Combinations of the Selective Phosphatidylinositol 3-Kinase-Delta (PI3Kdelta) Inhibitor GS–1101 (CAL-101) with Rituximab and/or Bendamustine Are Tolerable and Highly Active in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia (CLL): Results From a Phase I Study

PI3Kdelta drives proliferation and survival in malignant B-cells. GS-1101 is an orally bioavailable, small-molecule inhibitor of PI3Kdelta that has shown considerable monotherapy activity when given at dose levels of ³100 mg BID in patients with heavily pretreated CLL.

This Phase 1 combination study has evaluated repeated 28-day cycles of GS-1101 in combination with rituximab and/or bendamustine in patients with previously treated CLL. GS-1101 was administered starting on Day 1 of Cycle 1 with rituximab (R) (375 mg/m² given weekly for 8 doses) (GS-1101/R regimen), with bendamustine (B) (90 mg/m² given on Days 1 and 2 of each cycle for 6 cycles) (GS-1101/B regimen), or in combination with R (375 mg/m², on Day 1 of each cycle for 6 cycles) and B (90 mg/m² given on Days 1 and 2 of each cycle for 6 cycles) (GS-1101/BR regimen). Initial cohorts of patients received a GS-1101 dose of 100 mg/dose BID in the GR or GB regimens. Thereafter, all patients received a GS-1101 dose of 150 mg/dose BID. Tumor response was evaluated according to standard criteria (Hallek 2008). Chemokine/cytokine plasma levels were assessed at baseline and on Day 28 of therapy using multiplexed bead suspension arrays.

The study enrolled a total of 51 patients with CLL. Patient characteristics and safety and efficacy results are depicted in the table

The majority of patients had bulky adenopathy and had undergone extensive prior therapy, with virtually all patients receiving prior rituximab and many receiving prior bendamustine. Grade ³3 adverse events and lab abnormalities were generally consistent with those expected with each of the single agents. Lymph node shrinkage was rapid, and almost all evaluable patients had reductions in lymphadenopathy. As reported by investigators, the overall response rates (ORR) for the GS-1101/R, GS-1101/B, and GS-1101/BR regimens were 78%, 82% and 87%, respectively. With a minimum follow-up of ³40 weeks for all regimens, 1-year progression-free survival (PFS) rates were 74%, 88% and 87% in the GS-1101/R, GS-1101/B, and GS-1101/BR treatment groups, respectively. Disease-associated chemokines/cytokines were commonly elevated at baseline and were significantly reduced by GS-1101-based combination treatment.

A favorable safety profile and lack of overlapping toxicities allows the oral PI3Kdelta inhibitor, GS-1101, to be delivered at the full single-agent starting dose when coadministered with chemoimmunotherapies in heavily pretreated patients with CLL. GS-1101-based combination therapies with rituximab and/or bendamustine offer major and rapid reductions in lymphadenopathy and durable tumor control. Based on these results, Phase 3 trials evaluating the efficacy of GS-1101 in combination with R or BR have been initiated (NCT01539512 [GS-1101/placebo+R], NCT01569295 [GS-1101/placebo+BR]).

Coutre:Gilead: Consultancy. Off Label Use: Phase 1 trial of GS-1101 (CAL-101)-based combination therapy. Leonard:Gileade: Consultancy. Barrientos:Gilead: Research Funding. de Vos:Gilead: Consultancy. Sharman:Gilead: Honoraria, Research Funding. Holes:Gilead: Employment. Lannutti:Gilead Sciences Inc: Employment. Johnson:Gilead Sciences: Employment. Miller:Gilead: Employment. Jahn:Gilead: Employment.