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

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

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.

Study Overview

• Status: Recruiting
• Conditions: Relapsed/Refractory Aggressive B-Cell Malignancies
• Intervention / Treatment: Biological: ONCT-808; Drug: Bridging Therapy

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 57
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Ariadne Jerue; Phone Number: 858-761-8062; Email: ajerue@oncternal.com

Study Locations

• United States
  • California
    • Duarte, California, United States, 91010
      • Recruiting
      • City of Hope National Medical Center
      • Contact: MD
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Recruiting
      • Massachusetts General Hospital
      • Contact: MD
    • Boston, Massachusetts, United States, 02215
      • Recruiting
      • Dana Farber Cancer Institute
      • Contact: MD
  • Texas
    • Houston, Texas, United States, 77030
      • Recruiting
      • The University of Texas MD Anderson Cancer Center
      • Contact: MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Phase 1: Dose Escalation; 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; 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.; Drug: Bridging Therapy; Bridging therapy can be oral chemotherapy or IV radiotherapy/chemotherapy per institution's guidelines
Experimental: Phase 2: Dose Expansion; Patients with LBCL or MCL will receive ONCT-808 for each RP2D regimen determined in Phase 1.	Biological: ONCT-808; 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.; Drug: Bridging Therapy; Bridging therapy can be oral chemotherapy or IV radiotherapy/chemotherapy per institution's guidelines

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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

Collaborators and Investigators

• Sponsor: Oncternal Therapeutics, Inc
• Investigators: Principal Investigator: Michael Wang, MD Anderson; Principal Investigator: Matthew Wei, City of Hope Medical Center

Study record dates

Study Major Dates

• Study Start (Actual): May 9, 2023
• Primary Completion (Estimated): December 1, 2026
• Study Completion (Estimated): December 1, 2037

Study Registration Dates

• First Submitted: September 23, 2022
• First Submitted That Met QC Criteria: October 18, 2022
• First Posted (Actual): October 20, 2022

Study Record Updates

• Last Update Posted (Actual): November 30, 2023
• Last Update Submitted That Met QC Criteria: November 29, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Keywords: Immune System Diseases; Lymphoma; Lymphoma, Non-Hodgkin; CAR-T cell therapy; Adoptive cellular therapy; ROR1; Lymphoma, B-Cell; Lymphoproliferative Disorders; Immunoproliferative Disorders; Lymphatic Diseases; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Mantle Cell; Autologous CAR-T cell therapy; Cellular immunotherapy
• Additional Relevant MeSH Terms: Behavioral Symptoms; Aggression; Neoplasms
• Other Study ID Numbers: ONCT-808-101

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No