Combinations of the Phosphatidylinositol 3-Kinase-Delta (PI3Kδ) Inhibitor Gs-1101 (CAL-101) with Rituximab and/or Bendamustine Are Tolerable and Highly Active in Previously Treated, Indolent Non-Hodgkin Lymphoma: Results From a Phase I Study

PI3Kδ drives proliferation and survival in malignant B-cells. GS-1101 is an orally bioavailable, small-molecule inhibitor of PI3Kδ that has shown considerable monotherapy activity when given at dose levels of ≥100 mg BID in patients with heavily pretreated indolent non-Hodgkins lymphoma (iNHL).

This Phase 1 combination study has evaluated repeated 28-day cycles of GS-1101 with rituximab and/or bendamustine in patients with previously treated iNHL. 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 received a GS-1101 dose of 100 mg/dose BID. Thereafter, all patients received a GS-1101 dose of 150 mg/dose BID. Tumor response was evaluated according to standard criteria (Cheson 2007). Chemokine/cytokine plasma levels were assessed at baseline and on Day 28 of therapy using multiplexed bead suspension arrays.

The study enrolled 76 patients with iNHL. Patient characteristics, histological sub-typing, safety, and efficacy results are depicted in the table.

The majority of patients were >60 years of age and had undergone extensive prior therapy. Grade ≥3 adverse events and lab abnormalities were generally consistent with those expected with each of the single agents. Lymph node shrinkage was rapid and all evaluable patients had reductions in lymphadenopathy, resulting in overall response rates (ORR) of 77%, 85%, and 77% for the GS-1101/R, GS-1101/B, and GS-1101/BR regimens, respectively. Complete responses (with bone marrow confirmation) were observed in 13%, 16%, and 30% of patients. With median follow-up duration ranging from 28 to 48 weeks, 1-year progression- free survival (PFS) rates were >75% in all treatment groups. Disease-associated chemokines/cytokines were commonly elevated at baseline and were significantly reduced by GS-1101-based combination treatment.

A lack of overlapping toxicities allows the oral PI3Kδ inhibitor, GS-1101, to be delivered at the full single-agent starting dose when coadministered with chemoimmunotherapies in heavily pretreated patients with iNHL. GS-1101-based combination therapy with rituximab and/or bendamustine offers major and rapid reductions in lymphadenopathy. All 3 regimens provide durable tumor control. The data from this trial support the development of Phase 3 combination trials of GS-1101 with rituximab- and/or bendamustine-containing regimens in patients with iNHL.

Fowler:Gilead Sciences: Membership on an entity's Board of Directors or advisory committees. Off Label Use: Phase I trial of GS-1101, a PI3K delta inhibitor, in B cell malignancies. de Vos:Gilead Sciences: Membership on an entity's Board of Directors or advisory committees. Schreeder:Gilead Sciences: Research Funding. Leonard:Gilead: Consultancy. Coutre:Gilead Sciences: Membership on an entity's Board of Directors or advisory committees. Sharman:Gilead: Honoraria, Research Funding. Boccia:Gilead Sciences: Research Funding. Barrientos:Gilead Sciences: Research Funding. Holes:Gilead: Employment. Lannutti:Gilead Sciences Inc: Employment. Johnson:Gilead Sciences: Employment. Jahn:Gilead: Employment. Miller:Gilead: Employment. Godfrey:Gilead Sciences: Employment.