CCTG LY18‐A phase I master protocol of novel combination therapy for patients with relapsed or refractory lymphoma ‐ the RGDP‐Venetoclax substudy

Introduction: Therapies for relapsed/refractory (r/r) large B cell lymphomas are expanding. Chemo-immunotherapy and autologous stem cell transplant (ASCT) remains an important therapeutic option with survival benefit. About 50% of patients (pts) have an adequate response to salvage therapy which is required to proceed to ASCT. Novel salvage regimens may increase response and transplantation rate. Methods: LY.18 is a Canadian Cancer Trials Group Phase I platform trial of novel salvage regimens for patients with r/r large B cell lymphoma. RGDP (rituximab, gemcitabine, dexamethasone, cisplatin) plus venetoclax (RGDP-V) was evaluated in adult pts with diffuse large B cell lymphoma, primary mediastinal B cell lymphoma, transformed follicular lymphoma, or high-grade B cell lymphoma after one prior line of therapy. RGDP was administered at standard doses (Crump, JCO, 2014) for up to 3 cycles pre-transplant. V was administered at increasing dose levels (200–800 mg) according to a 3+3 design, with dose limiting toxicity (DLT) assessed in cycle one. The recommended Phase 2 dose (RP2D) was the primary outcome. Pts with a partial or complete response (PR or CR) could proceed to ASCT. Response was assessed using both the Lugano criteria and RECIL. Results: Since Sept 2020, 18 pts have been treated at 5 dose levels. Severe myelotoxicity was noted in the first dose level with 2 DLTs observed in the first 4 pts. The trial was amended to mandate G-CSF days 9 to 14 with each cycle of therapy (Table 1). Median age was 59, 4 pts were ≥65 years, 8 were female, median ECOG was 1 (range 0 to 3). Two of 3 pts experienced a DLT at the 800 mg dose. The recommended phase 2 dose (RP2D) is RGDP-V 400 mg days 4 to 10 of cycle 1, and days 1 to 10 of cycles 2 and 3. There were 7 serious adverse events in 5 pts, including febrile neutropenia (n = 3); grade 2 bacteremia (n = 1); and grade 3 abdominal pain, C2 fracture from fall, and supraventricular tachycardia (n = 1 each), all unrelated. There were 4 deaths on trial; 3 disease related, 1 from transplant-related complications. All grade treatment emergent adverse events occurring in at least 20% of patients were tinnitus, abdominal pain, constipation, diarrhea, dyspepsia, fatigue, pain, headache, and back pain. Grade 3 or greater anemia was seen in 33%, neutropenia in 78%, and thrombocytopenia in 61% of pts. The ORR in 16 evaluable pts was 75% (12/16) (95% CI: 51.7%–92.4%) by both Lugano criteria and RECIL; 2 pts were in CR by Lugano criteria and 3 pts by RECIL. Responses were seen across all dose levels. Stem cell collection >2.0 × 106 CD34+cells/kg was achieved in 9 of 10 pts in whom it was attempted. All 10 pts were successfully transplanted. 4 pts received CART therapy, 1 following progression post ASCT. Conclusion: RGDP-V 400 mg is safe and feasible with encouraging early response rates. Neutropenia was a key toxicity and can be mitigated with prophylactic G-CSF. LY.18 will expand to include 6 more patients at the RP2D. The research was funded by: AbbVie Corporation, Hoffmann-La Roche Ltd Keywords: Aggressive B-cell non-Hodgkin lymphoma, Combination Therapies Conflicts of interests pertinent to the abstract. S. Assouline Consultant or advisory role: Abbvie, BMS, AstraZeneca, Janssen, BeiGene, Pfizer, Roche Research funding: Novartis Canada D. Villa Honoraria: Janssen, BeiGene, AstraZeneca, Abbvie, BMS/Celgene, Kite/Gilead, Merck, Roche, ONO Pharmaceuticals, Zetagen Research funding: Roche, AstraZeneca A. Hay Research funding: AbbVie, Janssen, Merck, Seattle Genetics, Roche, Karyopharm M. Crump Honoraria: Kyte/Gilead and Novartis Research funding: Roche and Epizyme (Institution) R. Kridel Research funding: Abbvie, Acerta Educational grants: Eisai A. Shamy Consultant or advisory role: Abbvie, BMS, BeiGene, Tahoe, Roche Honoraria: Abbvie, BMS, BeiGene, Tahoe, Roche A. Gerrie Honoraria: Abbvie, Astrazeneca, Janssen, Beigene K. Savage Consultant or advisory role: Seagen Honoraria: BMS, Merck, AstraZeneca, Janssen, Abbvie Research funding: BMS(self), Roche(Institution) Other remuneration: Regeneron(DSMC), Beigen (Steering Committee) L. Shepherd Research funding: AbbVie, Janssen, Merck, Seattle Genetics, Roche, Karyopharm J. Kuruvilla Consultant or advisory role: Abbvie, Antengene, BMS, Gilead, Karopharym, Merck, Roche and Settale Genetics Honoraria: Abbvie, Amgen, Astra Zeneca, BMS, Gilead, Incyte, Janssen, Karyopharm, Merck, Novartis, Pfizer, Roche and Seattle Genetics Research funding: Roche, Astra Zeneca and Merck Other remuneration: DSMB for Karyopharm