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

NCT03929666 | Completed Phase 2 FDA Drug

• 1 other identifier: ZWI-ZW25-201
• Study Type: interventional
• Target: 74
• Locations: 4 countries
• Sites: 23

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).

Conditions

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

Keywords

HER2; Bispecific antibody; Biparatopic antibody; Immunotherapy; Gastric cancers; Esophageal cancers; Gastroesophageal junction (GEJ) cancers; Chemotherapy; FP; mFOLFOX6; Capecitabine; Cisplatin; 5-FU; Leucovorin (folinic acid); Oxaliplatin; XELOX; Gastrointestinal cancers; Gastroesophageal adenocarcinoma; Biliary tract cancer; Colorectal cancer; Intrahepatic cholangiocarcinoma; Extrahepatic cholangiocarcinoma; Gall bladder

Outcome Measures

Primary Outcomes (4)

• Incidence of dose-limiting toxicities (DLTs) (Part 1)

  Number of participants who experienced a DLT. DLTs include adverse events considered to be related to study treatment, including the evaluated dose level of ZW25, any component or combination of the components of a chemotherapy regimen, or the combination of ZW25 plus a chemotherapy regimen.

  Up to 6 weeks

• Incidence of adverse events (Part 1)

  Number of participants who experienced an adverse event

  Up to 11 months

• Incidence of lab abnormalities (Part 1)

  Number of participants who experienced a maximum severity of Grade 3 or higher post-baseline laboratory abnormality, including either hematology and chemistry. Grades are defined using National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE), version 5.0.

  Up to 11 months

• Objective response rate (ORR) (Part 2)

  Number of participants who achieved a best response of either complete response (CR) or partial response (PR) during treatment according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1

  Up to 10 months

Secondary Outcomes (12)

• Objective response rate (ORR) (Part 1)

  Up to 10 months

• Disease control rate (Parts 1 and 2)

  Up to 10 months

• Duration of response (Parts 1 and 2)

  Up to 2 years

• Clinical benefit rate (Parts 1 and 2)

  Up to 2 years

• Progression-free survival (Parts 1 and 2)

  Up to 2 years

Study Arms (5)

ZW25 + FP

EXPERIMENTAL

ZW25 plus fluorouracil (5-FU) and cisplatin

Drug: ZW25 (Zanidatamab); Drug: Cisplatin; Drug: Fluorouracil

ZW25 + mFOLFOX6

EXPERIMENTAL

ZW25 plus 5-FU, leucovorin, and oxaliplatin

Drug: ZW25 (Zanidatamab); Drug: Fluorouracil; Drug: Leucovorin; Drug: Oxaliplatin

ZW25 + XELOX

EXPERIMENTAL

ZW25 plus capecitabine and oxaliplatin

Drug: ZW25 (Zanidatamab); Drug: Capecitabine; Drug: Oxaliplatin

ZW25 + mFOLFOX6 with bevacizumab

EXPERIMENTAL

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

Drug: ZW25 (Zanidatamab); Drug: Fluorouracil; Drug: Leucovorin; Drug: Oxaliplatin; Drug: Bevacizumab

ZW25 + CisGem

EXPERIMENTAL

ZW25 plus cisplatin and gemcitabine

Drug: Cisplatin; Drug: Gemcitabine

Interventions

ZW25 (Zanidatamab) DRUG

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

ZW25 + FP; ZW25 + XELOX; ZW25 + mFOLFOX6; ZW25 + mFOLFOX6 with bevacizumab

Capecitabine DRUG

Administered orally twice daily (PO bid)

ZW25 + XELOX

Cisplatin DRUG

Administered IV

ZW25 + CisGem; ZW25 + FP

Fluorouracil DRUG

Administered IV

ZW25 + FP; ZW25 + mFOLFOX6; ZW25 + mFOLFOX6 with bevacizumab

Leucovorin DRUG

Administered IV

ZW25 + mFOLFOX6; ZW25 + mFOLFOX6 with bevacizumab

Oxaliplatin DRUG

Administered IV

ZW25 + XELOX; ZW25 + mFOLFOX6; ZW25 + mFOLFOX6 with bevacizumab

Bevacizumab DRUG

Administered IV

ZW25 + mFOLFOX6 with bevacizumab

Gemcitabine DRUG

Administered IV

ZW25 + CisGem

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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)

Sponsors & Collaborators

• Jazz Pharmaceuticals: lead

Study Sites (23)

USC/Norris Comprehensive Cancer Center

Los Angeles, California, 90033, United States

Location

Hoag Memorial Hospital Presbyterian

Newport Beach, California, 92663, United States

Location

H. Lee Moffitt Cancer Center

Tampa, Florida, 33612, United States

Location

University of Chicago

Chicago, Illinois, 60637, United States

Location

The Cancer and Hematology Centers

Grand Rapids, Michigan, 49503, United States

Location

Nebraska Methodist Hospital

Omaha, Nebraska, 68114, United States

Location

Memorial Sloan Kettering Cancer Center

New York, New York, 10065, United States

Location

Fox Chase Cancer Center

Philadelphia, Pennsylvania, 19111, United States

Location

Sarah Cannon Research Institute

Nashville, Tennessee, 37203, United States

Location

MD Anderson Cancer Center

Houston, Texas, 77030, United States

Location

Virginia Mason Medical Center

Seattle, Washington, 98101, United States

Location

The Ottawa Hospital Cancer Centre

Ottawa, Ontario, K1H 8L6, Canada

Location

Princess Margaret Cancer Center

Toronto, Ontario, M5G 2C1, Canada

Location

Centro de Investigacion Clinica SAGA

Santiago, 7500653, Chile

Location

Icegclinic Research & Care

Santiago, 8241479, Chile

Location

CECIM Biocinetic

Santiago, 8320000, Chile

Location

Centro Internacional de Estudios Clínicos

Santiago, 8420383, Chile

Location

Seoul National University Bundang Hospital

Seongnam-si, Gyeonggi-do, 13620, South Korea

Location

Pusan National University

Busan, 49241, South Korea

Location

Korea University Anam Hospital

Seoul, 02841, South Korea

Location

Seoul National University Hospital

Seoul, 03080, South Korea

Location

Severance Hospital

Seoul, 03722, South Korea

Location

Asan Medical Center

Seoul, 05505, South Korea

Location

Related Publications (1)

• 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.

  PMID: 40473445 DERIVED

MeSH Terms

Conditions

Biliary Tract Neoplasms; Colorectal Neoplasms; Stomach Neoplasms; Esophageal Neoplasms; Neoplasms; Gastrointestinal Neoplasms; Cholangiocarcinoma

Interventions

zanidatamab; Capecitabine; Cisplatin; Fluorouracil; Leucovorin; Oxaliplatin; Bevacizumab; Gemcitabine

Condition Hierarchy (Ancestors)

Digestive System Neoplasms; Neoplasms by Site; Biliary Tract Diseases; Digestive System Diseases; Intestinal Neoplasms; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases; Stomach Diseases; Head and Neck Neoplasms; Esophageal Diseases; Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type

Intervention Hierarchy (Ancestors)

Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Uracil; Pyrimidinones; Deoxyribonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Chlorine Compounds; Inorganic Chemicals; Nitrogen Compounds; Platinum Compounds; Formyltetrahydrofolates; Tetrahydrofolates; Folic Acid; Pterins; Pteridines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Coenzymes; Enzymes and Coenzymes; Coordination Complexes; Organic Chemicals; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• Phillip Garfin, MD, PhD

  Jazz Pharmaceuticals

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR
• Expanded Access: Yes

Study Record Dates

• First Submitted: February 22, 2019
• First Posted: April 29, 2019
• Study Start: August 29, 2019
• Primary Completion: August 30, 2025
• Study Completion: August 30, 2025
• Last Updated: September 12, 2025

Record last verified: 2025-09

Data Sharing

• IPD Sharing: Will not share

Locations

CL (4); US (11); KR (6); CA (2)