Clinical Safety and Activity In a Phase 1 Study of CAL-101, An Isoform-Selective Inhibitor of Phosphatidylinositol 3-Kinase P110δ, In Patients with Relapsed or Refractory Non-Hodgkin Lymphoma

The class I phosphatidylinositol 3-kinases (PI3Ks) regulate cellular functions relevant to oncogenesis. Expression of the PI3K p110δ isoform (PI3Kδ) is restricted to cells of hematopoietic origin where it plays a key role in B-cell proliferation and survival. In non-Hodgkin lymphoma (NHL) cells, constitutive PI3Kδ-dependent PI3K pathway activation is frequently observed. CAL-101 is an isoform-selective inhibitor of PI3Kδ that inhibits PI3K signaling and induces apoptosis of NHL cell lines in vitro.

This Phase 1 study evaluated the safety, pharmacokinetics and activity of orally administered CAL-101 in patients with relapsed or refractory hematologic malignancies. Sequential cohorts of patients were enrolled at progressively higher dose levels with cohort expansion based on toxicity profile and plasma exposure. CAL-101 was administered orally once or 2 times per day (QD or BID) continuously in 28-day cycles for up to 12 cycles (with the potential for more prolonged therapy on an extension protocol thereafter). Tumor response was evaluated based on standard criteria but without a requirement for PET imaging.

At data cutoff, the study had enrolled 55 patients with NHL; 28 patients had indolent NHL (follicular lymphoma n=15, small lymphocytic lymphoma n=6, Waldenstrom's macroglobulinemia n=4, marginal zone lymphoma n=3) and 27 had aggressive NHL (mantle cell lymphoma [MCL] n=18, diffuse large B-cell lymphoma [DLBCL] n=9). Patient characteristics included 69% males (38 vs 17 females), median age [range] of 68 [32-82] years, 44% with refractory disease and 56% with relapsed disease. The median [range] number of prior therapies was 5 [1-12]. The proportion of patients with specific prior therapies included: indolent NHL-rituximab 96%, alkylator 86%, anthracycline 50%, purine analog 36%; aggressive NHL-rituximab 100%, alkylator 100%, anthracycline/anthracenedione 96%, plus bortezomib 72% in MCL patients. CAL-101 dose levels were 50 mg BID (n=2), 100 mg BID (n=11), 150 mg BID (n=8), 200 mg BID (n=16), 350 mg BID (n=9) and 300 mg QD (n=9). The median [range] number of treatment cycles was 4 [1-16], with 16 (29%) patients continuing on treatment (11 on study and 5 on the extension protocol after 12 cycles). Symptomatic adverse events were infrequent, usually low-grade, and not clearly CAL-101-related. Grade ≥3 hematological laboratory abnormalities included neutropenia n= 5 (9%), lymphopenia n=3 (5%), and thrombocytopenia n=3 (5%) with uncertain relationship to CAL-101. Grade≥3 ALT/AST elevations occurred in 18 (33%) patients with onset 2–8 weeks after CAL-101 initiation and resolution 2–4 weeks after CAL-101 interruption; after resolution of ALT/AST changes, most patients were rechallenged at the same or a reduced dose of CAL-101 and the majority of these patients were able to resume treatment without recurrence of transaminase elevations. Partial responses were observed at all dose levels, with respective overall n/N (response rates) in evaluable patients of 15/24 (62%) for indolent NHL, 10/16 (62%) for MCL and 0/9 (0%) for DLBCL. Respective response rates by relapsed or refractory status were 9/13 (69%) and 6/11 (55%) for indolent NHL and 8/11 (73%) and 2/5 (40%) for MCL. The median duration of response had not been reached in indolent NHL patients; 5 patients have had response durations of ≥6 months with response durations ranging to >16 months. The median [range] duration of response was 3 months [1 month to 8 months] in MCL. Pharmacodynamic data have supported drug activity; plasma concentrations of chemokines CCL22 and CCL17 were elevated at baseline and showed significant decreases within 1 cycle of CAL-101 treatment (p<0.001 for both comparisons). An evaluation of pharmacokinetics indicated minimal increases in plasma C_max and AUC at CAL 101 doses >150 mg BID; these data, taken together with the tumor regression results, have proved helpful in supporting Phase 2–3 dose selection.

CAL-101, an oral PI3Kδ isoform-selective inhibitor, shows acceptable safety and promising pharmacodynamic and clinical activity in patients with indolent NHL and MCL. The high rate of tumor regressions and protracted durations of tumor control in heavily pretreated patients support advancing CAL-101 into additional studies, both as a single agent and in combination with chemo/immunotherapy.

Kahl:calistoga: Consultancy, Research Funding. Off Label Use: CAL-101 for relapsed lymphoma. Byrd:Calistoga Pharmaceutical Inc.: Equity Ownership. Flinn:calistoga: Research Funding. Wagner-Johnston:calistoga: Research Funding. Spurgeon:calistoga: Research Funding. Furman:GlaxoSmithKline: Clinical research funding, Consultancy, Research Funding, Speakers Bureau; Genentech: Clinical Research Funding, Consultancy, Research Funding, Speakers Bureau; Cephalon: Speakers Bureau, Speakers bureau; Calistoga: Consultancy, Honoraria; Celgene: Clinical Research, Consultancy, Research Funding. Brown:Genzyme: Research Funding; Celgene: Consultancy, Research Funding; Calistoga: Consultancy; Genentech: Consultancy. Coutre:calistoga: Research Funding. Lannutti:Calistoga Pharmaceutical Inc.: Employment. Ulrich:Calistoga Pharmaceuticals: Employment, Equity Ownership. Webb:Calistoga Pharmaceuticals: Employment. Peterman:Calistoga Pharmaceuticals: Employment. Holes:Calistoga Pharmaceuticals: Employment.