Introduction: The phosphatidylinositol-3-kinase (PI3K) pathway plays an important role in multiple cellular functions, including proliferation, differentiation, and trafficking, and deregulation of PI3K is a hallmark of many malignancies. The preferential expression of the PI3Kδ isoform on leukocytes provides an attractive target for hematologic malignancies. SHC014748M is a novel, potent, and highly selective PI3Kδ inhibitor. This study is a phase I, first-in-human study to assess the safety, tolerability and pharmacokinetics of SHC014748M in patients with relapsed or refractory indolent B-cell lymphomas (NCT03588598).
Methods: Dose escalation was performed in a 3+3 design in sequential cohorts at doses of 50-250 mg QD, and then dose expansion was conducted at the selected cohorts to find recommended Phase II dose (RP2D). Eligible patients were those with relapsed or refractory indolent B-cell lymphomas, having at least 1 measurable lesion, and with ECOG performance status 0-2. Patients received a single dose on day 1, and then after 3 days washout multiple dosing once daily was initiated until disease progression or unacceptable toxicity. Primary endpoints included safety, tolerability and pharmacokinetics. Secondary endpoints included overall response rate (ORR), lymph node response (LNR), time to response (TTR), progression-free survival (PFS) and duration of response (DOR).
Results: As of Jul 16, 2019, 38 patients with relapsed or refractory indolent B-cell lymphomas were enrolled in the study, including 23 with follicular lymphoma (FL), 11 with chronic lymphocytic leukemia/Small lymphocytic lymphoma (CLL/SLL), 1 with marginal zone lymphoma (MZL) and 3 with Waldenstrom’s macroglobulinemia (WM). 15 patients were treated in the dose escalation phase and 23 were treated in the dose expansion phase (12 in 150 mg cohort, 11 in 200 mg cohort). The average number of prior therapies was 2.2 (range 1-8), and 84 percent of patients had received rituximab before. No dose-limiting toxicities occurred. The most common adverse reactions were neutropenia (39.5%), fatigue (21.1%), thrombocytopenia (18.4%), diarrhea (13.2%), pneumonia (13.2%), cough (13.2%), lymphopenia (13.2%), anemia (13.2%) and rash (13.2%). Grade ≥ 3 adverse reactions were neutropenia (23.7%), pneumonia (13.2%), rash (7.9%) and diarrhea (5.3%). Among 14 FL patients who were available for efficacy evaluation, ORR was 57.1% (8 PR, 5 SD, 1 PD). Of 9 CLL/SLL evaluable patients, 5 (55.6%) had partial response, 3 (33.3%) had partial response with lymphocytosis, and 1 had stable disease. Of 3 WM patients, 1 had partial response and 2 had minor response.
Conclusion: SHC014748M was well tolerated and demonstrated promising clinical activity in patients with relapsed or refractory indolent B-cell lymphomas.