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

Study Overview
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Brief Summary
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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).

Detailed Description
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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.

Official Title
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Phase I Trial of ZW25 in Patients With Locally Advanced (Unresectable) and/or Metastatic HER2-expressing Cancers

Conditions
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HER2-expressing Cancers

Intervention / Treatment
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* Drug: ZW25 (Zanidatamab)
* Drug: Paclitaxel
* Drug: Capecitabine
* Drug: Vinorelbine
* Drug: Tucatinib
* Drug: Tucatinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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 ≥ 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) 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: 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) 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) 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 Patients in Part 3 TG7 must not have received prior capecitabine or tucatinib for metastatic disease Patients in Part 3 TG8 must not have received prior tucatinib therapy for metastatic disease

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ZW25 (Zanidatamab) Monotherapy and ZW25 Combination Therapy<br> | Drug: ZW25 (Zanidatamab)<br>* 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:<br>Drug: Paclitaxel<br>* Combination therapy with ZW25 - Part 3 Treatment Groups 1 and 4<br>Drug: Capecitabine<br>* Combination therapy with ZW25 - Part 3 Treatment Groups 2 and 5<br>Drug: Vinorelbine<br>* Combination therapy with ZW25 - Part 3 Treatment Groups 3 and 6<br>Drug: Tucatinib<br>* Combination therapy with ZW25 and Capecitabine - Part 3 Treatment Group 7<br>Drug: Tucatinib<br>* Combination therapy with ZW25 - Part 3 Treatment Group 8 (may be opened if recommended by the Safety Monitoring Committee and/or the sponsor)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The proportion of patients who experience dose-limiting toxicities (DLTs) (Part 1) |  | 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) |  | Throughout the duration of the study; up to 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Serum concentrations of ZW25 |  | Throughout the duration of the study; up to 2 years | 
| The proportion of patients who develop detectable anti-drug antibodies |  | 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 |  | Throughout the duration of the study; up to 2 years | 
| Progression free survival as defined by RECIST 1.1 criteria |  | 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) |  | Throughout the duration of the study; up to 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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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