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

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.

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