Zanidatamab for solid tumors with HER2 changes

Widening Treatment Options Among Adult Patients With HER2-overexpressing or Mutant Solid Cancers.

This study will try zanidatamab, an anti-HER2 drug, in adults with advanced endometrial, colorectal, head and neck, sarcoma, or non-small cell lung cancer whose tumors have specific HER2 changes.

Quick facts

• Phase: Phase 2
• Study type: Interventional
• Enrollment: 105 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: Unicancer (Academic / other)
• Drugs / interventions: zanidatamab, doxorubicin, prednisone
• Locations: 4 sites (Angers and 3 other locations)
• Trial ID: NCT07192068 on ClinicalTrials.gov

What this trial studies

This Phase 2, interventional trial gives zanidatamab to adults with advanced or metastatic endometrial, colorectal, head and neck, sarcoma, or non-small cell lung cancer that harbor defined HER2 alterations (IHC 3+ for several tumor types or activating HER2 mutations for NSCLC) with central pathology review. Eligible participants must have progressed after at least one prior therapy, have ECOG performance status ≤2, measurable disease by RECIST 1.1, and an expected survival >3 months. The primary endpoint is objective tumor response, measured as tumor size reduction per RECIST 1.1, with regular imaging and safety monitoring during treatment. Dosing and follow-up occur at participating French cancer centers, and prior standard anti-HER2 options should be exhausted where applicable.

Who should consider this trial

Good fit: Adults (≥18) with advanced or metastatic endometrial, colorectal, head and neck, sarcoma, or NSCLC whose tumors are HER2 IHC3+ (for non-NSCLC types) or have a HER2 activating mutation (for NSCLC), who progressed after at least one line of therapy, have ECOG ≤2 and measurable disease.

Not a fit: Patients without the specified HER2 overexpression or activating mutation, those who still have standard anti-HER2 therapy options available, or those with poor performance status or life expectancy ≤3 months are unlikely to benefit.

Why it matters

Potential benefit: If effective, zanidatamab could shrink tumors and offer a new targeted option for patients with HER2-altered cancers who have exhausted standard therapies.

How similar studies have performed: Zanidatamab is approved in Europe for biliary tract cancer and early-phase trials have shown promising responses in several HER2-altered tumor types, but its broad effectiveness across these cancers is not yet definitively proven.

Eligibility criteria

Inclusion Criteria:

1. Histologically or cytologically confirmed endometrial, colorectal, head \& neck, non-small cell lung cancer (NSCLC), or sarcoma
2. Patient with progressive, unresectable and/or advanced or metastatic disease harboring a locally performed, centrally reviewed HER2-overexpressing (IHC 3+ exclusively) for endometrial, colorectal, head \& neck cancers, or sarcoma or a HER2 activating mutation for NSCLC, determined on tissue (see Section 7.1.2 of the protocol)
3. Age ≥ 18 years at inclusion
4. Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2
5. Patient who progressed at least after 1 line of therapy, for whom there is no other standard therapeutic option available
6. Patient with a HER2 alteration covered by a standard marketed indication for any HER2 targeting therapy should be included after standard anti-HER2 strategy has been exhausted.
7. Estimated life expectancy \>3 months
8. Measurable disease according to RECIST1.1, whatever the disease location. Tumor lesions located in a previously irradiated area, or in an area subjected to other loco-regional therapy, are considered measurable if progression has been clearly demonstrated in the lesion
9. Adequate bone marrow function: absolute neutrophil count (ANC) ≥1.5 × 10⁹/L, platelet count ≥75 × 10⁹/L, and haemoglobin ≥9 g/dL. Transfusion is allowed with a 2-week washout period before treatment initiation
10. Adequate liver function: total bilirubin level ≤1.5 × the upper limit of normal (ULN) range (total bilirubin ≤3.0 ULN when the patient has documented Gilbert syndrome or liver metastasis), and aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels ≤2.5 × ULN (AST and ALT ≤5 ULN when documented tumor liver involvement)
11. Adequate cardiac function: left ventricular ejection fraction (LVEF) ≥ 50% at baseline as determined by either echocardiogram (ECHO) or multigated acquisition (MUGA) scan within 14 days before inclusion
12. Normal prothrombin time (PT) \>70% and partial thromboplastin time (PTT), except for patient who uses anticoagulants
13. Adequate renal function: estimated serum creatinine clearance ≥ 30 mL/min according to the Cockcroft-Gault formula
14. Man, and woman of childbearing potential must agree to use highly effective contraception for the duration of trial participation and as required after completing study treatment (refer to Table 6 in the protocol). Man must also agree to not donate sperm and women must agree to not donate oocytes during the specified period
15. Woman of childbearing potential must have a negative serum pregnancy test performed within 3 days before the date of treatment initiation
16. Availability of a suitable archived FFPE sample of primary or metastatic tumor tissue (archived FFPE is \<2 years old (desirable), maximum 5 years (accepted), buffered formalin fixed only. Fine-needle aspiration (cytology samples) and biopsies from sites of bone metastases are not acceptable) or patient accepts an optional biopsy under study
17. Willing and able to comply with the protocol for the duration of the study including scheduled visits, treatment plan, laboratory tests, specimen sampling for research, and other study procedures
18. Affiliated to a social security system
19. Patient must have signed a written informed consent form prior to any trial specific procedures. When the patient is physically unable to give their written consent, a trusted person of their choice, independent from the investigator or the sponsor, can confirm in signing the patient's consent.

Exclusion Criteria:

1. Patient, in the judgment of the investigator, who should be included in another recruiting study assessing an anti-HER2 therapy (including zanidatamab)
2. Patient who received prior treatment with HER2-directed therapy unless marketed for the study cohort indication.
3. Other primary malignancies within 3 years with the exception of adequately treated cone-biopsied in situ carcinoma of the cervix uteri and basal or squamous cell carcinoma of the skin. Cancer survivor, who has undergone potentially curative therapy for a prior malignancy, has no evidence of that disease for 4 years or more and is deemed at negligible risk for recurrence, is eligible for the trial
4. Any autoimmune, connective tissue or inflammatory disorder with pulmonary involvement not related to lung metastases (e.g. rheumatoid arthritis, Sjögren's syndrome, sarcoidosis)
5. Prior pneumonectomy
6. Patient with any condition or any evidence of severe or uncontrolled systemic diseases (e.g. active bleeding diatheses, active infection, or psychiatric illness) which in the investigator's opinion makes it undesirable for the patient to participate in the study or which would jeopardize compliance with the protocol. Screening for chronic conditions is not required for eligibility
7. History of myocardial infarction or unstable angina within 6 months prior to enrolment, troponin levels consistent with myocardial infarction, or clinically significant cardiac disease, such as ventricular arrhythmia requiring therapy, uncontrolled hypertension, or any history of symptomatic congestive heart failure
8. Evidence of spinal cord compression or brain metastases, defined as being clinically active and symptomatic, or requiring therapy with corticosteroids or anticonvulsants to control associated symptoms. Patient with clinically inactive or treated brain metastases who are asymptomatic (i.e. without neurologic signs or symptoms and do not require treatment with corticosteroids or anticonvulsants) may be included in the study. Patient must have a stable neurologic status and no evidence of radiographic progression for at least 2 weeks prior to first zanidatamab dosing
9. Patient with evidence of any leptomeningeal disease. If leptomeningeal disease has been reported radiographically on baseline magnetic resonance imaging (MRI), but is not suspected clinically by the investigator, the subject must be free of neurological symptoms.
10. Acute or chronic uncontrolled pancreatitis or Child-Pugh Class C liver disease
11. Patient with unresolved toxicities from previous anticancer therapy, defined as toxicities (other than alopecia) not yet resolved to grade ≤1 or baseline, as defined by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0. Patient with chronic Grade 2 toxicities may be enrolled at the discretion of the investigator after consultation and approval by the coordinating investigator.
12. Patient receiving chronic systemic corticosteroids dosed at \>10 mg prednisone or equivalent anti-inflammatory activity or any form of immunosuppressive therapy within 2 weeks of first zanidatamab dosing unless otherwise approved by the coordinating investigator. Patient who requires use of bronchodilators, inhaled or topical or ocular steroids, or local steroid injections may be included in the study
13. Treatment with anthracyclines within 90 days before first dose of zanidatamab and/or total lifetime load exceeding 360 mg/m2 doxorubicin or equivalent
14. A history of life-threatening hypersensitivity to monoclonal antibodies or recombinant proteins
15. Woman who is pregnant or breast-feeding
16. Participation in another therapeutic trial within the 30 days prior to entering the study. Participation in an observational trial would be acceptable
17. Patient unwilling or unable to comply with the medical follow-up required by the trial because of geographic, familial, social, or psychological reasons
18. Individual deprived of liberty or placed under protective custody or guardianship.

Where this trial is running

Angers and 3 other locations

• Institut de Cancérologie de l'Ouest — Angers, France (Active_not_recruiting)
• Chu Timone — Marseille, France (Recruiting)
• Institut de Cancérologie de Lorraine — Vandœuvre-lès-Nancy, France (Active_not_recruiting)
• Gustave Roussy — Villejuif, France (Recruiting)

Study contacts

• Principal investigator: Barbara PISTILLI, Dr — Gustave Roussy, VILLEJUIF
• Study coordinator: Céline MAHIER AIT OUKHATAR

Conditions Non-Small Cell Lung Cancer; Sarcoma; Head &Amp; Neck Cancer; Colorectal Carcinoma; Endometrial; zanidatamab; HER2 mutant