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 Relapsed or Refractory Chronic Lymphocytic Leukemia (CLL)

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 CLL. 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 (Hallek et al, 2008).

At data cutoff, the study had enrolled 27 patients with CLL. Patient characteristics and safety and efficacy results are depicted in the table. The majority of patients were >60 years of age, had bulky adenopathy, and had undergone extensive prior therapy. Grade ≥3 adverse events were generally consistent with those expected with each of the single agents. During combination therapy, the substantial majority of patients had marked reductions in lymphadenopathy, resulting in a ≥50% decrease in lymph node area in >75% of patients on all regimens. Lymph node shrinkage was rapid, generally occurring within ≤2 cycles. The lymphocyte mobilization that is expected with PI3Kδ inhibition was observed in some patients but was not as prominent as had previously been seen with single-agent GS-1101 therapy. More than 80% of patients receiving each regimen met criteria for CLL response. 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 116 (±36) to 33 (±5.5) pg/mL for CCL3 (p=0.022), from 217 (±83) to 55 (± 28) pg/mL) for CCL4 (p=0.052), from 220 (± 57) to 46 (± 6.6) pg/mL for CXCL13 (p=0.004), and from 100 (± 20) to 30 (± 3.6) pg/mL for TNFα (p=0.001).

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 CLL. GS-1101-based combination therapy with rituximab and/or bendamustine offers major and rapid reductions in lymphadenopathy. Patients with CLL are currently being enrolled in this study to receive GS-1101 with fludarabine or ofatumumab; data for all regimens will be presented. The data from this trial will be used to design Phase 3 combination studies of GS-1101 in patients with CLL.

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