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

Phase 2 Study of ZW25 Plus First-line Combination Chemotherapy in HER2-Expressing Gastrointestinal (GI) Cancers, Including Gastroesophageal Adenocarcinoma (GEA), Biliary Tract Cancer (BTC), and Colorectal Cancer (CRC)

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).

Study Overview

• Status: Active, not recruiting
• Conditions: HER2-expressing Gastrointestinal Cancers, Including Gastroesophageal Adenocarcinoma, Biliary Tract Cancer, and Colorectal Cancer
• Intervention / Treatment: Drug: Cisplatin; Drug: Fluorouracil; Drug: Gemcitabine; Drug: Oxaliplatin; Drug: ZW25 (Zanidatamab); Drug: Leucovorin; Drug: Capecitabine; Drug: Bevacizumab

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.

• Study Type: Interventional
• Enrollment (Actual): 74
• Phase: Phase 2

Expanded Access

Available outside the clinical trial. See expanded access record.

Contacts and Locations

• Study Contact: Name: Clinical Trial Disclosure & Transparency; Phone Number: 215-832-3750; Email: ClinicalTrialDisclosure@JazzPharma.com

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5G 2C1
      • Princess Margaret Cancer Center
• Chile
  • Santiago, Chile, 8331143
    • CeCim Biocinetic
  • Santiago, Chile, 7500653
    • Centro de Estudios Clínicos SAGA SpA
  • Santiago, Chile, 8241479
    • Icegclinic Research & Care
  • Santiago, Chile, 8330008
    • Meditek Ltda
• Korea, Republic of
  • Busan, Korea, Republic of, 49241
    • Pusan National University
  • Seoul, Korea, Republic of, 03080
    • Seoul National University Hospital
  • Seoul, Korea, Republic of, 03722
    • Severance Hospital
  • Seoul, Korea, Republic of, 05505
    • Asan Medical Center
  • Seoul, Korea, Republic of, 02841
    • Korea University Anam Hospital
  • Gyeonggi-do
    • Seongnam-si, Gyeonggi-do, Korea, Republic of, 13620
      • Seoul National University Bundang Hospital
• United States
  • California
    • Los Angeles, California, United States, 90033
      • USC/Norris Comprehensive Cancer Center
  • Florida
    • Tampa, Florida, United States, 33612
      • H. Lee Moffitt Cancer Center
  • Illinois
    • Chicago, Illinois, United States, 60637
      • University of Chicago
  • Michigan
    • Kalamazoo, Michigan, United States, 49007
      • Cancer and Hematology Centers of Western Michigan
  • Nebraska
    • Omaha, Nebraska, United States, 68114
      • Nebraska Methodist Hospital
  • New York
    • New York, New York, United States, 10065
      • Memorial Sloan Kettering Cancer Center
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19111
      • Fox Chase Cancer Center
  • Tennessee
    • Nashville, Tennessee, United States, 37203
      • Sarah Cannon Research Institute
  • Texas
    • Houston, Texas, United States, 77030
      • MD Anderson Cancer Center
  • Washington
    • Seattle, Washington, United States, 98101
      • Virginia Mason Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion:

• 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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: ZW25 + FP; ZW25 plus fluorouracil (5-FU) and cisplatin	Drug: Cisplatin; Administered IV; Drug: Fluorouracil; Administered IV; Drug: 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
Experimental: ZW25 + mFOLFOX6; ZW25 plus 5-FU, leucovorin, and oxaliplatin	Drug: Fluorouracil; Administered IV; Drug: Oxaliplatin; Administered IV; Drug: 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; Drug: Leucovorin; Administered IV
Experimental: ZW25 + XELOX; ZW25 plus capecitabine and oxaliplatin	Drug: Oxaliplatin; Administered IV; Drug: 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; Drug: Capecitabine; Administered orally twice daily (PO bid)
Experimental: ZW25 + mFOLFOX6 with bevacizumab; ZW25 plus 5-FU, leucovorin, oxaliplatin, and bevacizumab	Drug: Fluorouracil; Administered IV; Drug: Oxaliplatin; Administered IV; Drug: 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; Drug: Leucovorin; Administered IV; Drug: Bevacizumab; Administered IV
Experimental: ZW25 + CisGem; ZW25 plus cisplatin and gemcitabine	Drug: Cisplatin; Administered IV; Drug: Gemcitabine; Administered IV

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective response rate (ORR) (Part 1)	Number of participants who achieved a best response of either CR or PR during treatment per RECIST 1.1	Up to 10 months
Disease control rate (Parts 1 and 2)	Number of participants who achieved a best response of CR, PR, or stable disease (SD) during treatment per RECIST 1.1	Up to 10 months
Duration of response (Parts 1 and 2)	Median duration of response (in months) and range (minimum, maximum)	Up to 2 years
Clinical benefit rate (Parts 1 and 2)	Number of participants with SD for ≥ 24 weeks or a confirmed, best overall response of CR or PR per RECIST 1.1	Up to 2 years
Progression-free survival (Parts 1 and 2)	Median progression-free survival (in months) and range (minimum, maximum)	Up to 2 years
Overall survival (Parts 1 and 2)	Median overall survival (in months) and range (minimum, maximum)	Up to 2 years
Incidence of anti-drug antibodies (ADAs) (Parts 1 and 2)	Number of participants who develop ADAs	Up to 11 months
End of infusion concentration of ZW25 (Parts 1 and 2)		Up to 11 months
Maximum serum concentration of ZW25 (Parts 1 and 2)		Up to 11 months
Trough concentration of ZW25 (Parts 1 and 2)		Up to 11 months
Incidence of adverse events (Part 2)	Number of participants who experienced an adverse event	Up to 11 months
Incidence of lab abnormalities (Part 2)	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 CTCAE, version 5.0.	Up to 11 months

Collaborators and Investigators

• Sponsor: Jazz Pharmaceuticals
• Investigators: Study Director: Phillip Garfin, MD, PhD, Jazz Pharmaceuticals

Study record dates

Study Major Dates

• Study Start (Actual): August 29, 2019
• Primary Completion (Estimated): November 28, 2025
• Study Completion (Estimated): October 30, 2026

Study Registration Dates

• First Submitted: February 22, 2019
• First Submitted That Met QC Criteria: April 23, 2019
• First Posted (Actual): April 29, 2019

Study Record Updates

• Last Update Posted (Actual): March 5, 2024
• Last Update Submitted That Met QC Criteria: March 4, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: Capecitabine; Colorectal cancer; HER2; Immunotherapy; Cisplatin; Chemotherapy; Extrahepatic cholangiocarcinoma; Oxaliplatin; 5-FU; Bispecific antibody; Biparatopic antibody; Biliary tract cancer; XELOX; FP; Intrahepatic cholangiocarcinoma; Gastroesophageal adenocarcinoma; Gastric cancers; Esophageal cancers; Gall bladder; Gastroesophageal junction (GEJ) cancers; mFOLFOX6; Leucovorin (folinic acid); Gastrointestinal cancers
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Carcinoma; Neoplasms, Glandular and Epithelial; Digestive System Neoplasms; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Biliary Tract Diseases; Colorectal Neoplasms; Adenocarcinoma; Gastrointestinal Neoplasms; Biliary Tract Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Protective Agents; Antineoplastic Agents, Immunological; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Micronutrients; Vitamins; Antidotes; Vitamin B Complex; Fluorouracil; Capecitabine; Oxaliplatin; Bevacizumab; Leucovorin; Gemcitabine
• Other Study ID Numbers: ZWI-ZW25-201

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No