Whitehawk Therapeutics Opens First-in-Human Trial of MUC16-Directed ADC HWK-016 in Ovarian and Endometrial Cancers

Whitehawk Therapeutics has begun recruiting patients into a Phase 1 first-in-human clinical trial (NCT07470853) of HWK-016, a MUC16-directed antibody-drug conjugate, in adults with advanced solid tumors. The HWK-016 clinical trial focuses initially on platinum-resistant ovarian cancer and endometrial cancer, two indications where response rates to existing therapies remain low. HWK-016 is the only MUC16-targeted ADC in active clinical development, entering the clinic after the earlier failure of Roche's sofituzumab vedotin, which targeted a different epitope on the same protein. The trial is listed as an FDA-regulated drug study, with Catalyst Pharmaceutical Research serving as an industry collaborator.

The study, designated HWK-016-101, is a multicenter, open-label, dose-escalation and dose-expansion trial enrolling an estimated 265 participants across 12 US sites, including Memorial Sloan Kettering Cancer Center, Ohio State University Wexner Medical Center, and Karmanos Cancer Center. It consists of two parts: Part A evaluates HWK-016 as monotherapy in ovarian and endometrial cancers, while Part B tests HWK-016 in combination with bevacizumab in ovarian cancer only. Each part includes a Phase 1a escalation stage using a Bayesian optimal interval (BOIN) design, followed by Phase 1b expansion cohorts. HWK-016 is administered by intravenous infusion in 21-day cycles. Adults aged 18 and older are eligible; exclusion criteria include uncontrolled CNS metastases, corneal keratopathy, and prolonged QTcF interval (≥470 ms). Primary endpoints are determination of maximum tolerated dose, maximum administered dose, and recommended dose for expansion, assessed through incidence and severity of adverse events, dose-limiting toxicities, and serious adverse events during Cycle 1. Secondary endpoints include overall response rate and progression-free survival per RECIST v1.1, pharmacokinetic parameters (Cmax, AUC, half-life, clearance, volume of distribution) for the ADC, total antibody, and payload metabolites CPT116 and CPT119, as well as anti-drug antibody formation. Primary completion is projected for Q1 2028.

HWK-016 targets the membrane-bound, non-shed portion of MUC16, a transmembrane glycoprotein also known as CA-125 that is overexpressed in ovarian and endometrial cancers. This epitope selection distinguishes HWK-016 from sofituzumab vedotin, which bound the shed ectodomain of MUC16 and was neutralized by circulating CA-125 acting as an antigen sink. The ADC uses the CPT113 linker-payload platform, licensed from Hangzhou DAC Biotech, which carries a topoisomerase I inhibitor payload. Upon binding MUC16-expressing tumor cells, HWK-016 is internalized, and the payload is released intracellularly to induce DNA damage and apoptosis. The linker has been described as 10 to 100 times more stable than those used in typical ADCs, with a reported payload release ratio of approximately 0.01% on a molar basis. No peer-reviewed preclinical data for HWK-016 have been identified in the public literature. The combination with bevacizumab in Part B is rationalized by bevacizumab's established role in ovarian cancer and the hypothesis that VEGF inhibition may normalize tumor vasculature and improve ADC delivery.

The ovarian cancer ADC space has expanded since the 2022 US FDA approval of mirvetuximab soravtansine (Elahere, ImmunoGen/AbbVie), which targets folate receptor alpha in platinum-resistant disease. Several other ADCs are in clinical testing for ovarian cancer: raludotatug deruxtecan (Daiichi Sankyo/AstraZeneca, CDH6-directed, Phase I/II), datopotamab deruxtecan (Daiichi Sankyo/AstraZeneca, TROP2-directed, Phase II), and sacituzumab govitecan (Gilead, TROP2-directed, Phase II). Within the MUC16 target space specifically, Regeneron's CAR-T therapy 27T51 is in Phase I for recurrent ovarian cancer (NCT06564207), and oregovomab (OncoQuest) is in a Phase III trial combining an anti-CA-125 immunomodulatory antibody with chemotherapy (NCT04498117). HWK-016 is differentiated as the only ADC currently in the clinic that targets the non-shed epitope of MUC16 and employs a topoisomerase I inhibitor payload, a combination that has not been tested in humans before.

Whitehawk Therapeutics initiates Phase 1 first-in-human study of MUC16-targeted ADC HWK-016 in ovarian and endometrial cancers.

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