A Safety and Efficacy Study of ZW25 (Zanidatamab) Plus Combination Chemotherapy in HER2-expressing Gastroesophageal Adenocarcinoma

• ClinicalTrials.gov Identifier: NCT03929666
• Recruitment Status: Recruiting
• First Posted: April 29, 2019
• Last Update Posted: October 19, 2020
• Sponsor: Zymeworks Inc.
• Information provided by (Responsible Party): Zymeworks Inc.

Study Description

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 physician's choice of combination chemotherapy in HER2-expressing gastroesophageal adenocarcinoma (GEA). Eligible patients include those with unresectable, locally advanced, recurrent or metastatic HER2-expressing GEA.

Condition or disease	Intervention/treatment	Phase
HER2-expressing Gastroesophageal Adenocarcinoma	Drug: ZW25 (Zanidatamab); Drug: Capecitabine; Drug: Cisplatin; Drug: Fluorouracil; Drug: Leucovorin; Drug: Oxaliplatin	Phase 2

Expanded Access : An investigational treatment associated with this study is available outside the clinical trial.   More info ...

Detailed Description:

Part 1 of the study will first evaluate the safety and tolerability of ZW25 plus physician's choice of first-line combination chemotherapy (FP, mFOLFOX6, or XELOX) 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 physician's choice of combination chemotherapy in HER2-high GEA.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 146 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase 2 Study of ZW25 Plus First-line Combination Chemotherapy in HER2-Expressing Gastroesophageal Adenocarcinoma (GEA)
• Actual Study Start Date: August 29, 2019
• Estimated Primary Completion Date: February 28, 2022
• Estimated Study Completion Date: January 31, 2023

Arms and Interventions

Arm	Intervention/treatment
Experimental: ZW25 + FP; ZW25 plus fluorouracil (5-FU) and cisplatin	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: Cisplatin; Administered IV; Drug: Fluorouracil; Administered IV
Experimental: ZW25 + mFOLFOX6; ZW25 plus 5-FU, leucovorin, and oxaliplatin	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: Fluorouracil; Administered IV; Drug: Leucovorin; Administered IV; Drug: Oxaliplatin; Administered IV
Experimental: ZW25 + XELOX; ZW25 plus capecitabine and oxaliplatin	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: Oxaliplatin; Administered IV

Outcome Measures

Primary Outcome Measures :

1. 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.
2. Incidence of adverse events (Part 1) [ Time Frame: Up to 11 months ]
   Number of participants who experienced an adverse event
3. 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.
4. 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 Outcome Measures :

1. 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
2. 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
3. Duration of response (Parts 1 and 2) [ Time Frame: Up to 2 years ]
   Median duration of response (in months) and range (minimum, maximum)
4. 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
5. Progression-free survival (Parts 1 and 2) [ Time Frame: Up to 2 years ]
   Median progression-free survival (in months) and range (minimum, maximum)
6. Overall survival (Parts 1 and 2) [ Time Frame: Up to 2 years ]
   Median overall survival (in months) and range (minimum, maximum)
7. Incidence of anti-drug antibodies (ADAs) (Parts 1 and 2) [ Time Frame: Up to 11 months ]
   Number of participants who develop ADAs
8. End of infusion concentration of ZW25 (Parts 1 and 2) [ Time Frame: Up to 11 months ]
9. Maximum serum concentration of ZW25 (Parts 1 and 2) [ Time Frame: Up to 11 months ]
10. Trough concentration of ZW25 (Parts 1 and 2) [ Time Frame: Up to 11 months ]
11. Incidence of adverse events (Part 2) [ Time Frame: Up to 11 months ]
    Number of participants who experienced an adverse event
12. 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.

Eligibility Criteria

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

Criteria

Inclusion:

• Disease diagnosis:

  • Part 1: 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)
  • Part 2: Unresectable, locally advanced, recurrent or metastatic HER2-high GEA (IHC 3+, or IHC 2+ and FISH+ by central review)

• 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
• Treatment for GEA with prior 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. 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 anti-seizure medications, and stable for at least 1 month at the time of screening are eligible)
• Having clinically significant cardiac disease or known myocardial infarction or unstable angina (within 6 months before first study treatment dosing)
• QTc Fridericia (QTcF) > 470 ms for females and > 450 ms for males
• 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 other known chronic liver disease 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.)

Contacts and Locations

Contacts

Contact: Zymeworks Clinical Trial Resource; (206) 237-1030; medinfo@zymeworks.com

Locations

United States, California

USC/Norris Comprehensive Cancer Center; Recruiting

Los Angeles, California, United States, 90033

Principal Investigator: Syma Iqbal, MD

United States, Florida

H. Lee Moffitt Cancer Center; Recruiting

Tampa, Florida, United States, 33612

Contact: Rutika Mehta, MD

United States, New York

Memorial Sloan Kettering Cancer Center; Recruiting

New York, New York, United States, 10065

Principal Investigator: Geoffrey Ku, MD

United States, Pennsylvania

Fox Chase Cancer Center; Recruiting

Philadelphia, Pennsylvania, United States, 19111

Principal Investigator: Crystal Denlinger, MD

United States, Tennessee

Sarah Cannon Research Institute; Recruiting

Nashville, Tennessee, United States, 37203

Principal Investigator: Johanna Bendell, MD

United States, Texas

MD Anderson Cancer Center; Recruiting

Houston, Texas, United States, 77030

Principal Investigator: Jaffer Ajani, MD

United States, Washington

Virginia Mason Medical Center; Recruiting

Seattle, Washington, United States, 98101

Principal Investigator: Bruce Lin, MD

Canada, Ontario

The Ottawa Hospital Cancer Centre; Recruiting

Ottawa, Ontario, Canada, K1H 8L6

Principal Investigator: Rachel Goodwin, MD

Princess Margaret Cancer Center; Recruiting

Toronto, Ontario, Canada, M5G 2C1

Principal Investigator: Elena Elimova, MD

Korea, Republic of

Seoul National University Bundang Hospital; Recruiting

Seongnam-si, Gyeonggi-do, Korea, Republic of, 13620

Principal Investigator: Keun-Wook Lee, MD, PhD

Pusan National University; Recruiting

Busan, Korea, Republic of, 49241

Principal Investigator: Young Mi Seol, MD, PhD

Korea University Anam Hospital; Recruiting

Seoul, Korea, Republic of, 02841

Principal Investigator: Yeul Hong Kim, MD, PhD

Seoul National University Hospital; Recruiting

Seoul, Korea, Republic of, 03080

Principal Investigator: Do-Youn Oh, MD, PhD

Severance Hospital; Recruiting

Seoul, Korea, Republic of, 03722

Principal Investigator: Sun Young Rha, MD, PhD

Asan Medical Center; Recruiting

Seoul, Korea, Republic of, 05505

Principal Investigator: Yoon-Koo Kang, MD, PhD

Sponsors and Collaborators

Zymeworks Inc.

Investigators

• Study Director: Jonathan Grim, MD, PhD; Zymeworks Inc.

More Information

• Responsible Party: Zymeworks Inc.
• ClinicalTrials.gov Identifier: NCT03929666
• Other Study ID Numbers: ZWI-ZW25-201
• First Posted: April 29, 2019
• Last Update Posted: October 19, 2020
• Last Verified: October 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Zymeworks Inc.:

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

Additional relevant MeSH terms:

Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Leucovorin; Cisplatin; Fluorouracil; Capecitabine; Oxaliplatin; Antineoplastic Agents; Antimetabolites; Molecular Mechanisms of Pharmacological Action; Antimetabolites, Antineoplastic; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; Antidotes; Protective Agents; Vitamin B Complex; Vitamins; Micronutrients; Nutrients; Growth Substances