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Phase I Trial of ZW25 in Patients With Locally Advanced (Unresectable) and/or Metastatic HER2-expressing Cancers

Description

Brief Summary
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).


Detailed Description
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, or vinorelbine. 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.

Phase

N/A

Inclusion and Exclusion 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 gastroesophagel 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 (TG 4; ZW25 + paclitaxel) - HER2 IHC 3+ or IHC 2+/FISH+ breast cancer patients who have received prior therapy with trastuzumab, pertuzumab, and T-DM1 (TG 5; ZW25 + capecitabine) - HER2 IHC 3+ or IHC 2+/FISH+ breast cancer patients (TG 6) 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
  • 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)

  • 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/m

Sites

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