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出境医 / 临床实验 / 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

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 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 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.
Study Design
Layout table for study information
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
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
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
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
Layout table for eligibility information
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)
Contacts and Locations

Contacts
Layout table for location contacts
Contact: Zymeworks Clinical Trial Resource (206) 237-1030 medinfo@zymeworks.com

Locations
Layout table for location information
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: 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
Layout table for investigator information
Study Director: Jonathan Grim, MD, PhD Zymeworks Inc.
Tracking Information
First Submitted Date  ICMJE February 22, 2019
First Posted Date  ICMJE April 29, 2019
Last Update Posted Date April 20, 2021
Actual Study Start Date  ICMJE August 29, 2019
Estimated Primary Completion Date March 31, 2023   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: October 13, 2020)
  • 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
Original Primary Outcome Measures  ICMJE
 (submitted: April 23, 2019)
  • 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 or partial response during treatment according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: October 13, 2020)
  • 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.
Original Secondary Outcome Measures  ICMJE
 (submitted: April 23, 2019)
  • Objective response rate (ORR) (Part 1) [ Time Frame: Up to 10 months ]
    Number of participants who achieved a best response of either complete or partial response during treatment according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1
  • Disease control rate (Parts 1 and 2) [ Time Frame: Up to 10 months ]
    Number of participants who achieved a best response of complete response, partial response, or stable disease during treatment according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 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)
  • 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 Common Terminology Criteria for Adverse Events (CTCAE), version 5.0.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE 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
Official Title  ICMJE 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)
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).
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  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE HER2-expressing Gastrointestinal Cancers, Including Gastroesophageal Adenocarcinoma, Biliary Tract Cancer, and Colorectal Cancer
Intervention  ICMJE
  • 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
Study Arms  ICMJE
  • Experimental: ZW25 + FP
    ZW25 plus fluorouracil (5-FU) and cisplatin
    Interventions:
    • Drug: ZW25 (Zanidatamab)
    • Drug: Cisplatin
    • Drug: Fluorouracil
  • Experimental: ZW25 + mFOLFOX6
    ZW25 plus 5-FU, leucovorin, and oxaliplatin
    Interventions:
    • Drug: ZW25 (Zanidatamab)
    • Drug: Fluorouracil
    • Drug: Leucovorin
    • Drug: Oxaliplatin
  • Experimental: ZW25 + XELOX
    ZW25 plus capecitabine and oxaliplatin
    Interventions:
    • Drug: ZW25 (Zanidatamab)
    • Drug: Capecitabine
    • Drug: Oxaliplatin
  • Experimental: ZW25 + mFOLFOX6 with bevacizumab
    ZW25 plus 5-FU, leucovorin, oxaliplatin, and bevacizumab
    Interventions:
    • Drug: ZW25 (Zanidatamab)
    • Drug: Fluorouracil
    • Drug: Leucovorin
    • Drug: Oxaliplatin
    • Drug: Bevacizumab
  • Experimental: ZW25 + CisGem
    ZW25 plus cisplatin and gemcitabine
    Interventions:
    • Drug: Cisplatin
    • Drug: Gemcitabine
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: April 16, 2021) 		362
Original Estimated Enrollment  ICMJE
 (submitted: April 23, 2019) 		91
Estimated Study Completion Date  ICMJE April 30, 2024
Estimated Primary Completion Date March 31, 2023   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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)
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Zymeworks Clinical Trial Resource (206) 237-1030 medinfo@zymeworks.com
Listed Location Countries  ICMJE Canada,   Korea, Republic of,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03929666
Other Study ID Numbers  ICMJE ZWI-ZW25-201
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Zymeworks Inc.
Study Sponsor  ICMJE Zymeworks Inc.
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Jonathan Grim, MD, PhD Zymeworks Inc.
PRS Account Zymeworks Inc.
Verification Date April 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP

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