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1743 A Phase 1/2 Study of a ROR1-Targeting CAR T Cell Therapy (ONCT-808) in Adult Patients with Relapsed/Refractory (R/R) Aggressive B Cell Lymphomas (BCL)

Program: Oral and Poster Abstracts
Session: 628. Aggressive Lymphomas: Cellular Therapies: Poster I
Hematology Disease Topics & Pathways:
Research, Clinical trials, Lymphomas, Non-Hodgkin lymphoma, Clinical Research, Chimeric Antigen Receptor (CAR)-T Cell Therapies, Diseases, Aggressive lymphoma, Treatment Considerations, Biological therapies, Lymphoid Malignancies
Saturday, December 7, 2024, 5:30 PM-7:30 PM

Michael Wang, MD1, Patrick Connor Johnson, MD2, Salim Yazji, MD3*, Yisrael Katz, MD3*, Angela Pietrofeso3*, James Robinson, MS3*, Matthew Mei, MD4, Matthew J. Frigault, MD5*, James B. Breitmeyer, MD, PhD6 and Caron A. Jacobson, MD, MMSc7

1Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX
2Massachusetts General Hospital Cancer Center, Boston, MA
3Oncternal Therapeutics, San Diego, CA
4City of Hope Cancer Center, Duarte, CA
5Massachusetts General Hospital, Boston, MA
6Oncternal Therapeutics, Inc, San Diego, CA
7Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA

INTRODUCTION:
ROR1 is an oncoembryonic pseudo-tyrosine kinase receptor expressed on malignant cells across a variety of hematologic and solid malignancies. As such, ROR1 is an ideal therapeutic target with potential for maximizing on-target anti-tumor activity while minimizing off-target toxicity.

ONCT-808 utilizes a ROR1-binding moiety derived from zilovertamab, which, in a prior study of zilovertamab vedotin, demonstrated antitumor activity and no evidence of off-tumor toxicity in a population of heavily pretreated patients (pts) with aggressive lymphoma (Wang 2022, Spurgeon 2023).

ROR1-specific CAR T-cell therapy represents a promising modality for the treatment of aggressive BCL, particularly in pts who have previously failed or were ineligible for CD19 CAR T therapy.

METHODS:
This is a multicenter, open label, phase 1/2 study of ONCT-808 in R/R BCL (mantle cell lymphoma [MCL] and large BCL [LBCL]). ONCT-808 is administered as a single infusion following lymphodepletion with fludarabine and cyclophosphamide. The primary objective of phase 1 is to identify dose-limiting toxicities (DLTs) and establish a recommended phase 2 dose. Phase 1 consists of escalation at three provisional doses (0.3, 0.6, and 1 x 106 viable ONCT-808 cells/kg). Phase 2 will test two dose levels with a primary endpoint of overall response rate (ORR). Adverse events (AEs) are graded using CTCAE v5.0, except for cytokine release syndrome (CRS) and IEC-associated neurotoxicity syndrome (ICANS) which are based on ASTCT grading. Secondary endpoints include efficacy and pharmacokinetics.


RESULTS:
To date, 8 pts have been enrolled and underwent leukapheresis, with 100% success for cellular manufacturing; 2 pts withdrew consent prior to treatment. Of the 6 treated pts, 5 had relapsed following prior CD19 CAR T. During initial dose escalation, 3 pts with heavily pretreated R/R MCL (all males, median age 55 [range 50-57]), were treated at a dose of 1 x 106 viable ONCT-808 cells/kg; subsequently, one pt (80yo male, R/R diffuse LBCL [DLBCL] with high tumor burden), was treated at a higher dose of 3 x 106 cells/kg and died due to complications of shock. A modified dosing scheme starting at 0.3 x 106 cells/kg was subsequently incorporated, and 2 pts have been treated (R/R DLBCL, males, age 60, 62). No DLTs were reported during the 28-day evaluation window at 1 or 0.3 x 106 cells/kg doses. In these two dosing cohorts, AEs related to ONCT-808 included G1-2 CRS (4/5 pts), G2 ICANS (1/5), G3 pneumonia (1/5 pts), and G3-4 cytopenias (1/5 patients).

Response assessments were evaluated in 5 pts; 3 treated with ONCT-808 at 1 x 106 and 2 treated with 0.3 x 106 viable ONCT-808 CAR T cells/kg. Of 5 patients, at the Month 1 (M1) timepoint, 2 patients had demonstrated complete metabolic response (CMR) and 2 had demonstrated partial metabolic response (PMR). One patient with CMR had a confirmatory bone marrow biopsy and sustained CMR at M3 and M6 timepoints. Notably, the pt treated at the 3 x 106 cells/kg dose did not have histologic evidence of lymphoma on autopsy despite bulky disease at baseline, or evidence of immune-mediated inflammation in the brain. Preliminary PK demonstrates successful expansion and persistence of ROR1-positive CAR T cells, including beyond 12 months post-infusion.

CONCLUSIONS:
ONCT-808 is a novel ROR1-targeting CAR T therapy with promising early activity and appears to be well-tolerated at 0.3 x 106 and 1 x 106 viable cells/kg dose in patients with R/R BCL. Dose escalation continues towards optimizing activity and safety (NCT 05588440).

Disclosures: Wang: Physicians Education Resources: Honoraria; Catamount Medical Education: Honoraria; Genmab: Honoraria, Research Funding; Dava Oncology: Honoraria; MJH Life Sciences: Honoraria; South African Clinical Hematology Society: Honoraria; WedMD: Honoraria; Genentech: Consultancy, Research Funding; Scripps: Honoraria; Janssen: Honoraria; Studio ER Congressi: Honoraria; Oncternal: Consultancy, Research Funding; CAHON: Honoraria; bE Biopharma: Consultancy; Amphista Therapeutics Limited: Consultancy; Research to Practice: Honoraria; Merck: Consultancy, Honoraria; Miltenyi Biomedicine: Consultancy; NIH: Honoraria; MSC National Research Institute of Oncology: Honoraria; Lilly: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; InnoCare: Consultancy, Research Funding; Praxel: Consultancy; Nurix: Honoraria; Deciphera: Consultancy; ADC Therapeutics: Consultancy; Kite, a Gilead Company: Consultancy, Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; BioInvent: Consultancy, Honoraria, Research Funding; BMS/Celgene: Consultancy, Honoraria, Research Funding; Pepromene Oncology: Consultancy; Juno Therapeutics: Research Funding; BeiGene: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding; Acerta Pharma: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria. Johnson: Bristol Myers Squibb: Consultancy; Seagen: Consultancy; Incyte: Consultancy, Research Funding; ADC Therapeutics: Consultancy; Abbvie: Consultancy; AstraZeneca Pharmaceuticals LP: Consultancy, Research Funding; Medically Home: Research Funding. Yazji: Oncternal Therapeutics, Inc: Current Employment. Katz: Oncternal Therapeutics, Inc: Current Employment. Pietrofeso: Oncternal Therapeutics: Current Employment. Robinson: Oncternal Therapeutics: Current Employment. Mei: Novartis: Consultancy; Synethkine: Consultancy; SeaGen: Consultancy, Speakers Bureau; ADC Therapeutics: Consultancy; AstraZeneca: Consultancy; BMS: Research Funding; Incyte: Research Funding; Beigene: Research Funding; Genentech: Research Funding. Frigault: Oncternal Therapeutics: Current equity holder in publicly-traded company, Honoraria. Breitmeyer: Oncternal Therapeutics: Current Employment. Jacobson: Caribou Biosciences: Consultancy; Novartis: Consultancy; Daiichi Sankyo: Consultancy; ImmPACT Bio: Consultancy; Instil Bio: Consultancy; Ipsen: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding; Synthekine: Consultancy; Miltenyi: Consultancy; MorphoSys: Consultancy; Pfizer: Research Funding; Bristol Myers Squibb/Celgene: Consultancy; Abintus Bio: Consultancy; ADC Therapeutics: Consultancy; AbbVie: Consultancy.

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