A Study of ARV-766 Given by Mouth in Men With Metastatic Prostate Cancer

Phase 2Active Not RecruitingNCT05067140

Novartis Pharmaceuticals164 enrolled

Overview

This first-in-human, Phase 1/2, open-label study evaluates the safety, tolerability, pharmacokinetics, and preliminary antitumor activity of JSB462 (luxdegalutamide, previously ARV-766) administered as monotherapy and in combination with abiraterone in participants with metastatic prostate cancer. The study includes dose-escalation and cohort expansion components to determine the recommended Phase 2 dose and assess clinical activity.

The study consists of multiple parts. 1. Part A evaluates JSB462 monotherapy in a dose-escalation setting to determine safety, tolerability, dose-limiting toxicities, and the maximum tolerated dose or recommended Phase 2 dose (RP2D). Dose escalation follows an accelerated titration design transitioning to a 3+3 design. 2. Part B is a randomized cohort expansion evaluating JSB462 monotherapy at selected dose levels (e.g., 100 mg or 300 mg once daily) to further assess safety and preliminary antitumor activity at the RP2D. Participants are randomized in a 1:1 ratio. 3. Part C evaluates JSB462 in combination with abiraterone, administered with corticosteroid and ongoing androgen deprivation therapy. This part assesses safety, tolerability, pharmacokinetics, and defines a recommended dose for the combination regimen. An abiraterone lead-in period is implemented prior to combination treatment. The study population includes adult males with metastatic prostate cancer. In Parts A and B, participants have metastatic castration-resistant prostate cancer (mCRPC) following prior systemic therapy. Part C includes participants with metastatic prostate cancer, including those who may be naïve to novel hormonal agents. Primary objectives focus on safety and tolerability, including incidence of adverse events, laboratory abnormalities, and dose-limiting toxicities. In the expansion phase, antitumor activity is evaluated using prostate-specific antigen (PSA) response rates (e.g., PSA30 and PSA50). Secondary objectives include characterization of pharmacokinetics and further assessment of antitumor activity using endpoints such as objective response rate, radiographic progression-free survival, duration of response, and time to PSA progression. Tumor assessments are performed using modified Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 for soft tissue disease and Prostate Cancer Working Group 3 (PCWG3) criteria for bone disease, with imaging conducted at regular intervals. This study aims to characterize the clinical profile of JSB462 and explore its potential to overcome resistance mechanisms associated with androgen receptor signaling in metastatic prostate cancer.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

164

Conditions

Prostate Cancer Metastatic

Interventions

ARV-766DRUG

Parts A and C: Daily oral dosages are determined by cohort review committee after initial starting dose cohort and each subsequent cohort completes 28 days of treatment. Part B: 100mg or 300mg oral tablet(s) once daily in 28 day cycles.

AbirateroneDRUG

Abiraterone is administered orally in combination with ARV-766, typically on an empty stomach with water, in accordance with prescribing information and standard clinical practice.

Corticosteroid (e.g., prednisone/prednisolone)DRUG

Prednisone or prednisolone was administered in accordance with local prescribing information during treatment with abiraterone acetate.

Eligibility

Sex: MALEMin age: 18 Years

Medical Language ↔ Plain English

Key Inclusion Criteria for Parts A, B, and C: * Participants must be able to take oral medication without crushing, dissolving, or chewing tablets * Histological, pathological, or cytological confirmed diagnosis of adenocarcinoma of the prostate * Progression on approved systemic therapies for metastatic prostate cancer (at least one must be a second-generation androgen inhibitor, e.g., abiraterone, enzalutamide, darolutamide, apalutamide) (Parts A and B only) * Progressive mCRPC (Parts A and B only) defined as: * Serum testosterone levels \<50 ng/dL (or ≤0.50 ng/mL or 1.73 nmol/L) using testosterone assays with a sensitivity of ≤30 ng/dL, within 28 days before study drug treatment * Radiographic evidence of metastatic disease (soft tissue disease per modified RECIST 1.1 criteria or bone disease per PCWG3) * Disease progression on or following the most recent systemic therapy * Ongoing androgen deprivation therapy (ADT) with a gonadotropin releasing hormone analog or inhibitor, or orchiectomy (surgical or medical castration) (Parts A and B only) * Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 * Metastatic castration resistant or sensitive prostate cancer with radiographic evidence of metastatic disease (soft tissue disease per modified RECIST 1.1 criteria or bone disease per PCWG3) (Part C) Key Exclusion Criteria for Parts A, B, and C: * Known symptomatic brain metastases requiring steroids (above physiologic replacement doses) * Any other active malignancy within 3 years prior to enrollment, except for adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ or other low grade localized cancer. Eligibility for exception requires Sponsor approval * Any of the following in the previous 12 months: myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure (New York Heart Association class III or IV), cerebrovascular accident, transient ischemic attack, symptomatic pulmonary embolism, or other clinically significant episode of thromboembolic disease * Any of the following in the previous 6 months: congenital long QT syndrome, Torsade de Pointes, arrhythmias (including sustained ventricular tachyarrhythmia and ventricular fibrillation), left anterior hemiblock (bifascicular block). Ongoing cardiac dysrhythmias of National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Events (CTCAE) Grade ≥2, atrial fibrillation of any grade (Grade ≥2 in the case of asymptomatic lone atrial fibrillation). Anticoagulation (heparin/lovenox only) can be allowed if indicated * QTcF \>480 msec at baseline based on ECG * Active inflammatory gastrointestinal disease, chronic diarrhea, diverticulitis, or previous gastric resection or lap band surgery * Participants taking sensitive BCRP and P-glycoprotein (P-gp) substrates or substrates with narrow therapeutic indices, strong CYP3A4 inhibitors and inducers, restricted medications described in the study protocol and the Investigator's Brochure, and additionally for Part C, CYP2D6 substrates with a narrow therapeutic index * Inadequate bone marrow function defined as follows (with no transfusion of blood products or use of hematopoietic growth factors in the 28 days prior to start of therapy): * Absolute neutrophil count \<1,500/mm3 or \<1.5 × 109/L * Platelets \<100,000/mm3 or \<100 × 109/L * Hemoglobin \<9 g/dL * Inadequate renal function defined as estimated creatinine clearance (Clcr) ≤60 mL/min using Cockcroft-Gault formula or eGFR ≤60 mL/min/1.73m3 using the CKD-EPI equation * Electrolyte imbalances of clinically significant hypokalemia, hypomagnesemia, and/or hypocalcemia (Part C only) * Inadequate liver function defined as: * Total serum bilirubin \>1.5× upper limit of normal (ULN) unless the participant has documented Gilbert syndrome * Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) of \>2.5× ULN if there is NO liver involvement secondary to tumor OR \>5.0× ULN if there is liver involvement secondary to tumor * Prior treatment with a second-generation NHA such as abiraterone, enzalutamide, darolutamide, or apalutamide (Part C only). Note: prior chemotherapy is allowed. Other inclusion/exclusion criteria may apply.

Locations (17)

City of Hope National Medical

Duarte, California, United States

University of California San Diego - Moores Cancer Center

La Jolla, California, United States

Outcomes

Primary Outcomes

Part A: Incidence and severity of dose limiting toxicities (DLTs) during the first cycle of treatment

Number and proportion of participants experiencing dose-limiting toxicities during the DLT evaluation period to assess safety and determine the maximum tolerated dose (MTD) of ARV-766 and/or recommended Phase 2 dose (RP2D)

Time frame: Up to 28 days

Part C: Incidence and severity of dose limiting toxicities (DLTs) during the first cycle of treatment

Number and proportion of participants experiencing dose-limiting toxicities during the DLT evaluation period to determine the recommended dose of ARV-766 in combination with abiraterone

Time frame: Up to 28 Days

Parts A and C: Incidence rate of Adverse Events (AEs) and Serious Adverse Events (SAEs)

Adverse events as characterized by type, frequency, severity (as graded by NCI CTCAE v 5.0), timing, seriousness, and relationship to study drug.

Time frame: From first dose through approximately 30 days after last dose

Parts A and C: Incidence of laboratory abnormalities

Laboratory abnormalities as characterized by type, frequency, severity (as graded by NCI CTCAE v 5.0), and timing.

Time frame: From first dose through approximately 30 days after last dose

Part B: Prostate-Specific Antigen 30% Response Rate (PSA30)

Prostate Specific Antigen 30 (PSA30) Rate is defined as the proportion of participants who achieve a ≥30% decrease from baseline at any timepoint, confirmed by a second PSA measurement ≥3 weeks without any PSA progression in between

Time frame: 12 Weeks

Part B: Prostate-Specific Antigen 50% Response Rate (PSA50)

Prostate Specific Antigen 50 (PSA50) Rate is defined as the proportion of participants who achieve a ≥50% decrease from baseline at any timepoint, confirmed by a second PSA measurement ≥3 weeks without any PSA progression in between

Data from ClinicalTrials.gov

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Secondary Outcomes

Part A: Prostate-Specific Antigen 30% Response Rate (PSA30)

Time frame: 12 Weeks

Part A: Prostate-Specific Antigen 50% Response Rate (PSA50)

Time frame: 12 Weeks

Part A: Objective Response Rate (ORR)

Overall Response Rate (ORR) is defined as the proportion of participants achieving a confirmed complete response (CR) or partial response (PR) per PCWG3-modified RECIST 1.1 as assessed by the investigator

Time frame: 12 Weeks

Parts A and B: Radiographic Progression-Free Survival (rPFS)

Time from first dose to radiographic disease progression per modified RECIST Version 1.1 for soft tissue lesions and PCWG3 criteria for bone lesions, or death from any cause.

Time frame: Baseline to radiographic progression or death, whichever occurs first, assessed up to 68 months

Parts A and B: Duration of Response (DoR)

Duration of Response (DOR) is defined as the time between first documented CR/PR and disease progression or death due to any cause per PCWG3-modified RECIST 1.1 as assessed by the investigator

Time frame: From first documented response to disease progression or death, whichever occurs first, assessed up to 68 months

Parts A and B: Time to Prostate-Specific Antigen Progression

Time to PSA progression is the time interval from the date of first study drug dose to the date of PSA progression. The PSA progression date is defined as the date that a ≥25% increase and an absolute increase of ≥2 ng/mL above the nadir is documented, which is confirmed by a second consecutive value obtained 3 or more weeks later

Time frame: Baseline to prostate-specific antigen progression, assessed up to 68 months

Part A: Area Under the plasma Concentration-Time Curve (AUC) of ARV-766

Venous whole blood samples will be collected for ARV-766 characterization. Area under the plasma concentration-time curve from time zero to the time of last quantifiable concentration (AUClast), Area under the plasma concentration-time curve from time zero (pre-dose) extrapolated to infinite time (AUCinf) and Area under the plasma concentration-time curve from time zero during a dosing interval (AUCtau) will be listed and summarized using descriptive statistics.

Time frame: Cycle 1: Days 1 & 21 (0, 1, 2, 3, 4, 6, 8 and 12 hours), Day 2 (0 hour). Cycle 2 and beyond (0 hour). End of Treatment Visit (EOT): within 4 weeks from the last dose of ARV-766. 1 cycle = 28 days.

Part A: Maximum Observed Concentration (Cmax) of ARV-766

Venous whole blood samples will be collected for ARV-766 characterization. Cmax will be listed and summarized using descriptive statistics.

Part A: Time to Maximum Concentration (Tmax) of ARV-766

Venous whole blood samples will be collected for ARV-766 characterization. Tmax will be listed and summarized using descriptive statistics.

Part A: Last Measurable Concentration (Clast) of ARV-766

Venous whole blood samples will be collected for ARV-766 characterization. Clast will be listed and summarized using descriptive statistics.

Part A: Minimum Observed Concentration (Cmin) of ARV-766

Venous whole blood samples will be collected for ARV-766 characterization. Cmin will be listed and summarized using descriptive statistics.

Part A: Apparent total body clearance (CL/F) of ARV-766

Venous whole blood samples will be collected for ARV-766 characterization. CL/F will be listed and summarized using descriptive statistics.

Part A: Apparent Volume of Distribution (Vd/F) of ARV-766

Venous whole blood samples will be collected for ARV-766 characterization. Vd/F will be listed and summarized using descriptive statistics.

Part B: Incidence rate of Adverse Events (AEs) and Serious Adverse Events (SAEs)

Adverse events as characterized by type, frequency, severity (as graded by NCI CTCAE v 5.0), timing, seriousness, and relationship to study drug.

Time frame: From first dose through approximately 30 days after last dose

Part B: Incidence of laboratory abnormalities

Laboratory abnormalities as characterized by type, frequency, severity (as graded by NCI CTCAE v 5.0), and timing.

Time frame: From first dose through approximately 30 days after last dose

Part C: Area Under the plasma Concentration-Time Curve (AUC) of Abiraterone/ARV-766

Venous whole blood samples will be collected for Abiraterone/ARV-766 characterization. Area under the plasma concentration-time curve from time zero to the time of last quantifiable concentration (AUClast), Area under the plasma concentration-time curve from time zero (pre-dose) extrapolated to infinite time (AUCinf) and Area under the plasma concentration-time curve from time zero during a dosing interval (AUCtau) will be listed and summarized using descriptive statistics.

Time frame: Cycle 1 Days -8, -1, 1, 21, and 28; Cycle 2 Day 28; and Cycle ≥3 Day 28 (odd cycles only), with intensive post-dose PK on Days -1, 1, and 21; End of Treatment Visit (EOT): within 4 weeks from the last dose of ARV-766. 1 cycle = 28 days.

Part C: Maximum Observed Concentration (Cmax) of ARV-766

Venous whole blood samples will be collected for ARV-766 characterization. Cmax will be listed and summarized using descriptive statistics.

Part C: Time to Maximum Concentration (Tmax) of ARV-766

Venous whole blood samples will be collected for ARV-766 characterization. Tmax will be listed and summarized using descriptive statistics.

Part C: Last Measurable Concentration (Clast) of ARV-766

Venous whole blood samples will be collected for ARV-766 characterization. Clast will be listed and summarized using descriptive statistics.

Part C: Minimum Observed Concentration (Cmin) of ARV-766

Venous whole blood samples will be collected for ARV-766 characterization. Cmin will be listed and summarized using descriptive statistics.

Part C: Apparent total body clearance (CL/F) of ARV-766

Venous whole blood samples will be collected for ARV-766 characterization. CL/F will be listed and summarized using descriptive statistics.

Part C: Apparent Volume of Distribution (Vd/F) of ARV-766

Venous whole blood samples will be collected for ARV-766 characterization. Vd/F will be listed and summarized using descriptive statistics.