A Pivotal Multicenter Trial of Moxetumomab Pasudotox in Relapsed/ Refractory Hairy Cell Leukemia
- 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
- 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), relapse-free survival (RFS), duration of responses (CR
and PR), confirming safety, and evaluating immunogenicity and pharmacokinetics.
- Histologically confirmed, immunotoxin-na 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 systemic therapies, including at least 2 prior courses of
purine analog, or 1 if the response to this course lasted < 1 year, or if the patient
had unacceptable toxicity to purine analog.
- Age greater than or equal to 18 years
- 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.
Allocation: Non-Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Rate of CR in patients treated with study drug
Every 4 weeks
Robert J Kreitman, M.D.
National Cancer Institute (NCI)
United States: Federal Government
|National Institutes of Health Clinical Center, 9000 Rockville Pike||Bethesda, Maryland 20892|
|Memorial Sloan Kettering Cancer Center||New York, New York 10021|
|MD Anderson Cancer Center||Houston, Texas 77030-4096|
|Ohio State University||Columbus, Ohio 43210|