Trial of ZW25 (Zanidatamab) 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 : October 27, 2020
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Condition or disease | Intervention/treatment | Phase |
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HER2-expressing Cancers | Drug: ZW25 (Zanidatamab) Combination Product: Paclitaxel Combination Product: Capecitabine Combination Product: Vinorelbine | Phase 1 |
Expanded Access : An investigational treatment associated with this study is available outside the clinical trial. More info ...
Part 1 of the study will evaluate increasing doses of ZW25 to find the highest dose of ZW25 that does not cause unacceptable side effects (maximum-tolerated dose or MTD), the lowest safe dose with the highest rate of effectiveness (optimal biological dose or OBD), and/or other recommended dosages (RDs) of ZW25 in up to 7 dose-specific cohorts. Eligible patients include those with selected HER2-expressing locally advanced (unresectable) and/or metastatic cancers that have progressed after receipt of all therapies known to confer clinical benefit (or ineligible to receive therapy).
Part 2 of the study will further evaluate the safety, tolerability, and efficacy of ZW25 in patients with selected HER2-expressing locally advanced (unresectable) and/or metastatic cancers that have progressed after receipt of all therapies known to confer clinical benefit (or ineligible to receive therapy) in up to 5 separate disease-specific cohorts.
Part 3 of the study will evaluate the safety, tolerability, and efficacy of ZW25 combined with selected chemotherapy agents, including paclitaxel, capecitabine, or vinorelbine. Patients with selected HER2-expressing locally advanced (unresectable) and/or metastatic cancers that have progressed after at least 1 and no more than 3 prior systemic chemotherapy regimens will be evaluated in this part of the study.
Study Type : | Interventional (Clinical Trial) |
Estimated Enrollment : | 280 participants |
Allocation: | N/A |
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 : | January 31, 2022 |
Estimated Study Completion Date : | March 31, 2022 |

Arm | Intervention/treatment |
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Experimental: ZW25 (Zanidatamab) Monotherapy and ZW25 Combination Therapy |
Drug: ZW25 (Zanidatamab)
ZW25 administered IV once weekly, once every 2 weeks, or once every 3 weeks. Part 1: in multiple increasing doses; Part 2: ZW25 given at the MTD, OBD, or an RD identified in Part 1; Part 3: ZW25 given at the MTD, OBD, or an RD combined with one of the selected chemotherapy agents. Combination Product: Paclitaxel Part 3, Treatment Groups 1 and 4 chemotherapy combination Combination Product: Capecitabine Part 3, Treatment Groups 2 and 5 chemotherapy combination Combination Product: Vinorelbine Part 3, Treatment Groups 3 and 6 chemotherapy combination |
- The proportion of patients who experience dose-limiting toxicities (DLTs) (Part 1) [ Time Frame: Up to 8 months ]
- The proportion patients who experience laboratory abnormalities and/or adverse events as defined by CTCAE v4.03 that are related to treatment (Parts 2 and 3) [ Time Frame: Throughout the duration of the study; up to 2 years ]
- Serum concentrations of ZW25 [ Time Frame: Throughout the duration of the study; up to 2 years ]
- The proportion of patients who develop detectable anti-drug antibodies [ Time Frame: Throughout the duration of the study; up to 2 years ]
- 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 ]
- Progression free survival as defined by RECIST 1.1 criteria [ Time Frame: Throughout the duration of the study; up to 2 years ]
- The proportion patients who experience laboratory abnormalities and/or adverse events as defined by CTCAE v4.03 that are related to treatment (Part 1) [ Time Frame: Throughout the duration of the study; up to 2 years ]

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Ages Eligible for Study: | 18 Years and older (Adult, Older Adult) |
Sexes Eligible for Study: | All |
Accepts Healthy Volunteers: | No |
Inclusion Criteria:
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HER2-expressing cancer as follows:
Part 1:
- Cohorts 1 - 3: Any locally advanced (unresectable) and/or metastatic HER2-expressing (HER2 1+, 2+, or 3+ by IHC) cancer (including but not limited to breast, gastric, ovarian, colorectal and non-small cell lung) that has progressed after receipt of all therapies known to confer clinical benefit
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Cohort 4:
- HER2 IHC 2+ /FISH- breast cancer or gastroesophagel adenocarcinoma (GEA)
- HER2 IHC 3+ or HER2 IHC 2+ /FISH+ breast cancer or GEA
-
Any other HER2 IHC 3+ or FISH+ cancer
- HER2-overexpressing (3+ by IHC) or HER2-2+ and FISH+ breast cancer must have progressed after prior treatment with trastuzumab, pertuzumab, and T-DM1
- HER2-overexpressing (3+ by IHC) or HER2-2+ and FISH+ GEA must have progressed after prior treatment with trastuzumab
- Patients with colorectal cancer must be KRAS wild-type
- Patients with NSCLC must have ALK wild-type, EGFR wild-type, and ROS1 fusion negative as determined by standard methods
- Cohorts 5 - 6: HER2 IHC 3+ or HER2 IHC 2+ /FISH+ GEA must have progressed after prior treatment with trastuzumab
- Cohort 7 (only at selected sites): HER2 IHC 3+, HER2 IHC 2+ /FISH+, or HER2 IHC 2+ /FISH- breast cancer must have progressed after prior treatment with trastuzumab, pertuzumab, and T-DM1
Part 2:
Locally advanced (unresectable) and/or metastatic cancer that has progressed after receipt of all therapies known to confer clinical benefit (unless ineligible to receive a specific therapy) as follows:
- Cohort 1: HER2 IHC 2+/FISH- breast cancer
- Cohort 2: HER2 IHC 3+ or HER2 IHC 2+/FISH+ breast cancer
- Cohort 3: HER2 IHC 2+/FISH- GEA
- Cohort 4: HER2 IHC 3+ or HER2 IHC 2+/FISH+ GEA
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Cohort 5: Any other HER2 IHC 3+ or IHC 2+/FISH+ cancer, including the following:
- Cohort 5a: HER2 IHC 3+ or IHC 2+/FISH+ GI cancers other than GEA (patients with colorectal cancer must be KRAS wild-type.)
- Cohort 5b: Any other HER2 IHC 3+ or IHC 2+/FISH+ solid tumor types that are not breast or GI cancers (patients with NSCLC must have ALK wild-type, EGFR wild-type, and ROS1 fusion negative as determined by standard methods; patients with ovarian cancers must be KRAS wild type.)
Part 3:
Locally advanced (unresectable) and/or metastatic cancer as follows:
- HER2 IHC 1+ or IHC2+/FISH- breast cancer patients (TGs 1, 2, or 3) 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 (TGs 1, 2, or 3) 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- GEA patients (TGs 1 or 2) who have received at least 1 and no more than 3 prior systemic chemotherapy regimens
- HER2 IHC 3+ or IHC 2+/FISH+ GEA patients who have received prior therapy with trastuzumab (TG 4; ZW25 + paclitaxel)
- HER2 IHC 3+ or IHC 2+/FISH+ breast cancer patients who have received prior therapy with trastuzumab, pertuzumab, and T-DM1 (TG 5; ZW25 + capecitabine)
- HER2 IHC 3+ or IHC 2+/FISH+ breast cancer patients (TG 6) who have received prior therapy with trastuzumab, pertuzumab, and T-DM1
- ≥ 18 years of age
- ECOG performance status of 0 or 1
- Life expectancy of at least 3 months per the investigator's assessment.
- Adequate organ function
- Adequate cardiac left ventricular function, as defined by a LVEF >/= institutional standard of normal
- For Part 1 Cohorts 1 - 3: evaluable disease (target or non-target lesions) per RECIST version 1.1. For Part 1 Cohorts 4 - 7, and Parts 2 and 3: measurable disease (target lesions) per RECIST version 1.1
- Able to provide tumor sample (fresh or archived)
Exclusion Criteria:
- Experimental therapies within 4 weeks before first ZW25 dosing
- Treatment with other cancer therapy not otherwise specified within 4 weeks before ZW25 dosing
- Anthracyclines within 90 days before first ZW25 dosing or lifetime load exceeding 300 mg/m² adriamycin or equivalent
- Trastuzumab, pertuzumab, lapatinib, or T-DM1 within 3 weeks before first ZW25 dosing
- Patients in Part 3 TG4 must not have received prior taxanes
- Patients in Part 3 TG5 must not have received prior capecitabine for metastatic disease or received any prior fam-trastuzumab deruxtecan-nxki (DS-8201a)
- Untreated brain metastases (patients with treated brain mets who are off steroids and are stable for at least 1 month at the time of screening are eligible)
- Pregnant or breast-feeding women
- History of life-threatening hypersensitivity to monoclonal antibodies or to recombinant proteins or excipients in drug formulation
- 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)
- Peripheral neuropathy > Grade 2
- Clinically significant interstitial lung disease
- Known active hepatitis B or C or known infection with HIV
- Immunosuppressive corticosteroids equivalent to >15mg/day of prednisone within 2 weeks before first ZW25 dose
- QTc Fridericia (QTcF) > 450 ms
- Having clinically significant cardiac disease such as ventricular arrhythmia requiring therapy, uncontrolled hypertension or any history of symptomatic CHF
- Having known myocardial infarction or unstable angina within 6 months before first ZW25 dosing

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

Study Director: | Joseph Woolery, PharmD, BCOP | Zymeworks Inc. |
Responsible Party: | Zymeworks Inc. |
ClinicalTrials.gov Identifier: | NCT02892123 |
Other Study ID Numbers: |
ZWI-ZW25-101 |
First Posted: | September 8, 2016 Key Record Dates |
Last Update Posted: | October 27, 2020 |
Last Verified: | October 2020 |
Individual Participant Data (IPD) Sharing Statement: | |
Plan to Share IPD: | No |
HER2 Bispecific antibody Biparatopic antibody Immunotherapy Breast cancer Gastroesophageal adenocarcinoma (GEA) Gastric cancer |
Gastroesophageal junction (GEJ) cancer Ovarian cancer Non-small cell lung cancer (NSCLC) Chemotherapy Paclitaxel Capecitabine Vinorelbine |
Paclitaxel Vinorelbine Capecitabine Antineoplastic Agents, Phytogenic Antineoplastic Agents Tubulin Modulators |
Antimitotic Agents Mitosis Modulators Molecular Mechanisms of Pharmacological Action Antimetabolites, Antineoplastic Antimetabolites |