Phase II study of idelalisib, a selective inhibitor of PI3Kδ, for relapsed/refractory classical Hodgkin lymphoma

Abstract

Background: The phosphatidylinositol-3-kinase delta (PI3Kδ) inhibitor idelalisib has been shown to block downstream intracellular signaling, reduce the production of prosurvival chemokines and induce apoptosis in classical Hodgkin lymphoma (HL) cell lines. It has also been shown to inhibit regulatory T cells and myeloid-derived suppressor cells in other tumor models. We hypothesized that inhibiting PI3Kδ would have both direct and indirect antitumor effects by directly targeting the malignant cells as well as modulating the inflammatory microenvironment. We tested this hypothesis in a phase II study.

Patients and methods: We enrolled 25 patients with relapsed/refractory HL with a median age of 42 years and who had previously received a median of five therapies including 18 (72%) with failed autologous stem cell transplant, 23 (92%) with failed brentuximab vedotin, and 11 (44%) with prior radiation therapy. Idelalisib was administered at 150 mg two times daily; an increase to 300 mg two times daily was permitted at the time of disease progression.

Results: The overall response rate to idelalisib therapy was 20% (95% confidence interval: 6.8%, 40.7%) with a median time to response of 2.0 months. Seventeen patients (68%) experienced reduction in target lesions with one complete remission and four partial remissions. The median duration of response was 8.4 months and median progression-free survival was 2.3 months. The most common grade ≥3 adverse event was elevation of alanine aminotransferase (two patients, 8%). Diarrhea/colitis was seen in three patients and was grade 1-2. There was one adverse event leading to death (hypoxia).

Conclusions: Idelalisib was tolerable and had modest single-agent activity in heavily pretreated patients with HL. Rational combinations with other novel agents may improve response rate and duration of response.

Clinical trial registration: ClinicalTrials.gov # NCT01393106.

Keywords: Hodgkin lymphoma; PI3Kδ; idelalisib therapy.

© The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Figures

Figure 1.

Waterfall plot of percent change in SPD in nodal lesions. SPD, sum of the product of the greatest perpendicular diameters of target lymph nodes as documented radiographically. The red line represents a % change of −50% and is a criterion for lymphadenopathy response [20]. aOne patient was non-evaluable.

Figure 2.

Kaplan–Meier curve for progression-free survival (PFS). Progression-free survival was defined as the time from the start of idelalisib treatment to the date of documented disease progression or death due to any cause, whichever came first. The KM estimate of median PFS was 2.3 months. The KM estimate of the proportion of patients with PFS at six months was 28.9%.

Figure 3.

Kaplan–Meier curve for overall survival (OS). Overall survival was defined as the time from study day one until the date of death due to any cause, including data from long-term follow-up. The KM estimate of median OS was 19.8 months. The KM estimate of the proportion of surviving patients at six months was 88%. This figure depicts the KM curve for OS for the intent-to-treat analysis set, including long-term follow-up data.