Evaluation of Zanidatamab in Adult Patients with HER2-Overexpressing or Mutant Solid Tumors, Including Endometrial, Colorectal, Head & Neck, Sarcoma, and NSCLC

Trial ID: 2025-522169-31-00
Protocol: UC-GMP-2505
Sponsor: Unicancer

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Diseases & Conditions

Sarcoma Head and neck cancer HER2 mutant non-small cell lung cancer HER2 positive endometrial cancer

Objectives

The primary objective is to evaluate the antitumor activity of zanidatamab in adult patients with HER2-overexpressing or mutant solid tumors, specifically focusing on the confirmed objective response rate (ORR). Scope: 5.

Secondary objectives include:

Confirmed objective response rate as assessed by Blinded Independent Central Review (BICR).
Duration of response.
Progression-free survival.
Clinical benefit rate.
Overall survival.
Safety and tolerability of zanidatamab monotherapy according to NCI-CTC AE v 5.0.

Scope: 4, 5.

Participants

The sponsor did not provide the total number of participants. The study population consists of adult patients with HER2-positive solid tumors or non-small cell lung cancer. Eligible participants include those with histologically or cytologically confirmed endometrial cancer, colorectal cancer, head and neck cancer, or sarcoma exhibiting HER2-IHC3+ expression, or those with a HER2 mutation. Inclusion requires an ECOG performance status of ≤ 2, measurable disease according to RECIST1.1, and a life expectancy greater than 3 months. Participants must have progressed after at least one line of therapy with no other standard therapeutic options available. Required physiological parameters include adequate liver function, cardiac function with a left ventricular ejection fraction ≥ 50%, renal function with a creatinine clearance ≥ 30 mL/min, and sufficient bone marrow function. Availability of an archived FFPE sample or acceptance of a biopsy is necessary for molecular verification.

Plans and Procedures

This Phase II clinical trial is designed to evaluate the antitumor activity of zanidatamab in adult patients presenting with HER2-overexpressing or HER2-mutant solid tumors. The study includes specific cohorts of patients with endometrial, colorectal, head and neck, or sarcoma cancers expressing IHC 3+, as well as patients with non-small cell lung cancer harboring HER2 activating mutations. The primary endpoint is the confirmed objective response rate (ORR), assessed via RECIST 1.1 criteria. The investigative procedure involves the administration of zanidatamab via intravenous infusion. The study process begins with a screening visit to confirm eligibility through histological assessment, cardiac function evaluation, and laboratory testing of renal, hepatic, and bone marrow functions. Following inclusion, patients undergo treatment and subsequent follow-up visits to monitor progression-free survival, duration of response, clinical benefit rate, and overall survival. Safety is monitored through the incidence of adverse events. The trial is expected to continue through the recruitment and follow-up periods concluding in March 2030. Participant involvement may be subject to early termination based on disease progression or other clinical requirements specified in the protocol.

Treatment

The experimental therapeutic agent is zanidatamab, administered as JZP598. This substance is provided in the pharmaceutical form of powder for concentrate for solution for infusion. The specified dosage is 2400 mg, which is delivered via intravenous administration.

Efficacy

The primary efficacy endpoint is the confirmed objective response rate (ORR) for each cohort. This is determined based on the best overall response, representing the percentage of patients achieving a complete response (CR) or partial response (PR) during treatment or follow-up. Responses are assessed using RECIST1.1 by investigator assessment and must be confirmed by a follow-up scan occurring at least 4 weeks from the initial response assessment.

Secondary efficacy parameters include:

Confirmed ORR for each cohort as adjudicated by blinded independent central review (BICR).
Duration of response (DoR), defined as the time from the first assessment of a confirmed CR or PR until the first occurrence of progressive disease (PD) or death from any cause.
Progression-free survival (PFS), defined as the time from study registration to disease progression or death from any cause, provided by both investigators and BICR.
Clinical benefit rate (CBR), calculated as the percentage of patients achieving CR, PR, or stable disease (SD) for more than 16 weeks from inclusion, as assessed by investigators and BICR.
Overall survival (OS), defined as the time from study registration until death from any cause.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Histologically or cytologically confirmed endometrial, colorectal, head & neck, non-small cell lung cancer (NSCLC), or sarcoma
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)
Age ≥ 18 years at inclusion
Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2
Patient who progressed at least after 1 line of therapy, for whom there is no other standard therapeutic option available
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.
Estimated life expectancy >3 months
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
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
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)
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
Normal prothrombin time (PT) >70% and partial thromboplastin time (PTT), except for patient who uses anticoagulants
Adequate renal function: estimated serum creatinine clearance ≥ 30 mL/min according to the Cockcroft-Gault formula
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
Woman of childbearing potential must have a negative serum pregnancy test performed within 3 days before the date of treatment initiation
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
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
Affiliated to a social security system
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.

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Exclusion Criteria

Patient, in the judgment of the investigator, who should be included in another recruiting study assessing an anti-HER2 therapy (including zanidatamab)
Patient who received prior treatment with HER2-directed therapy unless marketed for the study cohort indication.
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
Any autoimmune, connective tissue or inflammatory disorder with pulmonary involvement not related to lung metastases (e.g. rheumatoid arthritis, Sjögren's syndrome, sarcoidosis)
Prior pneumonectomy
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
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
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
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
Acute or chronic uncontrolled pancreatitis or Child-Pugh Class C liver disease
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.
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
Treatment with anthracyclines within 90 days before first dose of zanidatamab and/or total lifetime load exceeding 360 mg/m2 doxorubicin or equivalent
A history of life-threatening hypersensitivity to monoclonal antibodies or recombinant proteins
Woman who is pregnant or breast-feeding
Participation in another therapeutic trial within the 30 days prior to entering the study. Participation in an observational trial would be acceptable
Patient unwilling or unable to comply with the medical follow-up required by the trial because of geographic, familial, social, or psychological reasons
Individual deprived of liberty or placed under protective custody or guardianship.