Trial of QLH12016 in Patients With Metastatic Castration Resistant Prostate Cancer

Study Overview
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Brief Summary
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To evaluate the tolerance, safety, pharmacokinetics, and preliminary anti-tumor activity of QLH12016 in patients with metastatic castration resistant prostate cancer

Detailed Description
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Subjects will use QLH12016 for the treatment of mCRPC.

Official Title
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Tolerance, Safety, Pharmacokinetics, and Preliminary Anti-tumor Activity of QLH12016 in Patients With Metastatic Castration Resistant Prostate Cancer

Conditions
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Prostate Cancer

Intervention / Treatment
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* Drug: QLH12016


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Voluntarily participate and sign a written informed consent form Male, aged ≥ 18 years ECOG：0-1 Expected survival time of at least 3 months Prostate adenocarcinoma confirmed by histological or cytological without neuroendocrine or small cell characters Continuous treatment with luteinizing hormone releasing hormone analogue or luteinizing hormone releasing hormone antagonist (drug castration), or previous bilateral orchiectomy (surgical castration); Subjects who did not receive bilateral orchiectomy must plan to maintain effective luteinizing hormone releasing hormone analog or luteinizing hormone releasing hormone antagonist treatment throughout the study period testosterone≤50 ng/dL or 1.7 nmol/L CRPC is defined as the occurrence of one or more of the following three events in a subject while undergoing castration treatment: ① PSA progression, defined as at least two increases in PSA levels (PSA value>1 ng/mL, interval of at least 1 week, consecutive 2 times, increase>50% from baseline); ② Disease progression as defined in RECIST v1.1; ③ The progression of skeletal diseases as defined by the PCWG3 standard, where bone scans reveal ≥ 2 or more new lesions Metastatic lesion with imaging evidence. At least one target lesion exists Received 1-2 lines of new endocrine therapy (such as enzalutamide, abiolone, etc.) after developing castration resistance（ArmA-C） Received 0-1 line chemotherapy treatment (such as docetaxel) during the hormone sensitive period and the castration resistance period（ArmA-C） Arm B: with specific biomarkers; Arm C: without specific biomarkers; Arm D: received 0 or 1 line of new endocrine therapy, and no chemotherapy during hormone sensitive and castration resistant stages The functional level of important organs must meet the following requirements (no blood components, hematopoietic stimulating factors, cell growth factors, leukemic drugs, platelet enhancing drugs, etc. are allowed to be used within 7 days before obtaining laboratory examination): Absolute neutrophil count ≥ 1.5 × 10^9/L; Platelets ≥ 100 × 10^9/L; Hemoglobin ≥ 100 g/L; Serum albumin ≥ 30 g/L; AST and ALT ≤ 2.5 × Upper limit of normal reference value (ULN), if accompanied by liver metastasis, ALT and AST ≤ 5 × ULN; Total bilirubin ≤ 1.5 × ULN (Gilbert syndrome≤ 3 × ULN); Serum creatinine ≤ 1.5 × ULN, if >1.5 × ULN, then the creatinine clearance rate (CLcr) ≥ 50 mL/min; LVEF>50% Effective contraceptive measures from signing the informed consent to 90 days after the last use of the study drug Recover from all AEs of previous anti-cancer treatment (i.e. ≤ grade 1, according to CTCAE v5.0), excluding alopecia (any grade) and peripheral sensory nerve ≤ grade 2, hypomagnesemia or lymphocytopenia, as well as other abnormalities that the benefit of receiving treatment is greater than the risk Exclusion Criteria: Metastasis of the central nervous system (CNS), leptomeningeal metastasis or spinal cord compression caused by metastasis (exceeding the physiological alternative dose) requiring hormone treatment Radiation therapy that has irradiated more than 25% of the bone marrow was performed within 4 weeks. Palliative radiation therapy is allowed to alleviate pain caused by bone metastasis during the study period Treatment with similar drugs Received other clinical trial drugs or major surgeries within 4 weeks (sufficient wound healing after major surgeries must undergo clinical evaluation) Systemic anti-cancer treatment within the first 2 weeks (bicalutamide, Mitomycin C or Nitroso urea 6 weeks, enzalutamide 5 weeks, and abiolone 4 weeks). Medications that maintain castration are allowed. Planned bilateral orchiectomy during the study treatment Inability to swallow, chronic diarrhea and bowel obstruction, or other factors affecting drug administration and absorption Epilepsy or disease that can induce seizure within 12 months (including a history of transient ischemic attack, stroke, brain trauma with disorders of consciousness, etc.) History of psychotropic substance abuse, alcoholism, or drug use, neurological or mental disorders, including dementia or hepatic encephalopathy Any of the following conditions occurs within 12 months: myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass grafting, symptomatic congestive heart failure (New York Heart Association III or IV), cerebrovascular accident, transient ischemic attack, symptomatic pulmonary embolism or other thromboembolic diseases with clinical significance Any of the following conditions within 6 months: congenital long QT syndrome, torsade de pointes ventricular tachycardia, arrhythmia (including persistent ventricular tachyarrhythmia and Ventricular fibrillation), left anterior half block (double vessel block) or persistent arrhythmia above NCI-CTCAE grade 2, Atrial fibrillation of any level (in the case of Asymptomatic isolated Atrial fibrillation, grade ≥ 2) Cardiovascular diseases under poor control, including angina pectoris, pulmonary hypertension or serious cardiac rhythm or conduction abnormalities QTcF>450 ms Active, uncontrolled bacterial, fungal, or viral infections, including but not limited to: 1) Active hepatitis B virus (HBV), hepatitis C virus (HCV) infected persons (hepatitis B surface antigen [HBsAg] positive or hepatitis B core antibody [HBcAb] positive, HBV DNA virus copy number ≥ 500 IU/mL, HCV antibody positive and HCV RNA higher than the detection limit of the analysis method); 2) Syphilis required treatment; 3) History of congenital immunodeficiency or organ transplantation, or HIV (HIV) positive Clinically uncontrollable third space effusion, such as pleural effusion, peritoneal effusion, pericardial effusion, etc. that cannot be controlled by drainage or other measures and cannot be included in the group according to the judgment of the investigator Other malignant tumors within 5 years (excluding cured basal cell skin cancer, papillary thyroid cancer, etc.) Concomitant diseases seriously endangering the safety of the subject or affect the completion of the study, such as hypertension (systolic pressure ≥ 160 mmHg and/or diastolic pressure ≥ 100 mmHg) that cannot be controlled by two or more antihypertensive drugs, diabetes not well controlled, etc History of hypertensive crisis or hypertensive encephalopathy Allergy to any study drug component Gastrointestinal perforation, gastrointestinal or non gastrointestinal fistula, or abdominal abscess within 6 months Any life-threatening bleeding event within 3 months, including the need for blood transfusion treatment, surgery or local treatment, and continuous medication treatment Subjects who may increase research related risks, interfere with the interpretation of research results, or are deemed unsuitable for inclusion by the researcher

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: QLH12016 dose escalation<br>Daily dosages are predetermined by Safety Monitoring Committee after the initial starting dose cohort at the end of Cycle 1 (each cycle is 28 days) | Drug: QLH12016<br>* according to the scheme description<br>|
| Experimental: QLH12016 in mCRPC with specific biomarkers<br>Daily dosage and schedule at a recommended Phase 2 dose based on data from Arm A | Drug: QLH12016<br>* according to the scheme description<br>|
| Experimental: QLH12016 in mCRPC without specific biomarkers<br>Daily dosage and schedule at a recommended Phase 2 dose based on data from Arm A | Drug: QLH12016<br>* according to the scheme description<br>|
| Experimental: QLH12016 in less pretreated mCRPC<br>Daily dosage and schedule at a recommended Phase 2 dose based on data from Arm A | Drug: QLH12016<br>* according to the scheme description<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Arm A： Incidence of Dose Limiting Toxicities | First Cycle Dose limiting toxicities characterized by type, frequency, severity (as graded by NCI CTCAE version 5.0), timing, seriousness, and relationship to study drug | 28 Days | 
| Arm A：Maximum Tolerated Dose | The Maximum Tolerated Dose determined by the Incidence of Dose Limiting Toxicities | 28 Days | 
| Arm A：Recommended Phase 2 Dose | Recommended Phase 2 Dose determined by the frequency of Incidence of Dose Limiting Toxicities | 28 Days | 
| Arm A：AE | The incidence, severity and correlation with the study drug of adverse events (AEs) evaluated according to the National Cancer Institute (NCI) - General Terminology of Adverse Events (CTCAE) Version 5.0 | 20 weeks | 
| Arm A：SAE | The incidence, severity and correlation with the study drug of Serious adverse event (SAE) evaluated according to the National Cancer Institute (NCI) - General Terminology of Adverse Events (CTCAE) Version 5.0 | 20 weeks | 
| Arm B-D：PSA Response Rate | a decrease of ≥ 50% in PSA levels from baseline to baseline, and reassessed PSA relief after ≥ 3 weeks in each arm | 20 weeks | 
| Arm B-D：Objective Response Rate | the percentage of CR/PR subjects in each arm | 20 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cmax | The highest plasma drug concentration | 20 weeks | 
| Tmax | The time blood drug concentration reaching Cmax | 20 weeks | 
| AUC | The area enclosed by the drug time curve and the time axis | 20 weeks | 
| Arm A：ORR | the percentage of CR/PR subjects | 20 weeks | 
| Arm A：PSA Response Rate | a decrease of ≥ 50% in PSA levels from baseline to baseline, and reassessed PSA relief after ≥ 3 weeks | 20 weeks | 
| Arm B-D：AE | The incidence, severity and correlation with the study drug of adverse events (AEs) evaluated according to the National Cancer Institute (NCI) - General Terminology of Adverse Events (CTCAE) Version 5.0 | 20 weeks | 
| Arm B-D：SAE | The incidence, severity and correlation with the study drug of Serious adverse event (SAE) evaluated according to the National Cancer Institute (NCI) - General Terminology of Adverse Events (CTCAE) Version 5.0 | 20 weeks | 
| DOR | The time between the initial evaluation of CR or PR and disease progression | 20 weeks | 
| DCR | the percentage of CR/PR/SD subjects | 20 weeks | 
| rPFS | The time between the first administration of the investigational drug and the first recording of disease progression (determined according to RECIST v1.1 and PCWG3) or the date of all-cause death (whichever occurs first) | 20 weeks | 
| OS | The time between the first trial drug administration and patient death due to various reasons | 20 weeks |