Interim results from a phase I study of CAL-101, a selective oral inhibitor of phosphatidylinositol 3-kinase p110d isoform, in patients with relapsed or refractory hematologic malignancies.

Abstract

3032 Background: The class I phosphatidylinositol 3-kinase (PI3K) p110δ isoform is primarily expressed in cells of hematopoietic origin and has a key role in B cell maturation and function. CAL-101 is a potent and selective inhibitor of p110δ that inhibits PI3K signaling and induces apoptosis of primary CLL and AML cells and a range of leukemia and lymphoma cell lines. Methods: An ongoing phase 1 study enrolled previously treated patients with select hematologic malignancies in a standard sequential dose escalation/cohort expansion design. CAL-101 was administered orally twice-a-day continuously for 28 days per cycle. Results: At data cutoff, 57 patients were enrolled (NHL n=29, CLL n=18, AML n=10), 49% had refractory disease, median number of prior regimens= 4.5. Dose levels were 50 mg (n=3), 100 mg (n=3), 200 mg (n=34) and 350 mg (n=17). Clinical responses were seen at all dose levels. The objective response rate was 9/15 in indolent NHL, 6/7 in mantle cell lymphoma, and 4/17 in CLL, with 14/16 evaluable CLL patients having >50% reduction in lymphadenopathy (mean decrease=75%). Durable responses of >6 months have been reached in 5 patients, with 9/19 responders still on therapy. The dose limiting toxicity was reversible increases in serum transaminases in 21% of patients dosed at 200 mg and 350 mg; 6/8 patients resumed at a lower dose without recurrence of the transaminitis. Hematological toxicity was infrequent. Plasma exposure increased with dose. Phospho-AKT (T308) as a marker of PI3K activation was measured in cells from a subset of CLL patients with circulating lymphocytes and was reduced by >90% following dosing. Accrual is continuing and updated data will be presented. Conclusions: CAL-101, an oral selective PI3K p110δ inhibitor, shows promising activity with acceptable toxicity in patients with relapsed or refractory B-cell malignancies. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Calistoga Pharmaceuticals Calistoga Pharmaceuticals Calistoga Pharmaceuticals Calistoga Pharmaceuticals Calistoga Pharmaceuticals