Relapsed/Refractory Aggressive B-Cell Malignancies
Conditions
Keywords
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
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.
Interventions
BIOLOGICALONCT-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.
DRUGBridging Therapy
Bridging therapy can be oral chemotherapy or IV radiotherapy/chemotherapy per institution's guidelines
Sponsors
Oncternal Therapeutics, Inc
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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) |
Countries
United States
Participant flow
Pre-assignment details
On September 12, 2024, Oncternal Therapeutics, Inc. announced its decision to discontinue the clinical trial evaluating ONCT-808, its ROR1-targeting autologous CAR T program for the treatment of patients with aggressive B-cell lymphoma. The study only enrolled the first few patients into the Phase 1 portion of the study and did not reach a RP2D recommendation. Hence, the Phase 2 portion of the study was not conducted.
Participants by arm
| Arm | Count |
|---|---|
| ONCT-808 1x10^6 CAR T Cells/kg ONCT-808 consists of autologous CD3/CD28 activated CD4 and CD8 T cells transduced with lentivirus vector expressing a chimeric antigen receptor (CAR) containing a Receptor-tyrosine kinase like Orphan Receptor 1 (ROR1)-directed scFv from zilovertamab (humanized antibody previously known as cirmtuzumab or UC-961) with 4-1BB and CD3 ζ signaling domains | 3 |
| ONCT-808 3x10^6 CAR T Cells/kg ONCT-808 consists of autologous CD3/CD28 activated CD4 and CD8 T cells transduced with lentivirus vector expressing a chimeric antigen receptor (CAR) containing a Receptor-tyrosine kinase like Orphan Receptor 1 (ROR1)-directed scFv from zilovertamab (humanized antibody previously known as cirmtuzumab or UC-961) with 4-1BB and CD3 ζ signaling domains | 2 |
| ONCT-808 0.3x10^6 CAR T Cells/kg ONCT-808 consists of autologous CD3/CD28 activated CD4 and CD8 T cells transduced with lentivirus vector expressing a chimeric antigen receptor (CAR) containing a Receptor-tyrosine kinase like Orphan Receptor 1 (ROR1)-directed scFv from zilovertamab (humanized antibody previously known as cirmtuzumab or UC-961) with 4-1BB and CD3 ζ signaling domains | 4 |
| Total | 9 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Death | 1 | 1 | 1 |
| Overall Study | Screen Fail | 0 | 1 | 1 |
| Overall Study | Sponsor Decision | 2 | 0 | 1 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | ONCT-808 1x10^6 CAR T Cells/kg | ONCT-808 3x10^6 CAR T Cells/kg | ONCT-808 0.3x10^6 CAR T Cells/kg | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Age, Categorical Between 18 and 65 years | 3 Participants | 1 Participants | 4 Participants | 8 Participants |
| Race/Ethnicity, Customized Hispanic | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Unknown | 0 Participants | 0 Participants | 2 Participants | 2 Participants |
| Race/Ethnicity, Customized White | 2 Participants | 2 Participants | 2 Participants | 6 Participants |
| Sex: Female, Male Female | 0 Participants | 1 Participants | 1 Participants | 2 Participants |
| Sex: Female, Male Male | 3 Participants | 1 Participants | 3 Participants | 7 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 3 | 1 / 1 | 1 / 2 |
| other Total, other adverse events | 3 / 3 | 1 / 1 | 2 / 2 |
| serious Total, serious adverse events | 3 / 3 | 1 / 1 | 0 / 2 |
Outcome results
Primary
To Evaluate the Incidence of Dose Limiting Toxicities (DLT)
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
Time frame: Up to 28 days after the one-time infusion of ONCT-808
Population: DLT-evaluable population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| ONCT-808 1x10^6 CAR T Cells/kg | To Evaluate the Incidence of Dose Limiting Toxicities (DLT) | 0 Participants |
| ONCT-808 3x10^6 CAR T Cells/kg | To Evaluate the Incidence of Dose Limiting Toxicities (DLT) | 1 Participants |
| ONCT-808 0.3x10^6 CAR T Cells/kg | To Evaluate the Incidence of Dose Limiting Toxicities (DLT) | 0 Participants |
Secondary
Best Metabolic Response Rate Post-Baseline
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)
Time frame: up to 1 year after the one-time infusion of ONCT-808
Population: Efficacy evaluable population
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| ONCT-808 1x10^6 CAR T Cells/kg | Best Metabolic Response Rate Post-Baseline | Partial Metabolic Response | 1 Participants |
| ONCT-808 1x10^6 CAR T Cells/kg | Best Metabolic Response Rate Post-Baseline | Complete Metabolic Response | 2 Participants |
| ONCT-808 1x10^6 CAR T Cells/kg | Best Metabolic Response Rate Post-Baseline | Not Done (i.e., response assessment was not conducted) | 0 Participants |
| ONCT-808 3x10^6 CAR T Cells/kg | Best Metabolic Response Rate Post-Baseline | Partial Metabolic Response | 0 Participants |
| ONCT-808 3x10^6 CAR T Cells/kg | Best Metabolic Response Rate Post-Baseline | Complete Metabolic Response | 0 Participants |
| ONCT-808 3x10^6 CAR T Cells/kg | Best Metabolic Response Rate Post-Baseline | Not Done (i.e., response assessment was not conducted) | 1 Participants |
| ONCT-808 0.3x10^6 CAR T Cells/kg | Best Metabolic Response Rate Post-Baseline | Complete Metabolic Response | 0 Participants |
| ONCT-808 0.3x10^6 CAR T Cells/kg | Best Metabolic Response Rate Post-Baseline | Not Done (i.e., response assessment was not conducted) | 2 Participants |
| ONCT-808 0.3x10^6 CAR T Cells/kg | Best Metabolic Response Rate Post-Baseline | Partial Metabolic Response | 0 Participants |