Metastatic Castration-resistant Prostate Cancer
Conditions
Keywords
Metastatic Prostate Cancer
Brief summary
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
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.
Interventions
DRUGONCT-534
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.
Sponsors
Oncternal Therapeutics, Inc
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Dose Limiting Toxicities Through Study Day 28 | Number of Participants with Dose Limiting Toxicities Through Study Day 28 | Incidence of DLTs through Study Day 28 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Reduction of Prostate-Specific Antigen (PSA) by More Than 50% | Up to 51 Weeks | Proportion of patients who achieve at least a 50% drop in PSA from baseline (PSA50) |
Countries
United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Dose Level 1: 40mg QD 40mg of single agent ONCT-534 to be administered daily in oral tablets
ONCT-534: 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. | 1 |
| Dose Level 2: 80mg QD 80mg of single agent ONCT-534 to be administered daily in oral tablets
ONCT-534: 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. | 1 |
| Dose Level 3: 160mg QD 160mg of single agent ONCT-534 to be administered daily in oral tablets
ONCT-534: 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. | 4 |
| Dose Level 4: 300mg QD 300mg of single agent ONCT-534 to be administered daily in oral tablets
ONCT-534: 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. | 3 |
| Dose Level 5: 600mg QD 600mg of single agent ONCT-534 to be administered daily in oral tablets
ONCT-534: 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. | 3 |
| Dose Level 6: 1200 mg QD 1200mg of single agent ONCT-534 to be administered daily in oral tablets
ONCT-534: 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. | 3 |
| BID Dose Level 1: 160 mg BID 600mg of single agent ONCT-534 to be administered daily in oral tablets
ONCT-534: 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. | 3 |
| BID Dose Level 2: 300 mg BID 300mg of single agent ONCT-534 to be administered twice daily in oral tablets
ONCT-534: 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. | 3 |
| Total | 21 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 |
|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 |
| Overall Study | Progressive Disease | 1 | 1 | 2 | 3 | 1 | 1 | 0 | 0 |
| Overall Study | Sponsor Decision | 0 | 0 | 1 | 0 | 2 | 1 | 3 | 3 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Dose Level 1: 40mg QD | Dose Level 2: 80mg QD | Dose Level 3: 160mg QD | Dose Level 4: 300mg QD | Dose Level 5: 600mg QD | Dose Level 6: 1200 mg QD | BID Dose Level 1: 160 mg BID | BID Dose Level 2: 300 mg BID | Total |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 53 years | 83 years | 70.3 years STANDARD_DEVIATION 3 | 67.3 years STANDARD_DEVIATION 4.5 | 70.0 years STANDARD_DEVIATION 9 | 76.0 years STANDARD_DEVIATION 5.6 | 67.7 years STANDARD_DEVIATION 11.7 | 74.0 years STANDARD_DEVIATION 7.2 | 69.8 years STANDARD_DEVIATION 8.1 |
| Race/Ethnicity, Customized Black or African American | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 3 Participants |
| Race/Ethnicity, Customized White | 1 Participants | 1 Participants | 4 Participants | 2 Participants | 3 Participants | 2 Participants | 2 Participants | 3 Participants | 18 Participants |
| Region of Enrollment United Kingdom | 0 participants | 0 participants | 0 participants | 0 participants | 1 participants | 1 participants | 0 participants | 1 participants | 3 participants |
| Region of Enrollment United States | 1 participants | 1 participants | 4 participants | 3 participants | 2 participants | 2 participants | 3 participants | 2 participants | 18 participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 1 Participants | 1 Participants | 4 Participants | 3 Participants | 3 Participants | 3 Participants | 3 Participants | 3 Participants | 21 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk |
|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 1 | 0 / 1 | 1 / 4 | 0 / 3 | 0 / 3 | 0 / 3 | 0 / 3 | 0 / 3 |
| other Total, other adverse events | 1 / 1 | 0 / 1 | 4 / 4 | 3 / 3 | 3 / 3 | 3 / 3 | 3 / 3 | 3 / 3 |
| serious Total, serious adverse events | 1 / 1 | 0 / 1 | 2 / 4 | 1 / 3 | 1 / 3 | 2 / 3 | 0 / 3 | 0 / 3 |
Outcome results
Primary
Dose Limiting Toxicities Through Study Day 28
Incidence of DLTs through Study Day 28
Time frame: Number of Participants with Dose Limiting Toxicities Through Study Day 28
Population: DLT-evaluable population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dose Level 1: 40mg QD | Dose Limiting Toxicities Through Study Day 28 | 0 Participants |
| Dose Level 2: 80mg QD | Dose Limiting Toxicities Through Study Day 28 | 0 Participants |
| Dose Level 3: 160mg QD | Dose Limiting Toxicities Through Study Day 28 | 0 Participants |
| Dose Level 4: 300mg QD | Dose Limiting Toxicities Through Study Day 28 | 0 Participants |
| Dose Level 5: 600mg QD | Dose Limiting Toxicities Through Study Day 28 | 0 Participants |
| Dose Level 6: 1200 mg QD | Dose Limiting Toxicities Through Study Day 28 | 0 Participants |
| BID Dose Level 1: 160 mg BID | Dose Limiting Toxicities Through Study Day 28 | 0 Participants |
| BID Dose Level 2: 300 mg BID | Dose Limiting Toxicities Through Study Day 28 | 0 Participants |
Secondary
Reduction of Prostate-Specific Antigen (PSA) by More Than 50%
Proportion of patients who achieve at least a 50% drop in PSA from baseline (PSA50)
Time frame: Up to 51 Weeks
Population: Efficacy-evaluable population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dose Level 1: 40mg QD | Reduction of Prostate-Specific Antigen (PSA) by More Than 50% | 0 Participants |
| Dose Level 2: 80mg QD | Reduction of Prostate-Specific Antigen (PSA) by More Than 50% | 0 Participants |
| Dose Level 3: 160mg QD | Reduction of Prostate-Specific Antigen (PSA) by More Than 50% | 0 Participants |
| Dose Level 4: 300mg QD | Reduction of Prostate-Specific Antigen (PSA) by More Than 50% | 0 Participants |
| Dose Level 5: 600mg QD | Reduction of Prostate-Specific Antigen (PSA) by More Than 50% | 0 Participants |
| Dose Level 6: 1200 mg QD | Reduction of Prostate-Specific Antigen (PSA) by More Than 50% | 0 Participants |
| BID Dose Level 1: 160 mg BID | Reduction of Prostate-Specific Antigen (PSA) by More Than 50% | 0 Participants |
| BID Dose Level 2: 300 mg BID | Reduction of Prostate-Specific Antigen (PSA) by More Than 50% | 0 Participants |
Post Hoc
Number of Subjects With Any Post-Baseline Decrease in PSA
Any reduction in PSA after Baseline (First Day of Treatment)
Time frame: Up to 51 Weeks
Population: Efficacy-evaluable Population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dose Level 1: 40mg QD | Number of Subjects With Any Post-Baseline Decrease in PSA | 0 Participants |
| Dose Level 2: 80mg QD | Number of Subjects With Any Post-Baseline Decrease in PSA | 0 Participants |
| Dose Level 3: 160mg QD | Number of Subjects With Any Post-Baseline Decrease in PSA | 2 Participants |
| Dose Level 4: 300mg QD | Number of Subjects With Any Post-Baseline Decrease in PSA | 1 Participants |
| Dose Level 5: 600mg QD | Number of Subjects With Any Post-Baseline Decrease in PSA | 0 Participants |
| Dose Level 6: 1200 mg QD | Number of Subjects With Any Post-Baseline Decrease in PSA | 2 Participants |
| BID Dose Level 1: 160 mg BID | Number of Subjects With Any Post-Baseline Decrease in PSA | 0 Participants |
| BID Dose Level 2: 300 mg BID | Number of Subjects With Any Post-Baseline Decrease in PSA | 0 Participants |