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An open-label, single-arm, phase 1 study to assess biomarker effects, efficacy and safety of ofatumumab in patients with refractory chronic lymphocytic leukemia.

ABSTRACT: This open-label, phase 1 study evaluated the effects of ofatumumab on QTc intervals, safety, efficacy, B-cell and neutrophil counts, complement levels, and cytokine and chemokine concentrations. Fourteen patients with fludarabine-refractory chronic lymphocytic leukemia received 12 ofatumumab infusions. A higher maximum infusion rate of 400 mL/h was tested at the first two doses and was well tolerated. The 43% overall response rate was similar to previous data (42-51%). B-cell depletion was observed along with complement consumption; median C2 and CH50 levels appeared lower during monthly dosing in patients who responded. Responding patients appeared to have higher median levels of certain pro-inflammatory cytokines and lower median levels of certain immunotolerant cytokines than patients who did not respond. Ofatumumab-induced complement-dependent cytotoxicity activity can be detected clinically by measuring complement and may be associated with clinical activity. The potential relationship between changes in complement or cytokines and clinical response to ofatumumab warrants further study.

SUBMITTER: Patton WN

PROVIDER: S-EPMC4654681 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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An open-label, single-arm, phase 1 study to assess biomarker effects, efficacy and safety of ofatumumab in patients with refractory chronic lymphocytic leukemia.

Patton William Nigel WN Lindeman Robert R Butler Andrew C AC Kipps Thomas J TJ Jewell Roxanne C RC Laubscher Kevin H KH Zhou Yan Yan YY Lewis Eric E Sedoti Donna D Witman Philip P Fang Lei L Chan Geoffrey G

Leukemia & lymphoma 20150902 10

This open-label, phase 1 study evaluated the effects of ofatumumab on QTc intervals, safety, efficacy, B-cell and neutrophil counts, complement levels, and cytokine and chemokine concentrations. Fourteen patients with fludarabine-refractory chronic lymphocytic leukemia received 12 ofatumumab infusions. A higher maximum infusion rate of 400 mL/h was tested at the first two doses and was well tolerated. The 43% overall response rate was similar to previous data (42-51%). B-cell depletion was obser ...[more]

PMID: 25721750

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Project description:The development of more effective and safer treatments, especially non-chemotherapeutics, is needed for patients with Waldenström's macroglobulinaemia. The aim of the study was to assess the safety and clinical activity of intravenous ofatumumab monotherapy for untreated and relapsed Waldenström's macroglobulinaemia.We did a phase 2, open-label, single-arm study at six centres (hospitals and cancer clinics) in the USA. Patients aged at least 18 years who were diagnosed with untreated or relapsed Waldenström's macroglobulinaemia and required treatment, received up to three cycles of weekly ofatumumab for 5 weeks. For cycle 1, patients received one of two treatment regimens. Group A received ofatumumab 300 mg during week 1 followed by 1000 mg during weeks 2-4. Because of the acceptable safety of the 1000 mg dose in treatment group A and clinical activity of the 2000 mg dose established in chronic lymphocytic leukaemia, the study was amended on Dec 9, 2009, to change cycle 1 for group B who received ofatumumab 300 mg during week 1 and 2000 mg during weeks 2-5. We followed up patients during weeks 5-16 for treatment group A and during weeks 6-16 for treatment group B (no treatment was given during this follow-up). Patients in both groups with stable disease or a minor response after 16 weeks were eligible to then receive a redosing cycle of ofatumumab 300 mg during week 1 and 2000 mg during weeks 2-5. We followed up patients during weeks 6-16 after the redosing cycle (no treatment was given during this follow-up). Patients responding to cycle 1 or the redosing cycle who developed disease progression within 36 months could receive cycle 2 of ofatumumab 300 mg during week 1 and 2000 mg during weeks 2-5. The primary endpoint for this study was the proportion of patients who achieved an overall response (complete responses plus partial responses plus minor responses) after each treatment cycle in the intent-to-treat population every 4 weeks starting at week 8. This trial is registered at www.ClinicalTrials.gov, NCT00811733, and is now complete.Between March 17, 2009, and Feb 24, 2011, we enrolled and assigned 37 patients to treatment (15 in treatment group A and 22 in treatment group B). All 37 were included in the efficacy and safety analyses. 19 (51%, 95% CI 34·4-68·1) of 37 patients achieved an overall response after cycle 1 and 22 (59%, 42·1-75·2) of 37 achieved an overall response after the redosing cycle; 15 (41%) with partial responses, seven (19%) with minor responses. 13 patients received treatment cycle 2; ten (77%) of the 13 achieved a response. All 37 patients had at least one adverse event; 16 (43%) patients had events of grade 3 or more (30 grade 3, one grade 4). The most common grade 3 or 4 adverse events were infusion reactions (four [11%] of 37), chest pain (two [5%] of 37), haemolysis (two [5%] of 37), and neutropenia (two [5%] of 37). Two (9%) of 22 patients (both in treatment group B) had an IgM flare. 12 patients reported serious adverse events; haemolysis and pyrexia were the most common (each occurring in two [5%] of 37 patients).A high proportion of patients achieved an overall response with ofatumumab monotherapy and this treatment was well tolerated, with a low incidence of IgM flare. This therapy might be a non-chemotherapeutic treatment option for patients with Waldenström's macroglobulinaemia, especially those with high IgM concentrations.GlaxoSmithKline and Genmab.

Dataset Information

An open-label, single-arm, phase 1 study to assess biomarker effects, efficacy and safety of ofatumumab in patients with refractory chronic lymphocytic leukemia.

Publications

An open-label, single-arm, phase 1 study to assess biomarker effects, efficacy and safety of ofatumumab in patients with refractory chronic lymphocytic leukemia.

Similar Datasets

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