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NCT Number: NCT07815665

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

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)

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Key information

Conditions

Metastatic Urothelial Carcinoma Carcinoma Carcinoma, Transitional Cell Metastatic Urothelial Carcinoma (UC) Neoplasms Neoplasms by Histologic Type Neoplasms, Glandular and Epithelial

Age range

18 year and older

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 2 / Phase 3

Primary location

Research Site, Phoenix, Arizona, United States

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About this study

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

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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.

Treatment and study plan

Ivonescimab Dose 1

Drug

First ivonescimab dose to be tested in Phase 2

enfortumab vedotin (EV)

Drug

Standard of care therapy

Pembrolizumab

Drug

200 mg

Ivonescimab Dose 2

Drug

Second Ivonescimab dose to be tested in Phase 2 part of the study

Ivonescimab RP3D

Drug

Recommended Phase 3 dose of Ivonescimab after Phase 2 data analysis

Primary outcomes

  1. Phase 2 Primary Outcome Measure

    Time frame: Through 90 days after the last study treatment

    Adverse events (AEs) as characterized by type, incidence, severity, seriousness, and relationship to study treatment

  2. Phase 2 Primary Outcome Measure

    Time frame: From first dose until approximately 30 days after the last study treatment, assessed up to 3 years

    Number of participants with clinical laboratory abnormalities

  3. Phase 2 Primary Outcome measure

    Time frame: From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 3 years

    Objective response rate (ORR)

  4. Phase 2 Primary Outcome Measure

    Time frame: From first dose until end of treatment, assessed up to 3 years

    PK characteristics: ivonescimab serum concentration profiles

  5. Phase 3 Primary Outcome Measure

    Time frame: From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 3 years.

    PFS per RECIST v1.1 by Independent Radiology Review Committee (IRRC)

  6. Phase 3 Primary Outcome Measure

    Time frame: From date of randomization until the end of study, assessed up to 4 years

    Overall Survival (OS)

Secondary outcomes

  1. Phase 2 Secondary Outcome Measure

    Time frame: From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 3 years

    PFS per RECIST v1.1 by investigator

  2. Phase 2 Secondary Outcome Measure

    Time frame: From date of randomization until the end of study, assessed up to 4 years

    Overall Survival (OS)

  3. Phase 2 Secondary Outcome Measure

    Time frame: From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 3 years

    Duration of Response (DOR)

  4. Phase 2 Secondary Outcome Measure

    Time frame: From time of initiation of first dose to 30 days after end of treatment.

    Incidence of anti-drug antibodies (ADA) against ivonescimab

  5. Phase 3 Secondary Outcome Measure

    Time frame: From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 3 years

    ORR

  6. Phase 3 Secondary Outcome Measure

    Time frame: From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 3 years

    DOR

  7. Phase 3 Secondary Outcome Measure

    Time frame: Through 90 days after the last study treatment

    AEs as characterized by type, incidence, severity, seriousness, and relationship to study treatment

  8. Phase 3 Secondary Outcome Measure

    Time frame: From first dose until approximately 30 days after the last study treatment, assessed up to 3 years

    Number of participants with clinical laboratory abnormalities

  9. Phase 3 Secondary Outcome Measure

    Time frame: From first dose until end of treatment, assessed up to 3 years

    PK characteristics: ivonescimab serum concentration profiles

  10. Phase 3 Secondary Outcome Measure

    Time frame: From time of initiation of first dose to 30 days after end of treatment

    Incidence of ADA against ivonescimab

Interested in participating?

Recruiting

Interested in participating?

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Sponsors and collaborators

Lead sponsor

Summit Therapeutics

Industry

Registry information

Official study title

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)

Acronym: HARMONi-GU1

Important dates

Study start
2026
Primary completion
2030
Study completion
2030
First posted
Sep 11, 2026
Registry last updated
Sep 11, 2026

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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