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

Official title

A First-in-Human, Open-label, Phase 1/2 Clinical Trial to Assess the Safety, Tolerability, Pharmacokinetics and Preliminary Efficacy of HMBD-501 in Patients With Advanced-Stage, Relapsed/Refractory HER3-Expressing Solid Tumors

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 HMBD-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 HMBD-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 HMBD-501. The results of the dose escalation will determine the RP2D and dosing schedule of HMBD-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 HMBD-501 in dose expansion cohorts.

Interventions

• Biological ENV-501
  ENV-501 is a HER3-targeted antibody-drug conjugate (ADC) with a humanized monoclonal antibody (mAb) conjugated with a chemotherapeutic payload via a linker.

Primary outcome measures

• Phase 1 (Dose Escalation): Frequency of treatment-emergent adverse events [Time frame: through study completion, an average of 6 months]
• Phase 2 (Dose Expansion): Objective Response Rate (ORR) [Time frame: through study completion, an average of 6 months]

Secondary outcome measures (12)

• Phase 1 (Dose Escalation): Disease Control Rate (DCR) [Time frame: through study completion, an average of 6 months]
• Phase 1 (Dose Escalation): Objective Response Rate (ORR) [Time frame: through study completion, an average of 6 months]
• Phase 1 (Dose Escalation): maximum blood concentration (Cmax) after a single dose [Time frame: At the end of Cycle 1 (each cycle is 21 days)]
• Phase 1 (Dose Escalation): time of maximum blood concentration (Tmax) after a single dose [Time frame: At the end of Cycle 1 (each cycle is 21 days)]
• Phase 1 (Dose Escalation): absorption to time t (AUC0-t) after a single dose [Time frame: At the end of Cycle 1 (each cycle is 21 days)]
• Phase 1 (Dose Escalation): absorption to end of the dosing period (AUC0-tau) after a single dose [Time frame: At the end of Cycle 1 (each cycle is 21 days)]
• Phase 1 (Dose Escalation): total absorption (AUC0-infinity) after a single dose [Time frame: At the end of Cycle 1 (each cycle is 21 days)]
• Phase 1 (Dose Escalation): drug half-life (t1/2) after a single dose [Time frame: At the end of Cycle 1 (each cycle is 21 days)]
• Phase 1 (Dose Escalation): minimum blood concentration (Cmin) after a single dose [Time frame: At the end of Cycle 1 (each cycle is 21 days)]
• Phase 1 (Dose Escalation): rate of clearance (CL) after a single dose [Time frame: At the end of Cycle 1 (each cycle is 21 days)]
• Phase 1 (Dose Escalation): steady-state volume of distribution (Vss) after a single dose [Time frame: At the end of Cycle 1 (each cycle is 21 days)]
• Phase 1 (Dose Escalation): Cmax at steady state [Time frame: through study completion, an average of 6 months]

Eligibility criteria

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:

• Unresectable or metastatic cutaneous melanoma (HER3+)
• Locally advanced or metastatic mutated EGFR (mEGFR) NSCLC (HER3+)
• Unresectable, locally advanced or metastatic breast cancer
• Relapsed or refractory solid tumors, with documented HER3+ expression such as Pancreatic Ductal Adenocarcinoma (PDAC) and gastric cancers, may be allowed in the protocol following sponsor approval on a case-by -case basis.
• If molecular pathology report to confirm HER3+ status is not available, willingness to undergo fresh tumor biopsy for retrospective assessment of HER3+ status following enrollment..
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-2.
• Contraceptive requirements:

• 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.
• 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:

• 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.
• 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:

• 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.
• 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:

• Any anti-tumor-directed drug therapy within 21 days or 5 times the elimination half-life (whichever is shorter).
• Treatment with investigational drugs within 21 days.
• Major surgery within 21 days.
• Radiation therapy ≤4 weeks or radiotherapy that included >30% of the bone marrow.
• Autologous or allogeneic stem cell transplantation or allogeneic tissue/organ transplant within 3 months.
• CYP3A4 strong inhibitor (including any prescription or non-prescription drugs or herbal supplements) ≤4 half-lives.
• CYP3A4 strong inducer ≤4 half-lives.
• 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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 5 centers

• Research Site — La Jolla
• Research Site — Indianapolis
• Research Site — Farmington Hills
• Research Site — Dallas
• Research Site — San Antonio

Australia · 2 centers

• Research Site — Campbelltown
• Research Site — Miranda

Identifiers

NCT: NCT06956690 · HMBD-501-101

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗