A Randomized, Active-Controlled, Double-blind, Multicenter, Phase 3 Clinical Study of Ivonescimab in Combination with FOLFOX versus Bevacizumab in Combination with FOLFOX for the First-line Treatment of Metastatic Colorectal Cancer (HARMONi-GI3)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Summit Therapeutics Inc.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Decision date (initial)

2026-02-13

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Summit Therapeutics Inc.

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy, Therapy, Pharmacokinetic, Pharmacogenetic, Others

To compare the progression-free survival (PFS) as assessed by blinded Independent Radiological Review Committee (IRRC) based on Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, of ivonescimab in combination with modified 5 FU, oxaliplatin, and leucovorin (mFOLFOX6) to bevacizumab in combination with mFOLFOX6.

Secondary objectives 5

1. To compare the overall survival (OS) of ivonescimab in combination with mFOLFOX6 to bevacizumab in combination with mFOLFOX6.
2. To compare objective response rate (ORR) and duration of response (DOR) as assessed by blinded IRRC based on RECIST v1.1, of ivonescimab in combination with mFOLFOX6 to bevacizumab plus mFOLFOX6.
3. To compare the safety and tolerability of ivonescimab in combination with mFOLFOX6 to bevacizumab in combination with mFOLFOX6.
4. To evaluate the pharmacokinetic (PK) profile of ivonescimab in combination with mFOLFOX6.
5. To evaluate the immunogenicity of ivonescimab in combination with mFOLFOX6.

Conditions and MedDRA coding

Metastatic colorectal cancer

Regulatory references

Scientific advice from competent authorities

European Medicines Agency, Food And Drug Administration, European Medicines Agency

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 5

1. Histologically or cytologically confirmed mCRC, not amenable to curative resection.
2. An Eastern Cooperative Oncology Organization Group (ECOG) performance status score of 0 or 1.
3. No prior systemic therapy for mCRC. NOTE:- If patients have received systemic therapy or radiotherapy for early-stage disease, >12 months must have elapsed since completion of neoadjuvant therapy and/or adjuvant therapy (including adjuvant oxaliplatin or radiotherapy) and prior to diagnosis of recurrent or metastatic disease.
4. At least one measurable tumor lesion according to RECIST v1.1 that is amenable to repeated accurate measurements. NOTE:- Brain metastases cannot be selected as target lesions and lesions that have received radiotherapy in the past cannot be selected as target lesions unless they have progressed following radiation
5. Known BRAF, KRAS and NRAS (extended RAS) mutation status from existing reports, or determined by testing tumor tissue utilizing a clinical assay.

Exclusion criteria 6

1. Patients with known MSI-H/dMMR disease as determined by a health authority approved assay (eg, FDA for United States, CE-IVD marked for Europe, PMDA for Japan, and NMPA for China) conducted at a local clinical laboratory or at the central laboratory.
2. Known BRAF V600E mutation status. known DPD deficiency (refer to local fluorouracil label or local clinical guidance for DPD status recommendation prior to starting treatment).
3. Patients who have received prior immunotherapy or anti-angiogenic therapy for colorectal cancer, including immune checkpoint inhibitors, immune checkpoint agonists, immune cell therapy and any other therapy based on the mechanism of action of tumor immunity or angiogenesis
4. Symptomatic central nervous system (CNS) metastases with hemorrhagic features, CNS metastasis ≥ 1.5 cm, CNS radiation within 7 days prior to randomization, potential need for CNS radiation within the first cycle, or leptomeningeal disease. NOTE:- Patients who have stopped corticosteroids or on stable corticosteroid therapy (prednisone ≤ 10 mg daily or equivalent) are allowed.
5. Resectable oligometastastic-only disease with multidisciplinary plan for complete resection of all disease.
6. Ascites requiring paracentesis within last 30 days.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. PFS by IRRC based on RECIST v1.1

Secondary endpoints 5

1. OS
2. ORR and DOR as assessed by IRRC based on RECIST v1.1
3. Safety assessment: incidence and severity of adverse events (AEs), clinically significant abnormal laboratory test results
4. Pharmacokinetic profile: Serum concentrations of ivonescimab in patients at different time points after ivonescimab administration
5. Immunogenicity assessment: Number and percentage of patients with detectable anti-ivonescimab antibody

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 4

Comparator 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Summit Therapeutics Inc.

Sponsor organisation

Summit Therapeutics Inc.

Address

2882 Sand Hill Road Suite 106

City

Menlo Park

Postcode

94025-7057

Country

United States

Scientific contact point

Organisation

Summit Therapeutics Inc.

Contact name

David Johnson

Public contact point

Organisation

Summit Therapeutics Inc.

Contact name

Medical information

Third parties 11

Locations

8 EU/EEA countries · 84 investigational sites

By country

Investigational sites

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 106 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

2 submissions — initial application plus substantial / non-substantial modifications