A Phase 1/2 Clinical Trial to Assess the Safety, Tolerability, Pharmacokinetics and Preliminary Efficacy of ENV-501 in Patients With HER3-Expressing Solid Tumors

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.

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.