Oncternal Therapeutics Axes B-Cell Lymphoma Trial for CAR-T Therapy ONCT-808
The company also discontinued its other clinical programs as well, which included small molecule and monoclonal antibody modalities.
Oncternal Therapeutics has made the decision to discontinue its phase 1/2 ONCT-808-101 clinical trial (NCT05588440) evaluating ONCT-808, an investigational chimeric antigen receptor T-cell (CAR-T) therapy, for the treatment of relapsed/refractory (r/r) aggressive B-cell lymphoma.1
The company stated that ONCT-808, which is autologous and targets Receptor Tyrosine Kinase-Like Orphan Receptor 1 (ROR1), had demonstrated antitumor activity at all dose levels tested as of a phase 1 interim analysis. Furthermore, Oncternal pointed out the observation of a complete metabolic response that lasted 8 months and that the CAR T-cells persisted long-term. In terms of safety, treatment emergent adverse events (AEs) were considered in line with expectations for CAR-T therapy. Although, the company noted that 1 patient, who was treated at the highest dose tested, died from complications of shock.
Alongside the ONCT-808 study, Oncternal is also discontinuing clinical trials for all other candidates in its pipeline, which include products of multiple modalities: ONCT-534, a dual action androgen receptor inhibitor being evaluated for metastatic castration resistant cancer; zilovertamab, an investigational monoclonal antibody intended to inhibit the function of ROR1 being evaluated as a combination therapy with ibrutinib for mantle cell lymphoma, chronic lymphocytic leukemia, and marginal zone lymphoma; and ONCT-216, an investigational targeted small-molecule inhibitor of the E26 transformation-specific family of oncoproteins being evaluated for Ewing sarcoma. The company cited available clinical data and capital requirements as driving factors in its decision to end the studies for ONCT-534 and ONCT-808. In addition to halting all product development activities, Oncternal also stated that it would be reducing its workforce in order to preserve resources as it explores strategic alternatives, which it noted could include asset sales, licensing or other strategic transactions, a merger, reverse merger, acquisition, or other business combination.
“The early results during dose escalation in the phase 1/2 studies of ONCT-534 in heavily pretreated patients are disappointing, as the study was supported by extensive preclinical data and was designed to address important unmet medical needs for patients with advanced prostate cancer,” James Breitmeyer, MD, PhD, the president and chief executive officer of Oncternal, said in a statement.1 “In light of these data and the challenging financing environment, we intend to explore strategic options with the hope of advancing and realizing value from our pipeline including ONCT-534, ONCT-808, zilovertamab, and ONCT-216.”
Late last year, Oncternal announced the death of the aforementioned patient in the ONCT-808-101 trial and gave additional details about the case.2 The patient, who was 80 years old and had bulky disease, was the first treated at the study’s second dose level, 3x106 CAR T-cells per kg. Following treatment with ONCT-808, the patient sustained a fatal grade 5 serious AE that was deemed to be consistent with cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome. Notably, no histological evidence of lymphoma was found in the patient’s initial autopsy report. In light of the patient’s death Oncternal stated that it was seeking to modify the trial’s protocol and had been in communication with the FDA regarding such changes.
Before this patient was treated, 3 other patients in the study had received ONCT-808 at a lower dose level: 1x106 CAR T-cells per kg. As of a December 4, 2023 data cutoff, 2 of these 3 patients demonstrated a complete metabolic response and 1 patient showed a partial response to the CAR-T therapy.
"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 December 2023 statement.2 “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."
