Clinical Trial Evaluating the Activity of Zanidatamab for the Treatment of Patients With Solid Tumors With an Alteration of the HER2 Gene.

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 diseaseharboring a locally performed, centrally reviewed HER2-overexpressing (IHC 3+exclusively) for endometrial, colorectal, head & neck cancers, or sarcoma or a HER2activating mutation for NSCLC, determined on tissue (see Section 7.1.2 of theprotocol)

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 otherstandard therapeutic option available

6. Patient with a HER2 alteration covered by a standard marketed indication for anyHER2 targeting therapy should be included after standard anti-HER2 strategy has beenexhausted.

7. Estimated life expectancy >3 months

8. Measurable disease according to RECIST1.1, whatever the disease location. Tumorlesions located in a previously irradiated area, or in an area subjected to otherloco-regional therapy, are considered measurable if progression has been clearlydemonstrated 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 Gilbertsyndrome or liver metastasis), and aspartate aminotransferase (AST) and alanineaminotransferase (ALT) levels ≤2.5 × ULN (AST and ALT ≤5 ULN when documented tumorliver involvement)

11. Adequate cardiac function: left ventricular ejection fraction (LVEF) ≥ 50% atbaseline 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 forpatient who uses anticoagulants

13. Adequate renal function: estimated serum creatinine clearance ≥ 30 mL/min accordingto the Cockcroft-Gault formula

14. Man, and woman of childbearing potential must agree to use highly effectivecontraception for the duration of trial participation and as required aftercompleting study treatment (refer to Table 6 in the protocol). Man must also agreeto not donate sperm and women must agree to not donate oocytes during the specifiedperiod

15. Woman of childbearing potential must have a negative serum pregnancy test performedwithin 3 days before the date of treatment initiation

16. Availability of a suitable archived FFPE sample of primary or metastatic tumortissue (archived FFPE is <2 years old (desirable), maximum 5 years (accepted),buffered formalin fixed only. Fine-needle aspiration (cytology samples) and biopsiesfrom sites of bone metastases are not acceptable) or patient accepts an optionalbiopsy under study

17. Willing and able to comply with the protocol for the duration of the study includingscheduled 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 specificprocedures. When the patient is physically unable to give their written consent, atrusted 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 anotherrecruiting study assessing an anti-HER2 therapy (including zanidatamab)

2. Patient who received prior treatment with HER2-directed therapy unless marketed forthe study cohort indication.

3. Other primary malignancies within 3 years with the exception of adequately treatedcone-biopsied in situ carcinoma of the cervix uteri and basal or squamous cellcarcinoma of the skin. Cancer survivor, who has undergone potentially curativetherapy for a prior malignancy, has no evidence of that disease for 4 years or moreand is deemed at negligible risk for recurrence, is eligible for the trial

4. Any autoimmune, connective tissue or inflammatory disorder with pulmonaryinvolvement not related to lung metastases (e.g. rheumatoid arthritis, Sjögren'ssyndrome, sarcoidosis)

5. Prior pneumonectomy

6. Patient with any condition or any evidence of severe or uncontrolled systemicdiseases (e.g. active bleeding diatheses, active infection, or psychiatric illness)which in the investigator's opinion makes it undesirable for the patient toparticipate 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 toenrolment, troponin levels consistent with myocardial infarction, or clinicallysignificant 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 clinicallyactive and symptomatic, or requiring therapy with corticosteroids or anticonvulsantsto control associated symptoms. Patient with clinically inactive or treated brainmetastases who are asymptomatic (i.e. without neurologic signs or symptoms and donot require treatment with corticosteroids or anticonvulsants) may be included inthe study. Patient must have a stable neurologic status and no evidence ofradiographic progression for at least 2 weeks prior to first zanidatamab dosing

9. Patient with evidence of any leptomeningeal disease. If leptomeningeal disease hasbeen reported radiographically on baseline magnetic resonance imaging (MRI), but isnot suspected clinically by the investigator, the subject must be free ofneurological symptoms.

10. Acute or chronic uncontrolled pancreatitis or Child-Pugh Class C liver disease

11. Patient with unresolved toxicities from previous anticancer therapy, defined astoxicities (other than alopecia) not yet resolved to grade ≤1 or baseline, asdefined by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0. Patient with chronic Grade 2 toxicities may be enrolled atthe discretion of the investigator after consultation and approval by thecoordinating investigator.

12. Patient receiving chronic systemic corticosteroids dosed at >10 mg prednisone orequivalent anti-inflammatory activity or any form of immunosuppressive therapywithin 2 weeks of first zanidatamab dosing unless otherwise approved by thecoordinating investigator. Patient who requires use of bronchodilators, inhaled ortopical 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/ortotal lifetime load exceeding 360 mg/m2 doxorubicin or equivalent

14. A history of life-threatening hypersensitivity to monoclonal antibodies orrecombinant proteins

15. Woman who is pregnant or breast-feeding

16. Participation in another therapeutic trial within the 30 days prior to entering thestudy. Participation in an observational trial would be acceptable

17. Patient unwilling or unable to comply with the medical follow-up required by thetrial because of geographic, familial, social, or psychological reasons

18. Individual deprived of liberty or placed under protective custody or guardianship.