Phase 2 trial of GS-9973, a selective syk inhibitor, and idelalisib (idela) in chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL).

Abstract

7059 Background: GS-9973 is an orally bioavailable, small-molecule, selective inhibitor of Spleen Tyrosine Kinase (Syk). The Kd of GS-9973 for Syk was 7.6 nM with no other kinase < 100 nM. Methods: This Phase 2 trial enrolled subjects (subj) with relapsed/refractory CLL (1 cohort) or NHL (4 cohorts). Subj underwent intra-subj dose escalation from GS-9973 400 mg and Idela 100 mg (400/100) BID up to a maximum of 800/150 BID. Plasma drug levels were obtained concurrently with plasma chemo/cytokine levels and phospho flow analysis of circulating leukemic cells. Results: This study initiated in July 2013. When enrollment was suspended, 66 subj with CLL (36) or NHL (30) had been enrolled. Median age was 68 (range 28 - 92), 53% were male. The median number of prior treatment regimens was 3 (range 1-9). Of the subj with investigator response assessments, 14 (70%) and 10 (50%) of 20 CLL subj had a decrease of > 50% and > 75% respectively in their measurable lymph node disease; 7 (35%) of 20 NHL subj achieved a decrease of > 50%. (iNHL 6/14; DLBCL 1/4; MCL 0/2). The study was terminated early due to the development of severe, steroid responsive, pneumonitis in 9 subj that occurred despite dose reduction in 4 after a median of 83 (raange 50-105) days on study. Reversible Grade 3 or 4 ALT elevations occurred in 10 (15%) subj. Treatment emergent adverse events occurring in ≥ 15% of subj were fatigue, nausea, pyrexia, rash, diarreha, headache, constipation and cough and were typically low grade. 5 subj died while on study: 2 from disease progression, 1 from pneumonitis, 1 from pneumonia, 1 from sepsis. Conclusions: Despite promising activity in CLL, the combination of GS-9973 and Idela resulted in an unexpectedly high rate of pneumonitis and resulted in stopping dosing of the combination These data need to be considered when designing future investigations combining inhibitors of B cell receptor signaling. Additional studies are needed to understand the underlying mechanism of pneumonitis seen with dual Syk and PI3k inhibition Clinical trial information: NCT01796470.