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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

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ClinicalTrials.gov Identifier: NCT03929666
Recruitment Status : Recruiting
First Posted : April 29, 2019
Last Update Posted : August 11, 2021
Sponsor:
Information provided by (Responsible Party):
Zymeworks Inc.

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).

Condition or disease Intervention/treatment Phase
HER2-expressing Gastrointestinal Cancers, Including Gastroesophageal Adenocarcinoma, Biliary Tract Cancer, and Colorectal Cancer Drug: ZW25 (Zanidatamab) Drug: Capecitabine Drug: Cisplatin Drug: Fluorouracil Drug: Leucovorin Drug: Oxaliplatin Drug: Bevacizumab Drug: Gemcitabine 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 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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 362 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 Gastrointestinal (GI) Cancers, Including Gastroesophageal Adenocarcinoma (GEA), Biliary Tract Cancer (BTC), and Colorectal Cancer (CRC)
Actual Study Start Date : August 29, 2019
Estimated Primary Completion Date : March 31, 2023
Estimated Study Completion Date : April 30, 2024


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

Experimental: ZW25 + mFOLFOX6 with bevacizumab
ZW25 plus 5-FU, leucovorin, oxaliplatin, and bevacizumab
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

Drug: Bevacizumab
Administered IV

Experimental: ZW25 + CisGem
ZW25 plus cisplatin and gemcitabine
Drug: Cisplatin
Administered IV

Drug: Gemcitabine
Administered IV




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.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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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:
    • 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)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03929666


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

Locations
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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, Michigan
Cancer and Hematology Centers of Western Michigan Recruiting
Kalamazoo, Michigan, United States, 49007
Principal Investigator: Sreenivasa Chandana, MD         
United States, Nebraska
Nebraska Methodist Hospital Recruiting
Omaha, Nebraska, United States, 68114
Principal Investigator: Joel Michalski, 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: Namrata Vijayvergia, 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
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
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Study Director: Jonathan Grim, MD, PhD Zymeworks Inc.
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Responsible Party: Zymeworks Inc.
ClinicalTrials.gov Identifier: NCT03929666    
Other Study ID Numbers: ZWI-ZW25-201
First Posted: April 29, 2019    Key Record Dates
Last Update Posted: August 11, 2021
Last Verified: August 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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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
Gastrointestinal cancers
Gastroesophageal adenocarcinoma
Biliary tract cancer
Colorectal cancer
Intrahepatic cholangiocarcinoma
Extrahepatic cholangiocarcinoma
Gall bladder
Additional relevant MeSH terms:
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Colorectal Neoplasms
Adenocarcinoma
Biliary Tract Neoplasms
Gastrointestinal Neoplasms
Intestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Colonic Diseases
Intestinal Diseases
Rectal Diseases
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Biliary Tract Diseases
Leucovorin
Gemcitabine
Bevacizumab
Fluorouracil
Capecitabine
Oxaliplatin
Antineoplastic Agents, Immunological
Antineoplastic Agents
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Physiological Effects of Drugs
Growth Inhibitors