An open-label randomized trial of zanidatamab for advanced HER2positive biliary tract cancer

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Jazz Pharmaceuticals Ireland Limited

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

12 Sep 2024 → ongoing

Decision date (initial)

2024-08-12

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Jazz Pharmaceuticals Ireland Limited

External identifiers

EU CT number

2023-508219-21-00

ClinicalTrials.gov

NCT06282575

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Others, Efficacy, Safety, Pharmacokinetic

Compare the efficacy of zanidatamab plus cisplatin plus gemcitabine (CisGem) with or without a programmed cell death 1 (PD-1) or programmed cell death ligand 1 (PDL1) inhibitor (PD-1/L1 inhibitor) versus CisGem with or without a PD1/L1inhibitor in participants with advanced or metastatic human epidermal growth factor receptor 2 (HER2)-positive (IHC 3+) biliary tract cancer (BTC)

Secondary objectives 7

1. Further, compare 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 (IHC 3+) BTC
2. Compare the efficacy of zanidatamab plus CisGem with or without a PD1/L1 inhibitor versus CisGem with or without a PD-1/L1 inhibitor in participants with HER2- positive BTC (IHC 3+; or IHC 2+/ISH+)
3. Further compare 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+)
4. Evaluate the safety of zanidatamab plus CisGem with or without a PD1/L1 inhibitor versus CisGem with or without a PD1/L1 inhibitor
5. Evaluate the pharmacokinetics (PK) of zanidatamab in combination with CisGem with or without a PD1/L1 inhibitor
6. Evaluate the immunogenicity of zanidatamab in combination with CisGem with or without a PD-1/L1 inhibitor
7. Evaluate 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 patient-reported physical functioning (PF) and BTC symptoms

Conditions and MedDRA coding

BTC - Biliary Tract Cancer

Study design 3 periods

Regulatory references

Scientific advice from competent authorities

European Medicines Agency

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 2

1. 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 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).
2. 7. 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 3

1. 1. 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.
2. 11. 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.)
3. 16. 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.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Progression-free survival (PFS) per the Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST 1.1) in the immunohistochemistry (IHC) 3+ subgroup

Secondary endpoints 11

1. Overall survival (OS) in the IHC 3+ subgroup
2. PFS per RECIST 1.1 in the overall population
3. OS in the overall population
4. Confirmed objective response rate (cORR) per RECIST 1.1
5. Duration of response (DOR) per RECIST 1.1
6. Frequency, severity, seriousness, and relatedness of treatment-emergent adverse events (AEs)
7. Serum concentrations of zanidatamab as a function of time post-dosing
8. Frequency, duration, and time of onset of antizanidatamab antibodies and neutralizing antibodies, if applicable, to zanidatamab
9. Time to definitive deterioration (TDD) from baseline in the IHC 3+ subgroup in patientreported global health status (GHS) score as measured by the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire – Core 30 (QLQC30)
10. TDD from baseline in the overall population in patientreported GHS score as measured by the EORTC QLQC30
11. Change from baseline in health economics and outcomes research/patient-reported outcome (HEOR/PRO) parameters using the EORTC QLQC30, Quality of Life Questionnaire – Cholangiocarcinoma and Gallbladder Cancer module (QLQ-BIL21), and 5level EuroQol5 Dimension (EQ-5D-5L)

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Auxiliary 4

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Jazz Pharmaceuticals Ireland Limited

Sponsor organisation

Jazz Pharmaceuticals Ireland Limited

Address

5th Floor, Waterloo Exchange, Waterloo Road Waterloo Exchange Waterloo Road

City

Dublin 4

Postcode

D04 E5W7

Country

Ireland

Scientific contact point

Organisation

Jazz Pharmaceuticals Ireland Limited

Contact name

Medical Monitor

Public contact point

Organisation

Jazz Pharmaceuticals Ireland Limited

Contact name

Medical Monitor

Third parties 4

Locations

10 EU/EEA countries · 67 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 115 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

12 submissions — initial application plus substantial / non-substantial modifications