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Trial of ZW25 (Zanidatamab) in Patients With Advanced HER2-expressing Cancers

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ClinicalTrials.gov Identifier: NCT02892123
Recruitment Status : Active, not recruiting
First Posted : September 8, 2016
Last Update Posted : April 18, 2024
Sponsor:
Information provided by (Responsible Party):
Jazz Pharmaceuticals

Study Description
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Brief Summary:
This is a first-in-human, 3-part study to investigate the safety, tolerability, and effectiveness of ZW25 (zanidatamab) by itself and combined with selected chemotherapy agents in patients with locally advanced (unresectable) and/or metastatic human epidermal growth factor receptor 2 (HER2)-expressing cancers. This study will also the evaluate the way the body absorbs, distributes, and eliminates ZW25 (pharmacokinetics or PK).

Condition or disease Intervention/treatment Phase
HER2-expressing Cancers Drug: ZW25 (Zanidatamab) Drug: Paclitaxel Drug: Capecitabine Drug: Vinorelbine Drug: Tucatinib Phase 1

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 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, vinorelbine, or capecitabine and tucatinib. 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 Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 279 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
Actual Study Start Date : September 30, 2016
Estimated Primary Completion Date : June 1, 2024
Estimated Study Completion Date : July 1, 2024

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
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 following selected drug combination:

Drug: Paclitaxel
Combination therapy with ZW25 - Part 3 Treatment Groups 1 and 4

Drug: Capecitabine
Combination therapy with ZW25 - Part 3 Treatment Groups 2 and 5

Drug: Vinorelbine
Combination therapy with ZW25 - Part 3 Treatment Groups 3 and 6

Drug: Tucatinib
Combination therapy with ZW25 and Capecitabine - Part 3 Treatment Group 7

Drug: Tucatinib
Combination therapy with ZW25 - Part 3 Treatment Group 8 (may be opened if recommended by the Safety Monitoring Committee and/or the sponsor)


Outcome Measures
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Primary Outcome Measures :
  1. The proportion of patients who experience dose-limiting toxicities (DLTs) (Part 1) [ Time Frame: Up to 8 months ]
  2. 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 ]

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 ]
  5. 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 ]

Eligibility Criteria
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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:

    • 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

    • Cohort 4:

      • HER2 IHC 2+ /FISH- breast cancer or gastroesophageal 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

    • 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 (TG4; ZW25 + paclitaxel)
    • HER2 IHC 3+, IHC 2+/FISH+ or otherwise HER2-positive per ASCO/CAP guidelines breast cancer patients who have received prior therapy with trastuzumab, pertuzumab, and T-DM1 (TG5; ZW25 + capecitabine)
    • HER2 IHC 3+, IHC 2+/FISH+ or otherwise HER2-positive per ASCO/CAP guidelines breast cancer patients (TG6) who have received prior therapy with trastuzumab, pertuzumab, and T-DM1
    • HER2 IHC 3+, IHC2+/FISH+, or otherwise HER2-positive per ASCO/CAP guidelines breast cancer patients (TG7) who have received prior therapy with trastuzumab, pertuzumab, and T-DM1
    • HER2 IHC 3+, IHC 2+/FISH+, or otherwise HER2-positive per ASCO/CAP guidelines breast cancer patients (TG8) who have received prior therapy with trastuzumab, pertuzumab, and T-DM1
  2. ≥ 18 years of age
  3. ECOG performance status of 0 or 1
  4. Life expectancy of at least 3 months per the investigator's assessment.
  5. Adequate organ function
  6. Adequate cardiac left ventricular function, as defined by a LVEF >/= institutional standard of normal
  7. 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
  8. Able to provide tumor sample (fresh or archived)

  9. For Part 3 TGs 7 and 8 only - based on screening brain MRI, patients must have one of the following:

    • No evidence of brain metastases
    • Untreated brain metastases not needing immediate local therapy. For patients with untreated CNS lesions > 2.0 cm on screening contrast brain MRI, discussion with and approval from the medical monitor is required prior to enrollment
    • Previously treated brain metastases that are either stable since treatment or have progressed since prior local CNS therapy, provided there is no clinical indication for immediate re-treatment with local therapy in the opinion of the investigator

Exclusion Criteria:

  1. Experimental therapies within 4 weeks before first ZW25 dosing
  2. Treatment with other cancer therapy not otherwise specified within 4 weeks before 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. Patients in Part 3 TG4 must not have received prior taxanes
  6. Patients in Part 3 TG5 must not have received prior capecitabine for metastatic disease or received any prior fam-trastuzumab deruxtecan-nxki (DS-8201a)
  7. With the exception of Part 3 TGs 7 and 8, 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)
  8. Pregnant or breast-feeding women
  9. History of life-threatening hypersensitivity to monoclonal antibodies or to recombinant proteins or excipients in drug formulation
  10. 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)
  11. Peripheral neuropathy > Grade 2
  12. Clinically significant interstitial lung disease
  13. Known active hepatitis B or C or known infection with HIV
  14. Immunosuppressive corticosteroids equivalent to > 15mg/day of prednisone within 2 weeks before first ZW25 dose
  15. QTc Fridericia (QTcF) > 450 ms
  16. Having clinically significant cardiac disease such as ventricular arrhythmia requiring therapy, uncontrolled hypertension or any history of symptomatic CHF
  17. Having known myocardial infarction or unstable angina within 6 months before first ZW25 dosing
  18. Patients in Part 3 TG7 must not have received prior capecitabine or tucatinib for metastatic disease
  19. Patients in Part 3 TG8 must not have received prior tucatinib therapy for metastatic disease
Contacts and Locations
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Top of Page Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

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


Locations
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Sponsors and Collaborators
Jazz Pharmaceuticals
More Information
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Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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Responsible Party: Jazz Pharmaceuticals
ClinicalTrials.gov Identifier: NCT02892123    
Other Study ID Numbers: ZWI-ZW25-101
First Posted: September 8, 2016    Key Record Dates
Last Update Posted: April 18, 2024
Last Verified: April 2024
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Keywords provided by Jazz Pharmaceuticals:
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
Tucatinib
Additional relevant MeSH terms:
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Paclitaxel
Vinorelbine
Capecitabine
Tucatinib
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Tubulin Modulators
 Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action
Antimetabolites, Antineoplastic
Antimetabolites
Protein Kinase Inhibitors
Enzyme Inhibitors