Sponsor: Jazz Pharmaceuticals (industry)
Phase: 3
Start date: July 19, 2024
Planned enrollment: 286
No investigational drugs.
Goal: Evaluate whether adding zanidatamab to first-line cisplatin/gemcitabine (CisGem), with or without a PD-1/L1 inhibitor (durvalumab or pembrolizumab per local practice), improves efficacy and maintains acceptable safety in HER2-positive advanced biliary tract cancer, with a primary focus on PFS in IHC 3+ tumors.
Patients: Adults with histologically or cytologically confirmed HER2-positive biliary tract cancer (gallbladder cancer, intrahepatic or extrahepatic cholangiocarcinoma), unresectable or metastatic, ECOG 0–1, and adequate organ function. Patients may have received up to two cycles of first-line CisGem with or without durvalumab or pembrolizumab. Exclusions include prior HER2-targeted therapy; prior checkpoint inhibitors other than durvalumab or pembrolizumab; active brain metastases; significant autoimmune disease, ILD/pneumonitis, severe infections; recent investigational therapy; and certain non-adenocarcinoma histologies.
Design: Multicenter, open-label, randomized phase 3 study comparing zanidatamab plus standard-of-care versus standard-of-care alone. Allocation is randomized with efficacy assessed primarily in the IHC 3+ subset and secondarily in the overall HER2-positive population. Approximately 286 participants will be enrolled.
Treatments: Experimental arm: zanidatamab combined with CisGem and optional PD-1/L1 inhibitor (durvalumab or pembrolizumab per local regulations). Control arm: CisGem with optional durvalumab or pembrolizumab per standard-of-care. Zanidatamab is a humanized bispecific/bi-epitopic anti-HER2 monoclonal antibody that binds two distinct HER2 epitopes to enhance receptor clustering, internalization, and immune-mediated cytotoxicity. It has shown antitumor activity and manageable safety in early-phase studies across HER2-expressing solid tumors, including biliary tract cancer, with responses observed particularly in IHC 3+ disease. The standard CisGem backbone is the established first-line regimen in advanced BTC; durvalumab or pembrolizumab may be added per current practice and local approvals.
Outcomes: Primary: Progression-free survival in participants with IHC 3+ tumors. Key secondary: Overall survival in IHC 3+ tumors; PFS and OS in all randomized participants; confirmed objective response rate; duration of response; safety and treatment-emergent adverse events; zanidatamab pharmacokinetics and immunogenicity (Cmax and anti-drug antibodies). Patient-reported outcomes include time to definitive deterioration in physical function (EORTC QLQ-C30) and symptom domains relevant to BTC (EORTC QLQ-BIL21: pain, jaundice, abdominal pain, pruritus) in IHC 3+ and overall populations.
Burden on patient: Moderate. Treatment requires intravenous infusions of gemcitabine and cisplatin on a 21-day schedule, with optional durvalumab or pembrolizumab infusions, plus additional zanidatamab infusions in the experimental arm, increasing chair time and visit frequency relative to chemotherapy alone. Baseline and on-treatment tumor assessments per RECIST, routine labs, and monitoring for chemotherapy- and immunotherapy-related toxicities are standard; added burdens include HER2 central testing on archival or new biopsy tissue and pharmacokinetic/immunogenicity blood draws for zanidatamab over multiple cycles. No intensive phase 1-style PK schedules are described, and imaging frequency is expected to align with standard practice, so overall burden is higher than SOC alone but typical for a phase 3 combination trial.
Inclusion Criteria
1. Histologically- or cytologically-confirmed Biliary Tract Cancer (BTC), including Gallbladder Cancer (GBC), Intrahepatic Cholangiocarcinoma (ICC), or Extrahepatic Cholangiocarcinoma (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 Cisplatin and Gemcitabine (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.
4. HER2-positive disease (defined as IHC 3+; or IHC 2+/ ISH+) by IHC and in situ Hybridization (ISH) assay (in participants with IHC 2+ tumors) at a central laboratory on new biopsy tissue or archival tissue from the most recent biopsy.
5. Assessable (measurable or non-measurable) disease as defined by Response Evaluation Criteria in Solid Tumors Version 1.1 (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. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
8. Adequate organ function
9. Females of childbearing potential must have a negative pregnancy test result.
10. Females of childbearing potential and males with a partner of childbearing potential must be willing to use 2 methods of birth control.
Exclusion Criteria
1. Prior treatment with a HER2-targeted agent
2. Prior treatment with checkpoint inhibitors, other than durvalumab or pembrolizumab
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. Use of systemic corticosteroids.
5. Brain metastases
6. Severe chronic or active infections
7. History of allogeneic organ transplantation.
8. Active or prior autoimmune inflammatory conditions
9. History of interstitial lung disease or non-infectious pneumonitis.
10. Participation in another clinical trial with an investigational medicinal product within the last 3 months.
11. Females who are breastfeeding
12. Any other medical, social, or psychosocial factors that, in the opinion of the investigator, could impact safety or compliance with study procedures.
13. Use of phenytoin
Ciudad Autónoma de Buenos Aires (caba), Buenos Altes, C1199ABB, Argentina
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San Salvador de Jujuy, Jujuy Province, 4600, Argentina
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Dallas, Texas, 75390, United States
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