Tolerability and Pharmacokinetics
The Phase 1, open-label, dose-escalation trial of IPI-145 is designed to evaluate the safety, pharmacokinetics (PK) and clinical activity of IPI-145 administered orally twice daily (BID) in patients with advanced hematologic malignancies. The maximum tolerated dose has not been reached at doses up to 75 mg BID. Thus, the trial is ongoing, and patients are now being enrolled in a dose-escalation cohort evaluating IPI-145 at a dose of 100 mg BID.
Data presented today showed that IPI-145 was well tolerated to date, and there have been no dose-related trends in adverse events. The most frequent Grade 3 and Grade 4 adverse events were cytopenias and liver enzyme elevations, which were managed by dose interruption and dose reduction. Of the 55 patients evaluable for tolerability, three (5 percent of) patients discontinued treatment due to an adverse event. Sixty-seven percent of all patients remain on study, and 90 percent of patients who did not experience progressive disease after two cycles remain on study.
Data also showed that IPI-145 is rapidly absorbed and demonstrates a linear PK profile through all dose levels analyzed thus far. The PK data suggest that IPI-145 completely inhibits PI3K-delta, with increasing suppression of PI3K-gamma at doses greater than or equal to 25 mg BID.Clinical Activity IPI-145 showed broad activity in patients with both B-cell and T-cell malignancies, including partial responses or complete responses in patients with chronic lymphocytic leukemia, indolent non-Hodgkin’s lymphoma, mantle cell lymphoma, Hodgkin’s lymphoma and T-cell lymphoma. Onset of activity appeared to be rapid, as evidenced by the median time to response (table below). Additionally, clinical activity reported for 16 of 19 responders occurred within the first two cycles of treatment. Clinical responses as of the November 20, 2012, data cutoff were as follows:
|Diagnosis*||Patients (n)||Best Response||
Median Time toResponse in Months(Range)
|iNHL||17||13||1||7||4||1||1.8 (1.7 – 2.8)|
|CLL/SLL||16||11||0||6||4 nodal responses||1||2.9 (1.8 - 5.6)|
|T-cell lymphoma||7||6||1||1||1||3||2.4 (1.8-3.1)|