ZANIDATAMAB for HER2-overexpressing solid tumors|Breast cancer|Gastric cancer|Non-small cell lung cancer|Colorectal cancer|Gastroesophageal cancer|Ovarian cancer|Endometrial cancer|Salivary gland cancer|Esophageal adenocarcinoma|Cervical cancer|Pancreatic cancer|Urothelial carcinoma

Inclusion criteria

• {"criterion_text":"- 1. Is at least 18 years of age inclusive at the time of signing the informed consent (or the legal age of adulthood per country-specific regulations).\n- 10. Has adequate hepatic function defined as follows: a. Total serum bilirubin of no more than 1.5 × ULN (≤ 1.5 × ULN) or less than 3 × ULN (< 3 × ULN) in the presence of Gilbert’s syndrome (unconjugated hyperbilirubinemia) or liver metastasis at baseline. b. Aspartate aminotransferase no more than 3.0 × ULN (≤ 3.0 × ULN) per institutional values (no more than 5.0 × ULN [≤ 5.0 × ULN] if liver metastases are present). c. Alanine aminotransferase no more than 3.0 × ULN (≤ 3.0 × ULN) per institutional values (no more than 5.0 × ULN [≤ 5.0 × ULN] if liver metastases are present).\n- 11. Has creatinine clearance of at least 30 mL/minute (ie, ≥ 30 mL/minute) as calculated per local institutional guidelines.\n- 12. Has LVEF of at least 50% (ie, ≥ 50%) as determined by either echocardiogram or multiple gated acquisition scan obtained within 4 weeks before the first dose of study intervention.\n- 13. Participant agrees to the following based on sex assigned at birth. a. Male participants: Male participants are eligible to participate if they agree to the following during the intervention period and for at least 4 months after the last dose of study intervention: • Refrain from donating fresh unwashed semen. • Use contraception as follows: − Use a male condom and should also be advised of the benefit of a female partner using a highly effective method of contraception, as a condom may break or leak, when having sexual intercourse with a WOCBP who is not currently pregnant. − Agree to use male condom when engaging in any activity that allows for passage of ejaculate to another person. b. Female participants: • A female participant is eligible to participate if she is not pregnant or breastfeeding and one of the following conditions applies: − Is a WONCBP as defined in Appendix 4 Contraceptive and Barrier Guidance. OR − Is a WOCBP and using a contraceptive method that is highly effective (with a failure rate of < 1% per year), with low user dependency, as described in Appendix 4 Contraceptive and Barrier Guidance, during the study intervention period and for at least 4 months after the last dose of study intervention. The investigator should evaluate the potential for contraceptive method failure (eg, noncompliance, recently initiated) in relationship to the first dose of study intervention. • A WOCBP must have a negative highly sensitive pregnancy test (urine or serum as required by local regulations) within 3 days before the first dose of study intervention (Section 8.3.6 Pregnancy Testing). − If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive. • Additional requirements for pregnancy testing during and after study intervention are provided in Section 8.3.6 Pregnancy Testing. • The investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy.\n- 14. Is capable of giving signed informed consent as described in Section 10.1.3, which includes compliance with the requirements and restrictions listed in the ICF and in this protocol.\n- 2. Participants with locally advanced, unresectable, or metastatic solid tumors (except BTC, defined as gallbladder cancer or cholangiocarcinoma) who have progressed following at least 1 prior systemic treatment for metastatic or advanced disease and have no available treatment options that have confirmed benefit. Prior treatment with HER2-targeted therapy is not permitted (Cohort 1 only). For participants with breast cancer (Cohort 2) or GEA (Cohort 3), prior HER2-targeted therapy is permitted and prior therapy with T-DXd is required.\n- 3. HER2 status: HER2 overexpression (IHC 3+) must be determined by a sponsordesignated central laboratory. For HER2 testing of breast cancer, the breast cancer algorithm scoring per current ASCO/CAP guidelines must be used. For HER2 testing of tumors other than breast cancer, the gastric algorithm scoring per current ASCO/CAP guidelines must be used. • All participants must have adequate tumor sample for submission for central HER2 testing. Submission of FFPE tumor tissue block is strongly preferred. If a tumor tissue block is not available, discussion with the sponsor should occur. • Archival FFPE tumor tissue blocks must be < 2 years from the date of biopsy or resection to the start of prescreening or screening. The most recently available archival or new FFPE tissue specimen should be used to determine HER2 status eligibility. If available, the tissue that is submitted for Cohort 2 and 3 participants who have received prior T-DXd should be obtained after T-DXd treatment. • Specimens with limited tumor content, FNA, or bone decalcified samples will not be accepted for HER2 testing. Additional details on sample requirement will be provided in the laboratory manual.\n- 4. This inclusion criterion was merged with inclusion criterion #3 in Protocol Amendment 02. To maintain the original protocol numbering list, this criterion was intentionally left blank.\n- 5. Presence of at least 1 measurable lesion as assessed by ICR at screening based on RECIST version 1.1.\n- 6. Has Eastern Cooperative Oncology Group performance status of 0 or 1.\n- 7. Has a life expectancy of at least 3 months, in the opinion of the investigator.\n- 8. Participants with history of treated and stable CNS metastases are eligible, provided the following criteria are met: a. Participants must also have measurable metastatic disease with HER2 overexpression (IHC 3+) outside the CNS. b. Participants with treated CNS metastases that are no longer symptomatic may be included in the study if they recovered to ≤ Grade 1 (CTCAE version 5.0 or higher) or baseline from the acute toxic effect associated with the treatment ≥ 7 days prior to Cycle 1 Day 1. See Exclusion Criterion #3 for requirements of recovery from prior toxicity. (Note: Participants still receiving corticosteroids for brain metastasis must be on stable or decreasing doses within 14 days of Cycle 1 Day 1, and participants must have no requirement for anticonvulsants within 14 days of Cycle 1 Day 1. Anticonvulsants are permitted for pre-existing well-controlled seizure disorder.) c. Prior stereotactic radiosurgery or stereotactic radiotherapy should be completed at least 7 days (≥ 7 days) before the first dose of study intervention. A minimum of 14 days must have elapsed between the end of whole brain radio therapy and the first dose of study intervention.\n- 9. Has adequate hematologic parameters defined as follows: a. Absolute neutrophil count of at least 1000/mm3 (≥ 1000/mm3). b. Platelet count of at least 75,000 (≥ 75,000); participants must not have had platelet transfusion within 30 days of the Screening Visit laboratory draw. c. Hemoglobin of at least 8 g/dL (≥ 8 g/dL); participants with chronic anemia (other than autoimmune hemolytic anemia) that is supported by intermittent red blood cell transfusions are eligible."}

Exclusion criteria

• {"criterion_text":"- 1. Has known or suspected leptomeningeal disease and/or untreated brain metastasis.\n- 10. Has any issue or condition that, in the opinion of the investigator, would contraindicate the participant’s participation in the study or confound the results of the study.\n- 11. Prior treatment with HER2-targeted therapy (Cohort 1 only).\n- 12. Has a history of trauma or major surgery within 4 weeks prior to Cycle 1 Day 1.\n- 13. Was treated with systemic antineoplastic therapy, including hormonal therapies for breast cancer, or any investigational therapy within 4 weeks or 5 half-lives (whichever is longer) prior to Cycle 1 Day 1. An exception to this is antibody-based anticancer therapy, which requires a ≥ 4 weeks washout period. A washout period of 14 days prior to Cycle 1 Day 1 is required after the last dose of radiation therapy. 14. Received zanidatamab at any time prior to the current\n- 14. Received zanidatamab at any time prior to the current study.\n- 15. CRC participants with known KRAS/NRAS and BRAF mutations.\n- 16. NSCLC participants with known ALK, EGFR mutations and ROS1 fusion.\n- 17. Female participants who are breastfeeding or pregnant, and female and male participants planning a pregnancy.\n- 18. Prior or concurrent invasive malignancy other than the disease under study, whose natural history or treatment has, in the opinion of the investigator or medical monitor, the potential to interfere with the safety or efficacy assessment of the investigational regimen.\n- 2. Has uncontrolled or significant cardiovascular disease, including any of the following: a. History of myocardial infarction within 6 months before Cycle 1 Day 1. b. Troponin levels consistent with myocardial infarction as defined by the manufacturer’s specifications within 28 days prior to Cycle 1 Day 1. c. History of symptomatic congestive heart failure (New York Heart Association Class II to IV). d. To maintain the original protocol numbering list, this criterion was intentionally left blank. e. Ventricular arrhythmia requiring therapy.\n- 3. Has ongoing toxicity related to prior cancer therapy that has not recovered to Grade 1 (ie, ≤ Grade 1, CTCAE version 5.0 or higher) severity at the time of Cycle 1 Day 1, with the following exceptions: a. Alopecia. b. Neuropathy resolved or recovered and no higher than Grade 2 (ie, ≤ Grade 2) in severity at the time eligibility is assessed. c. Congestive heart failure that was no more than Grade 1 (ie, ≤ Grade 1) in severity at the time of occurrence and resolved completely.\n- 4. Has uncontrolled infection or requiring IV antibiotics, antivirals, or antifungals within 14 days of Cycle 1 Day 1.\n- 5. Has known HIV infection. Participants should be tested for HIV during the Screening Visit if required by local regulations or institutional review board/independent ethics committee.\n- 6. Has active hepatitis B or C infection. a. Participants who are hepatitis B surface antigen positive are eligible if they have hepatitis B virus deoxyribonucleic acid less than 500 IU/mL (<500 IU/mL). b. Participants positive for hepatitis C antibody are eligible only if polymerase chain reaction is negative for hepatitis C ribonucleic acid.\n- 7. Has an active SARS-CoV-2 infection. Participants with prior infection that has resolved per investigator opinion/local institutions’ requirements and screening guidance are eligible.\n- 8. Has a history of life-threatening hypersensitivity to mAbs or to recombinant proteins or excipients in the drug formulation of zanidatamab.\n- 9. Has any serious underlying medical or psychiatric condition that would impair the ability of the participant to receive or tolerate the planned treatment at the investigational site."}

Primary endpoints

• {"endpoint_text":"- cORR per ICR as assessed by RECIST version 1.1","definition_or_measurement_approach":"Assessed by independent central review (ICR) using RECIST version 1.1"}

Secondary endpoints

• {"endpoint_text":"- 1. DOR per ICR as assessed by RECIST version 1.1 • Investigator-assessed cORR and DOR per RECIST version 1.1 • ICR- and investigator-assessed (per RECIST version 1.1): − TTR − DCR − PFS • OS","definition_or_measurement_approach":"Duration of response (DOR) and other tumour response metrics assessed by ICR and investigator per RECIST v1.1; includes time to response (TTR), disease control rate (DCR), progression-free survival (PFS) and overall survival (OS)"}
• {"endpoint_text":"- 2. Frequency of TEAEs and SAEs as graded by • NCI CTCAE version 5.0 or higher • Frequency of dose reductions • Frequency of discontinuations of treatment due to TEAEs","definition_or_measurement_approach":"Safety assessed by frequency and severity of treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs) graded per NCI CTCAE v5.0; counts of dose reductions and treatment discontinuations due to TEAEs"}
• {"endpoint_text":"- 3. Serum concentrations of zanidatamab","definition_or_measurement_approach":"Pharmacokinetic assessment: measurement of serum zanidatamab concentrations"}
• {"endpoint_text":"- 4. Frequency, duration, and time of onset of anti-zanidatamab antibodies and neutralizing antibodies, if applicable","definition_or_measurement_approach":"Immunogenicity assessments: detection and characterization of anti-drug antibodies (ADAs) and neutralizing antibodies including frequency, duration and time of onset"}
• {"endpoint_text":"- 5. The frequency and severity of symptomatic AEs prior to first dose of study intervention and during the on-treatment period, based on the PRO-CTCAE and EORTC Item Library • The percent of all treated participants reporting each level of side-effect bother while on treatment, based on the FACIT-GP5 •The level of side-effect bother reported over time per participant, summarized as the percent of time on treatment with high side-effect bother, based on the FACIT-GP5","definition_or_measurement_approach":"Patient-reported outcomes: symptomatic AEs via PRO-CTCAE and EORTC items; patient-reported bother and summary metrics via FACIT-GP5"}

Spain

Earliest CTIS Part Ii Submission Date

05-09-2025

Latest Decision Or Authorization Date

27-04-2026

Processing Time Days

234

Number Of Sites

5

Number Of Participants

125

Primary sponsor

Full Name

Jazz Pharmaceuticals Ireland Limited

Organisation Type

Pharmaceutical company

Country Of Registered Address

Ireland

Contract research organisations

Name

Medpace Finland Oy

Responsibilities

cro

Name

Sarah Cannon Research Institute LLC

Responsibilities

cro

Third parties

• {"country":"China","full_name":"Bioclinica Shanghai Co. Ltd.","duties_or_roles":"Imaging","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Eresearchtechnology Inc.","duties_or_roles":"Imaging","organisation_type":"Pharmaceutical company"}
• {"country":"Germany","full_name":"Fisher Clinical Services GmbH","duties_or_roles":"site of EU importation","organisation_type":"Pharmaceutical company"}
• {"country":"Finland","full_name":"Medpace Finland Oy","duties_or_roles":"cro","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Guardant Health Inc.","duties_or_roles":"4","organisation_type":"Laboratory/Research/Testing facility"}
• {"country":"United States","full_name":"Transperfect Translations International Inc.","duties_or_roles":"translations","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Bioclinica Inc.","duties_or_roles":"Imaging","organisation_type":"Laboratory/Research/Testing facility"}
• {"country":"United Kingdom","full_name":"Exco Intouch Limited","duties_or_roles":"Imaging","organisation_type":"Non-Pharmaceutical company"}
• {"country":"United States","full_name":"Medidata Solutions Inc.","duties_or_roles":"eCOA (Clinical Outcome Assessment); 1; 7","organisation_type":"Non-Pharmaceutical company"}
• {"country":"Belgium","full_name":"ArtiQ","duties_or_roles":"Imaging","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Laboratory Corporation Of America Holdings","duties_or_roles":"4","organisation_type":"Laboratory/Research/Testing facility"}
• {"country":"Germany","full_name":"BioClinica GmbH","duties_or_roles":"Imaging","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Almac Clinical Technologies LLC","duties_or_roles":"3","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"EPL Pathology Archives LLC","duties_or_roles":"Sample Long Term Storage","organisation_type":"Laboratory/Research/Testing facility"}
• {"country":"Germany","full_name":"eResearchTechnology GmbH","duties_or_roles":"Imaging","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"EPL Pathology Archives LLC","duties_or_roles":"Sample Long Term Storage","organisation_type":"Laboratory/Research/Testing facility"}
• {"country":"United States","full_name":"Sarah Cannon Research Institute LLC","duties_or_roles":"cro","organisation_type":"Laboratory/Research/Testing facility"}
• {"country":"Switzerland","full_name":"Labcorp Central Laboratory Services SARL","duties_or_roles":"4; 5","organisation_type":"Pharmaceutical company"}
• {"country":"Switzerland","full_name":"Fisher Clinical Services GmbH","duties_or_roles":"Secondary packaging and labelling","organisation_type":"Pharmaceutical company"}