Phase 1 Study of Lenalidomide and Ibrutinib in Combination with Rituximab in Relapsed and Refractory CLL and SLL

Background

Although effective, ibrutinib has a CR rate of 10% in relapsed/refractory CLL. Attempts to improve upon its activity include the addition of other agents. The combination of lenalidomide and rituximab has demonstrated an ORR 66%, CR 12% in this setting. Based on these data, we proposed a phase I study of rituximab, lenalidomide, and ibrutinib in relapsed/refractory CLL.

Methods

Patients with previously treated CLL or SLL requiring treatment with adequate organ function, ECOG <2, and measurable disease were eligible. Patients received rituximab 375 mg/m² Cycle 1-6 Day 1, lenalidomide as per cohort dose Cycle 1-12 Day 1-21, and ibrutinib 420 mg daily starting from Day 1 and continuing until progression or intolerance. Dose escalation used a standard 3+3 design from a starting level of lenalidomide 5 mg (DL1) and increasing to 15 mg (DL3) through 3 dose levels. Patients received allopurinol for tumor lysis prophylaxis. Aspirin was recommended for those at high risk for thrombosis. The primary endpoint was the recommended phase II doses (RP2D) of lenalidomide and ibrutinib for combination with rituximab in previously treated CLL/SLL. The secondary endpoints were safety and efficacy. Once the MTD was determined, there was to be a 10-patient expansion cohort.

Results

Twelve CLL patients were enrolled between May 2014 - January 2017: DL1 (n=3), DL2 (n=6), DL3 (n=3). Median age was 64 years (range 50-75); 83% were male, 67% had an ECOG score of 1, and 50% had Rai Stage III/IV disease. Prognostic features included: 42% del 13q, 42% trisomy 12, 25% del 11q, 8% del 17p, 67% umutated IGVH, 17% ZAP-70 expression 20%, and 50% CD38 expression > 30%. Patients had received a median of 1 prior therapy (1-7), primarily rituximab with fludarabine or bendamustine. Three pts had received lenalidomide > 2 years prior to enrollment; none had progressed on the agent. No patients had ibrutinib previously.

There were 2 dose-limiting toxicities of grade 4 neutropenia at DL3, thus DL2 (L 10 mg, I 420 mg) was found to be the RP2D. Six patients withdrew from study: 1 due to progressive disease, 5 due to persistent grade 4 neutropenia despite G-CSF support. Prolonged grade 4 neutropenia occurred at all dose levels; 1 patient in DL2 was able to continue with dose reduction.

Most common adverse events (all grades) were fatigue (67%), neutropenia (58%), infection (58%), thrombocytopenia (42%), edema (42%), pain (42%), rash (42%). Most common grade 3/4 adverse events were neutropenia (58%), thrombocytopenia (16%), and infection (16%). Serious adverse events included neutropenia, thrombocytopenia, hemolytic anemia, aspergillus pneumonia, rash, tumor lysis syndrome, urinary tract infection.

The ORR for all patients was 66.7%; 1 patient achieved a CR. In DL1, 2 patients had stable disease and 1 patient had progressive disease. One patient in DL3 was not evaluable for response assessment as they withdrew for toxicity. The ORR at the RP2D was 100% (1 CR). Most patients achieved their best response at the first assessment of 10 weeks. At median follow-up time of 6.8 months, the median time on treatment was 6.4 mo (0.66-25+). The 12-month PFS was 91.9% (50.8-98.7%). There was no progression at the RP2D.

Conclusion

The combination of rituximab, lenalidomide, and ibrutinib in relapsed/refractory CLL was associated with sustained grade 4 neutropenia, which prompted study withdrawal in several patients. It appeared to occur more frequently than previous reports with rituximab-lenalidomide (50%) or single-agent ibrutinib (30%). Preliminary ORR data of the regimen were comparable to prior reports of the rituximab-lenalidomide doublet and ibrutinib in this population. Furthermore, there was no significant improvement in CR rate. Given these findings, the study was terminated.