Calistoga Pharmaceuticals, Inc., the leader in the development of isoform-selective phosphatidylinositol 3 kinase (PI3K) inhibitors for the treatment of cancer and inflammatory diseases, today presented preclinical and clinical data on CAL-101, the Company's oral, delta selective PI3K inhibitor at the 15th Congress of the European Hematology Association in Barcelona, Spain. Results from the interim assessment of the ongoing Phase 1 clinical trial demonstrate clinical benefit in patients with relapsed or refractory indolent non-Hodgkin's lymphoma (NHL), mantle cell lymphoma (MCL), and chronic lymphocytic leukemia (CLL). Preclinical results assessing selected chemokines in plasma and circulating CLL cells from patients in the Phase 1 clinical trial support that CAL-101 inhibits chemokine signaling and production from CLL cells and the microenvironment. These results elucidate the novel biological effects of CAL-101 and are consistent with the single agent activity observed in Phase 1 evaluation, particularly the biologic activity observed in nearly all CLL patients.
“We continue to be encouraged with the clinical benefit we are observing with this novel mechanism and look forward to participating in future trials with CAL-101”
The clinical results presented were from an interim assessment of patients enrolled in the ongoing Phase 1 study of CAL-101 in patients with relapsed or refractory chronic lymphocytic leukemia (CLL), indolent and aggressive non-Hodgkin's lymphoma (NHL), acute myeloid leukemia (AML) and multiple myeloma (MM). Over half of the patients enrolled in the trial were refractory to their last therapy prior to entering the study, and the median number of prior treatment regimens was five. Patients received continuous, twice daily, oral dosing of CAL-101 on a 28-day cycle for up to 12 cycles.
Single agent CAL-101 treatment in patients with relapsed or refractory indolent non-Hodgkin's lymphoma (NHL), mantle cell lymphoma (MCL), and chronic lymphocytic leukemia (CLL), resulted in overall response rates of 57 percent, 67 percent, and 30 percent, respectively.
Overall, CAL-101 was generally well tolerated. A low incidence of hematological toxicity was observed. Some patients had elevation of liver transaminases, which was monitorable and reversible following discontinuation of dosing. Most patients who experienced an elevation in transaminases resumed CAL-101 at a reduced dose.
In the CLL patients, eighty-four percent of patients had bulky disease defined as lymph nodes greater than five centimeters in size; bulky disease is typically more difficult to treat. In 29 of 31, or 94 percent, of CLL patients, treatment with CAL-101 resulted in a greater than 50 percent decrease in their lymph node disease. In addition, 14 of 20, or 70 percent, of CLL patients with low platelet counts entering the study had meaningful improvements, which provides another indication of clinical benefit.
In a preclinical evaluation of CLL cells from patients, ant-IgM stimulation resulted in activation of the PI3K signaling pathway as measured by phosphorylated AKT and conferred a pro-survival effect that was abrogated by treating these cells with CAL-101. In-vitro secretion of the chemokines CCL3 and CCL4 produced by CLL cells was inhibited by CAL-101. These preclinical results were confirmed in the Phase 1 clinical trial. Following treatment with CAL-101, patients' CLL cells had a decrease in the level of phosphorylated AKT. The CLL patients' plasma concentrations of CCL3, CCL4 and CXCL13, chemokines thought to be produced by the tumor microenvironment, were reduced compared to prior to treatment.
In summary, these data support that inhibition of the PI3K delta pathway by CAL-101 results in cancer cell death and inhibition of pro-survival chemokines produced by CLL cells and the tumor microenvironment.
"We continue to be encouraged with the clinical benefit we are observing with this novel mechanism and look forward to participating in future trials with CAL-101," said Jennifer Brown, M.D., Ph.D., Dana Farber Cancer Institute, Boston, MA.
"These results demonstrate the clinical validation of our discovery of this novel approach targeting PI3K delta in patients with hematologic malignancies," said Mike Gallatin, Ph.D., President of Calistoga Pharmaceuticals. "We plan to continue our commitment to understanding the role of isoform selective PI3K inhibition and advancing our product candidates to validate the clinical benefit of these novel agents in patients with cancer and inflammatory diseases."
CAL-101 is a first-in-class inhibitor of the PI3K delta isoform. It is an orally administered small molecule, and exhibits a greater than 200-fold selectivity in cell-based assays for the delta isoform as compared to other class 1 PI3K isoforms. CAL-101 is designed to induce cancer cell death (apoptosis) and to inhibit the signaling pathways associated with cancer cell dependence on the tumor microenvironment.
In addition to CAL-101, Calistoga Pharmaceuticals has a pipeline of isoform-selective PI3K inhibitors including CAL-263, a delta isoform-selective PI3K inhibitor for treatment of patients with inflammatory diseases such as asthma, chronic obstructive pulmonary disease and rheumatoid arthritis.