TuHURA Biosciences has initiated a phase 1b/2a clinical trial (NCT06940440) evaluating its lead innate immune agonist IFx-Hu2.0 in combination with pembrolizumab for patients with noncutaneous Merkel cell carcinoma (MCC) of unknown primary origin. This study represents a strategic expansion beyond the company's planned phase 3 registrational trial, targeting a distinct patient population that would not be eligible for the upcoming pivotal study.
The newly launched multicenter, open-label trial addresses a significant unmet medical need, as up to 30% of MCC patients present without primary lesions in the skin. These patients typically have metastatic deep-seated tumors in the liver, lungs, or retroperitoneum, making them unsuitable for conventional intratumoral injection approaches.
"Like our planned Phase 3 accelerated approval trial, this Phase 1b/2a trial will also investigate the ability of IFx-Hu2.0 to increase the anti-tumor response rate when used alongside pembrolizumab in first line treatment of CPI naïve, metastatic MCC," said James Bianco, MD, president and chief executive officer of TuHURA Biosciences. "However, unlike the planned Phase 3 study, these are patients without skin lesions who present with metastatic deep-seated tumors in the liver, lungs or retroperitoneum."
Trial Design and Patient Population
The study will enroll 9 patients across three visceral lesion sites, with 3 patients per cohort targeting hepatic, pulmonary, and retroperitoneal lesions. Patients will receive weekly intratumoral injections of IFx-Hu2.0 at 0.1 mg for three consecutive weeks, administered via interventional radiology techniques to reach deep-seated tumors.
Pembrolizumab will be initiated within 48 hours of the first IFx-Hu2.0 dose and continued every three weeks for six months. The primary endpoints focus on safety and feasibility at day 49 (28 days post-final IFx-Hu2.0 dose), while secondary endpoints evaluate efficacy based on RECIST 1.1 criteria at three and six months.
Initial data from the trial are anticipated in late 2025 or early 2026, providing crucial insights into the feasibility of radiologically-guided administration of IFx-Hu2.0 to visceral tumors.
Mechanism and Previous Clinical Experience
IFx-Hu2.0 is specifically designed to address primary resistance to checkpoint inhibitors like pembrolizumab. In previous phase 1 and 1b studies involving melanoma and metastatic MCC, the compound demonstrated systemic antitumor immune responses when administered intratumorally into cutaneous, subcutaneous, or nodal lesions.
The drug's mechanism appears to overcome the underlying biology that prevents tumors from responding to checkpoint inhibitors, potentially making it applicable across multiple cancer types. TuHURA has previously demonstrated that IFx-Hu2.0 can overcome CPI resistance in melanoma, squamous cell carcinoma, and Merkel cell carcinoma—three unrelated types of skin cancers.
Broader Implications and Future Expansion
If the current trial demonstrates feasibility and safety for radiologically-administered IFx-Hu2.0, TuHURA plans to extend enrollment to various non-MCC cancers known to respond poorly to checkpoint inhibitors. This expansion strategy is based on the premise that the underlying mechanisms of CPI resistance are largely consistent across cancer types.
"Since the underlying biology of why tumors don't respond to CPIs is for the most part the same, then the mechanism of how IFx-Hu2.0 overcomes that resistance to CPIs should be independent of the type of cancer treated," Bianco explained. "If successful, this trial could expand the potential benefit of IFx-Hu2.0 to a wide variety of cancers."
Phase 3 Preparations Continue
Parallel to this phase 1b/2a study, TuHURA continues preparations for its randomized, placebo-controlled phase 3 trial (NCT06947928) of IFx-Hu2.0 combined with pembrolizumab versus pembrolizumab plus placebo in checkpoint inhibitor-naïve patients with advanced or metastatic MCC.
The phase 3 study will enroll patients with cutaneous lesions suitable for direct intratumoral injection. In the experimental arm, patients will receive IFx-Hu2.0 at 0.1 mg via intralesional injection once weekly for three weeks, alongside pembrolizumab at 200 mg intravenously every three weeks for up to two years.
The primary endpoint is objective response rate at 24 weeks, with progression-free survival per RECIST 1.1 as a key secondary endpoint. The FDA has agreed to lift a partial clinical hold on this trial, contingent on TuHURA fulfilling certain criteria in the second quarter of 2025.
Clinical Significance
Merkel cell carcinoma is a rare but aggressive neuroendocrine skin cancer with limited treatment options. While checkpoint inhibitors like pembrolizumab have shown activity in MCC, primary resistance remains a significant challenge. The development of combination approaches that can overcome this resistance represents a critical advancement for patients with this difficult-to-treat malignancy.
The current phase 1b/2a trial's focus on noncutaneous MCC addresses a particularly challenging subset of patients who have historically been excluded from intratumoral injection studies due to the inaccessibility of their lesions. Success in this population could significantly expand the addressable patient population for IFx-Hu2.0 and establish a new treatment paradigm for deep-seated tumors across multiple cancer types.
