Once-weekly ofatumumab in untreated or relapsed Waldenström's macroglobulinaemia: an open-label, single-arm, phase 2 study

Abstract

Background: 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.

Methods: 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.

Findings: 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).

Interpretation: 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.

Funding: GlaxoSmithKline and Genmab.

Conflict of interest statement

Declaration of interests

CGD, JS, QML, DS, RCJ, and TSL were employees of and owned stock in GlaxoSmithKline during the time of study conduct and initial publication development. CGD now works for Pfizer, JS now works for Incyte and TSL now works for Janssen. SL is an employee of and owns stock in Genmab A/S. RRF served as a consultant and member of a speaker bureau for GlaxoSmithKline. JPL has served as a consultant for Novartis Pharmaceuticals. ACK, SRH, CCH, RA, HAE, MC have no conflict of interest to disclose.

Copyright © 2017 Elsevier Ltd. All rights reserved.

Figures

Figure 1. Study schematic

Study schema for the OMB110921 study. For the first 15 patients in TGA, C1 consisted of intravenous ofatumumab 300 mg during Week 1 followed by 1,000 mg during Weeks 2–4. The next 22 patients were enrolled in TGB and received intravenous ofatumumab 300 mg during Week 1 followed by 2,000 mg during Weeks 2–5. Patients with SD or an MR at Week 16 of C1 were eligible to receive an RC consisting of ofatumumab 300 mg during Week 1 and 2,000 mg during Weeks 2–5. Patients who achieved a response in C1 or RC and then progressed within 36 months were eligible to receive C2. C1=Cycle 1. C2=Cycle 2. MR=minor response. OFA=ofatumumab. RC=redosing cycle. SD=stable disease. TGA=Treatment Group A. TGB=Treatment Group B.

Figure 2. Flow chart indicating treatment delivery for each treatment group

Patients were treated with weekly ofatumumab infusions at either 1,000 mg (TGA) or 2,000 mg (TGB). Patients received up to three cycles of treatment (C1, RC and C2). Only patients who had demonstrated a response (CR, PR, or MR) during either C1 or RC and subsequently progressed within 36 months were eligible for C2. AE=adverse event. C1=Cycle 1. C2=Cycle 2. CR=complete response. MR=minor response. PR=partial response. RC=redosing cycle. TGA=Treatment Group A. TGB=Treatment Group B.

Figure 3. Percent change in IgM from baseline to nadir for patients in C1+RC

Percent change in IgM from baseline to nadir for all patients (n=37). The median IgM percent change from baseline to nadir was −44% in TGA (n=15) and −39% in TGB (n=22). C1=Cycle 1. IgM=immunoglobin M. RC=redosing cycle. TGA=Treatment Group A. TGB=Treatment Group B.

Figure 4. Progression-free survival

Kaplan–Meier survival curves of PFS for patients in TGA and TGB. The median PFS is 558 days (95% CI 353–666 days) for TGA and 536 days (95% CI 414–1093 days) for TGB. The median PFS for the total population is 536 days (95% CI 424–654 days) for the overall study population (n=37). CI=confidence interval. PFS=progression-free survival. TGA=Treatment Group A. TGB=Treatment Group B.