Prospective registration

An open-label randomized trial of the efficacy and safety of zanidatamab with standard-of-care therapy against standard of care therapy alone for advanced HER2 positive biliary tract cancer

An open-label randomized trial of the efficacy and safety of zanidatamab with standard-of-care therapy against standard of care therapy alone for advanced HER2 positive biliary tract cancer

Dongxue Liao 

Cheng Ying 

23F, No.1 Dongzhimen South Avenue, Dongcheng District, Beijing, 100007, China

No. 1018 Huguang Road, No. 1066 Jinhu Road, Changchun City, Jilin Province

PPD Pharmaceutical Development (Beijing) CO., LTD.

Jilin Cancer Hospital

Yes

Jilin Provincial Cancer Hospital Drug/device clinical research Ethics Review Committee

Zhang Ning

No. 1018 Huguang Road, No. 1066 Jinhu Road, Changchun City, Jilin Province

Jilin Cancer Hospital

No. 1018 Huguang Road, No. 1066 Jinhu Road, Changchun City, Jilin Province

Jazz Pharmaceuticals Ireland Limited（global）/BeiGene (Suzhou) Co., Ltd.(China)

locally advanced unresectable or metastatic BTC

Interventional study

N/A

Parallel 

Main purpose: 1. To compare the effectiveness of Zanidatamab combined with CisGem with or without PD-1/L1 inhibitors versus CisGem with or without PD-1/L1 inhibitors in advanced or metastatic HER2-positive BTC subjects Secondary purpose: 1. To further compare the effectiveness of Zanidatamab combined with CisGem with or without PD-1/L1 inhibitors versus CisGem with or without PD-1/L1 inhibitors 2. To evaluate the safety of Zanidatamab combined with CisGem with or without PD-1/L1 inhibitors compared with CisGem with or without PD-1/L1 inhibitors 3. Evaluation of pharmacokinetics (PK) of Zanidatamab combined with CisGem with or without PD-1/L1 inhibitors 4. To evaluate the immunogenicity of Zanidatamab combined with CisGem with or without PD 1/L1 inhibitors 5. To evaluate the effects of Zanidatamab combined with CisGem with or without PD-1/L1 inhibitors on physical function (PF) and patient-reported symptoms compared with CisGem with or without PD-1/L1 inhibitors Exploratory purpose: 1. To evaluate the sustained antitumor effects of Zanidatamab combined with CisGem with or without PD 1/L1 inhibitors after initiation of new therapy 2. Evaluate the utility of potential biomarkers that may be associated with the efficacy, resistance, and/or safety of Zanidatamab combined with CisGem with or without PD-1/L1 inhibitors 3. To compare the effects of Zanidatamab combined with CisGem with or without PD-1/L1 inhibitors versus CisGem with or without PD-1/L1 inhibitors on disease-related pain and the use of opioids for pain control 4. To evaluate the effects of Zanidatamab combined with CisGem with or without PD-1/L1 inhibitors and CisGem with or without PD-1/L1 inhibitors on patients' reported health-related quality of life 5. To evaluate the effects of Zanidatamab combined with CisGem with or without PD-1/L1 inhibitors versus CisGem with or without PD-1/L1 inhibitors on overall impressions of patient-reported disease change and severity 6. To compare the effects of Zanidatamab combined with CisGem with or without PD-1/L1 inhibitors versus CisGem with or without PD-1/L1 inhibitors on patient-reported distress perception of treatment side effects

1. Histologically- or cytologically-confirmed BTC, including GBC, ICC, or ECC. 2. Locally advanced unresectable or metastatic BTC and not eligible for curative resection, transplantation, or ablative therapies. 3. Received no more than 2 cycles of systemic therapy which is limited to gemcitabine and cisplatin with or without a PD-1/L1 inhibitor (physician’s choice of durvalumab or pembrolizumab, where approved under local regulations) for advanced unresectable or metastatic disease. Participants who have received prior adjuvant or neoadjuvant treatment (including investigational products) for earlier stage disease are permitted as long as therapy was completed more than 6 months prior to expected date of C1D1. 4. HER2-positive disease (defined as IHC 3+; or IHC 2+/ ISH+) by IHC and ISH assay (in participants with IHC 2+ tumors) at a central laboratory on new biopsy tissue or archival tissue from the most recent biopsy. Note that fine needle aspirates (FNAs; cytology samples) and biopsies from sites of bone metastases are not acceptable. Testing may occur with tissue obtained at any time after diagnosis of BTC and before expected date of randomization. a. When the central laboratory is available, samples must be sent to the central laboratory prior to randomization for determination of HER2 status. If it has been confirmed with the medical monitor that a central laboratory is not available, sites may use local testing for HER2 to enroll participants with IHC 3+ tumors. In this case, samples still must be sent to the central laboratory for confirmatory analyses once the central laboratory becomes available. 5. Assessable (measurable or non-measurable) disease as defined by RECIST 1.1, per investigator assessment. 6. Male or female >= 18 years or age (or the legal age of adulthood per country-specific regulations). 7. ECOG performance status of 0 or 1. 8. Adequate hematologic function as follows: a. Absolute neutrophil count (ANC) >= 1.5 × 109/L b. Platelet count ≥ 100 × 109/L, not requiring transfusion support c. Hemoglobin (Hgb) >= 9 g/dL (participants with chronic anemia that is supported by intermittent red blood cell transfusions are eligible); 9. Adequate hepatic function, as defined by both: a. Aspartate aminotransferase (AST) <= 3 × upper limit of normal (ULN), and alanine aminotransferase (ALT) <= 3 × ULN. For participants with liver involvement, AST and ALT <= 5 × ULN is acceptable. b. Total bilirubin <= 1.5 × ULN, or <= 3 × ULN for participants with Gilbert’s disease; 10. Adequate renal function, as defined by estimated glomerular filtration rate (GFR) > 50 mL/min per local institutional standard method. 11. Left ventricular ejection fraction >= 50% as determined by either echocardiogram or multiple gated acquisition scan (MUGA). 12. Females of childbearing potential must have a negative serum/plasma or urine beta human chorionic gonadotropin (β-hCG) pregnancy test result within 3 days prior to expected date of C1D1. Females with false positive results can be enrolled if subsequent serum/plasma testing is negative. 13. Females of childbearing potential and males with a partner of childbearing potential must be willing to use 2 methods of birth control with a failure rate of less than 1% per year (HMA-CTFG, 2020) during the study and for 14 months after the last dose of cisplatin, 6 months after the last dose of gemcitabine, 5 months after the last dose of zanidatamab, 4 months after the last dose of pembrolizumab, and 3 months after the last dose of durvalumab. 14. Females must agree to not donate oocytes starting at screening and throughout the study period, and for at least 14 months after the last dose of cisplatin, 6 months after the last dose of gemcitabine, 5 months after the last dose of zanidatamab, 4 months after the last dose of pembrolizumab, and 3 months after the last dose of durvalumab. 15. Males must agree to use condoms and not to donate sperm starting at screening and throughout the study period, and for at least 11 months after the last dose of cisplatin, 5 months after the last dose of zanidatamab, and 3 months after the last dose of gemcitabine. 16. Participant has life expectancy of greater than 3 months, in the opinion of the investigator. 17. The participant must provide written informed consent. Participants who elect to be pre-screened for HER2 status must provide a separate written informed consent for collection, storage, and analysis of the tumor tissue.

1. Subjects who have previously received HER2-targeted drug therapy for breast cancer, except those who completed HER2-targeted therapy for breast cancer > 5 years before diagnosis of BTC. 2. Prior checkpoint inhibitor therapy, except for use of duvaliuzumab or pembrolizumab as part of systemic therapy up to 2 cycles prior to the projected C1D1 date permitted under inclusion criteria 3. Exclusion checkpoint inhibitors include, but are not limited to, other anti-PD-1, anti-PD-L1, anti-cytotoxic T lymphocyte-associated antigen (CTLA-4) antibodies. 3. The following subtypes of BTC were excluded: small cell carcinoma, neuroendocrine tumor, lymphoma, sarcoma, mixed tumor histology, and mucinous cystic tumor found in the biliary tract. 4. Received radiotherapy within 2 weeks prior to the estimated C1D1 date. 5. Major surgery within 4 weeks before the estimated C1D1 date. 6. A lifetime total load of anthracyclines exceeding 360 mg/ m2 doxorubicin or its equivalent. 7. A systemic corticosteroid equivalent to a dose of > 10 mg/ day of prednisone has been used in the 2 weeks prior to the estimated C1D1 date. Topical, ocular, intra-articular, intranasal, and/or inhaled corticosteroids are permitted. 8. Brain metastases: The presence of untreated central nervous system (CNS) metastases, symptomatic CNS metastases, or radiation therapy for CNS metastases within 4 weeks prior to the expected C1D1 date. The presence of treated stable brain metastases (defined as the subject being off steroids and anticonvulsants and having a stable nervous system with no evidence of radiological progression for at least 4 weeks at the time of screening) was allowed. 9. Known history of pia meningeal disease (LMD) or persistent LMD. If imaging studies report LMD, but the investigator does not suspect LMD clinically, and the subject has no neurological symptoms of LMD, the subject will be eligible for study enrollment. 10. In the investigator's judgment, there were poorly controlled seizures. 11. Peripheral neuropathy of grade 2 or above is present. 12. Complications of uncontrolled or active hepatobiliary disease, or untreated or ongoing complications following laparoscopic surgery or stenting, including but not limited to active cholangitis, unresolved biliary obstruction, infectious biliomas, or abscesses. Any complications must resolve at least 2 weeks before the expected C1D1 date. 13. Have prior or concurrent aggressive malignancies whose natural course of disease or treatment, in the opinion of the investigator or medical monitor, may interfere with the evaluation of the safety or efficacy of the study protocol. 14. Severe chronic or active infections requiring systemic parenteral antimicrobial, antifungal, or antiviral treatment; Or any other potentially life-threatening viral or bacterial infection (subjects receiving oral antibiotics must complete the planned course of treatment by the estimated C1D1 date). 15. Active hepatitis includes the following diseases: a. Acute or chronic hepatitis B (exception: Subjects who are positive for hepatitis B surface antigen [HbsAg] and have less than 500 IU/mL or 2,500 copies /mL of hepatitis B virus [HBV]DNA are eligible for study enrollment). Note: Subjects with detectable HbsAg or HBVDNA should be managed according to institutional or local standards. Subjects starting antiviral drugs at the time of screening should be treated > 2 weeks prior to the expected C1D1 date. b. Hepatitis C infection (exceptions: [i] Subjects with no history of curative viral therapy and a documented negative viral load are eligible for study enrollment; [ii] Subjects with a negative viral load who completed curative viral therapy >= 12 weeks prior to the projected C1D1 date were eligible for study enrollment. 16. Human immunodeficiency virus (HIV)-1 or HIV-2 infection (exception: Subjects with well-controlled HIV [i.e., CD4 >350/mm3 and undetectable viral load] are eligible for study enrollment.) 17. Active tuberculosis. 18. History of allogeneic organ transplantation. 19. Have an active or pre-existing autoimmune inflammatory disease, except: a. vitiligo or hair loss b. Stable hypothyroidism after thyroid replacement therapy c. Chronic skin conditions that do not require systemic treatment d. Celiac disease controlled by diet alone e. No active disease in the past 5 years after treatment by the attending physician 20. A history of life-threatening hypersensitivity to monoclonal antibodies or recombinant proteins or to any excipients in investigational drug formulations (cisplatin, gemcitabine, selected PD-1/L1 inhibitors or Zanidatamab). 21. Known allergy to any component of combination therapy. 22. The persistence of clinically significant toxicity (grade 2 or above) associated with previous cancer treatment, except for hair loss. 23. QTc (QTcF) corrected by Fridericia formula > 470 ms. Note: For subjects with long QTcF on the first electrocardiogram (ECG), three parallel ECG follow-up sessions may be performed to determine eligibility for inclusion. 24. Clinically significant heart disease, such as ventricular arrhythmia requiring treatment, uncontrolled high blood pressure, or any history of symptomatic congestive heart failure (CHF). Participants who were known to have had a myocardial infarction or unstable angina in the 6 months prior to the projected C1D1 date were also excluded. If CHF associated with anticancer therapy occurs in the past, it must be <= grade 1 at the time of occurrence and must have completely resolved. 25. History of interstitial lung disease or non-infectious pneumonia. 26. History of active primary immunodeficiency. 27. Participated in a clinical trial of another investigational drug product within the previous 3 months. 28. Acute or chronic uncontrolled pancreatitis or Child-Pugh grade C liver disease. 29. Women who are breastfeeding or pregnant, and women and men who plan to become pregnant. 30. Any other medical, social or psychosocial factors which, in the opinion of the investigator, may affect safety or adherence to the study procedure.

Randomization will be centralized using an interactive response technology (IRT) system that will assign subjects a unique randomization number but will not indicate the actual treatment assignment.

Open-label study

None

CRF