Evidence of Clinical Activity in a Phase 1 Study of CAL-101, An Oral P110Δ Isoform-Selective Inhibitor of Phosphatidylinositol 3-Kinase, in Patients with Relapsed or Refractory B-Cell Malignancies.

The class I phosphatidylinositol 3-kinases (PI3Ks) regulate a variety of cellular functions relevant to oncogenesis, including metabolism, proliferation and survival. The PI3K p110Δ isoform is primarily expressed in cells of hematopoietic origin and plays a key role in normal B cell maturation and function. CAL-101 is an oral, potent inhibitor of PI3K p110Δ (IC50 of 2.5 nM against purified enzyme and EC50 of 65 nM in a whole blood basophil assay) with 40 to 300-fold selectivity compared to other PI3K isoforms. This selectivity may provide a better therapeutic index relative to pan-PI3K inhibitors. In vitro studies of 0.1 to 10 uM CAL-101 showed inhibition of AKT phosphorylation and/or apoptotic effects against primary chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML) cells and against a range of leukemia, lymphoma and multiple myeloma (MM) cell lines.

A Phase 1 study was undertaken to evaluate the safety and clinical activity of CAL-101 in patients with select hematologic malignancies. During initial dose escalation, sequential cohorts of 3 patients with relapsed/refractory CLL or select B-cell non-Hodgkin's lymphoma (NHL) were enrolled to determine dose limiting toxicity (DLT). During subsequent cohort expansion, approximately 12 patients each with CLL, indolent NHL, aggressive NHL, and AML were to be enrolled. CAL-101 was administered orally twice daily (BID) continuously for 28 days per cycle. Clinical response was evaluated at the end of Cycles 1 and 2 and every 2 cycles thereafter.

To date, 43 patients have been enrolled and followed for at least 4 weeks, consisting of 17 patients with CLL, 9 patients with indolent NHL, 10 patients with aggressive NHL and 7 patients with AML. The demographic and disease characteristics were 33% female, mean age 65 (60% over age 65), 49% had refractory disease and the median number of prior regimens was 5. During dose escalation (n=12), 3 patients per cohort were administered dose levels of 50 mg, 100 mg, 200 mg or 350 mg BID. In cohort expansion 31 patients were enrolled to either 200 mg (n=17) or 350 mg (n=14) BID. The median duration of treatment at data cutoff was 3 cycles (range 1 to 10). Two patients discontinued early due to adverse events, one for acute on chronic renal failure and one for abnormal liver function tests (LFTs). DLTs were observed in 5 patients with increases in LFTs, which resolved following discontinuation of CAL-101 dosing. No patient had Grade 4 hematological toxicity. Serious infections were reported in 9 patients, with pneumonia being the most frequent. 41 patients were evaluable for clinical response. At data cutoff, the response rate in NHL was 10/18 (56%); all were partial responses (PR). Of the 9 patients with indolent NHL, 5 patients had PR and 2 patients had stable disease (SD) and remained on study. Of the 9 patients with aggressive NHL, 5 patients had PR (all with mantle cell lymphoma) and 1 patient had SD on study. Of the 17 patients with CLL, 6 patients had PR and 7 other patients had >50% reduction in lymphadenopathy and concurrent increase in peripheral blood lymphocytosis to >50% of baseline, suggesting compartmentalization shift of CLL cells. Lymphocytosis was maximal during the first 2 cycles and decreased thereafter. This effect of dislocating CLL cells from the tissue microenvironment suggests that CAL-101 treatment in combination with cytotoxic agents may be particularly active. Of the 6 patients with AML, no patient had responded and 2 patients remained on study. Clinical responses were observed in patients at all 4 dose levels administered. At data cutoff, the longest duration of response was 9 months in a patient with follicular lymphoma, which was longer than the response to any of the 6 prior regimens this patient received, including autologous hematopoietic stem cell transplant. Plasma exposure increased from 50 mg to 200 mg, without further change at 350 mg. At the 200 mg and 350 mg dose levels, mean peak and trough drug concentrations at the end of Cycle 1 were 5 uM and 1 uM, respectively. Enrollment in cohort expansion is continuing with the addition of patients with MM and updated data will be presented at the meeting.

Interim results from the first Phase 1 study to evaluate an oral PI3K p110Δ inhibitor, CAL-101, show promising activity in patients with relapsed or refractory B-cell malignancies with acceptable toxicity.

Byrd:Calistoga Pharmaceuticals, Inc: Consultant. Furman:Calistoga Pharmaceuticals, Inc: Consultant. Brown:Calistoga Pharmaceuticals, Inc: Consultant. Giese:Calistoga Pharmaceuticals, Inc: Employment, Ownership Interest. Yu:Calistoga Pharmaceuticals, Inc.: Employment, Ownership interest.