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

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.