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2017-05-23T16:13:07.000Z

The phase III COMPLEMENT 2 trial: ofatumumab plus FC improves PFS with manageable safety versus FC alone in patients with relapsed Chronic Lymphocytic Leukemia

May 23, 2017
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This month, in Leukemia & Lymphoma, Tadeusz Robak from the Medical University of Lodz and Copernicus Memorial Hospital, Lodz, Poland, and colleagues published results of the randomized, open-label, phase III COMPLEMENT 2 trial (NCT00824265).

The trial assessed fludarabine-cyclophosphamide plus ofatumumab (OFA+FC) versus fludarabine-cyclophosphamide (FC) alone in patients with relapsed (but not refractory) CLL. Patients were randomized 1:1 to each arm and the primary endpoint was Independent Review Committee (IRC)-assessed PFS.

In total, 365 pts enrolled; 183 patients were randomized to the OFA+FC arm and 182 to the FC arm. Median age of patients was 61 years (range, 32–90); 134 patients (37%) were over >65 years and 27 patients (7%) were over 75 years.

Key Highlights:

Treatment
  • OFA+FC treatment = six 28-day cycles; ofatumumab IV (cycle 1: 300mg day 1 and 1,000mg day 8; cycles 2–6: 1,000 mg day 1) plus fludarabine IV (25mg/m2) and cyclophosphamide IV (250mg/m2) on days 1–3 of each cycle
  • FC treatment = Fludarabine IV (25 mg/m2) and cyclophosphamide IV (250mg/m2) on days 1–3 for six 28-day cycles
Efficacy
  • Median follow-up = 1,034 days (approx. 34 months)
  • At data cut-off, pts who had progressed or died: OFA+FC = 56%; FC = 58%
  • IRC median PFS: OFA+FC = 28.9 months; FC = 18.8 months (HR, 0.67; 95% CI, 0.51–0.88; P = 0.0032)
  • Investigator median PFS: OFA+FC = 27.2 months; FC = 16.8 months (HR, 0.66; 95% CI, 0.51–0.85; P = 0.0009)
  • IRC median EFS: OFA+FC = 27.2 months; FC = 16.5 months (HR, 0.66; 95% CI, 0.51–0.86; P = 0.0012)
  • IRC time to progression: OFA+FC = 42.1 months; FC = 26.8 months (HR, 0.63; 95% CI, 0.45–0.87; P = 0.0036)
  • Median OS: OFA+FC = 56.4 months; FC = 45.8 months (HR, 0.78; 95% CI, 0.56–1.09; P = 0.1410)
  • IRC ORR: OFA+FC = 153 (84%); FC = 123 (68%; P = 0.0003)
  • CR: OFA+FC = 49 (27%); FC = 13 (7%)
  • MRD negativity at 3 months after last treatment: OFA+FC = 39 (21%); FC = 15 (8%; P = 0.0006)
  • MRD negativity at 6 months after last treatment: OFA+FC = 48 (26%); FC = 11 (6%; P < 0.0001)
  • Time to next anticancer therapy: OFA+FC = 48.1 months; FC = 40.1 months (HR, 0.73; 95% CI, 0.51–1.05; P = 0.0735)
  • IRC time to response: OFA+FC = 1.0 month; FC = 1.0 month (HR, 1.08; 95% CI, 0.85–1.37; P = 0.4490)
  • IRC DoR: OFA+FC = 29.6 months; FC = 24.9 months (HR, = 0.77; 95% CI, 0.56–1.05; P = 0.0878)
Safety
  • AEs of any grade: OFA+FC = 169 (93%); FC = 151 (85%)
  • AEs of grade 3: OFA+FC = 134 (74%); FC = 123 (69%)
  • AEs leading to treatment discontinuation: OFA+FC = 49 (27%); FC = 49 (28%)
  • Neutropenia was the most common AE, any grade: OFA-FC = 108 60%; FC = 77 (43%)
  • Thrombocytopenia and anemia were more common in FC pts than OFA+FC pts
  • Infections: OFA+FC = 70 (39%); FC = 65 (37%)
  • Fatal infections: OFA+FC = 5 (3%); FC = 3 (2%)
  • Infusion related reactions: OFA+FC = 108 (60%), caused withdrawal in 5 pts; FC = 50 (28%)
  • The most frequent treatment-related AEs (in >10% of pts) in OFA+FC and FC pts were neutropenia (58% vs. 41%), thrombocytopenia (26% vs. 32%), nausea (19% in both arms), anemia (15% vs. 26%), and leukopenia (14% vs. 6%)
  • A total of 38 pts (OFA+FC = 18; FC = 20) reported grade 3–4 neutropenia that occurred during treatment and had not resolved within 42 days of the last treatment dose
  • Late-onset neutropenia (grade 3–4 starting ≥42 days after last treatment dose) was reported in 18 pts (OFA+FC = 13 [7%]; FC = 5 [3%])
  • Deaths during treatment or ≤30 days post-treatment: 3 (2%) OFA+FC pts and 4 (2%) FC pts
  • A further 8 deaths occurred from 30–60 days after last dosing, 2 (1%) in OFA+FC pts and 6 (3%) in FC pts
  • CLL caused 32 /67 (18%) deaths in the OFA+FC arm and 31/69 (17%) deaths in the FC arm

The authors concluded that combining ofatumumab with fludarabine and cyclophosphamide demonstrated a “manageable safety profile” and showed “clinically important improvements in efficacy compared to FC alone” in patients with relapsed CLL.

Abstract:

In this multicenter, open-label, phase III study, patients with relapsed chronic lymphocytic leukemia (CLL) were randomized (1:1) to receive ofatumumab plus fludarabine and cyclophosphamide (OFA + FC) or FC alone; the primary endpoint being progression-free survival (PFS) assessed by an independent review committee (IRC). Between March 2009 and January 2012, 365 patients were randomized (OFA + FC: n = 183; FC: n = 182). Median IRC-assessed PFS was 28.9 months with OFA + FC versus 18.8 months with FC (hazard ratio = 0.67; 95% confidence interval, 0.51-0.88; p = .0032). Grade ≥3 adverse events (≤60 days after last dose) were reported in 134 (74%) OFA + FC-treated patients compared with 123 (69%) FC-treated patients. Of these, neutropenia was the most common (89 [49%] vs. 64 [36%]). OFA + FC improved PFS with manageable safety for patients with relapsed CLL compared with FC alone, thus providing an alternative treatment option for patients with relapsed CLL.

  1. Robak T. et al. Ofatumumab plus fludarabine and cyclophosphamide in relapsed chronic lymphocytic leukemia: results from the COMPLEMENT 2 trial. Leukemia & Lymphoma. 2017 May;58(5):1084-1093. DOI: 10.1080/10428194.2016.1233536. Epub 2016 Oct 12.

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