Interim Analysis Of Dose-Escalation Stage Of a Phase 1b Study Evaluating Safety and Pharmacology Of GS-9820, a Second-Generation, Selective, PI3Kd-Inhibitor in Recurrent Lymphoid Malignancies

In B-cells, phosphatidylinositol 3-kinase delta (PI3Kd) mediates a positive effect on cell survival, proliferation, growth, and metabolism. In addition, PI3Kd activity is critical for homing and retaining B cells in lymphoid tissues. In B-cell malignancies, increased activity of PI3Kd drives proliferation and survival of malignant B-cells and mediates trafficking to lymphoid tissues. GS-9820 is a second-generation, selective, small molecule inhibitor of PI3Kd under investigation for the treatment of lymphoid malignancies including non-Hodgkin's lymphoma (NHL) and chronic lymphocytic leukemia (CLL). The primary endpoint for the dose-escalation stage is to determine the maximally tolerated dose (MTD) and to assess safety including the incidence and severity of transaminase elevation, which has been observed to varying degrees with other PI3K inhibitors. We here report safety, efficacy and pharmacokinetics (PK) for the first four dose cohorts.

Subjects with recurrent lymphoid malignancies with measurable lymphadenopathy who had ≥ 1 prior therapy received GS-9820 at doses of 50, 100, 200, or 400 mg, administered orally twice daily (BID). Stage 1 is a dose escalation stage with a classic 3+3 design to evaluate the safety, efficacy and pharmacology of GS-9820. Intensive PK sampling was done on Day 1 and Day 29. Antitumor activity was evaluated every 2 months (mos) using standard response criteria, with adjustment for redistribution lymphocytosis, consistent with PI3Kd inhibition. Nodal PR (nPR) is defined as a ≥50% reduction in lymphadenopathy. Safety assessments include monitoring for transaminase elevation. Subjects may continue receiving GS-9820 indefinitely as needed.

As of July 15, 2013, 12 subjects were enrolled in 4 cohorts across the 50 to 400 mg dose range. Of the 8 subjects with CLL and 4 subjects with NHL enrolled, 9/12 remained on-study (Table 1). Reasons for discontinuation include disease progression (3). No dose-limiting toxicities have been reported. Importantly, transaminase elevation has not been observed. Among the 10 subjects with at least 1 post-baseline CT scan, 7/10 experienced reductions in lymph node (LN) size as best response and 4/10 subjects had nPR.

GS-9820 plasma exposures were less than dose-proportional, with mean pre-dose concentrations upon multiple-dosing above the in vitro protein-binding adjusted EC₅₀ at the doses tested, and exposure-driven trends in pharmacodynamic response (inhibition of basophil activation).

Severe adverse events (grade 3 or 4) occurred in 3 subjects: pneumonia, herpes, malaise, and gallbladder pain and none were considered related to study drug. Adverse events (AEs) occurring in > 1 subject included cough (n=5), malaise (n=3), fatigue (n=2), diarrhea (n=2), and increased creatinine (n=2). AEs considered related to study drug by the investigator occurred in 6 subjects and included grade 1 events of footpad neuropathy, diarrhea, edema, grade 2 events of hyperkalemia and increased creatinine, and a grade 4 event of neutropenia. Serious adverse events (SAEs) included pneumonia, Morbus Bowen's disease, and herpes. None of the SAEs were considered related to study drug by the investigator.

Interim analysis of the first 4 cohorts of a dose-escalation phase 1b study of GS-9820 in patients with recurrent lymphoid malignancies demonstrates clinical activity. Doses ranging from 50 mg to 400 mg BID are not associated with disease limiting toxicity or transaminase elevation.

Off Label Use: GS-9820 is a second-generation, selective, small molecule inhibitor of PI3Kƒ’ƒn under investigation for the treatment of lymphoid malignancies including non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL). Xin:Gilead Sciences: Employment. Ramanathan:Gilead Sciences: Employment. Aiello:Gilead Sciences: Employment. Jun:Gilead Sciences: Employment.