Final results of a phase 1b study of the safety and efficacy of the PI3Kδ inhibitor acalisib (GS-9820) in relapsed/refractory lymphoid malignancies

Final results of a phase 1b study of the safety and efficacy of the PI3Kδ inhibitor acalisib (GS-9820) in relapsed/refractory lymphoid malignancies Arnon P. Kater, Sanne H. Tonino, Marjolein Spiering, Martine E. D. Chamuleau, Roberto Liu, Adeboye Henry Adewoye, Jie Gao, Lyndah Dreiling, Yan Xin, Jeanette K. Doorduijn and Marie José Kersten, on behalf of the HOVON Lunenburg Lymphoma Phase I/II Consortium

Antitumor activity was evaluated using standard response criteria for the tumor types in patients enrolled, with adjustment to account for the effects on lymphocytosis observed with Bcell receptor inhibitors. Patients were assessed for tumor response by computerized axial tomography and/or magnetic resonance imaging at weeks 8, 16, 24, 36, and 48; and every 12 weeks thereafter through week 96. The findings of the IRC were considered primary for analyses of all tumor control endpoints.
Clinic/laboratory visits occurred at 1-to 2-week intervals through week 24, every 6 weeks between weeks 24 and 48, and every 12 weeks thereafter. Descriptions of any AEs, DLTs, serious AEs, or AEs leading to discontinuation of study treatment were collected. Adverse events were coded according to the Medical Dictionary for Regulatory Activities (MedDRA) version 19.0.

Statistical analyses
The sample size for this phase 1 study was not based on a formal statistical hypothesis; in the dose-escalation phase, each dose cohort was 3 patients, and 3 additional patients could be included if 1 DLT was observed. The total planned number of patients enrolled in stage 1 was up to 40. The rationale for expanding the 400 mg twice daily cohort was to further evaluate the safety and efficacy of the highest dose tested. With the assumption of 50% ORR based on the observed data, enrolling 30 patients should provide 80% power to detect the true ORR larger than 30%, with a 1-sided test with significance level of 0.1. With the assumption of 44% ORR, the power would be 60% with 30 patients.
As this was a nonrandomized study, the full analysis set was the same as the safety analysis set and included all patients who received ≥1 dose of acalisib. The safety analysis set was used in the analyses of patient characteristics, efficacy, and safety.
Measures of antitumor activity included ORR, defined as the proportion of patients who achieved a complete response (CR) and partial response (PR); TTR, defined as the interval from start of study treatment to the first documentation of CR or PR; DOR, defined as the interval from the first documentation of CR or PR to the earlier of the first documentation of definitive disease progression or death from any cause; LNR, defined as the proportion of patients who achieved a ≥50% decrease from baseline in the sum of the products of the greatest perpendicular diameters (SPD) of index lymph nodes; and PFS, defined as the interval from the start of study treatment to the earlier of the first documentation of definitive disease progression or death from any cause.
Definitive disease progression for patients with CLL was based on standard criteria and included progressive disease (PD) occurring for any reason other than lymphocytosis alone (ie, increasing lymphadenopathy, organomegaly, or bone marrow involvement; decreasing platelet count, hemoglobin, or neutrophil count).
Patient baseline characteristics, demographics, and safety were summarized using descriptive statistics. For binary variables, 95% confidence intervals (CIs) were calculated using the binomial distribution, and using Greenwood's formula with (complementary) log-log transformation for Kaplan-Meier estimates.      Figure 2. Kaplan-Meier curve of progression-free survival per disease type and IRC assessment in 29 patients treated with acalisib 400 mg twice daily. CLL, chronic lymphocytic leukemia; IRC, independent review committee NHL/HL Non-Hodgkin's and Hodgkin's lymphoma, PFS, progression-free survival.