WUC007-03: A Phase 2 Study of Anti-CD7 Allogenic CAR-T Cells (WT-7) in Patients with Relapsed/Refractory (R/R) T-Cell Acute Lymphoblastic Leukemia (T-ALL)/Lymphoblastic Lymphoma (LBL)

Background:T-ALL/LBL are highly aggressive hematologic cancers with high rates of relapse and mortality in both children and adults. Cluster of differentiation (CD) 7 is expressed in over 95% of T-ALL/LBL patients and limited effective treatment options are available for these patients. WT-7 is an allogeneic, fratricide-resistant genetically modified T cell transduced with a 2nd generation 4-1BB-CD3z chimeric antigen receptor (CAR) targeting human CD7. In a global first-in-human, phase 1/2 single-agent study of WT-7, 28 patients with R/R T-ALL/LBL were treated with WT-7 at varying dose levels (Aldoss, et al, EHA 2024). Patients ≥12 years old were included. The recommended phase 2 dose (RP2D) was 900M WT-7 cells following an enhanced lymphodepletion (eLD) regimen consisting of fludarabine 30mg/m²/day for four days and cyclophosphamide 1gm/m²/day for 3 days. WT-7 demonstrated an acceptable safety profile as well as dose-dependent anti-tumor activity at the RP2D, with 1) an overall response rate (ORR) of 91%, 2) a composite complete response (CRc) rate of 73%, MRD^neg 83% (n=8 with available sample for MRD testing) 3) a median duration of response (DOR) not reached (95%CI: 1.8, NE) with follow up of up to 9.9 months, and 4) CAR-T cell expansion peaking on day 10 (median 237,827 copies/µg of DNA) and persisting to day 90, with no development of anti-HLA or anti-CAR antibodies. WT-7 has the potential to address a significant unmet medical need for patients with CD7 positive R/R T-ALL/LBL, as patients who relapse have a poor prognosis.

Methods:WUC007-03, a single-agent, multicenter study, will evaluate patients 1 year of age and older with R/R T-ALL/LBL. The primary endpoint is CRc during the 3 months after WT-7 administration. CRc rate is defined as the proportion of patients that achieve a complete remission (CR) + CR with partial hematologic recovery (CRh) + CR with incomplete hematologic recovery (CRi). Secondary endpoints include DOR, percentage of patients who achieve best overall response (BOR) of CR or CRh at Month 6 without stem cell transplant (SCT) between WT-7 infusion and Month 6 response assessment, and percentage of patients who achieve CR, CRh or CRi and then proceed to SCT while in remission before Month 6 response assessment. Response assessments will take place on Day 28 (±3days), and at Months 3, 6, 12, and 24 (±14 days) by bone marrow (BM) aspirate and biopsy, and computerized tomography (CT)/PET, if applicable. Undetectable MRD disease is defined as <0.1% blasts in BM. MRD threshold is based on the Children's Oncology Group risk classification schema for T-ALL where patients with an end-of-consolidation MRD ≥0.1% are considered very high risk for relapse. After evaluation of safety in R/R T-ALL/LBL patients (n~30), patients in CR with detectable MRD may be enrolled to evaluate MRD conversion rate to undetectable, and hematological relapse-free survival (NCT06514794).

Eligibility: Patients ≥ 1 year old with evidence of T-ALL or T-LBL, as defined by the World Health Organization (WHO) classification, and R/R disease (≥5% blasts in the BM and/or evidence of extramedullary disease (EMD)) will be eligible for this study. For potential exploratory cohort, patients with detectable MRD disease (0.1-5% blasts in the BM as determined by a central flow-based assay) following first induction and consolidation, will also be eligible for this study following confirmation of safety in the R/R cohort.

Treatment: Enrollment will begin with a safety lead-in in the R/R cohort at a reduced dose of 600M cells with eLD. The purpose of this safety lead-in will be to 1) confirm that the safety data demonstrated in the Phase 1/2 trial is comparable for pediatric patients ages 1-11, and 2) validate the prior safety data in patients 12 years and older. Following this safety lead-in, all patients enrolled in the study will receive a single dose of the RP2D of 900M WT-7 on Day 0 following eLD conditioning.

Enrollment: Enrollment will take place at 19 sites globally and is targeted to begin by the end of 2024.

Ghobadi:Genentech: Research Funding; Wugen Inc: Consultancy; CRISPR Therapeutics: Consultancy; Bristol Myers Squibb: Consultancy; ATARABio: Consultancy; Amgen: Consultancy, Research Funding; Kite (Gilead company): Consultancy, Honoraria, Research Funding. Maude:Novartis: Research Funding; Wugen: Honoraria, Research Funding. Aldoss:Kite Pharma: Other: consulting fees; Pfizer: Honoraria, Other: consulting fees; Takeda Pharmaceuticals: Other: consulting fees; Jazz Pharmaceuticals: Other: consulting fees; AbbVie: Other: research support; Sobi: Other: consulting fees; Syndax Pharmaceuticals, Inc.: Other: consulting fees; Amgen: Honoraria, Other: consulting fees. Bajel:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees; Glaxo-Smith-Kline: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; Pfizer: Honoraria; Takeda: Honoraria; AbbVie: Membership on an entity's Board of Directors or advisory committees. Wayne:Kite: Research Funding. Faramand:Orca Bio: Research Funding; Novartis: Research Funding; Sanofi: Consultancy, Honoraria; Kite/Gilead: Membership on an entity's Board of Directors or advisory committees; Autolus: Membership on an entity's Board of Directors or advisory committees. Rijneveld:Vertex: Other: Advisory board. Zwaan:Innovative Therapies for Children with Cancer: Other: Leadership role; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Institutional grant ; Daiichi Sankyo, Inc.: Other: Institutional grant; Gilead Sciences, Inc.: Consultancy; Jazz Pharmaceuticals: Other: Institutional grant; Kura Oncology: Consultancy, Other: Institutional grant; Sanofi: Membership on an entity's Board of Directors or advisory committees, Other: Institutional fees; Bristol Myers Squibb: Consultancy; AbbVie: Other: Institutional grant ; Takeda Pharmaceuticals: Other: Institutional grant; Chair of the Medical Research committee MERC Utrech: Other: Leadership role; Pfizer: Other: Institutional grant; Incyte Corporation: Consultancy; Astra Zeneca: Consultancy; Beigene: Consultancy. Baruchel:Jazz: Membership on an entity's Board of Directors or advisory committees; Servier: Other: TRavel Grant, Symposium, Research Funding; Astra Zeneca: Research Funding; Wugen: Membership on an entity's Board of Directors or advisory committees. Boissel:Sanofi: Other; Pfizer: Other; Adveysa: Other; Amgen: Other. Schwartz:Akademie fuer Infektionsmedizin e.V., AMGEN, CSi Hamburg, Pfizer, SERB SAS: Consultancy, Honoraria, Other: Travel Grants, AdBoard Member. Bader:Medac, Novartis, Vertex: Other: Travel grants ; Amgen, Novartis, Vertex: Speakers Bureau. Lang:Novartis: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria; Incyte: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria; Enliven Therapeutics: Honoraria. Irons:Wugen: Current Employment. Ramsey:Wugen: Current Employment, Current holder of stock options in a privately-held company. Muth:Wugen: Current Employment, Current holder of stock options in a privately-held company. Simpson:Wugen: Current Employment, Current holder of stock options in a privately-held company. Dasgupta:Wugen: Current Employment, Current holder of stock options in a privately-held company. Moran:Wugen: Current Employment, Current equity holder in private company. Munroe:Wugen: Current Employment, Current holder of stock options in a privately-held company. del Rosario:Wugen: Current Employment, Current holder of stock options in a privately-held company. Wu:Wugen: Current Employment, Current holder of stock options in a privately-held company. Bakkacha:Wugen: Current Employment, Current holder of stock options in a privately-held company. Gonzalez:Wugen: Current Employment, Current holder of stock options in a privately-held company. Masters:Wugen: Current Employment, Current holder of stock options in a privately-held company. Hamil:Wugen: Current Employment, Current holder of stock options in a privately-held company. McNulty:Wugen: Current Employment, Current holder of stock options in a privately-held company. Cooper:Wugen: Current Employment, Current equity holder in private company, Current holder of stock options in a privately-held company. Davidson-Moncada:Wugen: Current Employment, Current holder of stock options in a privately-held company. DiPersio:RiverVest Venture Partners: Consultancy, Membership on an entity's Board of Directors or advisory committees; WUGEN: Current equity holder in private company, Research Funding; Magenta Therapeutics: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Vertex: Consultancy; Macrogenics: Research Funding; SPARC: Consultancy; Bioline Rx: Research Funding; hC Bioscience, Inc.: Membership on an entity's Board of Directors or advisory committees; NeoImmune Tech: Research Funding.