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

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