Obinutuzumab As Consolidation after Chemo-Immunotherapy Is Highly Effective in Achieving MRD Clearance from Bone Marrow and Peripheral Blood- Initial Results of UK NCRI Phase II/III Galactic Trial

Introduction:

In CLL achieving minimal residual disease (MRD) negativity has a survival advantage compared to MRD positive patients regardless of the approach used to achieve MRD negativity. The UK CLL207 phase II trial assessed consolidation with alemtuzumab following chemotherapy and showed that 38% of patients attained MRD negativity at 6 months post-consolidation. These patients had a significantly improved progression-free survival (PFS) compared to MRD positive patients. However, significant toxicity was associated with alemtuzumab. Obinutuzumab, a type II monoclonal antibody targeting the CD20 antigen has shown greater efficacy in CLL than previous anti-CD20 antibodies with respect to MRD, and appears to be less immune suppressive than alemtuzumab.

Methods:

The GALACTIC trial was a seamless phase II/III trial, with an overall planned sample size of 188 patients which was designed to test whether consolidation with obinutuzumab is safe and eradicates MRD (phase II) which subsequently leads to prolonged PFS (phase III), in patients with B-CLL who have recently responded to chemotherapy. Patients achieving a complete or partial response (CR/PR) 3-24 months after chemotherapy were eligible. Patients with lymph node >1.5cm were excluded. Eligible patients assessed as MRD positive were randomised to receive either consolidation therapy with obinutuzumab or no consolidation therapy. Obinutuzumab was given 1000mg weekly for first 4 doses (split over two days for first dose) and then 4 further doses fortnightly. Prophylaxis was given to reduce the risk of infusion-related reactions. Simon's 2-stage design was used to define stopping rules in phase II with 80% power, 1-sided sig. level of 10% and minimum efficacy rate of 15%. If 2/9 (stage I) and 6/23 (stage II) participants randomised to obinutuzumab achieved MRD negativity, the trial would continue to phase III. If fewer than 23 MRD assessments were recorded, 6 MRD negative results were still required.

Results:

GALACTIC opened in March 2015 and passed the stage I stopping rule in April 2016. The trial closed early in February 2017 due to poor recruitment likely due to the advent of novel targeted therapy, such as ibrutinib and venetoclax, for relapsed CLL. A total of 48 patients were enrolled of whom 19 were MRD negative and not entered into the randomisation. The remaining 29 MRD positive participants were randomised to consolidation therapy (n=14; 7 CR, 7 PR) or no consolidation therapy (n=15; 5 CR, 9 PR, 1 N/K). The median age was 69 (46, 82) with 55.2% >65 and 72.4% were male. Overall, 93.1% had received previous rituximab, 41.4% had received 2 or 3 lines of prior therapy and 55.2% had MRD level >0.3% at the time of trial entry. Overall 12 (85.7%) participants randomised to consolidation received all 8 infusions, two participants received 7 doses due to dose limiting toxicity, neutropenia and thrombocytopenia. At 6 months post-randomisation, 10 (71.4%) (80%CI: 50.8, 86.9) consolidation participants achieved MRD negativity by flow cytometry (sensitivity 10^-4) in bone marrow passing the stage II stopping rule. 13 (92.6%) achieved MRD negativity in the peripheral blood. In the consolidation arm, response rates were 13 (92.9%) CR and 1 (7.1%) PR, compared to 6 (40.0%) CR and 1 (6.7%) PR with no consolidation therapy. Two consolidated participants experienced 3 severe adverse reactions (serious infection (n=2), neutropenic sepsis (n=1)) which resolved. The most common adverse events in consolidation arm were thrombocytopenia (22.2%), infection (8.9%) and cough (8.4%), only 1% of events were infusion-related reactions.

Conclusion:

Consolidation therapy with obinutuzumab is highly effective at eradicating MRD by 6 months post-randomisation with 71.4% achieving an MRD negative bone marrow. Obinutuzumab is extremely well-tolerated with minimal infusion reactions and toxicity. Improvement in MRD was demonstrated and it can be postulated that consolidation may result in improvement of PFS and time to next treatment. However, long-term data is needed to establish this hypothesis.