Oncternal Therapeutics Proposes Protocol Changes Following Death of Patient Treated With CAR-T Therapy ONCT-808 in Phase 1/2 Trial


ONCT-808 targets ROR1 and is currently being evaluated for the treatment of r/r aggressive B-cell lymphoma.

An 80-year-old patient has died following treatment with Oncternal Therapeutics’ ONCT-808, an investigational chimeric antigen receptor T-cell (CAR-T) therapy being evaluated for the treatment of relapsed/refractory (r/r) aggressive B-cell lymphoma in the phase 1/2 ONCT-808-101 clinical trial (NCT05588440).1 The company has announced that it is seeking to modify study protocols in response to the patient’s death.

The patient, who had bulky disease, was the first treated at the study’s second dose level, 3x106 CAR T-cells per kg. Prior to treatment with ONCT-808, the patient had received 4 previous lines of therapy, including a CD19-directed CAR-T therapy. Following treatment with ONCT-808, the patient sustained a fatal grade 5 serious adverse event (AE) that was deemed to be consistent with cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome. Oncternal noted that based on his initial autopsy report, there was no histological evidence of lymphoma. The company is now seeking to modify the trial’s protocol, with potential modifications including the evaluation of lower doses of the CAR-T therapy and changes to the study’s eligibility criteria. Oncternal has communicated and aligned with the FDA regarding these proposals.

Three other patients were previously treated in ONCT-808-101 at the study’s initial dose of 1x106 CAR T-cells per kg. As of a December 4, 2023 data cutoff, 2 of these 3 patients showed a complete metabolic response and 1 patient showed a partial response, as assessed by FDG PET-CT. The company noted that among the common AEs in these 3 patients were cases of decreased blood counts, pneumonia, and grade 1-2 CRS.

"The safety of every patient who participates in our studies is of the utmost priority for us," Salim Yazji MD, the chief medical officer of Oncternal Therapeutics, said in a statement.1 “We believe these early disease response data indicate that ONCT-808 is a particularly potent autologous CAR-T product with the potential to address significant unmet needs for patients with aggressive B-cell malignancies. With this clear path forward, we plan to implement the protocol amendment as rapidly as possible."

Key Takeaways

  • An 80-year-old patient died following treatment with Oncternal Therapeutics' ONCT-808, an investigational CAR-T therapy for relapsed/refractory aggressive B-cell lymphoma.
  • The patient experienced a fatal grade 5 serious adverse event consistent with cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome.
  • The company is now seeking to modify the trial’s protocol, with potential modifications including the evaluation of lower doses of the CAR-T therapy and changes to the study’s eligibility criteria.

Previously, in November 2023, Oncternal noted that ONCT-808 had shown “encouraging expansion and persistence” in the first patient with advanced B-cell nonHodgkin lymphoma treated in the trial.2 At the time, the company stated that in addition to an initial data readout expected in December 2023, further data updates from the trial are expected in 2024.

ONCT-808 is an autologous CAR-T therapy and targets Receptor Tyrosine Kinase-Like Orphan Receptor 1 (ROR1).1 Oncternal has developed a manufacturing process for ONCT-808 that it expects will take less time than the methods currently used for FDA-approved CAR-T therapies, thus reducing wait-times for patients.

The investigational new drug application for ONCT-808-101 was originally cleared by the FDA in October 2022.3 Preclinical data, from research conducted by Oncternal’s collaborator, the Karolinska Institute in Stockholm, were presented at the European Hematology Association (EHA) 2022 Hybrid Congress in June 2022.4 The data demonstrated ROR1 CAR-mediated target recognition and cell activation when expressed in either T-cells or natural killer (NK) cells. In addition, ROR1 CAR T-cells demonstrated dose-dependent antitumor activity in a mantle cell lymphoma mouse model.

“Despite recent significant advances in treating hematological malignancies with current CAR-based cell therapies, certain limitations remain, such as treatment failures due to tumor antigen escape, and toxicities including induction of immunodeficiencies like B-cell aplasia,” Evren Alici, MD, PhD, associate professor and group leader, Cell and Gene Therapy Group, Center for Hematology and Regenerative Medicine, Department of Medicine, Karolinska Institutet, said in a June 2022 statement.4 “Patients are in need of more effective treatment options. The ROR1-targeting cell therapies have shown strong activity in our lymphoma models. We are now working with our Oncternal colleagues to evaluate the therapies in models of other tumor indications. With our strong focus on NK cells, we are excited to further study ROR1 CAR-NK cells within our NextGnNK competence center."

1. Oncternal Therapeutics updates the status of its phase 1/2 study of ONCT-808, a ror1-targeting autologous CAR T, in patients with relapsed or refractory aggressive b-cell lymphoma. News release.Oncternal Therapeutics, Inc. December 26, 2023. Accessed January 2, 2024. https://investor.oncternal.com/news-releases/news-release-details/oncternal-therapeutics-updates-status-its-phase-12-study-onct
2. OncternalTherapeutics provides business update and announces third quarter 2023 financial results. News release. Oncternal Therapeutics, Inc. November 9, 2023. Accessed January 2, 2024. https://investor.oncternal.com/news-releases/news-release-details/oncternal-therapeutics-provides-business-update-and-announces-7
3. Oncternal Therapeutics receives IND clearance for ONCT-808, its autologous CAR T product candidate targeting ROR1 for the treatment of aggressive B cell lymphoma. News release. Oncternal Therapeutics, Inc. October 3, 2022. Accessed January 2, 2024. https://investor.oncternal.com/news-releases/news-release-details/oncternal-therapeutics-receives-ind-clearance-onct-808-its
4. Oncternal Therapeutics presents new preclinical data from its anti-ROR1 cell therapy collaboration with the Karolinska Institutet at the EHA2022 Congress. News release. Oncternal Therapeutics, Inc. June 10, 2022. Accessed January 2, 2024. https://investor.oncternal.com/news-releases/news-release-details/oncternal-therapeutics-presents-new-preclinical-data-its-anti
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