PHASE I STUDY OF MOXETUMOMAB PASUDOTOX IN ADULT PATIENTS WITH RELAPSED OR REFRACTORY ACUTE LYMPHOBLASTIC LEUKEMIA
Author(s): ,
Farhad Ravandi
Affiliations:
Leukemia,University of Texas - MD Anderson Cancer Center,Houston,United States
,
Jorge Cortes
Affiliations:
Leukemia,University of Texas - MD Anderson Cancer Center,Houston,United States
,
Deborah Thomas
Affiliations:
Leukemia,University of Texas - MD Anderson Cancer Center,Houston,United States
,
Michael Rytting
Affiliations:
Leukemia,University of Texas - MD Anderson Cancer Center,Houston,United States
,
Naval Daver
Affiliations:
Leukemia,University of Texas - MD Anderson Cancer Center,Houston,United States
,
Marina Konopleva
Affiliations:
Leukemia,University of Texas - MD Anderson Cancer Center,Houston,United States
,
Partow Kebriaei
Affiliations:
Leukemia,University of Texas - MD Anderson Cancer Center,Houston,United States
,
William Wierda
Affiliations:
Leukemia,University of Texas - MD Anderson Cancer Center,Houston,United States
,
Courtney DiNardo
Affiliations:
Leukemia,University of Texas - MD Anderson Cancer Center,Houston,United States
,
Carol Bivins
Affiliations:
Leukemia,University of Texas - MD Anderson Cancer Center,Houston,United States
,
Deborah McCue
Affiliations:
Pharmacy,University of Texas - MD Anderson Cancer Center,Houston,United States
,
Sherry Pierce
Affiliations:
Leukemia,University of Texas - MD Anderson Cancer Center,Houston,United States
,
Ann Richie
Affiliations:
Leukemia,University of Texas - MD Anderson Cancer Center,Houston,United States
Hagop Kantarjian
Affiliations:
Leukemia,University of Texas - MD Anderson Cancer Center,Houston,United States
(Abstract release date: 05/19/16) EHA Library. Ravandi F. 06/09/16; 132408; E859
Dr. Farhad Ravandi
Dr. Farhad Ravandi
Contributions
Abstract
Abstract: E859

Type: Eposter Presentation

Background
Moxetumomab pasudotox (MP), previously known as HA22 or CAT-8015, is a recombinant immunotoxin composed of the Fv fragment of a humanized IgG4 anti-CD22 monoclonal antibody fused to a 38-kDa truncated fragment of Pseudomonas exotoxin A. CD22 is expressed on the surface of blasts in over 90% of patients with precursor B-acute lymphoblastic leukemia (ALL) as well as in other lymphoid neoplasms and is an attractive target for monoclonal antibody-based therapy. MP and its predecessor compound, BL22 have been investigated for the treatment of patients with relapsed hairy cell leukemia (HCL) as well pediatric patients with relapsed B-ALL and have demonstrated promising activity.

Aims
This single center, phase I study was conducted to determine the maximum tolerated dose and potential efficacy of MP in adult patients with relapsed and/or refractory B-ALL.

Methods
Patients were eligible if they were 18 years or older, with previously treated B-ALL (either relapsed after having achieved prior response or refractory to prior therapy) and had adequate performance status and organ function with bilirubin ≤ 1.5 mg/dL, liver enzymes ≤ 2 x upper limit of normal (ULN) and creatinine ≤ 2 mg/dL. Patients with cardiac ejection fraction less than 40%, active hepatitis or HIV infection, history of microangiopathic hemolysis, symptomatic CNS involvement, recent prior therapy (including systemic chemotherapy in the past 14 days, monoclonal antibodies in the past month, or allogeneic stem cell transplant in the past 100 days) were excluded. Dose escalation in the phase I portion of the study was based on a standard 3 + 3 design starting at a dose of MP 30 µg/kg every other day (qod) for 6 doses with subsequent dose levels at 40 and 50 µg/kg qod for 6 doses and 50 µg/kg qod for 10 doses. All patients received appropriate premedication with hydroxyzine, ranitidine, corticosteroids and acetaminophen and were monitored for toxicity including previously identified risks of capillary leak syndrome and hemolytic uremic syndrome (HUS). All other supportive managements was based on standard institutional practice.

Results
Between December 2013 and September 2015, 16 patients with relapsed or refractory B-ALL were treated on this trial. Median age of the patients was 30 years (range, 18 – 67 years). Median number of prior therapies was 3 (range, 1 – 6). 4 patients had a prior allogeneic stem cell transplant and 3 had prior therapy with inotuzumab ozogamycin. 10 patients were refractory to their last prior therapy and 6 had relapsed from prior therapy (duration of prior CR less than 6 months in 2 and greater than 6 months in 4). Performance status was 0 in 2, 1 in 10 and 2 in 4 patients. Four patients had normal karyotype and 10 complex cytogenetic abnormalities which included t(4;11) in 1 patient. Another patient had t(1;19) and one patient had miscellaneous abnormality. CD22 expression was detected in all patients including 50-69% expression in 4, 70-89% expression in 4, and ≥ 90% expression in 8. The median number of courses of MP administered was 1 (range, 1-4) with 6 patients treated at 30 µg/kg, 4 patients at 40 µg/kg, and 6 patients at 50 µg/kg x 6 doses.  The final dose regimen of 100 µg/kg x 10 doses was not studied due to early termination of the study.  Only one DLT (grade 3 HUS) occurred at 50 µg/kg x 6 dose level; however, the study was terminated because the 10-dose schedule was not tolerated in a parallel pediatric trial. One patient with 5 prior regimens achieved a complete response (CR) which lasted 2.5 months. No other responses by standard criteria were reported. Non-hematological toxicity of grade 3/4 included reversible capillary leak syndrome (CLS) in 1 patient, weight gain in 2, ascites in 1, tumor lysis syndrome (TLS) in 1, elevation of liver enzymes in 3, and HUS in 1 patient. Grade 2 adverse events including CLS, edema and elevation of liver enzymes were noted in another 5 patients. No deaths directly attributable to therapy were reported.

Conclusion
MP at the doses studied in this trial is feasible and can produce response in patients with multiply relapsed B-ALL. The recommended dose for phase II trials is 50 µg/kg qod x 6 doses.

Session topic: E-poster

Keyword(s): Immunotoxin, Relapsed acute lymphoblastic leukemia
Abstract: E859

Type: Eposter Presentation

Background
Moxetumomab pasudotox (MP), previously known as HA22 or CAT-8015, is a recombinant immunotoxin composed of the Fv fragment of a humanized IgG4 anti-CD22 monoclonal antibody fused to a 38-kDa truncated fragment of Pseudomonas exotoxin A. CD22 is expressed on the surface of blasts in over 90% of patients with precursor B-acute lymphoblastic leukemia (ALL) as well as in other lymphoid neoplasms and is an attractive target for monoclonal antibody-based therapy. MP and its predecessor compound, BL22 have been investigated for the treatment of patients with relapsed hairy cell leukemia (HCL) as well pediatric patients with relapsed B-ALL and have demonstrated promising activity.

Aims
This single center, phase I study was conducted to determine the maximum tolerated dose and potential efficacy of MP in adult patients with relapsed and/or refractory B-ALL.

Methods
Patients were eligible if they were 18 years or older, with previously treated B-ALL (either relapsed after having achieved prior response or refractory to prior therapy) and had adequate performance status and organ function with bilirubin ≤ 1.5 mg/dL, liver enzymes ≤ 2 x upper limit of normal (ULN) and creatinine ≤ 2 mg/dL. Patients with cardiac ejection fraction less than 40%, active hepatitis or HIV infection, history of microangiopathic hemolysis, symptomatic CNS involvement, recent prior therapy (including systemic chemotherapy in the past 14 days, monoclonal antibodies in the past month, or allogeneic stem cell transplant in the past 100 days) were excluded. Dose escalation in the phase I portion of the study was based on a standard 3 + 3 design starting at a dose of MP 30 µg/kg every other day (qod) for 6 doses with subsequent dose levels at 40 and 50 µg/kg qod for 6 doses and 50 µg/kg qod for 10 doses. All patients received appropriate premedication with hydroxyzine, ranitidine, corticosteroids and acetaminophen and were monitored for toxicity including previously identified risks of capillary leak syndrome and hemolytic uremic syndrome (HUS). All other supportive managements was based on standard institutional practice.

Results
Between December 2013 and September 2015, 16 patients with relapsed or refractory B-ALL were treated on this trial. Median age of the patients was 30 years (range, 18 – 67 years). Median number of prior therapies was 3 (range, 1 – 6). 4 patients had a prior allogeneic stem cell transplant and 3 had prior therapy with inotuzumab ozogamycin. 10 patients were refractory to their last prior therapy and 6 had relapsed from prior therapy (duration of prior CR less than 6 months in 2 and greater than 6 months in 4). Performance status was 0 in 2, 1 in 10 and 2 in 4 patients. Four patients had normal karyotype and 10 complex cytogenetic abnormalities which included t(4;11) in 1 patient. Another patient had t(1;19) and one patient had miscellaneous abnormality. CD22 expression was detected in all patients including 50-69% expression in 4, 70-89% expression in 4, and ≥ 90% expression in 8. The median number of courses of MP administered was 1 (range, 1-4) with 6 patients treated at 30 µg/kg, 4 patients at 40 µg/kg, and 6 patients at 50 µg/kg x 6 doses.  The final dose regimen of 100 µg/kg x 10 doses was not studied due to early termination of the study.  Only one DLT (grade 3 HUS) occurred at 50 µg/kg x 6 dose level; however, the study was terminated because the 10-dose schedule was not tolerated in a parallel pediatric trial. One patient with 5 prior regimens achieved a complete response (CR) which lasted 2.5 months. No other responses by standard criteria were reported. Non-hematological toxicity of grade 3/4 included reversible capillary leak syndrome (CLS) in 1 patient, weight gain in 2, ascites in 1, tumor lysis syndrome (TLS) in 1, elevation of liver enzymes in 3, and HUS in 1 patient. Grade 2 adverse events including CLS, edema and elevation of liver enzymes were noted in another 5 patients. No deaths directly attributable to therapy were reported.

Conclusion
MP at the doses studied in this trial is feasible and can produce response in patients with multiply relapsed B-ALL. The recommended dose for phase II trials is 50 µg/kg qod x 6 doses.

Session topic: E-poster

Keyword(s): Immunotoxin, Relapsed acute lymphoblastic leukemia

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