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).
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:
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
