Patient case: 45-year-old female with cervical cancer; genetic feature: ERBB2 (S310Y)

Clinical trial: Trial of ZW25 in Patients With Advanced HER2-expressing Cancers

Summary: To evaluate the maximal tolerated dose (MTD), optimal biological dose (OBD) or other recommended dose (RD), and overall safety and tolerability of ZW25 in patients with locally advanced (unresectable) and/or metastatic HER2-expressing cancers.

Detailed description: Part 1, Dose Escalation: Patients with any HER2-expressing cancer that is either HER2 1+, 2+ or 3+ by immunohistochemistry (IHC) and has progressed after all standard of care therapies will receive escalating doses of ZW25 in order to identify either the highest dose of study drug possible that will not cause unacceptable side effects or the dose of study drug which is thought to be associated with optimal biologic activity.
  Part 2, Dose Expansion: Patients will be enrolled into one of the below cohorts based the level of HER2 expression and cancer type.
  -  Cohort 1: HER2 IHC 2+/FISH negative breast cancer
  -  Cohort 2: HER2 IHC 3+ or HER2 IHC 2+/FISH positive breast cancer
  -  Cohort 3: HER2 IHC 2+/FISH negative gastric/ GEJ cancer
  -  Cohort 4: HER2 IHC 3+ or HER2 IHC 2+/FISH positive gastric/GEJ cancer
  -  Cohort 5: Any other HER2 IHC 3+ or FISH positive cancer
  Patients in Part 2 will receive the dose of study drug identified in Part 1 of the study. These patients will be followed to further evaluate the safety of ZW25 as well as to explore anti-tumor activity.
  Part 3, Combination Therapy Expansion: Patients with HER2-expressing breast or gastric/GEJ cancers will be treated with ZW25 in combination with one of several chemotherapy regimens including paclitaxel, capecitabine and vinorelbine.

Eligibility: Inclusion Criteria:
  1. HER2-expressing cancer as follows:
  Part 1:
  Any locally advanced (unresectable) and/or metastatic HER2-expressing (HER2 1+, 2+, or 3+ by IHC) cancer that has progressed after receipt of all therapies known to confer clinical benefit
  -  HER2-overexpressing (3+ by IHC) or HER2 2+ and FISH positive breast cancer must have progressed after prior treatment with trastuzumab, pertuzumab, and T‑DM1
  -  HER2-overexpressing (3+ by IHC) or HER2 2+ and FISH positive gastric cancer must have progressed after prior treatment with trastuzumab
  Part 2:
  − Locally advanced (unresectable) and/or metastatic cancer that has progressed after receipt of all therapies know to confer clinical benefit (unless ineligible to receive a specific therapy) as follows:
  -  Cohort 1: HER2 IHC 2+/FISH negative breast cancer
  -  Cohort 2: HER2 IHC 3+ or HER2 IHC 2+/FISH positive breast cancer
  -  Cohort 3: HER2 IHC 2+/FISH negative gastric/GEJ cancer
  -  Cohort 4: HER2 IHC 3+ or HER2 IHC 2+/FISH positive gastric/GEJ cancer
  -  Cohort 5: Any other HER2 IHC 3+ or FISH positive cancer
  -  Pts with colorectal cancer must be KRAS wild-type
  -  Pts with NSCLC must have ALK wild-type, EGFR wild-type, and ROS1 fusion negative
  Part 3:
  Locally advanced (unresectable) and/or metastatic cancer as follows:
  -  HER2 IHC 1+ or IHC2+/FISH- breast cancer patients 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 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- gastric/GEJ cancer patients who have received at least 1 and no more than 3 prior systemic chemotherapy regimens.
  2. ≥ 18 years of age
  3. ECOG 0 or 1
  4. Adequate hepatic function, as follows:
  -  AST ≤2.5 x ULN (if liver or bone mets are present, ≤5 x ULN)
  -  ALT ≤2.5 x ULN (if liver or bone metastases are present, ≤5 x ULN)
  -  Total bilirubin ≤1.5 x ULN
  5. Adequate renal function (within normal limits or calculated glomerular filtration rate >50)
  6. Hematological function:
  -  ANC ≥1.5 x 10⁹/L
  -  Platelet count ≥75 x 10⁹/L (Parts 1 and 2), ≥100 x 10⁹/L (Part 3)
  -  Hemoglobin ≥9 g/dL
  -  PT and PTT <1.5 x ULN
  7. Adequate cardiac left ventricular function
  8. For Part 1, cohorts 1-3: evaluable disease (per RECIST version 1.1). For Part 1, cohorts 4-6 and Parts 2 and 3: measurable disease (per RECIST version 1.1)
  9. Able to provide a fresh formalin-fixed, paraffin-embedded (FFPE) tumor sample for central evaluation of HER2 status prior to enrolment; if a fresh biopsy is not feasible, sponsor approval is required and archived tumor biopsy must be provided for centralized testing by sponsor
  - For Parts 1 and 3, eligibility may be based on local read of fresh or archived tumor biopsy. Archived or fresh FFPE biopsy must be provided for retrospective centralized review.
  10. Willingness to use 2 methods of birth control during the study and for 12 months after the last dose of ZW25
  Exclusion Criteria:
  1. Experimental therapies within 4 weeks before first ZW25 dosing
  2. Other cancer therapy including chemotherapy, small molecules, and antibodies within 5 half-lives of the cancer therapy before first 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. Untreated brain metastases (pts with treated brain mets who are off steroids and anticonvulsants and stable for at least 1 month at the time of Screening are eligible)
  6. Pregnant or breast-feeding women
  7. History of life-threatening hypersensitivity to monoclonal antibodies or to recombinant proteins or excipients in drug formulation
  8. 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)
  9. Peripheral neuropathy >Grade 2
  10. Clinically significant interstitial lung disease
  11. Known active hepatitis B or C or known infection with HIV
  12. Immunosuppressive corticosteroids equivalent to >15mg/day of prednisone within 2 weeks before first ZW25 dose
  13. QTc Fridericia (QTcF) >450 ms
  14. Having clinically significant cardiac disease such as ventricular arrhythmia requiring therapy, uncontrolled hypertension or any history of symptomatic CHF
  15. Having known myocardial infarction or unstable angina within 6 months before first ZW25 dosing

Relevance to patient case: possibly relevant