Phase I study of CAL-101, an isoform-selective inhibitor of phosphatidylinositol 3‐kinase P110d, in patients with previously treated chronic lymphocytic leukemia.

Abstract

6631 Background: 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. CAL-101 is an isoform-selective inhibitor of PI3Kδ that induces apoptosis of chronic lymphocytic leukemia (CLL) cells. Methods: This phase I study evaluated CAL-101 in patients with previously treated hematologic cancers. CAL-101 was administered orally 1 or 2 times per day (QD or BID) continuously in 28-day cycles, until disease progression or unacceptable toxicity. Efficacy analyses were based on standard criteria. Results: At data cutoff, the study had enrolled 54 patients with CLL. Patient characteristics included: median [range] age of 62 [37‐82] years; 82% males; 72% with refractory disease, 81% with bulky disease, 36% with del(17p), and a median [range] of prior therapies of 5 [2‐15]. CAL-101 dose levels were 50 mg, 100 mg, 150 mg, 200 mg, and 350 mg BID; and 300 mg QD. The median [range] of CAL‐101 treatment cycles was 8 [1-19]. Grade ≥3 adverse events included pneumonia (24%), neutropenia (24%), thrombocytopenia (7%), neutropenic fever (7%), anemia (6%) and ALT/AST increase (6%). CAL‐101 reduced lymphadenopathy by ≥50% in 80% of patients. A transient increase of >50% from baseline in peripheral absolute lymphocyte counts occurred in 58% of patients. The overall intention-to-treat response rate by IWCLL 2008 criteria was 26%. Medians for duration of response and progression-free survival had not been reached (>11 months), with 46% of patients continuing on treatment. CAL-101 reduced constitutive overexpression of phospho‐AKT in patient CLL cells and normalized plasma concentrations of CCL3, CCL4, and CXCL13. PK analyses showed minimal increases in plasma Cmax and AUC at doses >150 mg BID. Accrual is ongoing and updated data will be presented. Conclusions: CAL-101, an oral PI3Kδ-selective inhibitor, shows acceptable safety and promising clinical activity in heavily pretreated patients with CLL. Dose‐response assessments support the 150 mg BID dose for future single-agent and combination chemo/immunotherapy studies.