A Clinical Study of ONCT-808 in Subjects With Relapsed or Refractory B-Cell Malignancies

Study Overview
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Brief Summary
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This is a Phase 1/2 study to investigate the safety and efficacy of the CAR-T therapy, ONCT-808, in patients with relapsed/refractory (R/R) aggressive B cell malignancies.

Detailed Description
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Study ONCT-808-101 is a Phase 1/2, single-arm, open-label, multi-center study to evaluate the safety and tolerability, pharmacokinetics, and anti-tumor activity of ONCT-808 in subjects with aggressive B cell lymphoma (BCL), including large B-cell lymphoma (LBCL) and mantle cell lymphoma (MCL). The study will be separated into two distinct phases designated as Phase 1 and Phase 2. After the safety and tolerability of ONCT-808 have been assessed to select the recommended Phase 2 dose (RP2D) in Phase 1, Phase 2 will commence to further validate the dose and evaluate the safety and efficacy of ONCT-808. In Phase 2, subjects with LBCL or MCL will be enrolled into 2 separate dose expansion cohorts.

Official Title
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Phase 1/2 Multi-Center Study to Evaluate the Safety and Efficacy of ONCT-808 in Adult Subjects With Relapsed or Refractory Aggressive B-Cell Malignancies

Conditions
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Relapsed/Refractory Aggressive B-Cell Malignancies

Intervention / Treatment
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* Biological: ONCT-808
* Drug: Bridging Therapy


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Over 18 years old Histologically confirmed aggressive B-cell NHL, including: MCL, with diagnosis confirmed by cyclin D1 overexpression or evidence of t (11;14) translocation LBCL, including: DLBCL NOS Primary mediastinal LBCL High-grade BCL DLBCL arising from follicular lymphoma Follicular lymphoma grade 3B Richter's syndrome Availability of archival tissue for immunohistology, or willing to undergo baseline biopsy if not available R/R with no available therapy. Subject must have: Received prior systemic therapy that has included an alkylating agent, anthracycline, and an anti-CD20 mAb Received and progressed after autologous hematopoietic stem cell transplant (HSCT) or is ineligible for or has refused to receive HSCT Received prior approved CD19 CAR T-cell therapy or is ineligible for or has refused CD19 CAR-T Minimum washout period between previous systemic therapy and leukapheresis includes: Chemotherapy: at least 14 days or 5 half-lives, whichever is shorter Autologous HSCT: at least 3 months CD19 CAR T-cell therapy: at least 6 months ≥1 measurable lesion per Lugano criteria (Cheson, 2014) Subject has Fluorodeoxyglucose (FDG)-avid disease. Subject has an ECOG performance status of 0 or 1. Subject has adequate organ function: ALC ≥100/uL ANC ≥1000/uL (≥500/uL if due to lymphoma; growth factors allowed) Hgb ≥8 g/dL (transfusion allowed) Platelets ≥75,000/uL (≥50,000/uL if due to lymphoma; transfusion allowed) CrCL ≥50 ml/min; AST/ALT ≤2.5x ULN, T. bili ≤1.5 mg/dl (except Gilbert's) EF ≥50% by ECHO/MUGA; NCS ECG, NCS pleural effusion; O2 sat >92% Subject has an estimated life expectancy of >12 weeks Key Exclusion Criteria: Prior ROR1-targeted therapy Current or anticipated systemic immunosuppressive therapy (e.g., prednisone >5 mg) from LD chemo until Day 28 post ONCT-808 dosing If receiving anticoagulation therapy, subject is unable to hold therapy for 3 days prior and 28 days following ONCT-808 administration Known CNS involvement by malignancy within 6 months H/o or current CNS disorder (e.g., seizure, CVA, dementia, cerebellar disease, cerebral edema, posterior reversible encephalopathy syndrome or any autoimmune disease with CNS involvement) within 6 months of study entry Clinically significant cardiovascular disease (e.g., MI, UA, CABG, or CHF grade ≥2 NYHA within 12 months of planned ONCT-808 dosing) or serious arrhythmia requiring medication Evidence of HIV infection or active HBV, HCV Systemic fungal infection requiring medication in the last 12 months H/o Covid-19 infection with residual lung infiltrate/fibrosis H/o other malignancy except non-melanoma skin cancer or carcinoma in situ not in remission for ≥2 years H/o autoimmune disease resulting in end organ injury or require systemic immunosuppression within last 2 years H/o allogeneic HSCT or organ transplant

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1: Dose Escalation<br>Patients will receive a conditioning regimen of cyclophosphamide and fludarabine intravenously (IV) followed by ONCT-808 IV infusion escalated sequentially with a target dose consistent with the dose required by cohort being enrolled to determine Phase 2 dose (RP2d) regimen(s). Participants may receive bridging therapy that is appropriate to the subject's disease and treatment history if clinically indicated to maintain disease stability. | Biological: ONCT-808<br>* A single infusion of ONCT-808 autologous CAR-T cell infusion will be administered intravenously Phase 1: Dose Escalation with bridging therapy as needed Phase 2: Patients with LBCL or MCL will be enrolled into two separate dose expansion cohorts.<br>Drug: Bridging Therapy<br>* Bridging therapy can be oral chemotherapy or IV radiotherapy/chemotherapy per institution's guidelines<br>|
| Experimental: Phase 2: Dose Expansion<br>Patients with LBCL or MCL will receive ONCT-808 for each RP2D regimen determined in Phase 1. | Biological: ONCT-808<br>* A single infusion of ONCT-808 autologous CAR-T cell infusion will be administered intravenously Phase 1: Dose Escalation with bridging therapy as needed Phase 2: Patients with LBCL or MCL will be enrolled into two separate dose expansion cohorts.<br>Drug: Bridging Therapy<br>* Bridging therapy can be oral chemotherapy or IV radiotherapy/chemotherapy per institution's guidelines<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To evaluate the incidence, severity, and relationship of Dose Limiting Toxicities (DLT) |  | 28 days after last dose of ONCT-808 | 
| To evaluate the incidence, severity, and relationship of Treatment Emergent Adverse Events (TEAE) |  | Up to 24 months | 
| To select a RP2D of ONCT-808 |  | Up to 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To evaluate the Overall Response Rate (ORR) of ONCT-808 | Evaluate ORR rate according to Lugano 2014 (Cheson, 2014) | Up to 48 months | 
| To evaluate the Complete Response (CR) of ONCT-808 | Evaluate CR rate according to Lugano 2014 (Cheson, 2014) | Up to 48 months | 
| To evaluate the Duration of Response (DOR) of ONCT-808 | Evaluate DOR according to Lugano 2014 (Cheson, 2014) | Up to 48 months | 
| Pharmacokinetics of ONCT-808 | Evaluate the expansion and persistence of ROR1 CAR-positive T cells in peripheral blood | Up to 15 years | 
| Safety and Tolerability of ONCT-808 | Objective to further characterize the safety profile, including incidence, severity, and relationship of TEAEs | Up to 15 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Lymphoma, Lymphoma, B-Cell, Lymphoma, Large B-Cell, Diffuse, Lymphoma, Mantle Cell, Lymphoproliferative Disorders, Lymphatic Diseases, Immunoproliferative Disorders, Immune System Diseases, Lymphoma, Non-Hodgkin, ROR1, CAR-T cell therapy, Autologous CAR-T cell therapy, Adoptive cellular therapy, Cellular immunotherapy