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


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.


BACKGROUND
ClinicalTrials.gov # NCT01393106.
Division of Medical Oncology, Department of Medicine, Fred Hutchinson Cancer Research Center, University of Washington, Seattle.
A K
AK
Gopal
Division of Cancer Medicine, Department of Lymphoma/Myeloma, University of Texas MD Anderson Cancer Center, Houston.
M A
MA
Fanale
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York.
C H
CH
Moskowitz
Division of Medical Oncology, Department of Medicine, Fred Hutchinson Cancer Research Center, University of Washington, Seattle.
A R
AR
Shustov
Clinical research, Gilead Sciences Inc., Foster City, USA.
S
S
Mitra
Clinical research, Gilead Sciences Inc., Foster City, USA.
W
W
Ye
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York.
A
A
Younes
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York.
A J
AJ
Moskowitz
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D058534:Class I Phosphatidylinositol 3-Kinases / Q000037:antagonists & inhibitors / Q000235:genetics*; D018572:Disease-Free Survival; D064420:Drug-Related Side Effects and Adverse Reactions / Q000145:classification / Q000503:physiopathology; D005260:Female; D006689:Hodgkin Disease / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D006801:Humans; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D011687:Purines / Q000008:administration & dosage* / Q000009:adverse effects; D052999:Quinazolinones / Q000008:administration & dosage* / Q000009:adverse effects
D011687:Purines; D052999:Quinazolinones; D058534:Class I Phosphatidylinositol 3-Kinases; C486018:PIK3CD protein, human; C552946:idelalisib
Hodgkin lymphoma; PI3Kδ; idelalisib therapy