have PFTs. FEV1 will be assessed after bronchodilator therapy.
  • Patients with history of thrombotic microangiopathy or TTP-HUS.
  • Patients with QTc elevation > grade 1
  • Patient on high dose estrogen (defined as > 0.625 mg/day of an estrogen compound.
  • Patients with clinical evidence of disseminated intravascular coagulation (grade 3-4)

Trial Contact Information

Trial Lead Organizations/Sponsors

National Cancer Institute

Robert KreitmanPrincipal Investigator

Elizabeth J Maestri, R.N.Ph: (301) 402-5633
  Email: maestrie@mail.nih.gov

Trial Sites

U.S.A.
Maryland
  Bethesda
 NIH - Warren Grant Magnuson Clinical Center
 For more information at the NIH Clinical Center contact National Cancer Institute Referral Office Ph: 888-624-1937
Ohio
  Columbus
 Arthur G. James Cancer Hospital and Richard J. Solove Research Institute at Ohio State University Comprehensive Cancer Center
Texas
  Houston
 M. D. Anderson Cancer Center at University of Texas

Link to the current ClinicalTrials.gov record.
NLM Identifer NCT01829711
ClinicalTrials.gov processed this data on August 25, 2014

Note: Information about this trial is from the ClinicalTrials.gov database. The versions designated for health professionals and patients contain the same text. Minor changes may be made to the ClinicalTrials.gov record to standardize the names of study sponsors, sites, and contacts. Cancer.gov only lists sites that are recruiting patients for active trials, whereas ClinicalTrials.gov lists all sites for all trials. Questions and comments regarding the presented information should be directed to ClinicalTrials.gov.

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