A Study of Ivonescimab in Combination With Enfortumab Vedotin vs Pembrolizumab in Combination With Enfortumab Vedotin in Metastatic Urothelial Carcinoma

A Randomized Phase 2/3 Study of Ivonescimab in Combination With Enfortumab Vedotin vs Pembrolizumab in Combination With Enfortumab Vedotin in Previously Untreated Locally Advanced or Metastatic Urothelial Carcinoma (HARMONi-GU1)

A Randomized, Open-Label, Multicenter, Phase 2/3 Clinical Study of Ivonescimab in Combination with Enfortumab Vedotin vs Pembrolizumab in Combination with Enfortumab Vedotin in Previously Untreated Locally Advanced or Metastatic Urothelial Carcinoma (HARMONi-GU1)

This Phase 2/3 study will be conducted in 2 parts. The first part is a Phase 2 randomized, open-label, 2 dose levels, parallel-arm study with the primary objective to evaluate safety and identify the recommended Phase 3 dose (RP3D) of ivonescimab in combination with EV. The second part is a randomized, open-label Phase 3 study with the primary objective to evaluate the efficacy and safety of ivonescimab (RP3D) plus EV versus pembrolizumab plus EV in patients with previously untreated LA/mUC.

For Phase 2 portion, patients will be randomized 1:1 to two arms consisting of 2 different dosages of ivonescimab.

• Arm A: Ivonescimab Dose 1 + EV
• Arm B: Ivonescimab Dose 2 + EV For Phase 3 portion, patients will be randomized 1:1 to the experimental arm (ivonescimab + EV) and the control arm (pembrolizumab + EV).
• Arm 1 (experimental): Ivonescimab RP3D + EV
• Arm 2 (SoC): Pembrolizumab 200 mg + EV

Inclusion Criteria:

• 18 years and older
• ECOG 0-1
• Life expectancy ≥ 6 months
• Histologically documented unresectable LA/mUC (transitional cell carcinoma) of the bladder, renal pelvis, ureter, or urethra with ≥50% urothelial carcinoma component
• No prior systemic therapy for LA/mUC
• At least one measurable non-cerebral lesion according to RECIST v1.1
• Adequate organ function

Exclusion Criteria:

• Locally advanced disease that is resectable or suitable for local therapy with curative intent.
• Tumors containing any small cell or neuroendocrine differentiation
• Ongoing sensory or motor neuropathy Grade 2 or higher.
• Radiographic findings consistent with a high risk of bleeding
• History of perforation of the gastrointestinal tract and/or fistula, history of gastrointestinal obstruction, extensive bowel resection within 6 months prior to first dose.