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

Phase 1

Terminated

• Conditions: Relapsed/Refractory Aggressive B-Cell Malignancies
• Interventions: Biological: ONCT-808; Drug: Bridging Therapy

• Registration Number: NCT05588440
• Lead Sponsor: Oncternal Therapeutics, Inc

Brief Summary

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

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 Timeline

• Study First Submitted: 2022-09-23
• Study First Submitted QC: 2022-10-18
• Study First Posted: 2022-10-20
• Study Start: 2023-05-09
• Primary Completion: 2024-09-12
• Study Completion: 2024-09-12
• Results First Submitted: 2024-10-14
• Status Verified: 2024-11
• Results First Submitted QC: 2024-11-27
• Last Update Submitted: 2024-11-27
• Results First Posted: 2024-12-05
• Last Update Posted: 2024-12-05

Recruitment & Eligibility

• Status: TERMINATED
• Sex: All
• Target Recruitment: 57

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

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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

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Phase 1: Dose Escalation	ONCT-808	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.
Phase 1: Dose Escalation	Bridging Therapy	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.
Phase 2: Dose Expansion	ONCT-808	Patients with LBCL or MCL will receive ONCT-808 for each RP2D regimen determined in Phase 1.
Phase 2: Dose Expansion	Bridging Therapy	Patients with LBCL or MCL will receive ONCT-808 for each RP2D regimen determined in Phase 1.

Primary Outcome Measures

Name	Time	Method
To Evaluate the Incidence of Dose Limiting Toxicities (DLT)	Up to 28 days after the one-time infusion of ONCT-808	This is based on subject treated with ONCT-808. ONCT-808 1x10\^6 CAR T cells/kg: n=3 ONCT-808 3x10\^6 CAR T cells/kg: n=1 ONCT-808 0.3x10\^6 CAR T cells/kg: n=2

Secondary Outcome Measures

Name	Time	Method
Best Metabolic Response Rate Post-Baseline	up to 1 year after the one-time infusion of ONCT-808	This is based on subject treated with ONCT-808. ONCT-808 1x10\^6 CAR T cells/kg: n=3 ONCT-808 3x10\^6 CAR T cells/kg: n=1 ONCT-808 0.3x10\^6 CAR T cells/kg: n=2; Response assessments were evaluated using fluorodeoxyglucose (FDG) positron-emission tomography-computed tomography (PET-CT) per the Lugano classification (Cheson, 2014)

Trial Locations

Locations (4)

City of Hope National Medical Center; 🇺🇸 Duarte, California, United States

Massachusetts General Hospital; 🇺🇸 Boston, Massachusetts, United States

Dana Farber Cancer Institute; 🇺🇸 Boston, Massachusetts, United States

The University of Texas MD Anderson Cancer Center; 🇺🇸 Houston, Texas, United States