An open-label randomized trial of zanidatamab for advanced HER2-positive biliary tract cancer

Phase 3

• Conditions: Health Condition 1: C249- Malignant neoplasm of biliary tract, unspecified

• Registration Number: CTRI/2024/08/072371
• Lead Sponsor: Jazz Pharmaceuticals Ireland Limited

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Last Update Posted: 19 August 2024

Recruitment & Eligibility

• Status: ot Yet Recruiting
• Sex: Not specified
• Target Recruitment: 0

Inclusion Criteria

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 with gemcitabine and a platinum agent (eg, CisGem or GEMOX) 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 and above, 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) greater than or equal to 1.5 × 10 (to the power of 9)/L

b. Platelet count greater than or equal to 100 × 10 (to the power of 9)/L, not requiring transfusion support

c. Hemoglobin (Hgb) greater than or equal to 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) less than or equal to 3 × upper limit of normal (ULN), and alanine

aminotransferase (ALT) less than or equal to 3 × ULN. For participants with liver involvement, AST

and ALT less than or equal to 5 × ULN is acceptable.

b. Total bilirubin less than or equal 1.5 × ULN, or less than or equal to 3 × ULN for participants with Gilbert’s disease

10. Adequate renal function, as defined by estimated glomerular filtration rate (GFR) greater than 50 mL/min per local institutional standard method.

11. Left ventricular ejection fraction greater than or equal to 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 (ß-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. <br/

Exclusion Criteria

1. Prior treatment with a HER2-targeted agent, with the exception of participants who completed HER2-targeted treatment for breast cancer greater than 5 years prior to their diagnosis of BTC.

2. Prior treatment with check point inhibitors, other than durvalumab or pembrolizumab as part of the up to 2 cycles of systemic therapy allowed prior to expected date of C1D1 per Inclusion Criterion 3. Exclusionary checkpoint inhibitors include, but are not limited to

anti-PD-1, anti-PD-L1, anti-cytotoxic 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 expected date of C1D1.

5. Had major surgery within 4 weeks of expected date of C1D1.

6. Total lifetime load of anthracycline exceeding 360 mg/m2 doxorubicin or equivalent.

7. Use of systemic corticosteroids administered at doses equivalent to greater than 10 mg per day of prednisone within 2 weeks of expected date of C1D1. 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 expected date of C1D1. 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.

11. Grade 2 or greater peripheral neuropathy.

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 expected date of C1D1.

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 expected date of C1D1).

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 greater than 2 weeks p

Study & Design

• Study Type: Interventional
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Progression-free survival (PFS) per the Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST 1.1) in the immunohistochemistry (IHC) 3+ subgroupTimepoint: The time from the date of randomization to the date of documented disease progression (per RECIST 1.1) per investigator, or death from any cause