Duvelisib in Patients with Relapsed/Refractory Peripheral T-Cell Lymphoma from the Phase 2 Primo Trial: Dose Optimization Efficacy Update and Expansion Phase Initial Results
Authors: Pro Barbara , Brammer Jonathan E. , Casulo Carla , Jacobsen Eric , Mead Monica , Mehta-Shah Neha , Zain Jasmine M. , Zinzani Pier Luigi , Lustgarten Stephanie , Youssoufian Hagop , Horwitz Steven M. 
Published: November 2020

Relapsed or refractory (R/R) peripheral T-cell lymphoma (PTCL) is an aggressive lymphoma with a median overall survival (OS) of 6 months. Most approved therapies have overall response rates (ORR) of &lt; 30%, low complete response (CR) rates, and short progression free survival (PFS). Duvelisib (DUV), a dual PI3K-δ,γ inhibitor, is FDA approved at 25 mg twice daily (BID) for the treatment of R/R chronic lymphocytic leukemia or small lymphocytic lymphoma after ≥ 2 lines of prior therapy and R/R follicular lymphoma after ≥ 2 prior systemic therapies, the latter based on accelerated approval. DUV monotherapy demonstrated an ORR of 50% in patients (pts) with R/R PTCL in a Phase 1 study across multiple subtypes (Horwitz, Blood 2018). In the Phase 2, open-label, multi-center, PRIMO trial of DUV in R/R PTCL, the initial results of the dose-optimization phase (N=33) showed a 54% ORR in the 75 mg BID (N=13) and 35% in the 25 mg BID (N=20) cohorts by investigator assessment (INV) , the primary endpoint (Horwitz, ASH 2019). We report mature dose-optimization results and the initial results of a planned preliminary assessment (N=20) of the dose-expansion (NCT03372057; supported by Verastem Oncology).
In the dose-optimization phase, pts received DUV at 25 mg (Cohort 1) or 75 mg BID (Cohort 2). Pts were evaluable if they completed 1 cycle (28 days) of DUV and had ≥ 1 efficacy assessment. The dose-expansion phase is ongoing with a targeted enrollment of 100 pts; pts were eligible if they had histologically confirmed R/R PTCL after ≥2 cycles of a prior standard regimen and a CD4 lymphocyte count of ≥ 50/mm3 (0.05 x 109/L). Based on the initial dose-optimization results, it was determined pts will receive DUV starting at 75 mg BID for 2 cycles to achieve more rapid tumor control, followed by 25 mg to try to maintain long-term disease control and mitigate the potential for later onset toxicities. Pts were to be maintained on therapy continuously until progressive disease (PD) or unacceptable toxicity. For those at 25mg BID, it was permitted for the dose to be re-escalated to 75 mg BID if an assessment shows PD and the pt had not required a dose modification due to toxicity. The primary endpoint is ORR by an Independent Review Committee (IRC), and secondary endpoints include duration of response (DOR), PFS, OS, disease control rate, and safety; all analyses consisted of pts that received at least 1 dose of DUV. The statistical analysis plan was amended to take a preliminary assessment of ORR after approximately 20 pts were evaluated for response in the dose-expansion phase, consistent with the number of pts that were evaluated in the dose-optimization phase (Cohort 2).
Dose-Optimization Phase Efficacy Update: As of the data cutoff, 2 pts (1 each cohort) remain on treatment. Efficacy data are summarized in Table 1. Of those pts that achieved a CR, 1 in each cohort proceeded to undergo stem cell transplant or consolidated radiation therapy with curative intent, and are censored in the DOR assessment .
Dose-Expansion Phase Initial Summary: As of the data cutoff of 23 March 2020, a total of 25 pts have been dosed, 20 of whom underwent at least 1 disease response assessment (Table 1). Pts had a median age of 61 years (range, 21-86 years) and a median of 2 prior therapies (range, 1-6). Forty-five percent (9/20) of pts remain on treatment (5 responders, 3 with assessments not yet performed, 1 on treatment with stable disease);11 pts discontinued due to PD (n=7), adverse events (n=2) , or to under go transplant (n=2). Responses occurred in 8/20 pts: PTCL-NOS (4 CR, 1 partial response [PR]), ALCL (1 PR), AITL (1 CR) and SPTCL (1 CR). The most frequent adverse events seen were neutrophil count decreased (25%), ALT increased (21%), WBC decreased (21%) and lymphocyte count decreased (21%).
In summary, the DUV data observed to date show consistent response rates in a R/R PTCL pt population. The safety profile observed in PRIMO to date is consistent with the current safety profile of DUV. The mature dose-optimization phase results demonstrated a median DOR of 12.2 months for the 75 mg BID cohort. The preliminary results from the PRIMO dose-expansion cohort (75 mg BID followed by 25 mg BID dosing) show an ORR of 40 % and CR rate of 30% (6/20) by INV assessment. These data support continued evaluation of DUV as a treatment option for R/R PTCL. Updated data from the planned interim analysis after 40 pts enroll (occurred June 2020) will be presented.

Disclosures
Pro: Verastem Oncology: Research Funding. Brammer:Bristol-Myers Squibb: Research Funding; Celgene: Research Funding; Seattle Genetics: Honoraria, Speakers Bureau; Kymera: Honoraria; Verastem Oncology: Other: Travel. Jacobsen:Takeda: Honoraria; Merck, Pharmacyclics, F. Hoffmann-LaRoche, Novartis: Research Funding; Acerta, AstraZeneca, Merck: Consultancy. Mehta-Shah:Corvus: Research Funding; Verastem: Research Funding; Celgene: Research Funding; Bristol Myers-Squibb: Research Funding; Genetech/Roche: Research Funding; C4 Therapeutics: Consultancy; Karyopharm Therapeutics: Consultancy; Innate Pharmaceuticals: Research Funding; Kyowa Hakko Kirin: Consultancy. Zain:Seattle Genetics: Research Funding; Kyowa Kirlin: Research Funding; Mundai Pharma: Research Funding. Zinzani:Immune Design: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sandoz: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celltrion: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Verastem: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kirin Kyowa: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; EUSA Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TG Therapeutics, Inc.: Honoraria, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Eusapharma: Consultancy, Speakers Bureau; Kyowa Kirin: Consultancy, Speakers Bureau; Immune Design: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Lustgarten:Verastem Oncology: Current Employment, Current equity holder in publicly-traded company. Youssoufian:Verastem Oncology: Current Employment, Current equity holder in publicly-traded company. Horwitz:Janssen: Consultancy; GlaxoSmithKline: Consultancy; Daiichi Sankyo: Research Funding; C4 Therapeutics: Consultancy; Beigene: Consultancy; Portola: Consultancy, Research Funding; Mundipharma: Consultancy; Innate Pharma: Consultancy; Corvus: Consultancy; Trillium: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Millenium/Takeda: Consultancy, Research Funding; Kyowa Hakka Kirin: Consultancy, Research Funding; Infinity/Verastem: Research Funding; Forty Seven: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Aileron: Consultancy, Research Funding; ADCT Therapeutics: Consultancy, Research Funding; Vividion Therapeutics: Consultancy; Verastem: Consultancy, Research Funding; Myeloid Therapeutics: Consultancy; Miragen: Consultancy; Kura Oncology: Consultancy; ASTEX: Consultancy; Affirmed: Consultancy.

OffLabel Disclosure:
Duvelisib (DUV), a dual PI3K-δ,γ inhibitor, is 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 2 prior systemic therapies, the latter based on accelerated approval. This indication is approved under accelerated approval based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. Duvelisib is not approved for Peripheral T-Cell Lymphoma. This study is investigating treatment or outcomes that have not received approval from a Health Authority. The information presented is not intended to convey conclusions of safety or efficacy. There is no guarantee that the outcome of these studies will result in approval by a Health Authority.