Overview

This study is a Phase 1/2, first-in-human, open-label, clinical trial to assess the safety, tolerability, pharmacokinetics and preliminary efficacy of ENV-501 in patients with advanced-stage, relapsed and/or refractory human epidermal growth factor receptor 3 (HER3)-expressing solid tumors. The study consists of 2 phases: a dose escalation phase (Phase 1) and a dose expansion phase (Phase 2).

The primary objectives of Phase 1 are to characterize the overall safety and tolerability profile of increasing doses of ENV-501 in patients with advanced-stage solid tumors and identify the recommended Phase 2 dose (RP2D) of ENV-501. During Phase 1, successive cohorts of patients will receive escalating doses of ENV-501. The results of the dose escalation will determine the RP2D and dosing schedule of ENV-501 to be administered in the Phase 2 part of the study. The primary objective of Phase 2 is to evaluate the preliminary clinical efficacy of ENV-501 in dose expansion cohorts.

Eligibility

Inclusion Criteria:

• Body weight ≥ 40 kg.
• Willing and able to provide signed written informed consent before any study-related screening procedures are performed.
• Patients with histologically or cytologically confirmed diagnosis of advanced-stage or metastatic HER3+ solid tumors that are relapsed or refractory to or ineligible for standard therapy, or for whom no standard therapy is available; or the patient has documented their refusal of standard of care therapies. These include the

  following

  1. Unresectable or metastatic cutaneous melanoma (HER3+)
  2. Locally advanced or metastatic mutated EGFR (mEGFR) NSCLC (HER3+)
  3. Unresectable, locally advanced or metastatic hormone receptor (HR)+/human epidermal growth factor receptor 2 (HER2)- breast cancer (HER3+)

• If molecular pathology report to confirm HER3+ status is not available, willingness

  to undergo fresh tumor biopsy for assessment of HER3+ status.

• Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-2.
• Contraceptive requirements:
  1. Women of childbearing potential (WOCBP) must use contraception from at least 28 days prior to study start, during the study, and for at least 6 months after the last dose of study drug.
  2. Males who are sexually active with partner(s) who are WOCBP must agree to use a male condom with spermicide beginning at study start, during the study and for at least 6 months after the last dose of study drug.
• Females must:
  1. Agree to not donate eggs (ova, oocytes) for the purposes of assisted reproduction during the study and for at least 6 months after the last dose of study drug.
  2. Agree to not breastfeed and do not plan to become pregnant during the study and for at least 6 months after the last dose of study drug.
• Males must:
  1. Agree to not donate sperm beginning at study start, during the study, and for at least 6 months after the last dose of study drug.
  2. Agree to not plan to father a child beginning at study start, during the study, and for at least 6 months after last dose of study drug.
• Willingness and ability to comply with scheduled visits, treatment plan, laboratory

  tests, and other study procedures.

Exclusion Criteria:

• Any of the following treatment interventions within the specified time frame prior to study drug administration at study start:
  1. Any anti-tumor-directed drug therapy within 21 days or 5 times the elimination half-life (whichever is shorter).
  2. Treatment with investigational drugs within 21 days.
  3. Major surgery within 21 days.
  4. Radiation therapy ≤4 weeks or radiotherapy that included >30% of the bone marrow.
  5. Autologous or allogeneic stem cell transplantation or allogeneic tissue/organ transplant within 3 months.
  6. CYP3A4 strong inhibitor (including any prescription or non-prescription drugs or herbal supplements) ≤4 half-lives.
  7. CYP3A4 strong inducer ≤4 half-lives.
  8. OATP1B inhibitor (including any prescription or non-prescription drugs or herbal supplements) ≤4 half-lives.
• Prior treatment with a HER3-targeted ADC or any exatecan- or

  exatecan-derivative-conjugated ADC inhibitor as last line of therapy.

• Prior treatment with a topoisomerase I inhibitor as last line of therapy.
• Primary immune deficiency (e.g. congenital syndromes).
• Active and uncontrolled infections requiring intravenous antibiotic or antiviral treatment within 2 weeks prior to study start.
• Known/suspected hypersensitivity against ENV-501, human or humanized immunoglobulin Gs (IgGs), or their ingredients.
• History of noninfectious or drug-induced pneumonitis or interstitial lung disease (ILD).
• Known seropositivity (except after vaccination or confirmed cure for hepatitis) for human immunodeficiency virus (HIV), hepatitis B virus (HBV), or hepatitis C virus (HCV).
• Leptomeningeal disease, symptomatic or uncontrolled (active) brain metastasis (note: brain metastases not requiring steroids or anti-epileptic therapy are allowed if stable for ≥4 weeks prior to study start and patient is neurologically stable).
• Pregnant or WOCBP who have a positive b-human chorionic gonadotropin (HCG) test result at Screening or within 7 days prior to study start.
• Patients with second malignancies that are active (uncontrolled, metastatic) or requiring therapy.
• Patient who is an immediate family member (spouse, parent, child, or sibling; biological or legally adopted) of personnel directly affiliated with the study site or the Sponsor.