A Study of Trastuzumab Deruxtecan (T-DXd) and Cetuximab in People With Colorectal Cancer

Starting soon · Phase 2

Conditions studied: Colorectal Cancer, Adenocarcinoma of the Colon, Adenocarcinoma of the Rectum

In brief

The purpose of this study is find out whether the combination of trastuzumab deruxtecan (T-DXd) and cetuximab is an effective treatment for participants with metastatic and/or unresectable colorectal cancer that expresses low levels of HER2 and that has gotten worse after receiving standard treatment.

Key facts

Study ID

NCT07691489

Run by

Memorial Sloan Kettering Cancer Center

People needed

27

Starts

2026-08-01

Expected to finish

2029-06-01

Last updated by the study team

2026-07-09

Who can join

Age: 18 and older. Sex: any. Healthy volunteers: not accepted.

You may qualify if…

• Have histologically confirmed adenocarcinoma of the colon or rectum that is metastatic and/or unresectable.
• Unless otherwise contraindicated, participants must have received regimens containing the following agents: fluoropyrimidine (e.g., 5-fluorouracil or capecitabine), oxaliplatin, irinotecan, and if the tumor is MSI-H/MMRd, a PD-(L)1 directed antibody. There is no maximum number of prior lines of therapy.
• Prior anti-HER2 therapies other than T-DXd are allowed, with a washout period of at least 4 weeks.
• Prior anti-EGFR therapies, including cetuximab, are allowed, with a washout period of at least 4 weeks.
• Have progression of unresectable or metastatic CRC after last systemic therapy (as confirmed by Investigator) or be intolerant of last systemic therapy.
• Participants with KRAS/NRAS or BRAF-mutant colorectal tumors are eligible.
• Willing and able to undergo baseline tumor biopsy, preferably of a lesion that has progressed since the last treatment, if feasible.
• Have confirmed HER2-low mCRC, defined in this study by having tumor tissue tested at a CLIA-certified laboratory as HER2 IHC 1+ or 2+, as determined by Ventana's PATHWAY anti-HER2 (clone 4B5), an FDA-approved assay following the package insert's interpretational manual for gastric cancer, regardless of amplification by FISH. Archival tissue may be used for determination of HER2 status as long as tissue was obtained after last dose of most recent HER2-targeted therapy, if applicable.
• Have radiographically measurable disease according to RECIST v1.1, with at least one site of disease that is measurable and that has not been previously irradiated. If the participant has had previous radiation to the target lesion(s), there must be evidence of progression since radiation.
• Age ≥18 years on the day of signing informed consent.
• Have an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1.
• Have parameters demonstrating adequate organ function, as defined below, obtained ≤14 days prior to the first study treatment, unless otherwise noted:
• System / Laboratory value
• Hematologic:
• Absolute neutrophil count (ANC) / ≥1500/mm3 (G-CSF administration is not allowed within 14 days prior to screening assessment of bone marrow function, or at any time after this day and prior to initiation of treatment with study drug) Hemoglobin / ≥9.0 g/dL (Red blood cell transfusion is not allowed within 14 days prior to screening assessment of bone marrow function, or at any time after this day and prior to initiation of treatment with study drug) Platelet count / ≥100,000/mm3 (Platelet transfusion is not allowed within 14 days prior to screening assessment of bone marrow function, or at any time after this day and prior to initiation of treatment with study drug)
• Renal:
• Serum creatinine or creatinine clearance (as calculated using the Cockcroft-Gault equation) / ≤1.5 x ULN or ≥50 mL/min
• Hepatic:
• Alanine aminotransferase (ALT), Aspartate aminotransferase (AST) / ≤2.5 x ULN if no liver metastases or ≤5x ULN if liver metastases are present Total bilirubin / ≤1.5 x ULN if no liver metastases or <3x ULN in the presence of documented Gilbert's syndrome (unconjugated hyperbilirubinemia) or liver metastases at baseline Serum albumin / ≥2.5 g/dL
• Coagulation Left ventricular ejection fraction (LVEF) as assessed by echocardiogram documented ≤28 days prior to study treatment / ≥50%
• Have adequate treatment washout before enrollment (study treatment) as defined below:
• Treatment / Washout Period
• Major surgery / ≥4 weeks Radiation therapy / ≥4 weeks (if palliative stereotactic radiation therapy without abdominal involvement, ≥2 weeks) Chemotherapy (including antibody drug therapy, retinoid therapy) / ≥3 weeks for chemotherapeutics, ≥4 weeks for antibody drug therapy (e.g. bevacizumab, ramucirumab, cetuximab, trastuzumab) Immunotherapy / ≥4 weeks Cytochrome P450 (CYP)3A4 strong inhibitor, OATP inhibitor / ≥3 elimination half-lives of the inhibitor
• Evidence of post-menopausal status or negative serum pregnancy test for females of childbearing potential (Section 6.3) who are sexually active with a non-sterilized male partner. For women of childbearing potential, a negative result for serum pregnancy test (test must have a sensitivity of at least 25 mIU/mL) must be available at the screening visit.
• Male and female participants of reproductive/childbearing potential (Section 6.3) must agree to use a highly effective form of contraception or avoid intercourse during and upon completion of the study and for at least 7 months for females and 4 months for males after the last dose of study drug. Oral contraception alone is not acceptable; additional barrier methods in conjunction with spermicide must be used. Methods considered as highly effective methods of contraception include:

You may not qualify if…

• Involvement in the planning and/or conduct of the study (applies to both Investigator staff and/or staff at the study site).
• Previous enrollment in the present study.
• Currently participating in another interventional clinical trial.
• Clinically significant cardiopulmonary disease, such as:
• History of arrhythmia (multifocal premature ventricular contractions, bigeminy, trigeminy, ventricular tachycardia), which is symptomatic or requires treatment (CTCAE v5.0 ≥ Grade 3), symptomatic or uncontrolled atrial fibrillation despite treatment, or asymptomatic sustained ventricular tachycardia. Participants with atrial fibrillation controlled by medication are permitted.
• Congenital long QT syndrome.
• Corrected QT interval (QTcF) prolongation to >470 msec (females) or >450 msec (males) based on average of the screening triplicate 12-lead ECG.
• History of QT prolongation associated with other medications that required discontinuation of that medication.
• History of symptomatic congestive heart failure (CHF) (New York Heart Association Class II to IV), left ventricular systolic dysfunction, or decrease in ejection fraction.
• History of myocardial infarction, unstable angina, vascular stenting, angioplasty, or other cardiac surgery within 6 months prior to first dose of study treatment.
• Uncontrolled or poorly controlled hypertension (>180 mmHg systolic or >130 mmHg diastolic) despite medical treatment.
• History of non-infectious ILD/pneumonitis that required steroids, current ILD/pneumonitis, or suspected ILD/pneumonitis that cannot be ruled out by imaging at screening.
• Severe dyspnea at rest (CTCAE v5.0 ≥ Grade 3) due to complications of advanced malignancy or hypoxia requiring supplemental oxygen therapy.
• Lung-specific intercurrent clinically significant illnesses including, but not limited to, any underlying pulmonary disorder (e.g. pulmonary emboli within three months of the study enrollment, severe asthma, severe chronic obstructive pulmonary disease [COPD], restrictive lung disease pleural effusion, etc.).
• Any autoimmune, connective tissue, or inflammatory disorders (including Rheumatoid arthritis, Sjogren's, and sarcoidosis) where there is documented, or a suspicion of pulmonary involvement at the time of screening. Full details of the disorder should be recorded in the eCRF for participants who are included in the study.
• Prior pneumonectomy (complete).
• Any concomitant medications that are known to be associated with Torsades de Pointes or potent inducers of cytochrome P450 3A4 (CYP3A4).
• Uncontrolled infection requiring IV antibiotics, antivirals, or antifungals.
• A pleural effusion, ascites, or pericardial effusion that requires drainage, peritoneal shunt, or Cell-free and Concentrated Ascites Reinfusion Therapy (CART).
• History of severe hypersensitivity reactions to either the drug substances or inactive ingredients in the drug product(s).
• History of severe hypersensitivity reactions to other monoclonal antibodies.
• History of tick bite(s).
• History of allergy to red meat.
• Any toxicity related to prior anticancer therapies that has not resolved to ≤ Grade 1, with the following exceptions:
• Alopecia and neuropathy, which must have resolved to ≤ Grade 2.

Where it is running

• Memorial Sloan Kettering at Basking Ridge (Limited Protocol Activities) — Basking Ridge, New Jersey, United States
• Memorial Sloan Kettering Monmouth (Limited Protocol Activities) — Middletown, New Jersey, United States
• Memorial Sloan Kettering at Bergen (Limited Protocol Activities) — Montvale, New Jersey, United States
• Memorial Sloan Kettering Cancer Center @ Suffolk-Commack (Limited protocol activity) — Commack, New York, United States
• Memorial Sloan Kettering Westchester (Limited Protocol Activities) — Harrison, New York, United States
• Memorial Sloan Kettering Cancer Center (All Protocol Activities) — New York, New York, United States
• Memorial Sloan Kettering at Nassau (Limited Protocol Activities) — Uniondale, New York, United States

Full record on ClinicalTrials.gov

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