A Study to Investigate the Safety and Tolerability of Oral INR731 Single Agent or in Combination With Androgen Receptor Pathway Inhibitor (ARPI) in Patients With Metastatic Prostate Cancer

Phase 1RecruitingNCT07570979

Novartis Pharmaceuticals208 enrolled

Overview

The purpose of this study is to assess the safety, tolerability, pharmacokinetics/pharmacodynamics, preliminary anti-tumor activity, and recommended dose of INR731 as a single agent and in combination with standard-of-care androgen receptor pathway inhibitors (ARPIs) in adult patients with metastatic prostate cancer.

This is a first-in-human, open-label, phase I, multi-center study which consists of three treatment arms: INR731 single agent (Arm A), and INR731 in combination with enzalutamide (Arm B) or abiraterone (Arm C). The single agent arm has a dose escalation part followed by a dose expansion part. Once the single agent recommended dose(s) is determined during dose escalation, the study may proceed to dose expansion to further explore safety, tolerability and preliminary anti-tumor activity. The single agent dose expansion part will include a post-standard of care (SOC) metastatic castration resistant prostate cancer (mCRPC) group and patients with time to castration resistance (TTCR) \<12 months. The combination arms have a dose escalation of INR731 in combination with enzalutamide or abiraterone followed by a dose expansion of INR731 in combination with enzalutamide only. The combination dose escalation will be conducted in patients with mCRPC who have progressed following standard of care (post-SOC). During combination escalation, once the safety and tolerability of INR731 with the combination agent(s) is assessed, the study may proceed to dose expansion. The combination dose expansion part will include first-line (1L) mCRPC patients with no prior treatment in the mCRPC setting.

Study Type

INTERVENTIONAL

Allocation

NON_RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

208

Conditions

Eligibility

Sex: MALEMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: * An Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) ≤2. * Participants must have histological and/or cytological confirmation of adenocarcinoma of the prostate. Participants with mixed histology (neuroendocrine) are eligible as long as the non-adenocarcinoma feature is the minority component. * At least 1 metastatic lesion (according to local radiology assessment by the investigator) present on baseline CT, MRI, or bone scan imaging obtained ≤28 days prior to Cycle 1 Day 1 (C1D1). * Patients must have a castrate level of serum/plasma testosterone (\<50 ng/dL or \<1.7 nmol/L). * Ongoing androgen deprivation therapy (ADT) either via orchiectomy and/or ongoing gonadotropin-releasing hormone (GnRH) analog or inhibitor is allowed. * Participants must be mCRPC patients who have either progressed on or are not candidates for other SOC. Prior taxane, poly(ADP) ribose polymerase (PARP) inhibitor, and lutetium Lu 177 vipivotide tetraxetan (Pluvicto) are allowed. Combination expansion patients, however, must be 1L mCRPC with no prior treatment in the mCRPC setting. Treatment within the mHSPC setting does not affect eligibility. Exclusion Criteria: * Age \< 18 years old. * Histological and/or cytological confirmation of non-adenocarcinoma of the prostate. * Patients with biochemical recurrence only or those without evidence of metastatic disease by radiographical imaging (CT/MRI or bone scan) are not eligible. * Patients previously treated with a cereblon-based degrader. * Patients who are HIV+ or immune compromised. * Use of agents known to prolong QT interval unless they can be permanently discontinued for the duration of the study * Treatment with an investigational agent within 7 days (or 5 half-lives, whichever is longer) of the anticipated Cycle 1 Day 1 (C1D1). Other protocol-defined inclusion/exclusion criteria may apply.

Locations (9)

Mass General Hospital

Boston, Massachusetts, United States

RECRUITING

Mary Crowley Cancer Research

Dallas, Texas, United States

RECRUITING

Novartis Investigative Site

Melbourne, Victoria, Australia

RECRUITING

Novartis Investigative Site

Toronto, Ontario, Canada

RECRUITING

Novartis Investigative Site

Montreal, Quebec, Canada

RECRUITING

Novartis Investigative Site

Dresden, Saxony, Germany

RECRUITING

Novartis Investigative Site

Hirakata, Osaka, Japan

RECRUITING

Novartis Investigative Site

Seoul, South Korea

RECRUITING

Novartis Investigative Site

Seoul, South Korea

RECRUITING

Outcomes

Primary Outcomes

Incidence and severity of dose-limiting toxicities (DLTs)

A DLT is defined as an adverse event or abnormal laboratory value of Common Terminology Criteria for Adverse Events (CTCAE) grade ≥ 3 that occurs within the first 28 days and not clearly and incontrovertibly assessed as due to disease progression, intercurrent illness, concomitant medication, or extraneous causes with the exceptions defined in the study protocol. Other clinically significant toxicities may be considered to be DLTs, even if not CTCAE grade 3 or higher.

Time frame: 28 days

Incidence and severity of Adverse Events (AEs) and Serious Adverse Events (SAEs)

Incidence and severity of AEs and SAEs, including changes in laboratory values, vital signs and electrocardiograms (ECGs) qualifying and reported as AEs.

Time frame: Up to approximately 24 months

Frequency of dose interruptions and reductions

Number of participants with dose interruptions and/or reductions to assess the tolerability.

Time frame: Up to approximately 24 months

Dose intensity

Dose intensity defined as the ratio of actual cumulative dose received and actual duration of exposure.

Time frame: Up to approximately 24 months

Secondary Outcomes

Overall Response Rate (ORR)

ORR is defined as proportion of patients achieving a confirmed complete response (CR) or partial response (PR) per Prostate Cancer Working Group 3 (PCWG3)-modified Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) as assessed by the investigator.

Time frame: Up to approximately 24 months

Disease Control Rate (DCR)

DCR is defined as proportion of patients achieving a CR, PR or stable disease (SD) per PCWG3-modified RECIST v1.1 as assessed by the investigator.

Time frame: Up to approximately 24 months

Radiological Progression Free Survival (rPFS)

rPFS is defined as the time from the date of start of treatment to the date of the first documented radiological progression according to PCWG3-modified RECIST v1.1 or death due to any cause.

Time frame: Up to approximately 24 months

Prostate-Specific Antigen 50% response rate (PSA50 rate)

PSA50 rate is defined as the proportion of patients who achieve a ≥50% decrease in prostate-specific antigen (PSA) from baseline at any timepoint, confirmed by a second PSA measurement ≥3 weeks later without any PSA progression in between.

Time frame: Up to approximately 24 months

Area under the plasma concentration-time curve (AUC) of INR731

Pharmacokinetic (PK) parameters based on plasma concentrations of INR731.

Time frame: From pre-dose up to 24 hours after dosing on Cycle 1 Day 1 and Day 15. One cycle = 28 days.

Maximum plasma concentration (Cmax) of INR731

PK parameters based on plasma concentrations of INR731.

Time frame: From pre-dose up to 24 hours after dosing on Cycle 1 Day 1 and Day 15. One cycle = 28 days.

Time to reach maximum plasma concentration (Tmax) of INR731

PK parameters based on plasma concentrations of INR731.

Time frame: From pre-dose up to 24 hours after dosing on Cycle 1 Day 1 and Day 15. One cycle = 28 days.

Trough concentration (Ctrough) of INR731

PK parameters based on plasma concentrations of INR731.

Time frame: From pre-dose up to 24 hours after dosing on Cycle 1 Day 1 and Day 15. One cycle = 28 days.

Plasma concentrations of study drugs

Concentration versus time profiles of study drugs.

Time frame: From pre-dose up to 24 hours after dosing on Cycle 1 Day 1 and Day 15. One cycle = 28 days.

Progression Free Survival (PFS)

PFS is defined as time from date of start of treatment to the first documented progression (radiological, clinical, or PSA progression) or death from any cause, whichever occurs first.

Time frame: Up to approximately 24 months

A Study to Investigate the Safety and Tolerability of Oral INR731 Single Agent or in Combination With Androgen Receptor Pathway Inhibitor (ARPI) in Patients With Metastatic Prostate Cancer

Overview

Conditions

Interventions

Eligibility

Locations (9)

Outcomes

Primary Outcomes

Secondary Outcomes

Central Contacts