The oral phosphoinositide 3-kinase (PI3K) dual inhibitor duvelisib appeared to be active and tolerable at a range of doses and across a variety of advanced hematologic malignancies, according to results from an open-label, dose-escalation, phase I study published in Blood.
“Findings from this … first clinical evaluation of duvelisib support continued development as a potential contributor to the lymphoma and leukemia treatment paradigm,” wrote Ian W. Flinn, MD, PhD, of the Sarah Cannon Research Institute in Nashville, Tennessee, and co-authors.
The trial included 210 patients (median age = 66.5 years; range = 25-86 years) who received duvelisib twice-daily continuously in 28-day cycles until disease progression or unacceptable toxicity. Most patients were male (62.3%; n=132), white (88.1%; n=185), and had an Eastern Cooperative Oncology Group performance status score of 1 (65.2%).
Participants were heavily pretreated, the researchers noted: The median number of prior therapies was three (range = 0-11 therapies), and 133 patients (63.3%) had received three or more prior systemic regimens. Patient diagnoses included indolent non-Hodgkin lymphoma (NHL; n=31; 14.8%), relapsed/refractory chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL; n=55; 26.2%), treatment-naïve CLL (n=18; 8.6%), T-cell NHL (n=35; 16.7%), and other (n=71; 33.8%; the most common diagnoses in this cohort were aggressive NHL [n=26; 12.4%], mantle cell lymphoma [n=10; 4.8%], acute myeloid leukemia [n=6; 2.9%], and myelodysplastic syndromes [n=6; 2.9%]).
In the dose-escalation phase, 31 adult patients with advanced hematologic malignancies received duvelisib at eight doses (ranging from 8-100 mg) in a standard 3+3 design. People in this cohort had disease that progressed following or was refractory to established therapy. Those with previous exposure to PI3K inhibitors or a diagnosis of overt leptomeningeal leukemia or central nervous system lymphoma were excluded.
In the dose-expansion cohort (n=179), enrollment criteria were similar, except patients who previously received PI3K inhibitors and those with inadequate bone marrow function were eligible for inclusion.
The median duration of duvelisib treatment was 16 weeks (range = 0.3-166.6 weeks) across all dosing groups. Twenty patients with relapsed/refractory CLL/SLL (36.4%) and 12 patients with treatment-naïve CLL (66.7%) remained on duvelisib for more than one year (or at least 12 cycles of 28 days each).
In the dose-escalation phase, four patients experienced dose-limiting toxicities, including grade 4 neutropenia at 15 mg, grade 3 cellulitis at 75 mg, and grade 3 alanine transaminase (ALT) and aspartate transaminase (AST) and rash at 100 mg. Based on these results, the researchers determined the maximum tolerated dose of duvelisib to be 75 mg.
Pharmacokinetic analyses included 207 patients from both cohorts. The researchers found that a single dose of duvelisib was rapidly absorbed, reaching peak concentration within two hours. A single dose also induced rapid reductions in phospho-AKT (p-AKT), “a key mediator of PI3K signaling,” that were sustained at 24 hours in most patient samples, the authors wrote.
as a potential
—Ian W. Flinn, MD, PhD
Peak p-AKT and Ki-67 effects were achieved at the duvelisib 25 mg dose, prompting investigators to select this dose for future evaluation in phase II and III studies.
The most common any-grade hematologic AEs associated with duvelisib were neutropenia (n=81; 38.6%), anemia (n=52; 24.8%), and thrombocytopenia (n=40; 23.3%). The most common any-grade non-hematologic AEs were diarrhea (n=88; 41.9%), fatigue (n=85; 40.5%), and pyrexia (n=74; 35.2%). The researchers also observed ALT (n=81; 38.6%) and AST (n=79; 37.6%) elevations early in treatment, with a median time of onset of 1.2 months (range not provided).
“Not surprisingly, given the patient population, infections of all grades were common, reported in 128 (61%) patients,” the investigators observed, with the most frequent being upper respiratory tract infections (n=34; 16.2%). Based on safety findings, the study protocol was amended to require mandatory pneumocystis prophylaxis and herpes simplex virus prophylaxis.
Eleven patients (5%) experienced fatal AEs, eight of which were related to infections.
“While the study was not designed to detect significant differences between dose levels, there did not appear to be a notable difference in the safety profile of duvelisib by dose,” the authors reported. In the two largest cohorts (25 mg and 75 mg), the rates of severe AEs were 80 percent and 87 percent, respectively.
The overall response rate (defined as complete response [CR] or partial response [PR]) in each disease subtype were:
- 56% (n=31/55) in relapsed/refractory CLL, including 1 CR
- 83% (n=15/18) in treatment-naïve CLL, all PR
- 58% (n=18/31) in indolent NHL, including 6 CRs
- 32% (n=6/19) in cutaneous T-cell lymphoma, all PRs
- 50% (n=8/16) in peripheral T-cell lymphoma, including 3 CRs
“In extensively pretreated patients with relapsed/refractory leukemia or lymphoma and previously untreated CLL, duvelisib monotherapy demonstrated clinically meaningful activity,” the authors concluded.
Based on the study’s findings, the researchers selected a 25 mg dose for future studies. Two ongoing studies are evaluating this dose of duvelisib: DYNAMO, a phase II study, is evaluating the agent in patients with relapsed indolent NHL, and DUO, a phase III study, is evaluating duvelisib in patients with relapsed/refractory CLL.
This early-phase study is limited by its lack of a comparator arm and mixture of previously treated and untreated patients across a variety of cancers.
Infinity Pharmaceuticals and Verastem provided financial support for this study.
The authors report financial relationships with Infinity Pharmaceuticals and Verastem. Infinity Pharmaceuticals and Acumen Medical Communications provided editorial support.
Flinn IW, O’Brien S, Kahl B, et al. Duvelisib, a novel oral dual inhibitor of PI3K-δ,γ, is clinically active in advanced hematologic malignancies. Blood. 2017 November 30. [Epub ahead of print]