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

Overview

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).

Full Title of Study: “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)”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Non-Randomized
    • Intervention Model: Parallel Assignment
    • Primary Purpose: Treatment
    • Masking: None (Open Label)
  • Study Primary Completion Date: November 28, 2025

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.

Interventions

  • 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)
  • Drug: Cisplatin
    • Administered IV
  • Drug: Fluorouracil
    • Administered IV
  • Drug: Leucovorin
    • Administered IV
  • Drug: Oxaliplatin
    • Administered IV
  • Drug: Bevacizumab
    • Administered IV
  • Drug: Gemcitabine
    • Administered IV

Arms, Groups and Cohorts

  • Experimental: ZW25 + FP
    • ZW25 plus fluorouracil (5-FU) and cisplatin
  • Experimental: ZW25 + mFOLFOX6
    • ZW25 plus 5-FU, leucovorin, and oxaliplatin
  • Experimental: ZW25 + XELOX
    • ZW25 plus capecitabine and oxaliplatin
  • Experimental: ZW25 + mFOLFOX6 with bevacizumab
    • ZW25 plus 5-FU, leucovorin, oxaliplatin, and bevacizumab
  • Experimental: ZW25 + CisGem
    • ZW25 plus cisplatin and gemcitabine

Clinical Trial Outcome Measures

Primary Measures

  • Incidence of dose-limiting toxicities (DLTs) (Part 1)
    • Time Frame: Up to 6 weeks
    • 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.
  • Incidence of adverse events (Part 1)
    • Time Frame: Up to 11 months
    • Number of participants who experienced an adverse event
  • Incidence of lab abnormalities (Part 1)
    • Time Frame: Up to 11 months
    • 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.
  • Objective response rate (ORR) (Part 2)
    • Time Frame: Up to 10 months
    • 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

Secondary Measures

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

Participating in This Clinical Trial

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)

Gender Eligibility: All

Minimum Age: 18 Years

Maximum Age: N/A

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • Jazz Pharmaceuticals
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Official(s)
    • Phillip Garfin, MD, PhD, Study Director, Jazz Pharmaceuticals

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