A Phase 1 Study of the Selective Phosphatidylinositol 3-Kinase-Delta (PI3Kδ) Inhibitor, Cal-101 (GS-1101), in Combination with Rituximab and/or Bendamustine in Patients with Previously Treated, Indolent Non-Hodgkin Lymphoma (iNHL)

PI3Kδ is expressed in cells of hematopoietic origin where it regulates survival and proliferation of normal and malignant B-cells. CAL-101 (GS-1101) is an orally bioavailable, small-molecule inhibitor that selectively targets PI3Kδ. A prior Phase 1 study established 150 mg/dose BID as an appropriate single-agent starting dose for GS-1101 and demonstrated that GS-1101 monotherapy is associated with substantial clinical activity in patients with hematologic malignancies.

This Phase 1 study has evaluated repeated 28-day cycles of GS-1101 in combination with rituximab and/or bendamustine in patients with previously treated iNHL. GS-1101 (G) was administered starting on Day 1 of Cycle 1 with rituximab (R) (375 mg/m² given weekly for 8 doses, GR regimen), with bendamustine (B) (90 mg/m² given on Days 1 and 2 of each cycle for 6 cycles, GB 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, GRB regimen). Initial cohorts of patients received GS-1101 at a dose of 100 mg/dose BID in the GR or GB regimens. Thereafter, all patients received GS-1101 at a dose of 150 mg/dose BID in the GR, GB, or GRB regimens. Chemokine/cytokine plasma levels were assessed at baseline and on Day 28 of therapy using multiplexed bead suspension arrays. Tumor response was evaluated according to standard criteria (Cheson et al. 2007).

At data cutoff, the study had enrolled 37 patients with iNHL. Patient characteristics, histological subtyping, 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 were generally consistent with those expected with each of the single agents. All evaluable patients had reductions in lymphadenopathy, resulting in an overall response rate (ORR) of >65% for all regimens. In 3 patients among the 24 patients receiving either GB or GRB, 3 complete responses were observed. Lymph node shrinkage was rapid; responses generally occurred within ≤2 cycles. Disease-associated chemokines/cytokines were commonly elevated at baseline and were reduced by GS-1101 treatment; in 20 evaluable patients, mean (±SEM) values declined from 302 (±68) to 62 (±14) pg/mL for CCL17 (p=0.001), from 2512 (±332) to 879 (± 88) pg/mL) for CCL22 (p=0.0001), from 517 (± 88) to 107 (± 34) pg/mL for CXCL13 (p=0.0001), and from 33 (± 5.4) to 18 (± 1.8) pg/mL for TNFα (p=0.007).

A favorable safety profile and lack of overlapping toxicities allows the oral PI3Kδ inhibitor, CAL-101 (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. The data from this trial will be used to design Phase 3 combination studies of GS-1101 in patients with iNHL.

de Vos:Gilead Sciences Inc: Consultancy. Flinn:Gilead Sciences Inc: Research Funding. Coutre:Gilead Sciences Inc: Consultancy. Leonard:Gilead Sciences Inc: Consultancy. Fowler:Gilead Sciences Inc: Consultancy. Sharman:calistoga: Honoraria; Pharmacyclics: Honoraria; Genentech: Honoraria; Rigel: Research Funding; Portola: Consultancy; Pharmacyclics: Consultancy; Gilead: Consultancy. Holes:Gilead: Employment. Lannutti:Gilead: Employment. Johnson:Gilead Sciences Inc: Employment. Jahn:gILEAD: Employment. Miller:Gilead: Employment.