Clinical trial NCT01829711: Moxetumomab Pasudotox for Advanced Hairy Cell Leukemia
Official title: A Pivotal Multicenter Trial of Moxetumomab Pasudotox in Relapsed/ Refractory Hairy Cell Leukemia
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Leukemia, Hairy Cell
Keywords: Moxetumomab Pasudotox
CAT-8015
Anti-cd22 recombinant immunotoxin
Biologic Therapy
Monoclonal Antibody
Pseudomonas Exotoxin
Targeted Therapy
Lead sponsor: MedImmune LLC
Sponsor class: INDUSTRY
First posted: 2013-04-11
Enrollment: 80
Sex: ALL
Minimum age (years): 18
Maximum age (years): 100
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief 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.

Detailed description: Background:

* Hairy cell leukemia (HCL) 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 response (CR) rate in patients with chemoresistant 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
* Currently there are no approved agents with significant efficacy for HCL patients after failure of standard therapy

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 moxetumomab pasudotox intravenously (IV) on days 1, 3 and 5 of each 28 day cycle for a maximum of 6 cycles or until disease progression, unacceptable toxicity occurs, the subject begins alternate therapy, or documented CR (for subjects who have no assessable minimal residual disease and not to exceed 6 cycles). If less than or equal to 2 of the first 25 patients do not achieve durable CR, no additional patients will be accrued.
* 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
* Patients must be Pseudomonas-immunotoxin naive
* Patients must have had at least 2 prior purine analogs, or at least 1 course of purine analog and 1 of either rituximab or BRAF inhibitor.
* Men or women age greater than or equal to 18 years.
* ECOG performance status less than or equal to 2.
* Patients must have adequate organ function

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
* Patients with clinically significant ophthalmologic findings during screening
* Pregnant or breastfeeding females.
* Positive for Hepatitis B core antibody or surface antigen unless the patient is on Lamivudine or Entecavir and Hepatitis B Viral DNA load is less than 2000 IU/mL.
* Active second malignancy requiring treatment other than minor resection of indolent cancers like basal cell and squamous skin cancers
* HIV-positive patients unless taking appropriate anti-HIV medications with a CD4 count of greater than 200.
* History of allogeneic bone marrow transplant.
* Patients with history of both thromboembolism and known congenital hypercoagulable conditions.
* Uncontrolled pulmonary infection, pulmonary edema.
* Adequate oxygen saturation
* Radioimmunotherapy within 2 years prior to enrollment in study.
* Adequate hematologic function
* Adequate lung function
* Patients with history of thrombotic microangiopathy or thrombotic microangiopathy / hemolytic uremic syndrome
* Patients with QTc interval (Friderica) elevation \> 500 msec based on at least 2 separate 12-lead ECGs
* Patient on high dose estrogen
* Patients with clinical evidence of disseminated intravascular coagulation

Primary outcomes:
measure: Percentage of Participants With Durable Complete Response (CR) Assessed by Blinded Independent Central Review
timeFrame: Full disease assessment (CBC, bone marrow and imaging) at end of treatment (EOT; up to 24 weeks) and post EOT Day 181; CBC monthly for 6 months post EOT, every 3 months post Day 181 for first 2 years and every 6 months thereafter (approximately 6 years)
measure: Percentage of Participants With Durable CR by Investigator's Assessment
timeFrame: Full disease assessment (CBC, bone marrow and imaging) at end of treatment (EOT; up to 24 weeks) and post EOT Day 181; CBC monthly for 6 months post EOT, every 3 months post Day 181 for first 2 years and every 6 months thereafter (approximately 6 years)
Secondary outcomes:
measure: Percentage of Participants With Minimal Residual Disease (MRD) Positive or MRD Negative CR Assessed by Blinded Independent Central Review
timeFrame: Prior to each treatment cycle, EOT (up to 24 weeks), monthly from the EOT assessment until the Day 181 assessment (only for CBC), at follow-up visits every 3 months for the next 24 months, and every 6 months thereafter (approximately 6 years)
measure: Percentage of Participants With MRD Positive or MRD Negative CR by Investigator's Assessment
timeFrame: Prior to each treatment cycle, end of treatment, and at follow-up visits every 3 months for the next 24 months and every 6 months thereafter (Approximately 6 years)
measure: Time to CR Assessed by Blinded Independent Central Review
timeFrame: Prior to each treatment cycle, EOT (up to 24 weeks), monthly from the EOT assessment until the Day 181 assessment (only for CBC), at follow-up visits every 3 months for the next 24 months, and every 6 months thereafter (approximately 6 years)
measure: Duration of CR Assessed by Blinded Independent Central Review
timeFrame: Prior to each treatment cycle, EOT (up to 24 weeks), monthly from the EOT assessment until the Day 181 assessment (only for CBC), at follow-up visits every 3 months for the next 24 months, and every 6 months thereafter (approximately 6 years)
measure: Duration of Hematologic Remission
timeFrame: Prior to each treatment cycle, EOT (up to 24 weeks), monthly from the EOT assessment until the Day 181 assessment (only for CBC), at follow-up visits every 3 months for the next 24 months, and every 6 months thereafter (approximately 6 years)
measure: Time to Hematologic Remission
timeFrame: Prior to each treatment cycle, EOT (up to 24 weeks), monthly from the EOT assessment until the Day 181 assessment (only for CBC), at follow-up visits every 3 months for the next 24 months, and every 6 months thereafter (approximately 6 years)
measure: Percentage of Participants With Objective Response (OR) Assessed by Blinded Independent Central Review
timeFrame: Prior to each treatment cycle, EOT (up to 24 weeks), monthly from the EOT assessment until the Day 181 assessment (only for CBC), at follow-up visits every 3 months for the next 24 months, and every 6 months thereafter (approximately 6 years)
measure: Percentage of Participants With Objective Response by Investigator's Assessment
timeFrame: Prior to each treatment cycle, end of treatment, and at follow-up visits every 3 months for the next 24 months and every 6 months thereafter (Approximately 6 years)
measure: Time to Objective Response Assessed by Blinded Independent Central Review
timeFrame: Prior to each treatment cycle, EOT (up to 24 weeks), monthly from the EOT assessment until the Day 181 assessment (only for CBC), at follow-up visits every 3 months for the next 24 months, and every 6 months thereafter (approximately 6 years)
measure: Duration of Objective Response Assessed by Blinded Independent Central Review
timeFrame: Prior to each treatment cycle, EOT (up to 24 weeks), monthly from the EOT assessment until the Day 181 assessment (only for CBC), at follow-up visits every 3 months for the next 24 months, and every 6 months thereafter (approximately 6 years)
measure: Progression-free Survival (PFS) Assessed by Blinded Independent Central Review
timeFrame: Prior to each treatment cycle, EOT (up to 24 weeks), monthly from the EOT assessment until the Day 181 assessment (only for CBC), at follow-up visits every 3 months for the next 24 months, and every 6 months thereafter (approximately 6 years)
measure: Time to Treatment Failure (TTF) Assessed by Blinded Independent Central Review
timeFrame: Prior to each treatment cycle, EOT (up to 24 weeks), monthly from the EOT assessment until the Day 181 assessment (only for CBC), at follow-up visits every 3 months for the next 24 months, and every 6 months thereafter (approximately 6 years)
measure: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs)
timeFrame: From the start of study treatment (Day 1) through 4-6 weeks after last dose of Cycle 6 (28-day cycle) (approximately 7 months)
measure: Number of Participants With Abnormal Clinical Laboratory Results Reported as TEAEs
timeFrame: From the start of study treatment (Day 1) through 4-6 weeks after last dose of Cycle 6 (28-day cycle) (approximately 7 months)
measure: Number of Participants With Abnormal Vital Signs Reported as TEAEs
timeFrame: From the start of study treatment (Day 1) through 4-6 weeks after last dose of Cycle 6 (28-day cycle) (approximately 7 months)
measure: Number of Participants With Abnormal Electrocardiogram (ECG) Reported as TEAEs
timeFrame: From the start of study treatment (Day 1) through 4-6 weeks after last dose of Cycle 6 (28-day cycle) (approximately 7 months)
measure: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Moxetumomab Pasudotox
timeFrame: Cycle 1 Day 1 (pre-dose; 5 mins and 3 hr post dose); Cycle 1 Day 5 (pre-dose; 5 mins, 1 hr, 3 hr, and 6 hrs post dose); and Cycle 2 Day 1 (pre-dose; 5 mins and 3 hr post dose)
measure: Maximum Observed Plasma Concentration (Cmax) of Moxetumomab Pasudotox
timeFrame: Cycle 1 Day 1 (pre-dose; 5 mins and 3 hr post dose); Cycle 1 Day 5 (pre-dose; 5 mins, 1 hr, 3 hr, and 6 hrs post dose); and Cycle 2 Day 1 (pre-dose; 5 mins and 3 hr post dose)
measure: Time of Last (Tlast) Measurable Concentration of Moxetumomab Pasudotox
timeFrame: Cycle 1 Day 1 (pre-dose; 5 mins and 3 hr post dose); Cycle 1 Day 5 (pre-dose; 5 mins, 1 hr, 3 hr, and 6 hrs post dose); and Cycle 2 Day 1 (pre-dose; 5 mins and 3 hr post dose)
measure: Area Under the Plasma Concentration-time Curve From Time Zero to Time of the Last Quantifiable Concentration (AUC0-last) of Moxetumomab Pasudotox
timeFrame: Cycle 1 Day 1 (pre-dose; 5 mins and 3 hr post dose); Cycle 1 Day 5 (pre-dose; 5 mins, 1 hr, 3 hr, and 6 hrs post dose); and Cycle 2 Day 1 (pre-dose; 5 mins and 3 hr post dose)
measure: Area Under the Plasma Concentration-time Curve From Time Zero to 3 Hours (AUC0-3hr) Post End of Moxetumomab Pasudotox
timeFrame: Cycle 1 Day 1 (pre-dose; 5 mins and 3 hr post dose); Cycle 1 Day 5 (pre-dose; 5 mins, 1 hr, and 3 hr post dose); and Cycle 2 Day 1 (pre-dose; 5 mins and 3 hr post dose)
measure: Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of Moxetumomab Pasudotox
timeFrame: Cycle 1 Day 1 (pre-dose; 5 mins and 3 hr post dose); Cycle 1 Day 5 (pre-dose; 5 mins, 1 hr, 3 hr, and 6 hrs post dose); and Cycle 2 Day 1 (pre-dose; 5 mins and 3 hr post dose)
measure: Area Under the Plasma Concentration-time Curve Extrapolated (AUCExt) of Moxetumomab Pasudotox
timeFrame: Cycle 1 Day 1 (pre-dose; 5 mins and 3 hr post dose); Cycle 1 Day 5 (pre-dose; 5 mins, 1 hr, 3 hr, and 6 hrs post dose); and Cycle 2 Day 1 (pre-dose; 5 mins and 3 hr post dose)
measure: Systemic Clearance (CL) of Moxetumomab Pasudotox
timeFrame: Cycle 1 Day 1 (pre-dose; 5 mins and 3 hr post dose); Cycle 1 Day 5 (pre-dose; 5 mins, 1 hr, 3 hr, and 6 hrs post dose); and Cycle 2 Day 1 (pre-dose; 5 mins and 3 hr post dose)
measure: Terminal Half Life (t1/2) of Moxetumomab Pasudotox
timeFrame: Cycle 1 Day 1 (pre-dose; 5 mins and 3 hr post dose); Cycle 1 Day 5 (pre-dose; 5 mins, 1 hr, 3 hr, and 6 hrs post dose); and Cycle 2 Day 1 (pre-dose; 5 mins and 3 hr post dose)
measure: Percentage of Participants With Positive Anti-drug Antibodies (ADA), Neutralizing Anti-drug Antibodies (nAb) and Specificity (CD22 and PE38) Positive to Moxetumomab Pasudotox
timeFrame: Pre-infusion on Day 1 of Cycles 1, 2, 3, and 5; at the End of Treatment (4 to 6 weeks after the last dose; approximately 7 months)
Other outcomes:
Locations:
city: Duarte
country: United States
facility: Research Site
state: California
city: Los Angeles
country: United States
facility: Research Site
state: California
city: Miami
country: United States
facility: Research Site
state: Florida
city: Chicago
country: United States
facility: Research Site
state: Illinois
city: Baltimore
country: United States
facility: Research Site
state: Maryland
city: Bethesda
country: United States
facility: Research Site
state: Maryland
city: Albuquerque
country: United States
facility: Research Site
state: New Mexico
city: New York
country: United States
facility: Research Site
state: New York
city: Houston
country: United States
facility: Research Site
state: Texas
city: Antwerp
country: Belgium
facility: Research Site
city: Gent
country: Belgium
facility: Research Site
city: Edmonton
country: Canada
facility: Research Site
state: Alberta
city: Brno
country: Czechia
facility: Research Site
city: Caen
country: France
facility: Research Site
city: Le Chesnay Cedex
country: France
facility: Research Site
city: Pessac Cedex
country: France
facility: Research Site
city: Pierre-Bénite
country: France
facility: Research Site
city: Rouen Cedex 1
country: France
facility: Research Site
city: Strasbourg Cedex
country: France
facility: Research Site
city: Berlin
country: Germany
facility: Research Site
city: Giessen
country: Germany
facility: Research Site
city: Heidelberg
country: Germany
facility: Research Site
city: Dublin
country: Ireland
facility: Research Site
city: Haifa
country: Israel
facility: Research Site
city: Bologna
country: Italy
facility: Research Site
city: Genova
country: Italy
facility: Research Site
city: Milano
country: Italy
facility: Research Site
city: Siena
country: Italy
facility: Research Site
city: Bergen
country: Norway
facility: Research Site
city: Gdańsk
country: Poland
facility: Research Site
city: Łódź
country: Poland
facility: Research Site
city: Belgrade
country: Serbia
facility: Research Site
city: Barcelona
country: Spain
facility: Research Site
city: Sutton
country: United Kingdom
facility: Research Site
Study officials:
affiliation: MedImmune LLC
name: MedImmune LLC
role: STUDY_DIRECTOR
References:
citation: Bouroncle BA. Thirty-five years in the progress of hairy cell leukemia. Leuk Lymphoma. 1994;14 Suppl 1:1-12.
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.
citation: Sharpe RW, Bethel KJ. Hairy cell leukemia: diagnostic pathology. Hematol Oncol Clin North Am. 2006 Oct;20(5):1023-49. doi: 10.1016/j.hoc.2006.06.010.
citation: Kreitman RJ, Tallman MS, Robak T, Coutre S, Wilson WH, Stetler-Stevenson M, Fitzgerald DJ, Lechleider R, Pastan I. Phase I trial of anti-CD22 recombinant immunotoxin moxetumomab pasudotox (CAT-8015 or HA22) in patients with hairy cell leukemia. J Clin Oncol. 2012 May 20;30(15):1822-8. doi: 10.1200/JCO.2011.38.1756. Epub 2012 Feb 21.
citation: Kreitman RJ, Dearden C, Zinzani PL, Delgado J, Karlin L, Robak T, Gladstone DE, le Coutre P, Dietrich S, Gotic M, Larratt L, Offner F, Schiller G, Swords R, Bacon L, Bocchia M, Bouabdallah K, Breems DA, Cortelezzi A, Dinner S, Doubek M, Gjertsen BT, Gobbi M, Hellmann A, Lepretre S, Maloisel F, Ravandi F, Rousselot P, Rummel M, Siddiqi T, Tadmor T, Troussard X, Yi CA, Saglio G, Roboz GJ, Balic K, Standifer N, He P, Marshall S, Wilson W, Pastan I, Yao NS, Giles F. Moxetumomab pasudotox in relapsed/refractory hairy cell leukemia. Leukemia. 2018 Aug;32(8):1768-1777. doi: 10.1038/s41375-018-0210-1. Epub 2018 Jul 20.
citation: Kreitman RJ, Dearden C, Zinzani PL, Delgado J, Robak T, le Coutre PD, Gjertsen BT, Troussard X, Roboz GJ, Karlin L, Gladstone DE, Kuptsova-Clarkson N, Liu S, Patel P, Rotolo F, Mitry E, Pastan I, Giles F; Study 1053 investigators. Moxetumomab pasudotox in heavily pre-treated patients with relapsed/refractory hairy cell leukemia (HCL): long-term follow-up from the pivotal trial. J Hematol Oncol. 2021 Feb 24;14(1):35. doi: 10.1186/s13045-020-01004-y.
citation: Abou Dalle I, Ravandi F. Moxetumomab pasudotox for the treatment of relapsed and/or refractory hairy cell leukemia. Expert Rev Hematol. 2019 Sep;12(9):707-714. doi: 10.1080/17474086.2019.1643231. Epub 2019 Aug 1.