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The first patient to receive an elevated dose of ONCT-808 died after showing signs consistent with cytokine release syndrome as well as immune effector cell-associated neurotoxicity syndrome, according to Oncternal. The company said it has had discussions with FDA on limiting future CAR-T doses. Oncternal Therapeutics has reported the death of a patient in a clinical trial following an elevated dose of its autologous CAR-T therapy aimed at aggressive B-cell lymphomas. The phase 1/2 dose-escalation study had begun treating at least three patients with relapsed or refractory cases of the blood cancers, including people who had not seen lasting benefits from previous CAR-T therapies directed at the CD19 protein. Oncternal’s approach, known as ONCT-808, instead targets the cell receptor ROR1. According to the company’s Dec. 26 release, after receiving an initial dose of 1 million CAR-T cells per kilogram, two of the three patients showed complete metabolic responses, while the third demonstrated a partial response to the treatment. At that time, side effects included decreased blood counts, pneumonia and milder cases of cytokine release syndrome, the systemic immune response often seen with CAR-T therapies. The first patient to receive the next-higher dose level—which tripled the number of CAR-T cells to 3 million per kg—died after showing signs consistent with cytokine release syndrome as well as immune effector cell-associated neurotoxicity syndrome, according to Oncternal. The company described the patient as an 80-year-old male with bulky disease who had undergone four previous lines of cancer treatment, including CD19 CAR-T therapy, while an initial autopsy found no evidence of his remaining lymphoma. Oncternal said it “has been in communication and is aligned with” the FDA regarding proposed changes to its clinical trial protocol going forward, namely lower doses of ONCT-808 and a narrowing of the study’s eligibility criteria. The single-arm study, led by investigators at MD Anderson Cancer Center and City of Hope, aims to enroll more than 50 patients, including those with large B-cell lymphoma or mantle cell lymphoma. "The safety of every patient who participates in our studies is of the utmost priority for us,” Oncternal’s chief medical officer, Salim Yazji, said in the company’s statement.  “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,” Yazji said. “With this clear path forward, we plan to implement the protocol amendment as rapidly as possible.” Earlier this year, Oncternal partially realigned its portfolio around ONCT-808, as well as its dual-action androgen receptor inhibitor, dubbed ONCT-534, which has begun dosing patients with metastatic, castration-resistant prostate cancer in a phase 1/2 study that is set to read out in mid-2024. ONCT-534 also received a fast track designation from the FDA in October. In early April, the company aimed to free up cash by ending the development of its Bruton’s tyrosine kinase inhibitor zilovertamab—including canceling a phase 3 study that combined it with Johnson & Johnson and AbbVie’s Imbruvica in mantle cell lymphoma—after citing an increasingly crowded market for BTK-targeting drugs. Those moves have extended Oncternal’s projected cash runway into 2025, the company reiterated during its third-quarter earnings report in early November. Oncternal tallied just over $40 million in cash and equivalents as of late September. At the time, the company said it plans to deliver additional clinical data readouts from ONCT-808 in 2024.