A Clinical Study of ONCT-808 in Subjects With Relapsed or Refractory 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 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.

Eligibility Criteria:
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