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.
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.
