A Phase I Trial of PI3Kαδ Inhibitor Copanlisib in Combination with Nivolumab in Patients with Richter's Transformation (RT) or Transformed Non-Hodgkin Lymphoma (tNHL)
Authors: Shouse Geoffrey , Siddiqi Tanya , Popplewell Leslie L. , Muir Alexandra , Melgar Ivana , Gonzales Brandy , Orand Kirsten , Puverel Sandrine , Wang Lili , Kittai Adam S , Chen Lu , Davids Matthew S. , Danilov Alexey V. 
Published: November 2021

Abstract
Background. Despite advances in targeted and cellular therapy, outcomes among patients with RT and tNHL remain dismal. Copanlisib (COPA) is a selective, small molecule, PI3K inhibitor which preferentially targets the p110αδ isoforms . COPA has shown clinical efficacy in NHL and is an approved therapy for follicular lymphoma (FL). Nivolumab is a PD-1 antagonist which has demonstrated activity in Hodgkin lymphoma as well as NHL. Furthermore, combined targeting of PI3K and PD-1 has demonstrated synergy in pre-clinical lymphoma models. Here we report initial results of a phase 1 study of COPA in combination with nivolumab in patients with R/R RT or tNHL (NCT03884998).
Methods. This ongoing multicenter, open-label, phase I, investigator-sponsored study is enrolling patients with RT or tNHL, age ≥18 years, whose disease had relapsed or was refractory to ≥1 prior line of therapy. The phase I portion of the study followed a standard 3+3 design with three planned dose levels of COPA administered IV (dose level [DL]1 - 45 mg on days 1, 8 and 15; DL2 - 60 mg on days 1, 8 and 15; DL "-1" - 45 mg on days 1 and 15 of a 28-day cycle). Nivolumab 240 mg was given IV on days 1 and 15. Patients received up to 24 cycles of therapy. The primary study objective was to evaluate the maximum tolerated dose (MTD) of the combination; secondary objectives included preliminary measures of efficacy by Lugano criteria including PET/CT scans. Exploratory objectives included pharmacodynamic endpoints. Dose limiting toxicities (DLT) were defined as grade ≥4 hematologic &gt; 7 days or grade ≥3 non-hematologic toxicities.
Results. Of the eleven patients enrolled, 8 had RT and 3 had transformed FL (tFL); 91% (10/11) were men. Median age was 70 (43-77) years, 82% (9/11) had an ECOG performance status ≤1. Patients had received a median of 3 prior lines of therapy (range, 1-8), including three patients (1 RT, 2 FL) who had undergone CAR T cell therapy. Eight patients were treated at DL1 (45 mg COPA), of which 2 patients did not complete the DLT period due to rapidly progressive disease and were replaced. No DLTs were observed at this dose level. At DL2 (60 mg COPA), three DLTs (grade 4 febrile neutropenia and grade 4 thrombocytopenia in another patient) were observed among the three patients treated. Therefore, the MTD and recommended phase 2 dose (RP2D) of COPA in combination with nivolumab was determined to be 45 mg on days 1, 8, 15. The most common treatment-related adverse events (AEs, any grade) were anemia and neutropenia (Table 1). Five pts discontinued therapy due to progressive disease; one due to intercurrent infection (coccidiomycosis, unrelated to study drugs), two due to DLTs noted above. Three patients remain on treatment. Among the seven efficacy-evaluable patients who completed at least one cycle of therapy, median time on treatment was 2 months (range, 2-9 months). Of these, four patients achieved a response per the investigators' assessment (tFL: 2 partial responses; RT: 1 complete response and 1 partial response). Efficacy assessment is ongoing and will be reported at the meeting.
Discussion. We identified COPA 45 mg IV on days 1, 8 and 15 as the MTD/RP2D in combination with nivolumab in patients with R/R RT and tFL. This combination was well-tolerated at the MTD/RP2D, and the study is currently enrolling patients in an expansion cohort to further characterize the efficacy of this regimen.
Figure 1 Figure 1.

Disclosures
Shouse: Beigene Pharmaceuticals: Honoraria; Kite Pharmaceuticals: Speakers Bureau. Siddiqi: Kite Pharma: Membership on an entity's Board of Directors or advisory committees; Juno therapeutics: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BeiGene: Other: DSM Member, Speakers Bureau; PCYC: Speakers Bureau; Jannsen: Speakers Bureau; Dava Oncology: Honoraria; ResearchToPractice: Honoraria. Popplewell: Pfizer: Other: Travel; Novartis: Other: Travel; Hoffman La Roche: Other: Food. Kittai: Janssen: Consultancy; Bristol-Meyers Squibb: Consultancy; Abbvie: Consultancy. Davids: MEI Pharma: Consultancy, Research Funding; Surface Oncology: Research Funding; AbbVie: Consultancy; BeiGene: Consultancy; Merck: Consultancy; Ascentage Pharma: Consultancy, Research Funding; Eli Lilly and Company: Consultancy; BMS: Consultancy, Research Funding; Janssen: Consultancy; Celgene: Consultancy; Astra-Zeneca: Consultancy, Research Funding; Adaptive Biotechnologies: Consultancy; Research to Practice: Consultancy; Verastem: Consultancy, Research Funding; Takeda: Consultancy; MEI Pharma: Consultancy; TG Therapeutics: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Genentech: Consultancy, Research Funding. Danilov: Genentech: Consultancy, Honoraria, Research Funding; Astra Zeneca: Consultancy, Honoraria, Research Funding; SecuraBio: Research Funding; Bristol-Meyers-Squibb: Honoraria, Research Funding; Rigel Pharm: Honoraria; Takeda Oncology: Research Funding; Bayer Oncology: Consultancy, Honoraria, Research Funding; Gilead Sciences: Research Funding; Pharmacyclics: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Beigene: Consultancy, Honoraria; TG Therapeutics: Consultancy, Research Funding.