ARX517 as Monotherapy and in Combination Regimens in Subjects With Metastatic Castration-resistant Prostate Cancer

Study Overview
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Brief Summary
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This is a phase 1/2 study to assess the safety and tolerability of ARX517 as monotherapy or in combination in adult subjects with Metastatic castration-resistant prostate cancer (mCRPC).

Detailed Description
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This is a first-in-human, Phase 1/2, multicenter, open-label study to evaluate the safety, PK, PDy, and preliminary anti-tumor activity of ARX517 as monotherapy or in combination in adult subjects with mCRPC with serum testosterone level < 50 ng/dL at screening who are resistant or refractory to standard therapies. Phase 1a (dose-escalation) and Phase 1b (dose-expansion) stages will identify the MTD and/or RP2Ds. Phase 2 will randomize subjects to receive ARX517 at the RP2Ds or ICT as comparator. The ICT to be used in Phase 2 will be determined after reviewing all available clinical data in Phase 1.

Official Title
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A Phase 1/2, Multicenter, Open-Label, Dose-escalation, and Dose-expansion Study to Evaluate the Safety, Pharmacokinetics, and Anti-tumor Activity of ARX517 as Monotherapy and in Combination Regimens, With Randomized Comparison to Investigator's Choice of Treatment, in Subjects With Metastatic Castration-resistant Prostate Cancer Who Are Resistant or Refractory to Prior Standard Therapies

Conditions
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Prostate Cancer

Intervention / Treatment
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* Drug: ARX517
* Drug: Enzalutamide


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Male subjects ≥ 18 years at the first time of providing written informed consent. Histologically confirmed prostate adenocarcinoma. Documented metastatic disease and evidence of disease progression Castration-resistant prostate cancer defined as surgical or medical castration with serum testosterone levels of ≤ 50 ng/dL (1.73 nM) at Screening. For patients who have not undergone an orchiectomy, must be undergoing treatment with a luteinizing hormone-releasing hormone (LHRH) agonist or antagonist and must agree to continue such therapy while on study treatment. Ongoing therapy with (and willing to continue with) a gonadotropin-releasing hormone agonist or antagonist (unless prior orchiectomy) AND serum testosterone level < 50 ng/dL at Screening. Prior receipt of the following for metastatic prostate cancer: at least two lines of treatment at least two Food and Drug Administration (FDA)-approved therapies with at least one being a second-generation androgen receptor signaling inhibitor (e.g., abiraterone, darolutamide, apalutamide, or enzalutamide). Adequate blood counts Key Exclusion Criteria: Symptomatic and/or untreated central nervous system (CNS) metastases. Patients with asymptomatic, untreated CNS metastases are eligible provided they have been clinically stable (neurologically stable and not requiring steroids for at least 28 days prior to enrollment) History of any invasive malignancy (other than primary) within previous 2 years prior to the enrollment date that requires active therapy Marked baseline prolongation of QT/QT interval corrected for heart rate (QTc), e.g., a triplicate average QTc interval > 480 milliseconds (CTCAE Grade 1) using Fridericia's QT correction formula. Prior history of interstitial lung disease, pneumonitis, or other clinically significant lung disease within 12 months prior to enrollment date Clinically significant ocular findings by a qualified ophthalmologist or optometrist including active ocular infections or chronic corneal disorders Phase 1b combination cohort subjects only: Any gastrointestinal disorder, including stents, defects or malabsorption, that would interfere with absorption of orally administered study drug in the opinion of the investigator. Phase 1b combination cohort subjects only: Prior receipt of strong CYP2C8 inhibitors, strong CYP3A4 inducers, and CYP3A4, CYP2C9 and CYP2C19 substrates with a narrow therapeutic index within 14 days or five half-lives (if known), whichever is shorter, prior to enrollment. If discontinuation is medically not feasible, enrollment may be allowed with Sponsor approval.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: This is a first-in-human, Phase 1/2, multicenter, open-label study to evaluate the safety, PK, PDy, and preliminary anti-tumor activity of ARX517 as monotherapy or in combination in adult subjects with mCRPC with serum testosterone level < 50 ng/dL at screening who are resistant or refractory to standard therapies. Phase 1a (dose-escalation) and Phase 1b (dose-expansion) stages will identify the MTD and/or RP2Ds. Phase 2 will randomize subjects to receive ARX517 at the RP2Ds or ICT as comparator. The ICT to be used in Phase 2 will be determined after reviewing all available clinical data in Phase 1.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ARX517 Alone and Combination Cohorts (Phase 1)<br>Monotherapy: ARX517 will be administered via intravenous (IV) infusion every 3, or 4 weeks. Combination Cohorts: ARX517 + enzalutamide | Drug: ARX517<br>* ARX517 is an ADC consisting of a humanized anti-PSMA monoclonal antibody (mAb) (IgG1κ) covalently conjugated to two (2) proprietary microtubule-disrupting toxins referred to as AS269.<br>Drug: Enzalutamide<br>* Enzalutamide is the FDA approved drug<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1: Assess incidence of adverse events | Incidence and severity of adverse events or serious adverse events of ARX517 will be assessed to determined the safety and tolerability of the treatment using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events version 5 (CTCAE). | 1.5 Years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1: Area under the serum concentration-time curve (AUC) for ARX517 | Pharmacokinetic parameter area under the serum concentration-time curve (AUC) will be analyzed through different analytes such as ADC, total antibody, and pAF-AS269 | 3 Year | 
| Phase 1: Area under the serum concentration-time curve (AUC) for enzalutamide | Pharmacokinetic parameter area under the serum concentration-time curve (AUC) will be analyzed | 3 Year | 
| Phase 1: Maximum serum concentration (Cmax) for ARX517 | Pharmacokinetic parameter maximum serum concentration (Cmax) will be analyzed through different analytes such as, ADC, total antibody, and pAF-AS269 | 3 Year | 
| Phase 1: Maximum serum concentration (Cmax) for enzalutamide | Pharmacokinetic parameter maximum serum concentration (Cmax) will be analyzed | 3 Year | 
| Phase 1: Trough concentration (Ctrough) for ARX517 | Pharmacokinetic parameter trough concentration (Ctrough) will be analyzed through different analytes such as, ADC, total antibody, and pAF-AS269 | 3 Year | 
| Phase 1: Trough concentration (Ctrough) for enzalutamide | Pharmacokinetic parameter trough concentration (Ctrough) will be analyzed. | 3 Year | 
| Phase 1: Incidence of ADA against ARX517 | To assess the incidence of anti-drug antibodies (ADA) against ARX517 at selected timepoints | 3 year | 
| Overall survival (OS) | Overall survival (OS) is defined as the time from first dose of study therapy to the date of death (any cause). Subjects who are alive will be censored at the last known time that the subject was alive. | 3 year | 
| Assess changes in serum prostate specific antigen (PSA) levels | Proportion of subjects who show a confirmed reduction of 30% and 50% from baseline in serum prostate specific antigen (PSA) levels (PSA30, PSA50) | 3 year | 
| Progression-free survival (PFS) | PFS is defined as the time between date of first dose of study therapy and date of progression or death, whichever occurs first, will be computed for response evaluable subjects. Subjects will be censored at time of subsequent therapy | 3 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ADC, Antibody drug conjugate, Prostate neoplasma, Castration-resistant, PSA increased, PSMA, Prostate specific membrane antigen, PSMA ADC, Prostate Cancer