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Trial of ZW25 in Patients With Advanced HER2-expressing Cancers

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ClinicalTrials.gov Identifier: NCT02892123
Recruitment Status : Recruiting
First Posted : September 8, 2016
Last Update Posted : December 18, 2018
Sponsor:
Information provided by (Responsible Party):
Zymeworks Inc.

Brief Summary:
To evaluate the maximal tolerated dose (MTD), optimal biological dose (OBD) or other recommended dose (RD), and overall safety and tolerability of ZW25 in patients with locally advanced (unresectable) and/or metastatic HER2-expressing cancers.

Condition or disease Intervention/treatment Phase
HER2-expressing Cancers Drug: ZW25, HER2 inhibitor Combination Product: Paclitaxel Combination Product: Capecitabine Combination Product: Vinorelbine Phase 1

Detailed Description:

Part 1, Dose Escalation: Patients with any HER2-expressing cancer that is either HER2 1+, 2+ or 3+ by immunohistochemistry (IHC) and has progressed after all standard of care therapies will receive escalating doses of ZW25 in order to identify either the highest dose of study drug possible that will not cause unacceptable side effects or the dose of study drug which is thought to be associated with optimal biologic activity.

Part 2, Dose Expansion: Patients will be enrolled into one of the below cohorts based the level of HER2 expression and cancer type.

  • Cohort 1: HER2 IHC 2+/FISH negative breast cancer
  • Cohort 2: HER2 IHC 3+ or HER2 IHC 2+/FISH positive breast cancer
  • Cohort 3: HER2 IHC 2+/FISH negative gastric/ GEJ cancer
  • Cohort 4: HER2 IHC 3+ or HER2 IHC 2+/FISH positive gastric/GEJ cancer
  • Cohort 5: Any other HER2 IHC 3+ or FISH positive cancer

Patients in Part 2 will receive the dose of study drug identified in Part 1 of the study. These patients will be followed to further evaluate the safety of ZW25 as well as to explore anti-tumor activity.

Part 3, Combination Therapy Expansion: Patients with HER2-expressing breast or gastric/GEJ cancers will be treated with ZW25 in combination with one of several chemotherapy regimens including paclitaxel, capecitabine and vinorelbine.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 150 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase I Trial of ZW25 in Patients With Locally Advanced (Unresectable) and/or Metastatic HER2-expressing Cancers
Study Start Date : September 2016
Estimated Primary Completion Date : December 2019
Estimated Study Completion Date : December 2019


Arm Intervention/treatment
Experimental: ZW25 Monotherapy and ZW25 Combination Therapy Drug: ZW25, HER2 inhibitor
ZW25 administered IV once weekly or once every two weeks. Part 1: in multiple escalating doses; Part 2: ZW25 administered at MTD/OBD or RD from Part 1; Part 3: ZW25 administered at MTD/OBD or RD in combination with one of several selected chemotherapies.

Combination Product: Paclitaxel
Part 3, Treatment Group 1 chemo combination

Combination Product: Capecitabine
Part 3, Treatment Group 2 chemo combination

Combination Product: Vinorelbine
Part 3, Treatment Group 3 chemo combination




Primary Outcome Measures :
  1. The proportion of patients experiencing dose limiting toxicities [ Time Frame: Up to 8 months (Part 1) ]
  2. The proportion patients who experience laboratory abnormalities and/or adverse events as defined by CTCAE v4.03 that are related to treatment [ Time Frame: Throughout the duration of the study; up to 2 years ]

Secondary Outcome Measures :
  1. Serum concentrations of ZW25 [ Time Frame: Throughout the duration of the study; up to 2 years ]
  2. The proportion of patients who develop detectable anti-drug antibodies [ Time Frame: Throughout the duration of the study; up to 2 years ]
  3. The proportion of patients with an objective response (partial response or complete response) as defined by RECIST 1.1 criteria [ Time Frame: Throughout the duration of the study; up to 2 years ]
  4. Progression free survival as defined by RECIST 1.1 criteria [ Time Frame: Throughout the duration of the study; up to 2 years ]


Information from the National Library of Medicine

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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 Criteria:

  1. HER2-expressing cancer as follows:

    Part 1:

    Any locally advanced (unresectable) and/or metastatic HER2-expressing (HER2 1+, 2+, or 3+ by IHC) cancer that has progressed after receipt of all therapies known to confer clinical benefit

    • HER2-overexpressing (3+ by IHC) or HER2 2+ and FISH positive breast cancer must have progressed after prior treatment with trastuzumab, pertuzumab, and T‑DM1
    • HER2-overexpressing (3+ by IHC) or HER2 2+ and FISH positive gastric cancer must have progressed after prior treatment with trastuzumab

    Part 2:

    − Locally advanced (unresectable) and/or metastatic cancer that has progressed after receipt of all therapies know to confer clinical benefit (unless ineligible to receive a specific therapy) as follows:

    • Cohort 1: HER2 IHC 2+/FISH negative breast cancer
    • Cohort 2: HER2 IHC 3+ or HER2 IHC 2+/FISH positive breast cancer
    • Cohort 3: HER2 IHC 2+/FISH negative gastric/GEJ cancer
    • Cohort 4: HER2 IHC 3+ or HER2 IHC 2+/FISH positive gastric/GEJ cancer
    • Cohort 5: Any other HER2 IHC 3+ or FISH positive cancer

      • Pts with colorectal cancer must be KRAS wild-type
      • Pts with NSCLC must have ALK wild-type, EGFR wild-type, and ROS1 fusion negative

    Part 3:

    Locally advanced (unresectable) and/or metastatic cancer as follows:

    • HER2 IHC 1+ or IHC2+/FISH- breast cancer patients who have received at least 1 and no more than 3 prior systemic chemotherapy regimens
    • HER2 IHC 3+ or IHC 2+/FISH+ breast cancer patients who have received prior therapy with trastuzumab, pertuzumab, and T-DM1, at least 1 and no more than 3 prior systemic chemotherapy regimens
    • HER2 IHC 2+ or 3+ FISH+ or FISH- gastric/GEJ cancer patients who have received at least 1 and no more than 3 prior systemic chemotherapy regimens.
  2. ≥ 18 years of age
  3. ECOG 0 or 1
  4. Adequate hepatic function, as follows:

    • AST ≤2.5 x ULN (if liver or bone mets are present, ≤5 x ULN)
    • ALT ≤2.5 x ULN (if liver or bone metastases are present, ≤5 x ULN)
    • Total bilirubin ≤1.5 x ULN
  5. Adequate renal function (within normal limits or calculated glomerular filtration rate >50)
  6. Hematological function:

    • ANC ≥1.5 x 10⁹/L
    • Platelet count ≥75 x 10⁹/L (Parts 1 and 2), ≥100 x 10⁹/L (Part 3)
    • Hemoglobin ≥9 g/dL
    • PT and PTT <1.5 x ULN
  7. Adequate cardiac left ventricular function
  8. For Part 1, cohorts 1-3: evaluable disease (per RECIST version 1.1). For Part 1, cohorts 4-6 and Parts 2 and 3: measurable disease (per RECIST version 1.1)
  9. Able to provide a fresh formalin-fixed, paraffin-embedded (FFPE) tumor sample for central evaluation of HER2 status prior to enrolment; if a fresh biopsy is not feasible, sponsor approval is required and archived tumor biopsy must be provided for centralized testing by sponsor

    - For Parts 1 and 3, eligibility may be based on local read of fresh or archived tumor biopsy. Archived or fresh FFPE biopsy must be provided for retrospective centralized review.

  10. Willingness to use 2 methods of birth control during the study and for 12 months after the last dose of ZW25

Exclusion Criteria:

  1. Experimental therapies within 4 weeks before first ZW25 dosing
  2. Other cancer therapy including chemotherapy, small molecules, and antibodies within 5 half-lives of the cancer therapy before first ZW25 dosing
  3. Anthracyclines within 90 days before first ZW25 dosing or lifetime load exceeding 300 mg/m² adriamycin or equivalent
  4. Trastuzumab, pertuzumab, lapatinib, or T‑DM1 within 3 weeks before first ZW25 dosing
  5. Untreated brain metastases (pts with treated brain mets who are off steroids and anticonvulsants and stable for at least 1 month at the time of Screening are eligible)
  6. Pregnant or breast-feeding women
  7. History of life-threatening hypersensitivity to monoclonal antibodies or to recombinant proteins or excipients in drug formulation
  8. Acute or chronic uncontrolled renal disease, pancreatitis or liver disease (with exception of patients with Gilbert's Syndrome, asymptomatic gall stones, liver metastases, or stable chronic liver disease per investigator assessment)
  9. Peripheral neuropathy >Grade 2
  10. Clinically significant interstitial lung disease
  11. Known active hepatitis B or C or known infection with HIV
  12. Immunosuppressive corticosteroids equivalent to >15mg/day of prednisone within 2 weeks before first ZW25 dose
  13. QTc Fridericia (QTcF) >450 ms
  14. Having clinically significant cardiac disease such as ventricular arrhythmia requiring therapy, uncontrolled hypertension or any history of symptomatic CHF
  15. Having known myocardial infarction or unstable angina within 6 months before first ZW25 dosing

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): NCT02892123


Contacts
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Contact: Linda Lai 1 (206) 260-2078 linda.lai@zymeworks.com
Contact: Nels Royer 1 (206) 260-2079 nels.royer@zymeworks.com

Locations
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United States, Alabama
University of Alabama Recruiting
Birmingham, Alabama, United States, 35294
United States, California
USC/Norris Cancer Center Recruiting
Los Angeles, California, United States, 90033
Hoag Family Cancer Institute Recruiting
Newport Beach, California, United States, 92663
United States, Colorado
University of Colorado Cancer Center Recruiting
Aurora, Colorado, United States, 80045
United States, Illinois
Rush University Medical Center Recruiting
Chicago, Illinois, United States, 60612
United States, Tennessee
Sarah Cannon - Tennessee Oncology Recruiting
Nashville, Tennessee, United States, 37203
United States, Texas
MD Anderson Cancer Center Recruiting
Houston, Texas, United States, 77030
Contact: Michelle Bhatt, PhD    832-751-9733    MMartinez7@mdanderson.org   
South Texas Accelerated Research Therapeutics (START) Recruiting
San Antonio, Texas, United States, 78229
Contact: Isabel Jimenez    210-593-5250    Isabel.jimenez@startsa.com   
United States, Washington
Northwest Medical Specialties Recruiting
Tacoma, Washington, United States, 98405
Contact: Linda Dhaene    253-428-8753    ldhaene@nwmsonline.com   
Canada, Ontario
The Ottawa Hosptial Cancer Center Recruiting
Ottawa, Ontario, Canada, K1H 8L6
Princess Margaret Cancer Centre Recruiting
Toronto, Ontario, Canada, M5G 2M9
Canada, Quebec
Jewish General Hospital Recruiting
Montréal, Quebec, Canada, H3T1E2
Sponsors and Collaborators
Zymeworks Inc.
Investigators
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Study Director: Diana F Hausman, MD Zymeworks Inc.

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Responsible Party: Zymeworks Inc.
ClinicalTrials.gov Identifier: NCT02892123     History of Changes
Other Study ID Numbers: ZWI-ZW25-101
First Posted: September 8, 2016    Key Record Dates
Last Update Posted: December 18, 2018
Last Verified: September 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

Keywords provided by Zymeworks Inc.:
HER2
bispecific antibody
biparatopic antibody
breast cancer
gastric cancer
gastroesophageal cancer
ovarian cancer
non-small cell lung cancer

Additional relevant MeSH terms:
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Antibodies
Capecitabine
Vinorelbine
Immunologic Factors
Physiological Effects of Drugs
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Antineoplastic Agents, Phytogenic
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators