A Phase 2, Randomized, Open-Label, 2-Arm Study Comparing 2 Intermittent Dosing Schedules of Duvelisib in Patients with Indolent Non-Hodgkin Lymphoma (iNHL) (TEMPO)
Authors: Karmali Reem , Youssoufian Hagop , Sprott Kam , Weaver David T. , Narasimhan Narayana , Lustgarten Stephanie , Patrick Gloria , Zalutskaya Alena , Gordon Leo I. 
Published: November 2019

Background
Duvelisib, an oral dual PI3K-δ and PI3K-γ inhibitor, is approved by the US Food and Drug Administration for the treatment of adult patients with relapsed or refractory (R/R) follicular lymphoma (FL) after ≥ 2 prior systemic therapies. In multiple phase 1-3 studies that included patients with iNHL, duvelisib was shown to be efficacious, with a favorable risk-benefit profile. This study will evaluate whether duvelisib efficacy at the approved 25 mg twice daily (BID) dose can be achieved and maintained with an acceptable or improved safety profile by the inclusion of prespecified 2-week drug holidays in patients with R/R iNHL.
Study Design and Methods
TEMPO is a randomized, open-label, multicenter, international, phase 2 study of duvelisib in adult patients with R/R iNHL in whom ≥ 1 line of prior therapy has failed. The primary objective is to evaluate the efficacy of duvelisib administered with prescribed drug holidays, with the primary endpoint of overall response rate (ORR) by the 2007 revised International Working Group criteria. Key secondary endpoints include ORR by the 2014 Lugano criteria, progression-free survival, overall survival, time to treatment failure, duration of response, lymph node response rate, time to the first response, adverse event profile, and determination of pharmacokinetics parameters. Exploratory objectives include assessment of quality of life and biomarkers of treatment response and toxicity.
Key inclusion criteria include histologically confirmed FL grades 1 to 3a, marginal zone lymphoma (splenic, nodal, or extranodal) or small lymphocytic lymphoma, radiological evidence of disease progression and ≥ 1 bidimensionally measurable lesion ≥ 1.5 cm, adequate organ function, and Eastern Cooperative Oncology Group performance status ≤ 2. Key exclusion criteria include prior allogeneic hematopoietic stem cell transplant; previous treatment with a PI3K inhibitor; history of drug-induced colitis or drug-induced pneumonitis; ongoing treatment for systemic infection; central nervous system NHL; prolonged QT interval; history of tuberculosis treatment within the 2 past years; history of stroke, unstable angina, myocardial infarction, or ventricular arrhythmia requiring medication or mechanical control within the past 6 months; history of or concurrent interstitial lung disease of any severity and/or severely impaired lung function; ongoing treatment with chronic immunosuppressants; and any unstable or severe uncontrolled medical condition.
A total of 102 patients are planned to be enrolled. Patients will be randomized 1:1 to 2 arms and stratified by number of prior therapies (1 or > 1), bulky disease status (longest diameter of baseline lesion < 5 cm or ≥ 5 cm), and time since last recurrence (≥ 24 months or < 24 months). In arm 1, patients will receive duvelisib 25 mg BID for one 10-week (W) cycle followed by 25 mg BID on W3 and W4 of each subsequent 4-week cycle. In arm 2, patients will receive duvelisib 25 mg BID on W1, W2, W5, W6, W9, and W10 of one 10-week cycle and then on W3 and W4 of each subsequent 4-week cycle. Patients will be treated until disease progression, unacceptable toxicity, or withdrawal. This study will test the null hypothesis that the ORR in each arm is ≤ 30% against the alternative that the ORR is ≥ 55%. The study has a 2-stage design. In stage 1, 15 patients will be enrolled in each arm, with response assessment after ≥ 3 cycles. If there are fewer than 6 partial or complete responses, consideration may be given to terminating the arm. Otherwise, in stage 2, 36 additional patients will be enrolled, for a total of 51 per arm. Enrollment is planned to be initiated in August 2019. Approximately 50 sites will be open for enrollment across the United States, Europe, and Asia.

Disclosures
Karmali: Takeda, BMS: Other: Research Funding to Institution; Gilead/Kite; Juno/Celgene: Consultancy, Speakers Bureau; Astrazeneca: Speakers Bureau. Youssoufian:Verastem Oncology: Consultancy, Equity Ownership. Sprott:SMOC Therapeutics: Employment, Equity Ownership; Verastem Oncology: Employment, Equity Ownership. Weaver:FemtoDx: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties: Inventor; Verastem Oncology: Employment, Equity Ownership, Patents & Royalties: Inventor; Hillstream Biopharma: Consultancy, Equity Ownership. Narasimhan:Verastem: Employment, Equity Ownership. Lustgarten:Verastem: Employment. Patrick:Verastem Oncology: Employment. Zalutskaya:Verastem Inc: Employment, Equity Ownership. Gordon:Gilead: Other: Advisory Board; Juno/Celgene: Other: Advisory Board, Research Funding; Zylem LLC: Other: co-founder; research in nanoparticles in cancer; Bayer: Other: Advisory Board.

OffLabel Disclosure:
Duvelisib (DUV), a dual PI3K-delta,gamma inhibitor, is US FDA approved at 25 mg twice daily (BID) for the treatment of R/R chronic lymphocytic leukemia or small lymphocytic lymphoma after at least 2 lines of prior therapy and R/R follicular lymphoma after at least two prior systemic therapies.