A Study to Assess the Safety, Pharmacokinetics, and Anti-Tumor Activity of Oral HP518 in Patients With Metastatic Castration-Resistant Prostate Cancer

Study Overview
=================
Brief Summary
-----------------
The overall objective of this Phase 1 study is to evaluate the safety, PK, and anti-tumor activity of 12 weeks of daily oral dosing with HP518 after selecting the RP2D of HP518 based on assessments of multiple dose escalation in patients with progressive mCRPC.

Detailed Description
-----------------
This First in Human dose escalation and expansion study of HP518 in patients with mCRPC is being conducted not only to evaluate the safety and tolerability of orally administered HP518, but also to provide necessary information for efficacy analysis in future studies.

Official Title
-----------------
A Phase 1 Open-Label Study to Assess the Safety, Pharmacokinetics, and Anti-tumor Activity of Oral HP518 in Patients With Metastatic Castration-Resistant Prostate Cancer

Conditions
-----------------
Metastatic Castration-resistant Prostate Cancer

Intervention / Treatment
-----------------
* Drug: HP518 - Dose Escalation
* Drug: HP518 - Dose expansion


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Has histologically confirmed adenocarcinoma of the prostate. Has metastatic disease at study entry documented by 2 or more bone lesions on bone scan or by soft tissue disease observed by CT/MRI. Has disease progression while receiving any ADT, androgen biosynthesis inhibitors, or second-generation AR inhibitors. Must have recovered from toxicities related to any prior treatments Ongoing ADT with LHRH agonist/antagonist therapy or history of bilateral orchiectomy. ECOG performance status score of 0 to 1. Exclusion Criteria: Has received more than 1 line of chemotherapy for prostate cancer. Use of enzalutamide, and/or other second-generation AR inhibitors and/or abiraterone as follows: Received any agent within 4 weeks prior to the start of study drug. Discontinued agent without evidence of radiographic or PSA progression. Has had any anticancer treatments, including immunotherapy, chemotherapy, or radiotherapy (eg, 177Lu-PSMA-617, radium 223, PARP inhibitor) within 4 weeks prior to the first dose of HP518. Has gastrointestinal disorder affecting absorption (e.g., gastrectomy). Has significant cardiovascular disease. Use of an investigational agent, without evidence of radiographic or PSA progression, within 4 weeks prior to the first dose of HP518 or a period required by local regulation, whichever is longer.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
Male

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1 - Dose Escalation, 25mg/d (Cohort 1)<br>Oral tablet(s), once daily in 28-day cycles | Drug: HP518 - Dose Escalation<br>* Part 1: Dose escalation Daily oral dosage with the prescribed dose level based on Cohort assignment.<br>|
| Experimental: Part 1 - Dose Escalation 100mg/d (Cohort 2)<br>Oral tablet(s), once daily in 28-day cycles | Drug: HP518 - Dose Escalation<br>* Part 1: Dose escalation Daily oral dosage with the prescribed dose level based on Cohort assignment.<br>|
| Experimental: Part 1 - Dose Escalation 200mg/d (Cohort 3)<br>Oral tablet(s), once daily in 28-day cycles | Drug: HP518 - Dose Escalation<br>* Part 1: Dose escalation Daily oral dosage with the prescribed dose level based on Cohort assignment.<br>|
| Experimental: Part 1 - Dose Escalation 300mg/d (Cohort 4)<br>Oral tablet(s), once daily in 28-day cycles | Drug: HP518 - Dose Escalation<br>* Part 1: Dose escalation Daily oral dosage with the prescribed dose level based on Cohort assignment.<br>|
| Experimental: Part 1 - Dose Escalation 400mg/d (Cohort 5)<br>Oral tablet(s), once daily in 28-day cycles | Drug: HP518 - Dose Escalation<br>* Part 1: Dose escalation Daily oral dosage with the prescribed dose level based on Cohort assignment.<br>|
| Experimental: Part 1 - Dose Escalation 500mg/d (Cohort 6)<br>Oral tablet(s), once daily in 28-day cycles | Drug: HP518 - Dose Escalation<br>* Part 1: Dose escalation Daily oral dosage with the prescribed dose level based on Cohort assignment.<br>|
| Experimental: Part 2 - Dose Expansion<br>Oral tablet(s), once daily in 28-day cycles | Drug: HP518 - Dose expansion<br>* Part 2: Dose expansion Daily oral dosage with the highest dose with acceptable toxicity (RP2D) based on data from Part 1.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidences of Protocol-defined DLT during the DLT assessment period , characterized by type, frequency, severity (as graded by NCI CTCAE version 5.0), timing, seriousness, and relationship to study drug | To evaluate the safety and tolerability and determine the MTD and the RP2D of orally administered HP518 (Part 1) | 28 days | 
| Incidence of Treatment-Emergent Adverse Events characterized by type, frequency, severity (as graded by NCI CTCAE version 5.0), timing, seriousness | To evaluate the safety and tolerability and determine the MTD and the RP2D of orally administered HP518 (Part 1) | Through study completion, an average of 1 year | 
| Incidence of laboratory abnormalities, characterized by type, frequency, severity (as graded by NCI CTCAE version 5.0), and timing | To evaluate the safety and tolerability and determine the MTD and the RP2D of orally administered HP518 (Part 1) | Through study completion, an average of 1 year | 
| Incidence of vital signs abnormalities characterized by type, frequency, severity (as graded by NCI CTCAE version 5.0), and timing | To evaluate the safety and tolerability and determine the MTD and the RP2D of orally administered HP518 (Part 1) | Time Frame: Through study completion, an average of 1 year | 
| Incidence of ECG (PR, QRS, QT, and QTcF intervals) abnormalities characterized by type, frequency, severity (as graded by NCI CTCAE version 5.0), and timing | To evaluate the safety and tolerability and determine the MTD and the RP2D of orally administered HP518 (Part 1) | Through study completion, an average of 1 year | 
| Proportion of patients showing a PSA decline of ≥50% between baseline and Week 12 of dosing with HP518. |  | 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Assessment of pharmacokinetic parameters of HP518 : area under the concentration-time curve (AUC) |  | 12 weeks | 
| Assessment of pharmacokinetic parameters of HP518: Maximum concentration (Cmax) |  | 12 weeks | 
| Assessment of pharmacokinetic parameters of HP518: Time to maximum concentration (Tmax) |  | 12 weeks | 
| Assessment of pharmacokinetic parameters of HP518: apparent terminal elimination half-life (T1/2) |  | 12 weeks | 
| Assessment of pharmacokinetic parameters of HP518: apparent volume of distribution during the terminal phase after extravascular administration (Vz/F) |  | 12 weeks | 
| Assessment of pharmacokinetic parameters of HP518: oral clearance (CL/F) |  | 12 weeks | 
| Assessment of PSA50 from baseline to after 4 and 8 weeks of dosing with HP518 | To evaluate PSA50 from baseline to after 4 and 8 weeks of dosing with HP518 | 8 weeks | 
| Time to PSA progression using the PCWG3 definition (PSA >25% and >2 ng/mL above nadir, confirmed by progression at 2 time points at least 3 weeks apart) | To evaluate the time to PSA progression | Through study completion, an average of 1 year | 
| Time to radiographic progression using the RECIST v1.1 and PCWG3 definition | To evaluate radiographic progression per RECIST v1.1 and PCWG3 | Through study completion, an average of 1 year | 
| Radiographic response measured by RECIST 1.1 in patients with measurable soft tissue disease at baseline | To assess objective response by RECIST v1.1 (proportion of patients with a PR or CR) in patients with measurable soft tissue disease at baseline | Through study completion, an average of 1 year | 
| Change in number of AR N-term-positive CTCs/ml from baseline to week 12 |  | 12 weeks | 
| Genomic profiling using cfDNA |  | 12 weeks |