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Antibody-Based Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Moxetumomab pasudotox (Lumoxiti™) is a recombinant CD22-targeted immunotoxin moxetumomab pasudotox-tdfk (LUMOXITI™; hereafter moxetumomab pasudotox) developed by MedImmune and its parent company AstraZeneca. Moxetumomab pasudotox comprises the Fv fragment of a recombinant murine anti-CD22 monoclonal antibody fused to a 38 kDa fragment of Pseudomonas exotoxin-A, PE38. It was approved by the FDA in September 2018 for the treatment of adults with relapsed or refractory hairy cell leukemia (HCL) who have received at least two prior systemic therapies, including treatment with a purine nucleoside analog. Lumoxiti™ was studied in a single-arm, open-label clinical trial of 80 subjects who had received prior treatment for hairy cell leukemia with at least two systemic therapies, including a purine nucleoside analog. The trial measured durable complete response (CR), defined as maintenance of hematologic remission for more than 180 days after achievement of CR. 30% of subjects in the trial achieved durable CR, and the overall response rate was 75%.
Leukemias
Published in Pat Price, Karol Sikora, Treatment of Cancer, 2020
About 80% of patients with HCL can achieve long-term remissions following treatment with purine analogs, such as cladribine and pentostatin, with/without rituximab, and an OS approaching that of the general population. Responses, however, are not always durable; about 30% of the patients relapse, and subsequent responses are poor. At progression, therapies include the recently approved anti-CD22 immunotoxin, moxetumomab pasudotox, following at least two prior therapies, and the BRAF inhibitor, vemurafenib, which is being tested as monotherapy or combined with MEK inhibitors.174
Leukaemias of Mature B- and T/NK-Cells
Published in Tariq I. Mughal, Precision Haematological Cancer Medicine, 2018
A principal challenge in the treatment is the presence of infections which impacts the use of the purine analogues, in view of the associated myelosuppression. Following pre-clinical studies suggesting functionality of BRAF in HCLc, two phase II studies with a BRAF inhibitor, vemurafeneb, were completed in 2016. These observed responses were in 39% of patients with HCL refractory to purine therapy. Side effects were principally cutaneous, involving rash but interestingly, and rather worrisome, was the occurrence of low-grade cutaneous tumours; arthralgia and arthritis were also noted. Resistance to the BRAF inhibitor was, however, frequent, with the emergence of ERK-positive leukaemic cells, suggesting bypass reactivation of MEK and ERK as a resistance mechanism. In efforts to circumvent vemurafenib resistance, the combination of BRAF and MEK inhibitors, which oppose ERK-rephosphorylating mechanisms, and combining BRAF inhibitors with rituximab, are being tested. Vemurafenib is also being tested as a potential first-line treatment for patients who cannot receive purine analogues due to ongoing infections. Other investigational approaches of interest include the BTK inhibitor, ibrutinib, and an anti-CD22 immunotoxin conjugate, moxetumomab pasudotox (CAT08015). A phase I study of moxetumomab demonstrated remarkable activity, with 46% of patients with relapse/refractory disease achieving CR; a confirmatory single arm phase III study is in progress. The preliminary results are encouraging and in April 2018, the drug was granted a priority review by the US Food and Drug Administration.
Antibodies to watch in 2018
Published in mAbs, 2018
Hélène Kaplon, Janice M. Reichert
Moxetumomab pasudotox (HA22, CAT- 8015) is a recombinant immunotoxin containing the 38-kDa cytotoxic portion of Pseudomonas exotoxin A fused to an antibody variable fragment targeting CD22. In February 2016, moxetumomab pasudotox received orphan drug designation for hairy cell leukemia (HCL) in the US. The mAb is currently undergoing evaluation as a treatment for patients with relapsed or refractory HCL in a multicenter, single-arm study Phase 3 trial (NCT01829711). Patients receive moxetumomab pasudotox IV over 30 minutes on days 1, 3, 5 of each 28 day cycle for a maximum of 6 cycles or until disease progression, unacceptable toxicity, initiation of alternate therapy or documented CR. The primary objective of this study is to determine the rate of durable CR; the primary completion date was in May 2017. In a July 2017 pipeline update, AstraZeneca estimated that a BLA may be submitted in 2018.
Investigational treatment options in phase I and phase II trials for relapsed or refractory acute lymphoblastic leukemia in pediatric patients
Published in Expert Opinion on Investigational Drugs, 2021
Julie M. Asare, Cara A. Rabik, Bradley Muller, Patrick A. Brown, Stacy Cooper
Moxetumomab pasudotox is a murine anti-CD22 antibody linked to a fragment of Pseudomonas exotoxin A, that is FDA approved for the treatment of advanced hairy cell leukemia, that has also been studied in patients with B-ALL. Its toxicities include capillary leak syndrome as well as hemolytic uremic syndrome. After a multi-center, phase 1 dose finding study showed promising efficacy, an international phase 2 study of moxetumomab pasudotox was conducted in pediatric patients with relapsed/refractory B-ALL. A total of 32 patients were treated before the study was ended early for lack of response on an interim analysis, with a 10% complete response rate [26].
Refractory and relapsed hairy-cell leukemia (HCL): casting light on promising experimental drugs in clinical trials
Published in Expert Opinion on Investigational Drugs, 2023
A Phase 1 trial evaluating combined treatment with moxetumomab pasudotox and rituximab in relapsed HCL patients is ongoing (Table 2) (ClinicalTrials.gov Identifier: NCT03805932). The primary outcome of the study is to determine recommended safe dose of moxetumomab pasudotox and rituximab. Secondary outcomes include response rates, MRD-free rates and response duration.