A Phase I Study to Assess the Safety, Pharmacokinetics, and Anti-Tumor Activity of Oral HP518 in mCRPC Patients

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

Detailed Description
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This First in Human dose escalation and expansion study of HP518 in patients with progressive mCRPC after NHA and chemotherapy is being conducted not only to evaluate the safety and tolerability of orally administered HP518, but also to provide preliminary efficacy for the reference of future studies.

Official Title
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A Phase I/II Open-Label Study to Assess the Safety, Pharmacokinetics, and Antitumor Activity of Oral HP518 in Patients With Metastatic Castration-Resistant Prostate Cancer in China

Conditions
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Metastatic Castration-resistant Prostate Cancer

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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male, age ≥18 Patients with androgen receptor (AR) ligand binding domain (LBD) activation mutations (the dose expansion part of stage II) Has histologically confirmed adenocarcinoma of the prostate, but there are no known significant neuroendocrine differentiation or small cell characteristics. Has metastatic disease documented by 2 or more bone lesions by bone scan or soft tissue disease progression observed by CT/MRI at the beginning of study. the progression of the disease after receiving at least one new endocrine therapy and progressing with at least first-line chemotherapy. 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: Combination of research or commercially available drugs targeting AR Has had any other anticancer treatments, including immunotherapy, chemotherapy, or radiotherapy (eg, 177LuPSMA-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.

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1 - Dose Escalation, 400mg/d (Cohort1)<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<br>* Other names: Part 1 - Dose Escalation;|
| Experimental: Part 1 - Dose Escalation 500mg/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<br>* Other names: Part 1 - Dose Escalation;|
| Experimental: Part 2 - Dose Expansion Oral tablet(s)<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>* Other names: Part 2 - Dose Expansion Oral tablet(s);|

What is the study measuring?
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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 drugorally administered HP518 (Part 1) | 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 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 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 of orally administered HP518 (Part 1) | 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 of orally administered HP518 (Part 1) | Through study completion, an average of 1 year | 
| PSA50 response rate | Proportion of patients showing a PSA decline by ≥50% between baseline and Week 12 of dosing with HP518. | 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| area under the concentration-time curve (AUC) | Assessment of pharmacokinetic parameters of HP518 | 12 weeks | 
| Maximum concentration (Cmax) | Assessment of pharmacokinetic parameters of HP518 | 12 weeks | 
| Time to maximum concentration (Tmax) | Assessment of pharmacokinetic parameters of HP518 | 12 weeks | 
| Apparent terminal elimination half-life (T1/2) | Assessment of pharmacokinetic parameters of HP518 | 12 weeks | 
| apparent volume of distribution during the terminal phase after extravascular administration (Vz/F) | Assessment of pharmacokinetic parameters of HP518 | 12 weeks | 
| oral clearance (CL/F) | Assessment of pharmacokinetic parameters of HP518 | 12 weeks | 
| According to PCWG3 | evaluate PSA50 response rate: PSA decline by≥50% between baseline and 4 weeks/8 weeks/12 weeks( only Part 1) of dosing with HP518 | 8 weeks | 
| According to PCWG3, evaluate time to PSA progression | PCWG3 definition: PSA increase >25% and >2 ng/mL above nadir, confirmed by progression at 2 time points at least 3 weeks apart) nadir, confirmed by progression at 2 time points at least 3 weeks apart) | Through study completion, an average of 1 year | 
| Time to radiographic progression by investigator PCWG3 definition | using the RECIST v1.1 and PCWG3 definition | Through study completion, an average of 1 year | 
| Evaluate the modified best overall response mBOR by investigator | According to RECIST (version 1.1) and PCWG3 | Through study completion, an average of 1 year | 
| analyze the efficacy of patients with different AR phenotypes(Part 2) | According to genetic testing results | Through study completion, an average of 1 year |