Efficacy and Safety of Zanidatamab with Cisplatin and Gemcitabine in Advanced HER2-Positive Biliary Tract Cancer: A Randomized Controlled Trial
- Trial ID
- 2023-508219-21-00
- Protocol
- JZP598-302
Trial statistics
Objectives
The primary objective of this study is to compare the **efficacy** of zanidatamab in combination with cisplatin and gemcitabine (CisGem), with or without a programmed cell death 1 (PD-1) or programmed cell death ligand 1 (PD-L1) inhibitor, against CisGem with or without a PD-1/L1 inhibitor in participants with advanced or metastatic human epidermal growth factor receptor 2 (HER2)-positive (IHC 3+) **biliary tract cancer** (BTC). This comparison is clinically relevant as it aims to determine the potential benefits of adding zanidatamab to the standard-of-care therapy, which could lead to improved treatment outcomes for patients with this aggressive cancer type.
Secondary objectives include:
- Comparing the efficacy of zanidatamab plus CisGem with or without a PD-1/L1 inhibitor versus CisGem with or without a PD-1/L1 inhibitor in participants with HER2-positive BTC (IHC 3+; or IHC 2+/ISH+).
- Evaluating the safety of zanidatamab plus CisGem with or without a PD-1/L1 inhibitor versus CisGem with or without a PD-1/L1 inhibitor.
- Assessing the pharmacokinetics (PK) of zanidatamab in combination with CisGem with or without a PD-1/L1 inhibitor.
- Evaluating the immunogenicity of zanidatamab in combination with CisGem with or without a PD-1/L1 inhibitor.
- Assessing the effect of zanidatamab plus CisGem with or without a PD-1/L1 inhibitor versus CisGem with or without a PD-1/L1 inhibitor on physical functioning and patient-reported symptoms.
Participants
The clinical trial involves a total of **154 participants** diagnosed with **biliary tract cancer (BTC)**, specifically targeting those with advanced or metastatic human epidermal growth factor receptor 2 (HER2)-positive disease. The study population includes both male and female subjects aged **18 years and older**, reflecting a diverse age range. Participants were selected based on specific criteria, including a confirmed diagnosis of BTC and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, indicating they are in relatively good health despite their condition. The trial does not exclude based on gender, and both males and females are included. Participants are required to have adequate hematologic, hepatic, and renal function, and a life expectancy of more than three months. Lifestyle considerations such as diet and physical activity are not specified, but participants must adhere to strict contraceptive measures during and after the trial. The trial population includes individuals who are considered vulnerable, ensuring comprehensive representation within the study. The selection process ensures that participants have not received more than two cycles of systemic therapy for advanced disease, maintaining the integrity of the study's objectives.
Plans and Procedures
The clinical trial is designed to evaluate the efficacy and safety of **zanidatamab** in combination with standard-of-care therapy compared to standard-of-care therapy alone in patients with advanced HER2-positive biliary tract cancer. This is an open-label, randomized, controlled trial. The study will involve multiple investigational products, including **pembrolizumab**, **cisplatin**, **durvalumab**, and **gemcitabine**, all administered via intravenous infusion. The trial is expected to commence recruitment on September 8, 2024, and conclude by November 30, 2029, with a maximum treatment period of 18 months for zanidatamab.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as histologically-confirmed biliary tract cancer, HER2-positive status, and adequate organ function. Following randomization, participants will attend regular follow-up visits to monitor treatment response and adverse events. The primary endpoint is progression-free survival, assessed using RECIST 1.1 criteria. Secondary endpoints include overall survival, objective response rate, and treatment-emergent adverse events. The end-of-study visit will occur after the final treatment cycle or upon early termination.
Participant involvement is anticipated to last up to 18 months, depending on the treatment arm and individual response. Conditions that may lead to early termination include disease progression, unacceptable toxicity, or withdrawal of consent. The trial will adhere to rigorous ethical standards, ensuring informed consent and participant safety throughout the study duration.
Treatment
The clinical trial involves the administration of several treatments, including both experimental and non-experimental medications. The primary experimental medication is **Zanidatamab**, marketed under the name JZP598. It is provided as a **powder for concentrate for solution for infusion**. The maximum daily dose is 2400 mg, with a total maximum dose of 14400 mg over a treatment period of up to 18 months. The administration route is via **solution for infusion**. This medication is classified as a biological product and is over-labelled for clinical trial use.
**Pembrolizumab**, marketed as KEYTRUDA, is used as a non-experimental treatment. It is available as a **25 mg/mL concentrate for solution for infusion**. The maximum daily dose is 200 mg, with a total maximum dose of 1200 mg over a treatment period of up to 18 months. The administration is through **intravenous administration**. This product is over-labelled for clinical trial use.
**Cisplatin**, marketed as Cisplatinum Accord, is another non-experimental treatment. It is provided as a **1 mg/mL concentrate for solution for infusion**. The maximum daily dose is 25 mg/m², with a total maximum dose of 400 mg/m² over a treatment period of up to 6 months. The administration route is via **intravenous infusion**. This product is over-labelled for clinical trial use.
**Durvalumab**, marketed as IMFINZI, is also used in the study. It is available as a **50 mg/mL concentrate for solution for infusion**. The maximum daily dose is 1500 mg, with a total maximum dose of 9000 mg over a treatment period of up to 18 months. The administration is through **intravenous administration**. This product is over-labelled for clinical trial use.
**Gemcitabine**, marketed as Gemcitabin Hikma, is included as a non-experimental treatment. It is provided as a **38 mg/mL concentrate for solution for infusion**. The maximum daily dose is 1000 mg/m², with a total maximum dose of 16000 mg/m² over a treatment period of up to 6 months. The administration route is via **intravenous administration**. This product is over-labelled for clinical trial use.
Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the prescribed treatment regimens. All medications are administered in accordance with the study protocol, and any deviations are documented and addressed as per clinical trial guidelines.
Efficacy
Efficacy in this clinical trial will be assessed using several primary and secondary endpoints. The primary endpoint is **progression-free survival (PFS)** as per the Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST 1.1) in the immunohistochemistry (IHC) 3+ subgroup. Secondary endpoints include overall survival (OS) in the IHC 3+ subgroup, PFS per RECIST 1.1 in the overall population, OS in the overall population, confirmed objective response rate (cORR) per RECIST 1.1, and duration of response (DOR) per RECIST 1.1. Additionally, the trial will evaluate the frequency, severity, seriousness, and relatedness of treatment-emergent adverse events (AEs), as well as serum concentrations of zanidatamab over time post-dosing.
Further assessments will include the frequency, duration, and time of onset of antizanidatamab antibodies and neutralizing antibodies, if applicable, to zanidatamab. Patient-reported outcomes will be measured using the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire – Core 30 (QLQC30) to determine the time to definitive deterioration (TDD) from baseline in the IHC 3+ subgroup and the overall population. Changes from baseline in health economics and outcomes research/patient-reported outcome (HEOR/PRO) parameters will also be evaluated using the EORTC QLQC30, Quality of Life Questionnaire – Cholangiocarcinoma and Gallbladder Cancer module (QLQ-BIL21), and the 5-level EuroQol-5 Dimension (EQ-5D-5L).
Inclusion and Exclusion Criteria
Inclusion Criteria
- 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 CisGem 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 (See Section 7.1). Note that fine needle aspirates (FNAs; which obtain only cytology samples), cytology samples, brushings, and biopsies from sites of bone metastases are not acceptable. Biopsies obtained with a needle that provides intact tissue sample may be acceptable. Testing may occur with tissue obtained at any time after diagnosis of BTC and before randomization. 5. Assessable (measurable or non-measurable) disease as defined by RECIST 1.1, per investigator assessment. 6. Male or female ≥ 18 years of age (or the legal age of adulthood per country-specific regulations).
- Eastern Cooperative Oncology Group (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 (LVEF) ≥ 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 (72 hours) prior to randomization. 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-(HMA-CTCG, 2024)) during the study and for 14 months after the last dose of cisplatin, 6 months after the last dose of gemcitabine, 4 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, 4 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, 4 months after the last dose of zanidatamab, and 6 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.
Exclusion Criteria
- Prior treatment with a HER2-targeted agent, with the exception of participants who completed HER2targeted treatment for breast cancer > 5 years prior to their diagnosis of BTC. 2. Prior treatment with checkpoint inhibitors, other than durvalumab or pembrolizumab as part of the up to 2 cycles of systemic therapy allowed prior to randomization per Inclusion Criterion 3. Exclusionary checkpoint inhibitors include but are not limited to other anti-PD-1, anti-PD-L1, anticytotoxic T lymphocyte-associated antigen (CTLA)-4 antibodies. 3. The following BTC histologic subtypes are excluded: small cell cancer, neuroendocrine tumors, lymphoma, sarcoma, mixed tumor histology, and mucinous cystic neoplasms detected in the biliary tract region. 4. Received radiotherapy within 2 weeks of randomization. 5. Had major surgery within 4 weeks of randomization. 6. Total lifetime load of anthracycline exceeding 360 mg/m2 doxorubicin or equivalent. 7. Use of systemic corticosteroids administered at doses equivalent to > 10 mg per day of prednisone within 2 weeks of randomization. Topical, ocular, intra-articular, intranasal, and/or inhalation corticosteroids are permitted. 8. Brain metastases: Untreated central nervous system (CNS) metastases, symptomatic CNS metastases, or radiation treatment for CNS metastases within 4 weeks of randomization. Stable, treated brain metastases are allowed (defined as participants who are off steroids and anticonvulsants and are neurologically stable with no evidence of radiographic progression for at least 4 weeks at the time of screening). 9. Known history of or ongoing leptomeningeal disease (LMD). Participants will be eligible if LMD has been reported radiographically but is not suspected clinically by the investigator, and the participant does not have neurological symptoms of LMD. 10. Poorly controlled seizures in the judgment of the investigator.
- Grade 2 or greater peripheral neuropathy that is related to prior cancer therapy. 12. Concurrent uncontrolled or active hepatobiliary disorders or untreated or ongoing complications after laparoscopic procedures or stent placement, including but not limited to active cholangitis, unresolved biliary obstruction, infected biloma, or abscess. Any complications must be resolved at least 2 weeks prior to randomization. 13. Prior or concurrent invasive malignancy 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. 14. Severe chronic or active infections requiring systemic parenteral antibacterial, antifungal or antiviral therapy; or any other potentially life-threatening viral or bacterial infection (participants on oral antibiotics must complete the planned course of treatment prior to randomization). 15. Active hepatitis, including the following: a. Acute or chronic hepatitis B (Exception: Participants who are hepatitis B surface antigen [HBsAg] positive are eligible if they have hepatitis B virus (HBV) DNA less than 500 IU/mL or 2,500 copies/mL). Note: Participants with detectable HBsAg or detectable HBV DNA should be managed per institutional or local standards. Participants beginning antiviral agents at screening should be treated for > 2 weeks prior to randomization. b. Infection with hepatitis C (Exceptions: [i] Participants who have no history of curative viral treatment and are documented to be viral load negative are eligible; [ii] Participants who have completed curative viral therapy ≥ 12 weeks or on concurrent hepatitis C virus treatment prior to expected date of C1D1, and viral load is negative are eligible.)
- Infection with human immunodeficiency virus (HIV)-1 or HIV-2. (Exception: Participants with wellcontrolled HIV [ie, CD4 > 350/mm3 and undetectable viral load] are eligible.) 17. Active tuberculosis (TB). 18. History of allogeneic organ transplantation. 19. Active autoimmune disease that has required systemic treatment in past 2 years (ie, with use of disease-modifying agents, corticosteroids, or immunosuppressive drugs) with the exception of: a. Vitiligo or alopecia b. Endocrine disorders stable on replacement therapy (thyroxine, insuline, etc) c. Chronic skin conditions that do not require systemic therapy d. Celiac disease controlled by diet alone e. Primary sclerosing cholangitis Note: Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc) is not considered a form of systemic treatment of the autoimmune disease and is allowed. 20. History of life-threatening hypersensitivity to monoclonal antibodies or to recombinant proteins or excipients in the drug formulation of any of the agents in the trial (cisplatin, gemcitabine, the selected PD1/L1 inhibitor, or zanidatamab). 21. Known hypersensitivity to any components of the combination therapy. 22. Ongoing, clinically significant toxicity (Grade 2 or higher) associated with prior cancer therapies, with the exception of alopecia. 23. Clinically significant cardiac disease, such as ventricular arrhythmia requiring therapy, uncontrolled hypertension or any history of symptomatic congestive heart failure (CHF). Participants with known myocardial infarction or unstable angina within 6 months (180 days) prior to randomization are also excluded. Previous anticancer therapy-related CHF must have been ≤ Grade 1 at the time of occurrence and must have completely resolved. 24. History of interstitial lung disease or non-infectious pneumonitis. 25. History of active primary immunodeficiency. 26. Participation in another clinical trial with an investigational medicinal product within the last 3 months (90 days). 27. Acute or chronic uncontrolled pancreatitis or Child-Pugh Class C liver disease. 28. Females who are breastfeeding or pregnant, and females and males planning a pregnancy. 29. Any other medical, social, or psychosocial factors (eg, hearing impairment) that, in the opinion of the investigator, could impact safety or compliance with study procedures. 30. Use of prophylactic phenytoin.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Belgium | Not Recruiting | 08 Sept 2024 | 23 |
 Czechia | Not Recruiting | 08 Sept 2024 | 4 |
 Finland | Not Recruiting | 08 Sept 2024 | 3 |
 France | Recruiting | 08 Sept 2024 | 16 |
 Germany | Recruiting | 08 Sept 2024 | 10 |
 Italy | Recruiting | 08 Sept 2024 | 10 |
 Portugal | Recruiting | 08 Sept 2024 | 5 |
 Romania | Not Recruiting | 08 Sept 2024 | 4 |
 Spain | Recruiting | 08 Sept 2024 | 15 |
 Sweden | Not Recruiting | 08 Sept 2024 | 3 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
PEMBROLIZUMAB | Other | PHF00231MIG | INTRAVENOUS ADMINISTRATION | 200 | 18 | SCP150816110 |
Gemcitabin Hikma 38 mg/ml Konzentrat zur Herstellung einer Infusionslösung | Other | KONZENTRAT ZUR HERSTELLUNG EINER INFUSIONSLÖSUNG | INTRAVENOUS ADMINISTRATION | 1000 | 6 | PRD8684466 |
IMFINZI 50 mg/mL concentrate for solution for infusion. | Other | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS ADMINISTRATION | 1500 | 18 | PRD6651406 |
Cisplatinum Accord, 1 mg/ml, koncentrat do sporządzania roztworu do infuzji. | Other | KONCENTRAT DO SPORZADZANIA ROZTWORU DO INFUZJI | INTRAVENOUS INFUSION | 25 | 6 | PRD1951611 |
JZP598 | Test | POWDER FOR CONCENTRATE FOR SOLUTION FOR INFUSION | SOLUTION FOR INFUSION | 2400 | 18 | PRD10444188 |