Patient case: 54-year-old male with Gastric cancer. Genetic variant: PIK3CA (E545K). Other conditions: Depression.

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, a humanized bispecific monoclonal antibody targeting the extracellular domain of HER2, in patients with locally advanced (unresectable) and/or metastatic HER2-expressing cancers.

Detailed description: This study has 2 parts. In the first part of the study, 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.
  In the second part of the study, 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 2+ or 3+ or FISH positive cancer
  Patients 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.

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, 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 2+ or 3+ or FISH positive cancer
  -  Patients with colorectal cancer must be KRAS wild-type as determined by PCR
  -  Patients with NSCLC must have ALK wild-type, EGFR wild-type, and ROS1 fusion negative as determined by standard methods.
  2. Male or female, ≥ 18 years of age at the time of signing informed consent.
  3. ECOG performance status 0 or 1
  4. Adequate hepatic function, as follows:
  -  Aspartate aminotransferase (AST) ≤2.5 x the upper limit of normal (ULN) per institutional values (if liver or bone metastases are present, ≤5 x ULN)
  -  Alanine aminotransferase (ALT) ≤2.5 x ULN per institutional values (if liver or bone metastases are present, ≤5 x ULN)
  -  Total bilirubin ≤1.5 x ULN per institutional values
  5. Adequate renal function (within normal limits per institution or calculated glomerular filtration rate >50)
  6. Hematological function, as follows:
  -  Absolute neutrophil count (ANC) ≥1.5 x 109/L
  -  Platelet count ≥100 x 109/L
  -  Hemoglobin ≥9g/dL
  -  Prothrombin time (PT) and partial thromboplastin time (PTT) <1.5 x ULN
  7. Adequate cardiac left ventricular function, as defined by a left ventricular ejection fraction (LVEF) institutional standard of normal
  8. For Part 1: evaluable disease (target or non-target lesions as per RECIST version 1.1). For Part 2: measurable disease (target lesions 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 Part 1 only, eligibility may be based on local read (using ASCO/CAP guidelines) of fresh or archived tumor biopsy. However, archived or fresh FFPE biopsy must be provided for retrospective centralized review unless otherwise approved
  10. For female patients who are not surgically sterile or post-menopausal and for male patients with a partner of child bearing potential, willingness to use 2 methods of birth control with a failure rate of less than 1% per year during the study and for 12 months after the last dose of ZW25. These include, but are not limited to, established use of oral, implanted, or injected hormonal contraceptives; placement of intra-uterine device or intra-uterine system; or use of barrier methods such as condom or diaphragm together with a spermicide product
  Exclusion Criteria:
  1. Treatment with experimental therapies within 4 weeks before first ZW25 dosing
  2. Treatment with any other cancer therapy including chemotherapy, small molecules, and antibodies within 5 half-lives of the cancer therapy before first ZW25 dosing
  3. Treatment with anthracyclines within 90 days before first ZW25 dosing or lifetime load exceeding 300 mg/m2 before first ZW25 dosing adriamycin or equivalent before first ZW25 dosing
  4. Treatment with trastuzumab, pertuzumab, lapatinib, or T‑DM1 within 3 weeks before first ZW25 dosing
  5. Untreated brain metastases (patients with treated brain metastases who are off steroids and anticonvulsants and are 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 NCI-CTCAE version 4.03, 14 July 2010
  10. Clinically significant interstitial lung disease
  11. Known active hepatitis B or C or known infection with human immunodeficiency virus
  12. Use of immunosuppressive steroids within 3 months before first ZW25 dosing, except for chronic steroid doses of ≤15 mg per day of prednisone or equivalent dose for adrenal insufficiency
  13. QTc Fridericia (QTcF) >450 ms
  14. Having clinically significant cardiac disease such as ventricular arrhythmia requiring therapy, uncontrolled hypertension (defined as persistent systolic blood pressure >150 mm Hg and/or diastolic blood pressure >100 mm Hg on antihypertensive medications), 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: not relevant