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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 : April 20, 2021
Sponsor:
Information provided by (Responsible Party):
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