Recruitment

Recruitment Status
Recruiting
Estimated Enrollment
16

Summary

Conditions
Hairy Cell Leukemia
Type
Interventional
Phase
Phase 1
Design
Allocation: N/AIntervention Model: Sequential AssignmentMasking: None (Open Label)Primary Purpose: Treatment

Participation Requirements

Age
Between 18 years and 125 years
Gender
Both males and females

Description

Background: Hairy cell leukemia (HCL) is an indolent CD22+ B-cell leukemia comprising 2% of all leukemias, or approximately 1200 of the 62,130 new cases of leukemia/year in the US. HCL variant (HCLv), also CD22+, is 10-20% as common as HCL, but more common in the relapsed/refractory population due t...

Background: Hairy cell leukemia (HCL) is an indolent CD22+ B-cell leukemia comprising 2% of all leukemias, or approximately 1200 of the 62,130 new cases of leukemia/year in the US. HCL variant (HCLv), also CD22+, is 10-20% as common as HCL, but more common in the relapsed/refractory population due to its poor prognosis and response to standard purine analog chemotherapy. HCLv cells are CD25-negative and wild type for BRAF, so HCLv patients are not candidates for BRAF inhibitors. CD25+ classic-appearing HCL-cells that express unmutated IGHV4-34 are wild-type for BRAF, remain brightly CD22 positive, and confer a poor prognosis when treated with chemotherapy. Moxetumomab pasudotox-tdfk is a recombinant immunotoxin containing a variable domain (Fv) fragment of an anti-CD22 monoclonal antibody and truncated Pseudomonas exotoxin, which kills CD22+ cells by binding to CD22 via the Fv fragment, and induction of apoptotic cell death catalytic inhibition of protein synthesis in the cytosol. Moxetumomab pasudotox-tdfk in phase 1 testing demonstrated a high complete response (CR) rate in patients with chemoresistant HCL, without dose-limiting toxicity (DLT), but with reversible grade 2 hemolytic uremic syndrome (HUS) not requiring plasmapheresis. Moxetumomab pasudotox-tdfk completed multicenter phase 3 testing in 80 patients, meeting its CR endpoint, with 8.8% incidence each of capillary leak syndrome (CLS, grade 3-4 2.5%), and HUS (grade 3-4 6.3%), both reversible. Moxetumomab pasudotox-tdfk is the only known non-chemotherapy-containing regimen for HCL which can consistently eradicate minimal residual disease (MRD), and this is associated with prolonged CR durations. Recently, US Food and Drug Administration (FDA) has accepted the Biologics License Application (BLA) for moxetumomab pasudotox-tdfk as the treatment of adult patients with HCL. Patients who did not achieve CR, or CR with MRD, often made neutralizing antibodies to the bacterial-based toxin, and/or had collections of HCL cells not completely eradicated by moxetumomab pasudotox-tdfk. Both issues may be addressed by the addition of anti-CD20 monoclonal antibody (Mab) rituximab to Moxetumomab pasudotox-tdfk. Objective: -To determine the safety and toxicity of Moxetumomab pasudotox-tdfk and rituximab used at the planned dose level, in patients with HCL and HCLv. Eligibility: HCL or HCLv with at least 1 prior purine analog, and, for HCL patients with >=2-years 1 month response, at least 1 other therapy. Need for treatment, either 1) ANC <1/nL, 2) Hgb <10g/dL, 3) Plt <100/nL, 4) symptomatic splenomegaly, or enlarging HCL mass > 2cm in short axis Serum creatinine < 1.5 mg/dL, or creatinine clearance greater than or equal to 60 mL/min by Cockcroft-Gault equation, where creatinine clearance = (140 age)(Kg weight)/(72 times Creatinine). No uncontrolled infection or cardiopulmonary dysfunction Design: Phase I trial, single arm, non-randomized, dose escalation Administration: Doses: Moxetumomab pasudotox-tdfk 30-40 mcg/kg intravenous (iv) over 30 min, rituximab 375 mg/m^2 iv, 50-400 mg/hr. Rituximab day 1 (begin day -2 on cycle 1), Moxetumomab pasudotox-tdfk days 1, 3, and 5. Patients will receive up 4 cycles past documentation of CR without MRD, maximum 8. To prevent renal toxicity and hypovolemia, patients will be encouraged to drink water gradually, approximately 1 cup/hour or 6L/day, not going >3 hours without drinking from days 1 to 8 and to keep a hydration diary to record daily fluid consumption. To prevent rituximab toxicity, patients will receive prophylactic dexamethasone orally 0.5- 2 hours before the 1st dose of rituximab, and before subsequent doses until rituximab infusion reactions are not seen. Patients will also receive diphenhydramine, famotidine, and acetaminophen. Dexamethasone 4 mg orally (maximum 2 doses/day) will be given as needed to treat nausea or fever associated with Moxetumomab pasudotox-tdfk, which might prevent adequate water intake Statistical design: Up to 10-16 patients are intended to be treated in the trial; if a higher dose of Moxetumomab pasudotox-tdfk is used, total 16 evaluable subjects may be required.

Tracking Information

NCT #
NCT03805932
Collaborators
Not Provided
Investigators
Principal Investigator: Robert J Kreitman, M.D. National Cancer Institute (NCI)