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

Study Overview
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Brief Summary
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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
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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.

Official Title
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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)

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

Intervention / Treatment
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* Drug: ZW25 (Zanidatamab)
* Drug: Capecitabine
* Drug: Cisplatin
* Drug: Fluorouracil
* Drug: Leucovorin
* Drug: Oxaliplatin
* Drug: Bevacizumab
* Drug: Gemcitabine


Participation Criteria
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Eligibility Criteria
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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)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ZW25 + FP<br>ZW25 plus fluorouracil (5-FU) and cisplatin | Drug: ZW25 (Zanidatamab)<br>* Part 1: administered IV at dose levels and schedules determined by the Safety Monitoring Committee (SMC) Part 2: RD identified in Part 1<br>Drug: Cisplatin<br>* Administered IV<br>Drug: Fluorouracil<br>* Administered IV<br>|
| Experimental: ZW25 + mFOLFOX6<br>ZW25 plus 5-FU, leucovorin, and oxaliplatin | Drug: ZW25 (Zanidatamab)<br>* Part 1: administered IV at dose levels and schedules determined by the Safety Monitoring Committee (SMC) Part 2: RD identified in Part 1<br>Drug: Fluorouracil<br>* Administered IV<br>Drug: Leucovorin<br>* Administered IV<br>Drug: Oxaliplatin<br>* Administered IV<br>|
| Experimental: ZW25 + XELOX<br>ZW25 plus capecitabine and oxaliplatin | Drug: ZW25 (Zanidatamab)<br>* Part 1: administered IV at dose levels and schedules determined by the Safety Monitoring Committee (SMC) Part 2: RD identified in Part 1<br>Drug: Capecitabine<br>* Administered orally twice daily (PO bid)<br>Drug: Oxaliplatin<br>* Administered IV<br>|
| Experimental: ZW25 + mFOLFOX6 with bevacizumab<br>ZW25 plus 5-FU, leucovorin, oxaliplatin, and bevacizumab | Drug: ZW25 (Zanidatamab)<br>* Part 1: administered IV at dose levels and schedules determined by the Safety Monitoring Committee (SMC) Part 2: RD identified in Part 1<br>Drug: Fluorouracil<br>* Administered IV<br>Drug: Leucovorin<br>* Administered IV<br>Drug: Oxaliplatin<br>* Administered IV<br>Drug: Bevacizumab<br>* Administered IV<br>|
| Experimental: ZW25 + CisGem<br>ZW25 plus cisplatin and gemcitabine | Drug: Cisplatin<br>* Administered IV<br>Drug: Gemcitabine<br>* Administered IV<br>|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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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