Oncternal Therapeutics, Inc.

Oct. 22, 2024 -- Oncternal Therapeutics, Inc. (Nasdaq: ONCT) (the “Company”) today announced updated data from its Phase 1/2 Study of ONCT-534 for the treatment of patients with relapsed or refractory metastatic Castration-Resistant Prostate Cancer (mCRPC). Based on initial pharmacokinetic results, two additional dosing cohorts with twice daily (BID) oral dosing of ONCT-534 had been incorporated in the Phase 1/2 study ONCT-534-101 (NCT05917470). Overall, fifteen patients received ONCT-534 once daily (QD) in six dosing cohorts and six patients received ONCT-534 BID in two dosing cohorts. Based on a data cut off of September 30, 2024, the BID dosing schedule was well tolerated, with no related Grade 3 or higher toxicities. One patient, who experienced a rising PSA on ONCT-534 at 160 mg BID, had a subsequent 50% reduction in PSA after four weeks of ONCT-534 at 300 mg BID, and at the same time the CAT Scan showed a 16% reduction in target lesions compared to baseline. Enumeration and biomarker analysis of circulating tumor cells (CTCs) showed promising effects on expression of androgen receptor (AR)-regulated genes, and AR nuclear translocation in six additional patients. CTC analysis also showed that some patients who did not respond to ONCT-534 had prostate cancer that had developed neuroendocrine features, which are associated with AR independent disease. “While we still believe the decision to discontinue the ONCT-534-101 clinical trial remains the correct one in the current biotechnology environment, the updated clinical results highlight the potential of ONCT-534 in prostate cancer. We believe there is value in exploring BID dosing further, as well as studying ONCT-534 in earlier lines of therapy for advanced prostate cancer,” said James Breitmeyer, M.D., Ph.D., Oncternal’s President and CEO. “We continue to explore strategic alternatives for our product candidates, including ONCT-534, ONCT-808, zilovertamab and ONCT-216 in an ongoing effort to maximize value to our shareholders.” Oncternal Therapeutics is a clinical-stage biopharmaceutical company focused on the development of novel oncology therapies for the treatment of patients with cancers that have critical unmet medical need. Oncternal pursues drug development targeting promising, yet untapped biological pathways implicated in cancer generation or progression, focusing on hematological malignancies and prostate cancer. More information on our company and programs is available at https://oncternal.com/. ONCT-534 is an investigational dual-action androgen receptor inhibitor (DAARI) with demonstrated preclinical activity in prostate cancer models against both unmutated androgen receptor (AR), and against multiple forms of AR mutation and aberration. It is a potential treatment for patients with mCRPC with unmet medical need because of resistance to androgen receptor pathway inhibitors, including those with AR amplification, mutations in the AR ligand binding domain (LBD), or splice variants with loss of the AR LBD. It was investigated in Study ONCT-534-101 (NCT05917470) for the treatment of patients with mCRPC who are resistant to current AR pathway inhibitors. ONCT-808 is an investigational autologous chimeric antigen receptor T (CAR T) cell therapy that targets Receptor Tyrosine Kinase-Like Orphan Receptor 1 (ROR1) using the binding domain from zilovertamab. ONCT-808 has demonstrated activity in preclinical models against multiple hematological malignancies and solid tumors and has been shown to be specific for cancer cells expressing ROR1. Oncternal has developed a robust and reproducible manufacturing process that has the potential to reduce the time patients must wait for their individual CAR T therapy to be produced compared with currently approved CAR T products. It was investigated in Study ONCT-808-101 (NCT05588440) with relapsed or refractory aggressive B-cell lymphoma, including patients who have failed previous CD19 CAR T treatment. Zilovertamab (previously called cirmtuzumab and UC-961) is an investigational monoclonal antibody designed to inhibit the function of Receptor Tyrosine Kinase-Like Orphan Receptor 1 (ROR1). Zilovertamab has been evaluated in Phase 1/2 Study CIRM-0001 (NCT03088878) in combination with ibrutinib for the treatment of patients with mantle cell lymphoma (MCL), chronic lymphocytic leukemia (CLL) and marginal zone lymphoma (MZL), which resulted in 100% progression free survival (PFS) at 48 months in CLL patients whose tumors harbored del(17p)/p53 mutation, a population underserved by current treatment options. The U.S. Food and Drug Administration (FDA) has granted Orphan Drug Designation to zilovertamab for the treatment of CLL and MCL. The results of an investigator-sponsored, Phase 1b clinical trial of zilovertamab in combination with paclitaxel for the treatment of women with HER2-negative metastatic or locally advanced, unresectable breast cancer were recently published (Shatsky 2023). Zilovertamab was evaluated in an investigator-initiated Phase 1b study of zilovertamab in combination with docetaxel in patients with metastatic castration-resistant prostate cancer (NCT05156905), and an investigator-initiated Phase 2 clinical trial of zilovertamab in combination with venetoclax, a Bcl-2 inhibitor, in patients with relapsed/refractory (R/R) CLL (NCT04501939). ONCT-216 (previously called TK216) is an investigational targeted small-molecule inhibitor of the E26 transformation-specific (ETS) family of oncoproteins including fusion proteins. Tumorigenic fusion proteins involving the EWS protein and an ETS protein can be found in most cases of Ewing sarcoma. ETS-related translocations or overexpression are also found in many other tumors such as acute myeloid leukemia (AML), diffuse large B cell lymphoma (DLBCL), and prostate cancer. In preclinical models, ONCT-216 was observed to bind to EWS-FLI1, blocking the interaction between this fusion protein and other transcriptome proteins such as RNA helicase A, leading to tumor cell apoptosis and inhibiting tumor growth in animal models. The U.S. Food and Drug Administration (FDA) has granted Rare Pediatric Disease Designation, Orphan Drug Designation and Fast Track Status to ONCT-216 for the treatment of Ewing sarcoma. The results of a Phase 1/ 2 clinical trial of ONCT-216 in patients with Ewing sarcoma (NCT02657005) were recently published (Myers 2024). The content above comes from the network. if any infringement, please contact us to modify.

After disappointing efficacy data and a patient death, Oncternal Therapeutics is discontinuing two trials and looking for strategic alternatives. The San Diego company said it would end a Phase 1 trial investigating ONCT-534, a dual-action androgen receptor inhibitor, in patients with metastatic castration-resistant prostate cancer. In the early-stage study, the drug did not show clinically meaningful improvements in disease like prostate-specific antigen levels, the company said Thursday. Its other candidate, the ROR1-targeting autologous CAR-T dubbed ONCT-808, showed anti-tumor activity at all doses in aggressive B cell lymphoma. That included a complete metabolic response lasting eight months and long-term persistence of the CAR-T cells. While the asset also came with “expected treatment-emergent adverse events” for a CAR-T therapy, a patient died from “complications of shock” at the highest dose. Based on these results, the company said it would stop development, cut its workforce and look for other options, including asset sales, licensing or a merger or acquisition. “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,” president and CEO James Breitmeyer said in a statement. Oncternal’s stock $ONCT dipped nearly 3% on Friday morning, trading at $1.65. Zilovertamab is a monoclonal antibody designed to inhibit the function of ROR1. It is in separate investigator-led studies in metastatic castration-resistant prostate cancer and chronic lymphocytic leukemia . ONCT-216 is currently not listed in the company’s R&D pipeline . In April 2022, it discontinued recruiting subjects in a Phase 1/2 trial in Ewing sarcoma to “reallocate resources.”

Oncternal Therapeutics is laying off about ten employees, representing approximately 37% of its workforce. Credit: Andrii Yalanskyi via Shutterstock. Oncternal Therapeutics ’s stock has slumped after the company announced it is dropping its clinical trials and will lay off staff to save cash. The US-based biotech is discontinuing its clinical trials evaluating ONCT-534, a dual action androgen receptor inhibitor for metastatic castration-resistant prostate cancer, and ONCT-808, a ROR1-targeting autologous CAR-T candidate for patients with aggressive B-cell lymphoma. The biotech’s stock plummeted by 60%, dropping from $4.17 per share before market close on 11 September to $1.70 at market close on 12 September, the day of the announcement. This update comes after ONCT-534 failed to perform in the interim Phase I trial (NCT05917470) results. In the 20 enrolled patients, ONCT-534 did not show clinically meaningful improvements in disease, including prostate-specific antigen (PSA) levels. The patients were treated in eight dosing cohorts with varying schedules of administration and doses. In December 2023, Oncternal reported the death of a patient in a Phase I/II dose escalation study (NCT05588440) of B-cell lymphoma therapy ONCT-808. The patient, who was the first to receive a higher dose level in the study, died after showing signs consistent with cytokine release syndrome, as well as immune effector cell-associated neurotoxicity syndrome, said Oncternal. See Also: Itacitinib adipate by Incyte for Acute Myelocytic Leukemia (AML, Acute Myeloblastic Leukemia): Likelihood of Approval Itacitinib adipate by Incyte for Non-Hodgkin Lymphoma: Likelihood of Approval Oncternal’s CEO James Breitmeyer said: “The early results during dose escalation in the Phase I/II 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.” While Oncternal plans to explore alternative options for the programmes, it will discontinue all product development activities and take other steps to reduce costs, including reducing its workforce. In a 12 September SEC filing, Oncternal shared that it will slash its workforce by 37%. The layoffs – which it expects to complete by Q3 2024 – are estimated to incur workforce reduction-related charges of about $1m. The latest news adds to a string of failures from the company that terminated two trials investigating its tyrosine kinase inhibitor (TKI) zilovertamab in April 2023 to free up cash. One of these was a Phase III study that investigated the TKI in combination with Johnson & Johnson and AbbVie ’s blockbuster TKI Imbruvica (ibrutinib) in mantle cell lymphoma.