Metastatic Prostate Cancer
Conditions
Keywords
ADC, Antibody drug conjugate, Prostate neoplasia, Metastatic castration-resistant prostate cancer, PSMA, Prostate specific membrane antigen, PSMA ADC, Prostate Cancer
Brief summary
This is a phase 1 study to assess the safety and tolerability of ARX517 as monotherapy or combination therapy in adult subjects with metastatic prostate cancer (mPC).
Detailed description
This is a first-in-human (FIH), Phase 1, multicenter, open-label, dose-escalation and dose-expansion study to evaluate the safety, PK, pharmacodynamic (PDy), and preliminary anti-tumor activity of ARX517 alone, or in combination with androgen receptor pathway inhibitors (ARPIs), in adult subjects with metastatic prostate cancer .
Interventions
DRUGARX517
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.
DRUGApalutamide
Oral tablet and will be given once daily by mouth.
DRUGAbiraterone acetate
Oral tablet and will be given once daily by mouth.
DRUGPrednisone
Oral tablet and will be given once daily in metastatic castration-sensitive prostate cancer( mCSPC) and twice daily in metastatic castration-resistant prostate cancer (mCRPC) cohort by mouth.
Sponsors
Janssen Research & Development, LLC
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
This study has dose-escalation (Phase 1a) and dose-expansion (Phase 1b) stages to identify the maximum tolerated dose (MTD) and/or recommended development doses (RDDs) of ARX517. The initial treatment regimen is by weight-based infusion at an interval of every 3 weeks. In the Phase 1b dose expansion stage, the Sponsor will evaluate cohorts with alternative dose regimens to determine RDD(s). The term "alternative dose regimen" refers to any monotherapy treatment regimen where ARX517 is not given at a fixed interval of every 3 weeks. In the Phase 1b dose expansion stage, the Sponsor will also evaluate the safety and preliminary anti-tumor activity of ARX517 in combination with ARPIs (apalutamide or abiraterone acetate plus prednisone). ARPIs will be administered at the approved doses per product information. The starting dose of ARX517 to be given in combination with ARPIs will be determined by data emerging from the monotherapy dose expansion stage.
Eligibility
Sex/Gender
MALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Male and ≥18 years at the time of providing written informed consent. * Histologically confirmed prostate adenocarcinoma. * For subjects 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. Subjects enrolled to mCRPC cohorts must have serum testosterone levels of ≤50ng/dL (1.73nM at Screening). * Must receive prior treatment(s) as defined in the protocol for each cohort * Documented evidence of disease progression on or after the most-recent prior regimen for mCRPC cohorts * mCSPC combination cohorts: High volume metastatic disease documented by CT/MRI and/or 99mTC bone scan (for bone lesions) * Adequate blood counts * Must have at least 1 PSMA-positive metastatic lesion and no measurable PSMA-negative lesions by local assessment for alternative dosing regimen and combination cohorts. Key
Exclusion criteria
* Receipt of chemotherapy within 21 days prior to enrollment; hormonal therapy (not including LHRH analogs) within 7 days prior to enrollment; palliative radiation therapy within 7 days prior to enrollment; or any other anticancer therapy within 21 days prior to enrollment or other therapy for monotherapy cohorts * Receipt of more than 1 prior taxane regimen or non-taxane chemotherapy for prostate cancer for alternative dose regimen and mCRPC combination cohorts * Receipt prior apalutamide, enzalutamide, or darolutamide, or AAP for mCRPC combination cohorts * Receipt any prior chemotherapy or prior ARPI, and must be greater than 90 days of ADT prior to enrollment for mCSPC combination cohorts * Use of chronic systemic glucocorticoids equivalent to \> 10 mg prednisone daily. Note: short-term administration of systemic corticosteroids \> 10 mg prednisone equivalent (e.g., for allergic reactions or management of immune- or infusion-related AEs) is allowed. * 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 the previous 2 years prior to the enrollment date that requires active therapy or is at high risk of recurrence in the opinion of the investigator. * Marked baseline prolongation of QT/QT interval corrected for heart rate (QTc), e.g., a triplicate-average QTc interval \> 480 milliseconds (CTCAE Grade 2) using Fridericia's QT correction formula at any time within 28 days before enrollment, ongoing history of CTCAE Grade ≥2 QTc at enrollment, or anticipated need to perform repeat ECG evaluations to satisfy re-treatment criteria. * 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 unless approved by the Medical Monitor. * Peripheral neuropathy Grade ≥ 2 within 28 days prior to enrollment. * For combination cohorts with apalutamide: no prior history of seizure or condition that may predispose to seizure (including but not limited to prior cerebrovascular accident, TIA or loss of consciousness within the last 12 months, brain AVM, brain metastases). * 24-hour urine protein \> 1g/24h
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Assess incidence of adverse events | 1.5 Years | Incidence and severity of adverse events or serious adverse events of ARX517 alone or in combination with ARPIs will be assessed to determine the safety and tolerability of the treatment using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events version 5 (CTCAE). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Area under the serum concentration-time curve (AUC) for ARX517 alone or in combination with ARPIs | 3 Year | Pharmacokinetic parameter area under the serum concentration-time curve (AUC) will be analyzed through different analytes such as ADC, total antibody, and pAF-AS269 |
| Maximum serum concentration (Cmax) for ARX517 alone or in combination with ARPIs | 3 Year | Pharmacokinetic parameter maximum serum concentration (Cmax) will be analyzed through different analytes such as, ADC, total antibody, and pAF-AS269 |
| Trough concentration (Ctrough) for ARX517 alone or in combination with ARPIs | 3 Year | Pharmacokinetic parameter trough concentration (Ctrough) will be analyzed through different analytes such as, ADC, total antibody, and pAF-AS269 |
| Incidence of ADA against ARX517 alone or in combination with ARPIs | 3 year | To assess the incidence of anti-drug antibodies (ADA) against ARX517 at selected timepoints |
| Overall survival (OS) | 3 year | 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. |
| Assess changes in serum prostate specific antigen (PSA) levels | 3 year | Proportion of subjects who show a confirmed reduction of 30%, 50%,and 90% from baseline in serum prostate specific antigen (PSA) levels (PSA30, PSA50, PSA 90) |
| Progression-free survival (PFS) | 3 year | 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 |
Countries
United States
Contacts
STUDY_DIRECTORJanssen Research & Development, LLC Clinical Trial
Janssen Research & Development, LLC
Outcome results
None listed