A Clinical Study of ONCT-534 in Subjects With Metastatic Castration-resistant Prostate Cancer.

Study Overview
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Brief Summary
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A first-in-human clinical trial to test the investigational treatment ONCT-534 in participants with metastatic castration-resistant prostate cancer. The main questions it aims to answer are: What are the most tolerable doses of ONCT-534? (Phase 1) Does ONCT-534 have anti-tumor activity at tolerable doses? (Phase 2) This is a dose escalation and expansion study where participants will receive daily oral doses of ONCT-534.

Detailed Description
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This is a Phase 1/2 multi-center study to investigate the safety, tolerability, and anti-tumor acitivity of ONCT-534 in patients with relapsed or refractory metastatic castration-resistant prostate cancer. The study consists of 2 phases: a Phase 1 Dose Escalation and a Phase 2 Dose Expansion. During the dose escalation in Phase 1 a group of participants will be assigned a certain dose level. Once the dose level is considered safe, the next group will be assigned a higher dose level. The dose level may be raised or lowered depending on any safety events that occur throughout Phase 1. There will be approximately 27 participants enrolled in Phase 1. At the end of Phase 1, two dose levels will be chosen to be tested in Phase 2. During Phase 2, participants will be randomly assigned to 1 of the 2 dose levels chose in Phase 1. Approximately 16 participants will be enrolled in each of the 2 dose level groups, for a total of 32 participants.

Official Title
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A Phase 1/2 Study of ONCT-534 in Subjects With Metastatic Castration-Resistant Prostate Cancer

Conditions
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Metastatic Castration-resistant Prostate Cancer

Intervention / Treatment
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* Drug: ONCT-534


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject is ≥18 years of age Subject has histologically documented metastatic adenocarcinoma of the prostate confirmed by biopsy without neuroendocrine differentiation or small cell features. Subjects has a history of metastatic CRPC. Subject has R/R disease following treatment with at least one next-generation AR-signaling inhibitor. Subject has at least 1 measurable lesion according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 criteria or evaluable bony disease. Lesions that have been previously irradiated will be considered measurable only if progression has been documented following completion of radiation therapy. Subject has an Eastern Cooperative Oncology Group performance status of 0,1 or 2, and life expectancy of ≥ 6 months. Subject agrees to take or continue luteinizing hormone-releasing hormone agonist or antagonist therapy or has undergone bilateral orchiectomy. At least 2 weeks or five half-lives have elapsed, whichever is earliest, since last systemic therapy, including taxanes or other chemotherapy. At least one month has elapsed since systemic therapy with radionuclide pharmaceutical agents Subject has evidence of disease progression on or after their most recent systemic treatment Subject has a PSA level ≥ 10 ng/mL, or ≥ 2 ng/mL and ≥ 50% increase from nadir on prior therapy, whichever is lowest. Subject has serum testosterone < 50 ng/dL. Subject has adequate renal, hepatic, and pulmonary function Subject is committed to practice true abstinence, or use a highly effective method of contraception with any female partner of childbearing potential unless documented to be surgically sterile (i.e., vasectomy or bilateral orchiectomy) and to not make semen donations during the study and for 3 months after the last dose of study drug. Exclusion Criteria: Subject has small cell prostate cancer or neuroendocrine disease histology, including mixed histology. Subject has metastases to the brain or central nervous system Subject is receiving concurrent anti-cancer therapy (including chemotherapy, antibody therapy, immunotherapy, cellular therapy, or other experimental therapies) except for ongoing androgen inhibiting therapy such as luteinizing hormone-releasing hormone (LHRH) agonists. Supportive non-cancer directed therapies such as bisphosphonates or denosumab are allowed. Subjects taking a strong inhibitor of CYP3A4 or a substrate of CYP2C9 or CYP2C19 Subject had major surgery within 30 days prior to start of study drug. Subject has current, untreated pathologic long-bone fractures(s), or risk of imminent pathologic fracture(s). Subject has current or imminent spinal cord compression. Subject has an active seizure disorder or a history of seizure disorder(s). Subject has evidence of active human immunodeficiency virus infection, hepatitis B virus (HBV), or hepatitis C virus (HCV) Subject has any other serious illness or medical condition that would interfere with study participation Subject has abnormal electrocardiograms (ECGs) that are clinically significant, including average QTcF > 450 ms, or a history of Torsade de Pointes. Subject has any infection requiring parenteral antibiotic therapy or causing fever (temperature >100.5°F or 38.1°C) within 1 week prior to first dose. Clinically significant other malignancy with the potential to confound study assessments, with the exception of e.g., treated cutaneous squamous cell and basal carcinomas, non-muscle invasive bladder cancer, Rai Stage 0 CLL, and adequately treated Stage 1 to 2 non-cutaneous malignancy in remission for 5 years. Subject is unable to comply with the protocol and/or not willing or not available for follow-up assessments Subject has any medical intervention or other condition which, in the opinion of the Investigator, could compromise adherence with study requirements or otherwise compromise the study's objectives.

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
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose Level 1: 40mg<br>40mg of single agent ONCT-534 to be administered daily in oral tablets | Drug: ONCT-534<br>* ONCT-534 is a dual-action androgen receptor inhibitor (DAARI) with a novel mechanism of action that includes inhibition of AR function and degradation of the AR protein mediated by interaction with the N-terminal domain (NTD) of the AR. ONCT-534 has demonstrated preclinical activity in prostate cancer models against both unmutated androgen receptor (AR), and against multiple forms of AR alteration, including those with AR amplification, mutations in the AR ligand binding domain (LBD), and splice variants with loss of the AR LBD.<br>* Other names: UT-34;|
| Experimental: Dose Level 2: 80mg<br>80mg of single agent ONCT-534 to be administered daily in oral tablets | Drug: ONCT-534<br>* ONCT-534 is a dual-action androgen receptor inhibitor (DAARI) with a novel mechanism of action that includes inhibition of AR function and degradation of the AR protein mediated by interaction with the N-terminal domain (NTD) of the AR. ONCT-534 has demonstrated preclinical activity in prostate cancer models against both unmutated androgen receptor (AR), and against multiple forms of AR alteration, including those with AR amplification, mutations in the AR ligand binding domain (LBD), and splice variants with loss of the AR LBD.<br>* Other names: UT-34;|
| Experimental: Dose Level 3: 160mg<br>160mg of single agent ONCT-534 to be administered daily in oral tablets | Drug: ONCT-534<br>* ONCT-534 is a dual-action androgen receptor inhibitor (DAARI) with a novel mechanism of action that includes inhibition of AR function and degradation of the AR protein mediated by interaction with the N-terminal domain (NTD) of the AR. ONCT-534 has demonstrated preclinical activity in prostate cancer models against both unmutated androgen receptor (AR), and against multiple forms of AR alteration, including those with AR amplification, mutations in the AR ligand binding domain (LBD), and splice variants with loss of the AR LBD.<br>* Other names: UT-34;|
| Experimental: Dose Level 4: 300mg<br>300mg of single agent ONCT-534 to be administered daily in oral tablets | Drug: ONCT-534<br>* ONCT-534 is a dual-action androgen receptor inhibitor (DAARI) with a novel mechanism of action that includes inhibition of AR function and degradation of the AR protein mediated by interaction with the N-terminal domain (NTD) of the AR. ONCT-534 has demonstrated preclinical activity in prostate cancer models against both unmutated androgen receptor (AR), and against multiple forms of AR alteration, including those with AR amplification, mutations in the AR ligand binding domain (LBD), and splice variants with loss of the AR LBD.<br>* Other names: UT-34;|
| Experimental: Dose Level 5: 600mg<br>600mg of single agent ONCT-534 to be administered daily in oral tablets | Drug: ONCT-534<br>* ONCT-534 is a dual-action androgen receptor inhibitor (DAARI) with a novel mechanism of action that includes inhibition of AR function and degradation of the AR protein mediated by interaction with the N-terminal domain (NTD) of the AR. ONCT-534 has demonstrated preclinical activity in prostate cancer models against both unmutated androgen receptor (AR), and against multiple forms of AR alteration, including those with AR amplification, mutations in the AR ligand binding domain (LBD), and splice variants with loss of the AR LBD.<br>* Other names: UT-34;|
| Experimental: Dose Level #1<br>Recommended Phase 2 dose level #1 of single agent ONCT-534 to be administered daily in oral tablets | Drug: ONCT-534<br>* ONCT-534 is a dual-action androgen receptor inhibitor (DAARI) with a novel mechanism of action that includes inhibition of AR function and degradation of the AR protein mediated by interaction with the N-terminal domain (NTD) of the AR. ONCT-534 has demonstrated preclinical activity in prostate cancer models against both unmutated androgen receptor (AR), and against multiple forms of AR alteration, including those with AR amplification, mutations in the AR ligand binding domain (LBD), and splice variants with loss of the AR LBD.<br>* Other names: UT-34;|
| Experimental: Dose Level #2<br>Recommended Phase 2 dose level #2 of single agent ONCT-534 to be administered daily in oral tablets | Drug: ONCT-534<br>* ONCT-534 is a dual-action androgen receptor inhibitor (DAARI) with a novel mechanism of action that includes inhibition of AR function and degradation of the AR protein mediated by interaction with the N-terminal domain (NTD) of the AR. ONCT-534 has demonstrated preclinical activity in prostate cancer models against both unmutated androgen receptor (AR), and against multiple forms of AR alteration, including those with AR amplification, mutations in the AR ligand binding domain (LBD), and splice variants with loss of the AR LBD.<br>* Other names: UT-34;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Determination of the MTD of ONCT-534 | MTD will be determined using incidence of DLTs | 28 Days | 
| Assess safety and tolerability of ONCT-534 | Incidence of AEs and SAEs | 108 weeks | 
| Reduction of PSA by more than 50% | Proportion of patients who achieve PSA50 | 108 Weeks | 
| Time to reduction of PSA by more than 50% | Time in months to achieve PSA50 | 108 Weeks | 
| Reduction of PSA by more than 90% | Proportion of patients who achieve PSA590 | 108 Weeks | 
| Time to reduction of PSA by more than 90% | Time in months to achieve PSA90 | 108 Weeks | 
| Objective Response Rate | Proportion of subjects with a response to treatment (CR or PR) based on PCWG 3 and RECIST 1.1 | 108 Weeks | 
| Complete Response Rate | Proportion of subjects with CR based on PCWG 3 and RECIST 1.1 | 108 Weeks | 
| Duration of Response | Time in months between initial response (CR or PR) and the date of first disease progression, relapse or death. | 108 Weeks | 
| Progression Free Survival | Time in months between first study treatment dose date and date of first disease progression based on PCWG 3 and RECIST 1.1 or death. | 108 Weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Assess Maximum Plasma Concentration (Cmax) of ONCT-534 | The peak concentration of ONCT-534 in the body will be reported using descriptive statistics | 12 Weeks | 
| Assess Area Under the Curve (AUC) of ONCT-534 | AUC will be reported using descriptive statistics | 12 Weeks | 
| Correlate anti-tumor activity of ONCT-534 with AR phenotype | Correlation analyses will assess associations between objective responses and changes in AR levels or AR phenotype | 108 Weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Metastatic Prostate Cancer