Session: 704. Cellular Immunotherapies: Early Phase and Investigational Therapies: Poster III
Hematology Disease Topics & Pathways:
Research, clinical trials, Hodgkin lymphoma, Biological therapies, Lymphomas, Clinical Research, B Cell lymphoma, Chimeric Antigen Receptor (CAR)-T Cell Therapies, drug development, Diseases, aggressive lymphoma, Therapies, Lymphoid Malignancies, Study Population, Human
ROR1-targeted CAR T therapy offers several advantages that could address these challenges. By directing CAR T cells to specifically recognize and eliminate ROR1-expressing tumor cells, it offers a highly targeted approach with the potential for enhanced efficacy. Moreover, ROR1 is often highly expressed on aggressive BCL, making it a suitable therapeutic target. This focused approach may help overcome the limitations associated with current treatments and improve response rates. After birth ROR1 is predominantly expressed on malignant cells; therefore, this selective expression pattern may reduce the risk of toxicities, including off-tumor target elimination and non-specific activation of immune cells.
The development of ROR1-specific CAR T holds promise in enhancing the treatment outcomes for patients with aggressive BCL. With targeted action and potential to reduce toxicity, ROR1-specific CAR T cell therapy offers an innovative and novel strategy for improving patient outcomes in BCL. The ROR1 binding moiety for ONCT-808 is derived from zilovertamab. Zilovertamab vedotin showed preliminary evidence of efficacy and no evidence of on-target off-tumor toxicity in patients with advanced B cell malignancies (Wang 2022).
METHODS: This is a Phase 1/2, single-arm, open-label, multi-center trial to evaluate the safety and efficacy of ONCT-808 in pts with aggressive BCL, including large B-cell lymphoma (LBCL) and mantle cell lymphoma (MCL) with no approved therapy available. The study comprises two distinct phases: Phase 1 for dose escalation followed by Phase 2 for dose expansion.
In Phase 1, a standard 3+3 dose escalation design will be used with 3 provisional dose levels and expected sample size of up to 18 patients. Subjects will receive a conditioning regimen of intravenous (IV) cyclophosphamide and fludarabine, followed by ONCT-808 IV infusion. The dose of ONCT-808 will be sequentially escalated to determine the recommended Phase 2 dose (RP2D) for LBCL and MCL cohorts. Bridging therapy is permitted if clinically indicated. Phase 2 will enroll LBCL and MCL patients into separate dose expansion cohorts at the RP2D determined in Phase 1. ONCT-808 will be administered as a single IV infusion of autologous CAR T cells.
The primary outcomes include assessing the incidence, severity, and relationship of Dose Limiting Toxicities (DLT), Treatment Emergent Adverse Events (TEAE), and RP2D selection of ONCT-808. Secondary outcomes include evaluating the Overall Response Rate (ORR), Complete Response (CR) rate, Duration of Response (DOR), pharmacokinetics of ONCT-808, expansion, persistence of ROR1 CAR-positive T cells, overall safety and tolerability. Key inclusion criteria include histologically confirmed aggressive B-cell NHL, measurable lesions per Lugano criteria (Cheson, 2014), and relapsed/refractory (R/R) disease without available therapy (must be previously treated with systemic therapy, progressed after or ineligible for autologous HSCT, and received prior approved anti-CD19 CAR-T at least 6 months prior to enrollment unless refused/ineligible). Key exclusion criteria include previous ROR1-targeted therapy, ongoing immunosuppression, and CNS involvement.
The trial is currently active and patients have been treated in the phase 1 dose escalation.
Clinical Trial Identifier: NCT05588440
Disclosures: Wang: Genentech: Consultancy, Research Funding; Celgene: Other: Travel, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria; Deciphera: Consultancy; Miltenyi Biomedicine: Consultancy; Milken Institute: Consultancy; Merck: Consultancy, Honoraria; DTRM Biopharma (Cayman) Limited: Consultancy; Eli Lilly and Company: Consultancy, Research Funding; Oncternal: Consultancy, Research Funding; Bantam Pharmaceutical: Honoraria; VelosBio: Consultancy, Research Funding; Parexel: Consultancy; Pepromene Bio: Consultancy; Pharmacyclics: Consultancy, Honoraria, Research Funding; CAHON: Honoraria; Dava Oncology: Honoraria, Other: Travel; Eastern Virginia Medical School: Honoraria; WebMD: Honoraria; Leukemia & Lymphoma Society: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Kite, a Gilead Company: Consultancy, Honoraria, Other: Travel, Research Funding; BioInvent: Consultancy, Honoraria, Research Funding; BeiGene: Consultancy, Honoraria, Research Funding; Be Biopharma: Consultancy; AstraZeneca: Consultancy, Honoraria, Other: Travel, Research Funding; Amphista Therapeutics Limited: Consultancy; ADC Therapeutics America: Consultancy; Acerta Pharma: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria; Genentech: Consultancy, Research Funding; InnoCare: Consultancy, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Studio ER Congressi: Honoraria; Genmab: Honoraria, Research Funding; i3Health: Honoraria; IDEOlogy Health: Honoraria; Medscape: Honoraria; Meeting Minds Experts: Honoraria; MD Education: Honoraria; MJH Life Sciences: Honoraria; Moffit Cancer Center: Honoraria; NIH: Honoraria; Nurix: Honoraria; Oncology Specialty Group: Honoraria; OncLive: Honoraria; Physicians Education Resources (PER): Honoraria, Other: Travel; Practice Point Communications (PPC): Honoraria; Scripps: Honoraria; Juno Therapeutics: Research Funding; Loxo Oncology: Consultancy, Research Funding; Molecular Templates: Research Funding; Vincerx: Research Funding; Anticancer Association: Honoraria; BGICS: Honoraria; Clinical Care Options: Honoraria; Epizyme: Consultancy, Honoraria; Hebei Cancer Prevention Federation: Honoraria; Imedex: Honoraria; TS Oncology: Honoraria; Mumbai Hematology Group: Honoraria; OMI: Honoraria; Pharmacyclics: Honoraria; Physicians Education Resources: Honoraria; Practice Point Communications: Honoraria; CSTone: Consultancy. Frigault: Covance: Consultancy; BMS: Consultancy; Kite: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Arcellx: Research Funding. Yazji: Oncternal Therapeutics Inc.: Current Employment, Current equity holder in publicly-traded company. Katz: Oncternal Therapeutics Inc.: Current Employment, Current equity holder in publicly-traded company. Robinson: Oncternal Therapeutics Inc.: Current Employment, Current equity holder in private company, Current equity holder in publicly-traded company. Breitmeyer: Oncternal Therapeutics Inc.: Current Employment, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees. Mei: Morphosys: Research Funding; Beigene: Research Funding; EUSA: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; CTI: Membership on an entity's Board of Directors or advisory committees; Incyte: Research Funding, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees; Seagen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Research Funding. Jacobson: Kite, a Gilead company: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Other: Travel support; Bristol Myers Squibb/Celgene: Consultancy; Abbvie: Consultancy, Honoraria; ADC Therapeutics: Consultancy; AstraZeneca: Consultancy; Abintus Bio: Consultancy, Membership on an entity's Board of Directors or advisory committees; Caribou Bio: Consultancy; Instil Bio: Consultancy, Honoraria; ImmPACT Bio: Consultancy, Honoraria; Daiichi-Sankyo: Consultancy, Honoraria; Ipsen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Morphosys: Consultancy; Synthekine: Consultancy, Honoraria; Pfizer: Research Funding; Miltenyi Biotec: Consultancy; Sana: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Other: Travel support; Lonza: Consultancy, Honoraria, Other: Travel support; Epizyme: Consultancy, Honoraria; Bluebird Bio: Consultancy, Honoraria; Humanigen: Consultancy, Honoraria, Other: Travel support; Nkarta: Consultancy, Honoraria; Precision BioSciences: Consultancy, Honoraria, Other: Travel support; Clinical Care Options: Speakers Bureau; Axis: Speakers Bureau.