A phase 1 study of the PI3Kδ inhibitor idelalisib in patients with relapsed/refractory mantle cell lymphoma (MCL)

Abstract

Idelalisib, an oral inhibitor of phosphatidylinositol-3-kinase δ (PI3Kδ), was evaluated in a 48-week phase 1 study (50-350 mg daily or twice daily) enrolling 40 patients with relapsed or refractory mantle cell lymphoma (MCL). Primary outcome was safety and dose-limiting toxicity (DLT). Secondary outcomes were pharmacokinetic parameters, pharmacodynamic effects, overall response rate (ORR), progression-free survival (PFS), and duration of response (DOR). Patients without DLT and no evidence of disease progression after 48 weeks enrolled in the extension study. Patients had median age of 69 years (range, 52-83) and received median of 4 prior therapies (1-14); 17 of 40 patients (43%) were refractory to their most recent treatment. Median duration of idelalisib treatment was 3.5 months (range, 0.7-30.7), with 6 (15%) continuing extension treatment. Common grade ≥3 adverse events (AEs) included (total%/grade ≥3%) diarrhea (40/18), nausea (33/5), pyrexia (28/0), fatigue (25/3), rash (23/3), decreased appetite (20/15), upper respiratory infection (20/0), pneumonia (13/10), and alanine transaminase or aspartate transaminase elevations (60/20). ORR was 16 of 40 patients (40%), with CR in 2 of 40 patients (5%). Median DOR was 2.7 months, median PFS was 3.7 months, and 1-year PFS was 22%. These data provide proof of concept that targeting PI3Kδ is a viable strategy and worthy of additional study in MCL. This trial was registered at www.clinicaltrials.gov as #NCT00710528.

Figure 1

Dose-exposure relationship. Steady-state (day 28) idelalisib plasma exposures by idelalisib dosing regimen (N = 40). AUC_τ indicates area under the concentration-time curve over 12 (daily) or 24 hours (twice daily); BID, twice daily; C_τ, trough concentration; C_max, maximum concentration; QD, daily; SD, standard deviation.

Figure 2

Lymph node response. The best response with respect to tumor size during idelalisib treatment. There were 40 patients in total, and 1 patient (white bar) did not have an evaluation for response. A total of 32 out of 39 patients (82%) had some decrease in measurable disease. Shown are on-treatment percent changes in the sum of greatest perpendicular dimension (SPD) of measured lymph nodes. The dotted line shows the percentage change that represents the criterion for lymphadenopathy response, according to Cheson et al, where a indicates criterion for lymphadenopathy response.

Figure 3

Duration of response and progression-free survival. (A) KM estimate for DOR in patients with MCL (n = 16). (B) KM estimate for PFS in patients with MCL (N = 40). PFS (C) and DOR (D) in subgroups based on high (≥6) or low (<6) numbers of prior treatment regimens.