Results from the phase IIb ARCTIC clinical trial in previously untreated CLL: mitoxantrone/low-dose rituximab combo comes up short in non-inferiority trial

In the November 2017 issue of Leukemia, Dena R. Howard (Leeds Institute of Clinical Trials Research, University of Leeds) and Talha Munir (St James's University Hospital) of Leeds, United Kingdom) and colleagues published results from phase IIb non-inferiority ARCTIC trial in previously untreated chronic lymphocytic leukemia (CLL).

In this multicenter, randomized-controlled, open, phase IIB non-inferiority trial, patients were randomized 1:1 to fludarabine, cyclophosphamide and rituximab (FCR) or fludarabine, cyclophosphamide, mitoxantrone with low-dose rituximab (FCM-miniR), with treatment repeated every 28 days for a total of six cycles (ISRCTN16544962; EudraCT: 2009-010998-20). The study primary endpoint was complete remission (CR) rates according to International Workshop on Chronic Lymphocytic Leukemia (IWCLL) criteria. Secondary endpoints were progression-free survival (PFS), overall survival (OS), overall response rate, minimal residual disease (MRD) negativity, safety and cost-effectiveness. The primary objective was to assess whether FCM-miniR was non-inferior to FCR in terms of CR rates, including CR with incomplete marrow recovery (CRi), in patients with previously untreated CLL.

Key Highlights:

• The final analysis showed that FCM-miniR failed to meet the primary endpoint objective, as the FCM-miniR CR rate (55%) was far inferior compared to FCR (76%)
• FCM-miniR was less well tolerated than FCR, demonstrated an inferior response and MRD-negativity rate, as well as increased toxicity; therefore, it will not proceed to a confirmatory trial

Treatment:

• A total of 200 patients were recruited and randomized 1:1 to FCR or FCM-miniR, and stratified to ensure balance for center, Binet stage, age group (<65, 65) and sex
• The primary objective was to assess whether FCM-miniR was non-inferior to FCR in terms of CR rates, including CR with incomplete marrow recovery (CRi), in patients with previously untreated CLL
• Treatment with FCR or FCM-miniR was repeated every 28 days for a total of six cycles
  • Fludarabine and cyclophosphamide were administered orally at doses which are pharmacologically equivalent to the doses used when FCR is given intravenously for CLL
• Participants were assessed for response to treatment at 3 months post-treatment, 12, 18 and 24 months post-randomization, or until disease progression requiring treatment
  • Long-term annual follow-up for survival is performed until death
• The primary endpoint was the CR rate (including CRi) at 3 months post-treatment
  • Longer-term secondary endpoints included PFS, OS, time to MRD, relapse in participants who became MRD negative and cost-effectiveness

Efficacy:

• Of the 200 participants:
  • 141 (70.5%) received six cycles of treatment
    • FCR: 70 (70.0%), FCM-miniR: 51 (64.5%), FCM-miniR/FCR: 20 (95.2%)
  • 124 (62.0%) achieved a CR
    • FCR: 68 (68.0%), FCM-miniR: 39 (49.4%), FCM-miniR/FCR: 17 (81.0%)
  • 85 (42.5%) achieved MRD negativity assessed in the bone marrow at 3 months post-treatment
    • FCR: 45 (45.0%), FCM-miniR: 29 (36.7%), FCM-miniR/FCR: 11 (52.4%)
  • 74/149 (49.7%) achieved MRD negativity
    • FCR: 45 (54.2%), FCM-miniR: 29 (43.9%)
  • 184 (92.0%) achieved at least a PR
    • FCR: 94 (94.0%), FCM-miniR: 69 (87.3%), FCM-miniR/FCR: 21 (100%)
  • Of the total assessable participants, the ORR was 92.6% (163/176) with a higher proportion in the FCR group than FCM-miniR
    • FCR: 94/98 (95.9%), FCM-miniR: 69/78 (88.5%)

Safety:

• The safety population included 198 participants
• A total of 183 serious adverse events (SAEs) were reported from 104 (52.5%) participants, from a lower proportion receiving FCR (49.0%) compared to FCM-miniR (58.2%)
• A total of 145 serious adverse reactions were reported from 89 (44.9%) participants
  • FCR: 62 events from 41 (41.0%); FCM-miniR: 67 events from 39 (49.4%); FCM-miniR/FCR: 16 events from 9 (47.4%)
• The most commonly reported serious adverse reactions (SARs), 62.1% of events (n = 90), were infections and infestations
  • Ninety-six (48.5%) participants required hospitalization for an SAE with similar proportions in each treatment group
• Non-serious adverse events (AEs) were reported from 192 (97.0%) participants with similar proportions in each treatment group
• Of the 2163 AEs reported, 388 (17.9%) were graded as CTCAE grade 3 or above,
  • FCR: 168 (15.0%); FCM-miniR: 193 (22.4%); FCM-miniR/FCR: 27 (14.8%)
• There were 339 reports of neutropenia and 190 reports of thrombocytopenia
  • Neutropenia, FCR: 157 (14.1%), FCM-miniR: 152 (17.6%), FCM-miniR/FCR: 30 (16.4%)
  • Thrombocytopenia, FCR: 91 (8.1%), FCM-miniR: 89 (10.3%), FCM-miniR/FCR: 10 (5.5%)

In this phase IIb non-inferiority trial in CLL, patients randomized to FCM-miniR had a significantly lower CR rate than those randomized to FCR (54.7% vs 76.1%), clearly indicating that FCR is the more effective treatment. The study authors noted that this may be somewhat attributed to the higher toxicity associated with the addition of mitoxantrone, with 40-50% from either treatment arm having reported a SAR to FCR with 41.1% of participants receiving FCR reporting a SAR. FCM-miniR failed its objective of achieving non-inferiority to FCR in terms of the primary endpoint of CR at 3 months post-treatment. What’s more, FCM-miniR showed evidence of reduced efficacy as measured by MRD and survival, had increased toxicity, and had not proven itself cost-effective longer term. In light of these findings, FCM-miniR will not proceed to the next development phase, a larger definitive phase III trial.

Abstract

ARCTIC was a multicenter, randomized-controlled, open, phase IIB non-inferiority trial in previously untreated chronic lymphocytic leukemia (CLL). Conventional frontline therapy in fit patients is fludarabine, cyclophosphamide and rituximab (FCR). The trial hypothesized that including mitoxantrone with low-dose rituximab (FCM-miniR) would be non-inferior to FCR. A total of 200 patients were recruited to assess the primary end point of complete remission (CR) rates according to IWCLL criteria. Secondary end points were progression-free survival (PFS), overall survival (OS), overall response rate, minimal residual disease (MRD) negativity, safety and cost-effectiveness. The trial closed following a pre-planned interim analysis. At final analysis, CR rates were 76 FCR vs 55% FCM-miniR (adjusted odds ratio: 0.37; 95% confidence interval: 0.19–0.73). MRD-negativity rates were 54 FCR vs 44% FCM-miniR. More participants experienced serious adverse reactions with FCM-miniR (49%) compared to FCR (41%). There are no significant differences between the treatment groups for PFS and OS. FCM-miniR is not expected to be cost-effective over a lifetime horizon. In summary, FCM-miniR is less well tolerated than FCR with an inferior response and MRD-negativity rate and increased toxicity, and will not be taken forward into a confirmatory trial.