-Author name in bold denotes the presenting author
-Asterisk * with author name denotes a Non-ASH member
Clinically Relevant Abstract denotes an abstract that is clinically relevant.

PhD Trainee denotes that this is a recommended PHD Trainee Session.

Ticketed Session denotes that this is a ticketed session.

2104 A Phase I Study of Selinexor and R-ICE in Patients with Relapsed/Refractory Aggressive B-Cell Lymphomas

Program: Oral and Poster Abstracts
Session: 626. Aggressive Lymphoma (Diffuse Large B-Cell and Other Aggressive B-Cell Non-Hodgkin Lymphomas)—Results from Prospective Clinical Trials: Poster II
Hematology Disease Topics & Pathways:
Diseases, Therapies, Combinations, B-Cell Lymphoma, Lymphoid Malignancies
Sunday, December 6, 2020, 7:00 AM-3:30 PM

Sarah C. Rutherford, MD1, John N. Allan, MD1, Jia Ruan, MD, PhD1, Richard R. Furman, MD1, Kristy Richards, MD, PhD1*, Amelyn Rodriguez, BSN, RN, OCN1*, Kseniya Gololobova1*, Arcania Garcia1*, Leandro Cerchietti, MD1, Rossella Marullo, MD, PhD2, Zhengming Chen, PhD, MPH, MS1*, Jennifer Santamala, PharmD1*, Tsiporah B. Shore, MD1, Adrienne A. Phillips, MD1, Sebastian Mayer, MD1*, Jingmei Hsu, MD1, Usama Gergis, MD1, Silvia Senese1*, Trisha Ali-Shaw1*, Riyaad Rahim1*, Koen van Besien, MD, PhD1, John P. Leonard, MD1 and Peter Martin, FRCPC, MD, MS1

1Meyer Cancer Center, Weill Cornell Medicine, New York, NY
2Department of Medicine, Division of Hematology and Medical Oncology, Weill Cornell Medicine, New York, NY

Introduction: Patients (pts) with aggressive B-cell lymphomas who are relapsed or refractory to frontline therapy are typically treated with regimens including R-ICE (rituximab, ifosfamide, carboplatin, etoposide) followed by autologous stem cell transplant (ASCT) in responding pts. A minority of pts are cured with this approach, and the majority have poor outcomes. Selinexor is an oral, selective inhibitor of nuclear export, which activates tumor suppressor proteins and blocks translation of proteins that can contribute to chemoresistance, including MYC and BCL2. We conducted a phase I trial of selinexor plus R-ICE in pts with relapsed/refractory aggressive B-cell lymphomas. Methods: This phase I study used a 3+3 design with dose expansion. Eligible pts had diffuse large B-cell lymphoma (DLBCL), double hit lymphoma (DHL), and indolent lymphoma transformed to DLBCL. Treatment with 1 prior regimen administered with curative intent was required. Central nervous system (CNS) involvement was excluded. A separate cohort enrolled pts with Richter’s transformation (RT) from chronic lymphocytic leukemia; there was no requirement with regard to prior therapies for this group. Selinexor was initially dosed at 40 mg (DL-1), 60 mg (DL1) and 80 mg (DL2) on days (d) -5, -3, 1, 3, and 5 and R-ICE on d1-3 of a 21-d cycle. Because of CNS toxicity thought to be primarily related to ifosfamide, the protocol was amended so that R-ICE was given on d1-3 and selinexor following completion of ifosfamide on d3, 5, and 7 of each cycle. After 2 cycles, responding pts were eligible to receive SCT or chimeric antigen receptor (CAR) T-cell therapy at discretion of treating physician. Dose limiting toxicity (DLT) period was cycle 1 and included grade (gr) 4 febrile neutropenia; gr 4 neutrophils for ≥7d; gr 4 platelets for ≥10d; gr 3 nausea, vomiting, diarrhea, or fatigue lasting >3d; or gr ≥3 non-hematologic toxicities except alopecia, fatigue or electrolyte abnormalities correctable with supportive care. Results: 22 pts enrolled with median age 67 (range 34-79). 64% were male and 36% female. Stage was III-IV in 72%. IPI was intermediate to high risk in 77%. Diagnosis was DLBCL NOS in 12, DHL in 4, transformed indolent lymphoma in 2, primary mediastinal large B-cell lymphoma in 1, and RT in 3. 7 pts were treated on the initial dosing schedule. In the first group at DL1, 0/3 pts had DLT. At DL2, 2/2 pts had DLT (gr 3 altered mental status, AMS). In the second group at DL1, 1/2 pts had DLT (gr 3 AMS). The dosing schedule was then modified as noted above. 12 DLBCL pts were treated on the modified dosing schedule. At DL1, 2/3 pts had DLT (gr 5 sepsis, gr 4 platelets ≥10d). At DL-1, 1/6 pts had DLT (gr 3 abdominal infection). Selinexor 40 mg was declared the recommended phase 2 dose (RP2D) and 3 pts were enrolled in an expansion. 3 pts with RT were treated on the modified dosing schedule; 2 received selinexor and neither had DLT at DL1. Median number of cycles of selinexor plus R-ICE was 2 (range 1-3). Most common gr 3-4 toxicities were cytopenias and hyponatremia. Most common non-hematologic toxicities of all grades were hyponatremia, fatigue, transaminitis, and nausea. Of 21 pts who received selinexor plus R-ICE, objective response rate (ORR) was 71% with 7 complete responses (CR), 8 partial responses (PR), and 3 stable disease (SD). 5 underwent SCT (3 autologous, 2 allogeneic) and 8 received CAR T-cells. Those who underwent transplant have not required additional therapy to date. 4 complete responders did not receive ASCT in part related to difficulty mobilizing stem cells; 3 have not required additional therapy with follow up of 26, 46, and 46 months. At the RP2D in the DLBCL cohort (n=9), ORR was 78% with 4 CR, 3 PR, and 2 SD. Conclusions: We report the first data on the combination of selinexor, which is now FDA-approved as a single agent in relapsed/refractory DLBCL, and chemotherapy in pts with aggressive B-cell lymphomas. We identified a dosing schedule of selinexor with R-ICE (40 mg on d3, 5, and 7) that is worthy of further study based on initial efficacy, with attention to CNS toxicity and impact on stem cell collection.

Disclosures: Rutherford: Karyopharm: Consultancy, Research Funding; Regeneron: Research Funding; Seattle Genetics: Consultancy; LAM Therapeutics: Research Funding; Kite: Consultancy; Juno: Consultancy; AstraZeneca: Consultancy; Celgene: Consultancy; Dova: Consultancy; Genentech/Roche: Research Funding; Heron: Consultancy. Allan: Acerta, Genentech, Abbvie, Sunesis, Ascentage, Pharmacyclics, Janssen, AstraZeneca, BeiGene: Consultancy; Celgene, Genentech, Janssen, TG Therapeutics: Research Funding; Abbvie, Janssen, AstraZeneca, Pharmacyclics: Honoraria. Ruan: Celgene: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; Pharmacyclics: Research Funding; Seattle Genetics: Research Funding; Kite Pharma: Consultancy; Juno: Consultancy; BMS: Consultancy, Research Funding. Furman: Oncotarget: Consultancy; Loxo Oncology: Consultancy; Verastem: Consultancy; Beigene: Consultancy; AstraZeneca: Consultancy, Research Funding; Acerta: Consultancy; Abbvie: Consultancy; Genentech: Consultancy; Incyte: Consultancy; Janssen: Consultancy, Speakers Bureau; TG Therapeutics: Consultancy, Research Funding; Sunesis: Consultancy; Pharmacyclics: Consultancy. Cerchietti: BMS: Research Funding. Gergis: Incyte: Speakers Bureau; Merck: Speakers Bureau; Astellas: Consultancy, Speakers Bureau; Kite: Speakers Bureau; Mesoblast: Other: Ad Board; Jazz: Other: Ad board, Speakers Bureau. Leonard: ADC Therapeutics: Consultancy; MEI Pharma: Consultancy; Bayer: Consultancy; Epizyme: Consultancy; AstraZeneca: Consultancy; Miltenyi: Consultancy; Sutro: Consultancy; BMS/Celgene: Consultancy; Regeneron: Consultancy; Karyopharm: Consultancy; Roche/Genentech: Consultancy; Gilead/Kite: Consultancy; GenMab: Consultancy. Martin: Beigene: Consultancy; Bayer: Consultancy; I-MAB: Consultancy; Janssen: Consultancy; Sandoz: Consultancy; Karyopharm: Consultancy, Research Funding; Teneobio: Consultancy; Celgene: Consultancy; Cellectar: Consultancy; Incyte: Consultancy; Kite: Consultancy; Morphosys: Consultancy; Regeneron: Consultancy.

*signifies non-member of ASH