A Safety and Efficacy Study of ZW25 (Zanidatamab) Plus Combination Chemotherapy in HER2-expressing Gastrointestinal Cancers, Including Gastroesophageal Adenocarcinoma, Biliary Tract Cancer, and Colorectal Cancer

NCT ID: NCT03929666

Last Updated: 2025-09-12

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 74 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2019-08-29
• Study Completion Date: 2025-08-30

Brief Summary

This is a multicenter, global, Phase 2, open-label, 2-part, first-line study to investigate the safety, tolerability, and anti-tumor activity of ZW25 (zanidatamab) plus standard first-line combination chemotherapy regimens for selected gastrointestinal (GI) cancers. Eligible patients include those with unresectable, locally advanced, recurrent or metastatic HER2-expressing gastroesophageal adenocarcinoma (GEA), biliary tract cancer (BTC), or colorectal cancer (CRC).

Detailed Description

Part 1 of the study will first evaluate the safety and tolerability of ZW25 plus standard first-line combination chemotherapy (XELOX, FP, or mFOLFOX6 for GEA; mFOLFOX6 with or without bevacizumab for CRC; and CisGem for BTC) and will confirm the recommended dosage (RD) of ZW25 when administered in combination with each of these multi-agent chemotherapy regimens. Then, Part 2 of the study will evaluate the anti-tumor activity of ZW25 plus combination chemotherapy in HER2-expressing GEA, BTC, and CRC.

Conditions

HER2-expressing Gastrointestinal Cancers, Including Gastroesophageal Adenocarcinoma, Biliary Tract Cancer, and Colorectal Cancer

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

ZW25 + FP

ZW25 plus fluorouracil (5-FU) and cisplatin

Group Type: EXPERIMENTAL

ZW25 (Zanidatamab)

Intervention Type: DRUG

• Part 1: administered IV at dose levels and schedules determined by the Safety Monitoring Committee (SMC)
• Part 2: RD identified in Part 1

Cisplatin

Intervention Type: DRUG

Administered IV

Fluorouracil

Intervention Type: DRUG

Administered IV

ZW25 + mFOLFOX6

ZW25 plus 5-FU, leucovorin, and oxaliplatin

Group Type: EXPERIMENTAL

ZW25 (Zanidatamab)

Intervention Type: DRUG

• Part 1: administered IV at dose levels and schedules determined by the Safety Monitoring Committee (SMC)
• Part 2: RD identified in Part 1

Fluorouracil

Intervention Type: DRUG

Administered IV

Leucovorin

Intervention Type: DRUG

Administered IV

Oxaliplatin

Intervention Type: DRUG

Administered IV

ZW25 + XELOX

ZW25 plus capecitabine and oxaliplatin

Group Type: EXPERIMENTAL

ZW25 (Zanidatamab)

Intervention Type: DRUG

• Part 1: administered IV at dose levels and schedules determined by the Safety Monitoring Committee (SMC)
• Part 2: RD identified in Part 1

Capecitabine

Intervention Type: DRUG

Administered orally twice daily (PO bid)

Oxaliplatin

Intervention Type: DRUG

Administered IV

ZW25 + mFOLFOX6 with bevacizumab

ZW25 plus 5-FU, leucovorin, oxaliplatin, and bevacizumab

Group Type: EXPERIMENTAL

ZW25 (Zanidatamab)

Intervention Type: DRUG

• Part 1: administered IV at dose levels and schedules determined by the Safety Monitoring Committee (SMC)
• Part 2: RD identified in Part 1

Fluorouracil

Intervention Type: DRUG

Administered IV

Leucovorin

Intervention Type: DRUG

Administered IV

Oxaliplatin

Intervention Type: DRUG

Administered IV

Bevacizumab

Intervention Type: DRUG

Administered IV

ZW25 + CisGem

ZW25 plus cisplatin and gemcitabine

Group Type: EXPERIMENTAL

Cisplatin

Intervention Type: DRUG

Administered IV

Gemcitabine

Intervention Type: DRUG

Administered IV

Interventions

ZW25 (Zanidatamab)

• Part 1: administered IV at dose levels and schedules determined by the Safety Monitoring Committee (SMC)
• Part 2: RD identified in Part 1

Intervention Type: DRUG

Capecitabine

Administered orally twice daily (PO bid)

Intervention Type: DRUG

Cisplatin

Administered IV

Intervention Type: DRUG

Fluorouracil

Administered IV

Intervention Type: DRUG

Leucovorin

Administered IV

Intervention Type: DRUG

Oxaliplatin

Administered IV

Intervention Type: DRUG

Bevacizumab

Administered IV

Intervention Type: DRUG

Gemcitabine

Administered IV

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• Disease diagnosis:

• Part 1:
• GEA: Unresectable, locally advanced, recurrent or metastatic HER2-expressing GEA (IHC 3+ or 2+ with or without gene amplification based upon local assessment or central assessment)
• BTC: Unresectable, locally advanced, recurrent or metastatic HER2-expressing BTC (including intrahepatic cholangiocarcinoma [ICC], extrahepatic cholangiocarcinoma [ECC], or gallbladder cancer [GBC]) (IHC 3+ with or without gene amplification; or IHC 0, 1+ or 2+ with gene amplification, based upon central assessment)
• CRC: Unresectable, locally advanced, recurrent or metastatic HER2-expressing CRC (IHC 3+ with or without gene amplification; or IHC 0, 1+ or 2+ with gene amplification, based upon central assessment). Patients will be required to be extended RAS (KRAS and NRAS) and BRAF wild-type based upon central assessment.
• Part 2:
• GEA: Unresectable, locally advanced, recurrent or metastatic HER2-expressing GEA (IHC 3+, or IHC 2+ and FISH+ by central assessment)
• BTC: Same as Part 1
• CRC: Same as Part 1
• Tumor measurements as per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1:

• Part 1: Measurable or non-measurable disease
• Part 2: Measurable disease
• An Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0 or 1
• Adequate organ function
• Adequate cardiac left ventricular function, as defined by a LVEF >/= institutional standard of normal

Exclusion:

• Prior treatment with a HER2-targeted agent
• Prior systemic anti-cancer therapy (including investigational products) except prior adjuvant/neoadjuvant therapy, which must be completed at least 6 months prior to first study treatment dosing. For subjects with BTC and CRC the following additional exceptions apply:

• BTC: patients may have started therapy for advanced disease but may not have received more than one cycle of any standard gemcitabine-based chemotherapy regimen.
• CRC: patients may have started therapy for advanced disease but may not have received more than one cycle of 5-FU-based chemotherapy (< 1 month of therapy).
• Patients with certain contraindications to bevacizumab cannot be enrolled on the mFOLFOX6-2 with bevacizumab arm.
• Palliative radiotherapy is allowed if completed at least 2 weeks prior to first study treatment dosing
• Untreated known brain metastases (patients with treated brain metastases who are off steroids, off antiseizure medications, and stable for at least 1 month at the time of screening are eligible)
• Clinically significant cardiac disease, such as ventricular arrhythmia requiring therapy, uncontrolled hypertension or any history of symptomatic congestive heart failure (CHF). Patients with known myocardial infarction or unstable angina within 6 months prior to randomization are also excluded.
• QTc Fridericia (QTcF) > 470 ms. For patients with longer QTcF on initial electrocardiogram (ECG), follow-up ECG may be performed in triplicate to determine eligibility
• Peripheral neuropathy > Grade 1 per NCI-CTCAE v5.0
• Clinically significant interstitial lung disease
• Prior or concurrent malignancy whose natural history or treatment has the potential to interfere with the safety or efficacy assessment of the investigational regimen
• Active hepatitis B or hepatitis C infection or infection with Human Immunodeficiency Virus (HIV)-1 or HIV-2 (Exception: patients with well controlled HIV [e.g., CD4 > 350/mm3 and undetectable viral load] are eligible)

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Jazz Pharmaceuticals

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Phillip Garfin, MD, PhD

Role: STUDY_DIRECTOR

Jazz Pharmaceuticals

Locations

USC/Norris Comprehensive Cancer Center

Los Angeles, California, United States

Hoag Memorial Hospital Presbyterian

Newport Beach, California, United States

H. Lee Moffitt Cancer Center

Tampa, Florida, United States

University of Chicago

Chicago, Illinois, United States

The Cancer and Hematology Centers

Grand Rapids, Michigan, United States

Nebraska Methodist Hospital

Omaha, Nebraska, United States

Memorial Sloan Kettering Cancer Center

New York, New York, United States

Fox Chase Cancer Center

Philadelphia, Pennsylvania, United States

Sarah Cannon Research Institute

Nashville, Tennessee, United States

MD Anderson Cancer Center

Houston, Texas, United States

Virginia Mason Medical Center

Seattle, Washington, United States

The Ottawa Hospital Cancer Centre

Ottawa, Ontario, Canada

Princess Margaret Cancer Center

Toronto, Ontario, Canada

Centro de Investigacion Clinica SAGA

Santiago, , Chile

Icegclinic Research & Care

Santiago, , Chile

CECIM Biocinetic

Santiago, , Chile

Centro Internacional de Estudios Clínicos

Santiago, , Chile

Seoul National University Bundang Hospital

Seongnam-si, Gyeonggi-do, South Korea

Pusan National University

Busan, , South Korea

Korea University Anam Hospital

Seoul, , South Korea

Seoul National University Hospital

Seoul, , South Korea

Severance Hospital

Seoul, , South Korea

Asan Medical Center

Seoul, , South Korea

Countries

United States; Canada; Chile; South Korea

References

Elimova E, Ajani J, Burris H, Denlinger CS, Iqbal S, Kang YK, Kim JH, Lee KW, Lin B, Mehta R, Oh DY, Rha SY, Seol YM, Yang L, Ozog MA, Garfin PM, Ku G. Zanidatamab plus chemotherapy as first-line treatment for patients with HER2-positive advanced gastro-oesophageal adenocarcinoma: primary results of a multicentre, single-arm, phase 2 study. Lancet Oncol. 2025 Jul;26(7):847-859. doi: 10.1016/S1470-2045(25)00287-6. Epub 2025 Jun 2.

Reference Type: DERIVED

PMID: 40473445 (View on PubMed)

Other Identifiers

ZWI-ZW25-201

Identifier Type: -

Identifier Source: org_study_id