Dose Optimization of Duvelisib in Patients with Relapsed or Refractory Peripheral T-Cell Lymphoma from the Phase 2 Primo Trial: Selection of Regimen for the Dose-Expansion Phase
Authors: Horwitz Steven M. , Mehta-Shah Neha , Pro Barbara , Jacobsen Eric D , Casulo Carla , Brammer Jonathan E. , Haney Jeff , Youssoufian Hagop , Weaver David T. , Baglio Michael , Soto Jasminder , Narasimhan Narayana , Zain Jasmine 
Published: November 2019

Introduction
Relapsed or refractory (R/R) peripheral T-cell lymphoma (PTCL) carries a poor prognosis, with most approved therapies having response rates of &lt; 30% and limited 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. DUV exhibited potent activity against T-cell lymphoma cell lines in vitro, and DUV monotherapy at 25 or 75 mg BID demonstrated clinical activity in patients (pts) with R/R peripheral T-cell lymphoma (PTCL) in phase 1 studies [overall response rate (ORR), 50%] across multiple subtypes (Horwitz et al. Blood 2018; Horwitz et al. 2019 ICML). The phase 2 PRIMO trial was designed to determine an optimal regimen of DUV monotherapy in R/R PTCL and characterize the efficacy and tolerability of DUV in this disease. We report the results for the dose-optimization phase of the PRIMO trial (NCT03372057).
Methods
In the dose-optimization phase, pts with R/R PTCL, ECOG performance score of ≤ 2, and no history of allogeneic stem cell transplant were randomized to receive DUV 25 mg BID with an option for dose escalation (cohort 1) or DUV 75 mg BID (cohort 2) continuously until development of progressive disease or unacceptable toxicity (cycle = 28 days). The primary endpoint was investigator-assessed ORR, and secondary endpoints included duration of response and safety.
Results
A total of 33 pts (cohort 1, n = 20; cohort 2, n = 13) were treated in the dose-optimization phase (Table). Pts had a median of 1.5 years (range, 0.3-12.7 years) from initial diagnosis and a median of 2 prior therapies (range, 1-8). Patients were evaluable if they completed 1 cycle of DUV and had ≥ 1 efficacy assessment. Nonevaluable patients could be replaced. Response was assessed in the evaluable and overall populations. All patients in cohort 2 and 13 of 20 patients in cohort 1 were able to complete 1 cycle of therapy. Seven patients in cohort 1 discontinued therapy early due to disease progression and/or toxicity. Low CD4 counts (&lt; 50 cells/mm3; Common Terminology Criteria for Adverse Events grade 4) were associated with early discontinuation of DUV.
Most responses (cohort 1, 5/7; cohort 2, 6/7) were observed at the end of cycle 1. At a median follow-up of 20 weeks, the majority of responders (cohort 1, 4/7; cohort 2, 6/7) were still in response at the time of their last assessment. ORR as assessed by blinded independent central review could be determined for 31 patients and was 42% in cohort 1 and 67% in cohort 2.
Table. Analysis Populations and Investigator-Assessed Response
Pharmacokinetic analysis demonstrated a dose-related increase in exposure, with ≈ 2-fold increase in the steady-state exposure of DUV at the 75 vs 25 mg BID dosage, suggesting that adequate exposure can be more rapidly and reliably achieved with a higher dose of DUV. No differences were observed in pharmacodynamic markers (pAKT in monocytes and B cells) at 25 and 75 mg dose levels.
The most common (≥ 3 patients) grade ≥ 3 adverse events (AEs) in all patients receiving DUV were neutropenia (7), thrombocytopenia (5), and sepsis (4), with disease progression, pneumonia, aspartate aminotransferase elevation, lymphopenia, dyspnea, and rash observed in 3 patients. Serious AEs occurring in ≥ 2 patients were colitis, pyrexia, disease progression, sepsis, pneumonia, hyponatremia, dyspnea, pneumonitis, and respiratory failure. Overall, 12% of pts receiving DUV discontinued due to an AE.
Conclusions
These findings confirm that both 25 and 75 mg BID starting dosages of DUV are clinically active in pts with R/R PTCL, with complete responses in both cohorts. There were no unexpected toxicities. Early progression was seen more frequently in the 25 mg cohort, and higher initial exposure may be important in aggressive diseases. The expansion phase of the PRIMO trial will investigate DUV starting at 75 mg BID for 2 cycles to achieve rapid tumor response, followed by 25 mg BID to maintain long-term disease control and mitigate the potential for later onset toxicity.

Disclosures
Horwitz: Miragen: Consultancy; Celgene: Consultancy, Research Funding; Aileron: Research Funding; Aileron: Research Funding; Seattle Genetics: Consultancy, Research Funding; ADCT Therapeutics: Research Funding; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kyowa Hakko Kirin: Consultancy; Astex: Consultancy; Affimed: Consultancy; Kura: Consultancy; Infinity/Verastem: Consultancy, Research Funding; Portola: Consultancy; Affimed: Consultancy; Celgene: Consultancy, Research Funding; Millennium/Takeda: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Innate Pharma: Consultancy; Millennium/Takeda: Consultancy, Research Funding; Astex: Consultancy; ADCT Therapeutics: Research Funding; Portola: Consultancy; Mundipharma: Consultancy; Aileron: Research Funding; Portola: Consultancy; Forty-Seven: Research Funding; Trillium: Research Funding; Aileron: Research Funding; Celgene: Consultancy, Research Funding; Millennium/Takeda: Consultancy, Research Funding; Kura: Consultancy; Seattle Genetics: Consultancy, Research Funding; Astex: Consultancy; Forty-Seven: Research Funding; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; ADCT Therapeutics: Research Funding; Astex: Consultancy; Miragen: Consultancy; Kyowa Hakko Kirin: Consultancy; Millennium/Takeda: Consultancy, Research Funding; Affimed: Consultancy; Miragen: Consultancy; Mundipharma: Consultancy; Innate Pharma: Consultancy; Forty-Seven: Research Funding; Celgene: Consultancy, Research Funding; Innate Pharma: Consultancy; Innate Pharma: Consultancy; Mundipharma: Consultancy; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Consultancy, Research Funding; Affimed: Consultancy; Kyowa Hakko Kirin: Consultancy; Trillium: Research Funding; Forty-Seven: Research Funding; Kyowa Hakko Kirin: Consultancy; Kura: Consultancy; Infinity/Verastem: Consultancy, Research Funding; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Miragen: Consultancy; Trillium: Research Funding; Kura: Consultancy; Mundipharma: Consultancy; Infinity/Verastem: Consultancy, Research Funding; Trillium: Research Funding; Infinity/Verastem: Consultancy, Research Funding; Portola: Consultancy; ADCT Therapeutics: Research Funding. Mehta-Shah:Kiowa Hakka Kirin: Consultancy; Roche/Genentech: Research Funding; Bristol Myers Squibb: Research Funding; Verastem Pharmaceuticals: Research Funding; Celgene: Research Funding; Innate Pharmaceuticals: Research Funding. Pro:Takeda: Consultancy, Honoraria, Other: Travel Expenses; Celgene: Consultancy, Honoraria; Kyowa Hakka Kirin: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria, Other: Travel Expenses, Research Funding. Jacobsen:Pharmacyclics: Research Funding; Merck: Consultancy, Research Funding; Novartis: Research Funding; Takeda: Honoraria; Acerta: Consultancy; Astra-Zeneca: Consultancy; F. Hoffmann-LaRoche: Research Funding. Casulo:Celgene: Research Funding; Gilead: Honoraria, Other: Travel, accommodation, expenses; Roche: Other: Travel, accommodation, expenses. Brammer:Celgene: Research Funding; Seatlle Genetics: Honoraria, Speakers Bureau. Haney:Verastem Inc: Employment, Equity Ownership. Youssoufian:Verastem Oncology: Consultancy, Equity Ownership. Weaver:Verastem Oncology: Employment, Equity Ownership, Patents & Royalties: Inventor; Hillstream Biopharma: Consultancy, Equity Ownership; FemtoDx: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties: Inventor. Baglio:Verastem Oncology: Employment. Narasimhan:Verastem: Employment, Equity Ownership. Zain:Spectrum: Consultancy; Seattle Genetics: Consultancy.

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.