This study is to evaluate the safety, and preliminary antitumor activity of TYK-00540 combined with Enzalutamide in patients with metastatic castration-resistant prostate cancer (mCRPC) that have failed novel endocrine therapy
Age ≥18 years.
Metastatic castration-resistant prostate adenocarcinoma confirmed by pathology (with no neuroendocrine or small cell features indicated by the initial pathological examination), if pathological examination is performed in the subsequent CRPC stage, the accompanying other pathological types should not exceed 10%. Those with only pelvic lymph node metastasis or local recurrence and metastasis (such as in the bladder, rectum, etc.) cannot be included.
At the time of screening, testosterone levels were at castration levels (≤50ng/dL or 1.70nmol/L). If the patient had not previously undergone bilateral orchiectomy, they must be undergoing and voluntarily continue to receive LHRH agonists/antagonists for androgen deprivation therapy throughout the study treatment period.
During screening, if the disease progresses, that is, the subject experiences one or more of the following three conditions; PSA progression is defined as no PSA > 1ng/ml and at least two elevated PSA levels with an interval of ≥1 week. ② Disease progression as defined in RECIST 1.1; ③ Bone disease progression as defined by the PCWG3 standard refers to the discovery of ≥2 new lesions on bone scans.
Those who have previously received selective CDK2, CDK4 inhibitors, CDK4/6 inhibitors (e.g., Palbociclib, Ribociclib, Abemaciclib, Trilaciclib/G1T38, SHR6390, pirociclib) for treatment;
Previously received enzalutamide or two or more novel endocrine therapies for prostate cancer;
Isotope therapy with strontium-89, samarium or radium-223 was received within 12 weeks prior to the first administration;
Systemic treatment for prostate cancer (anti-androgen therapy, chemotherapy, targeted therapy, immunotherapy, or other interventional clinical trial drugs, except castration therapy drugs) has been received within 4 weeks prior to the first medication.
Single group
TYK-00540
DrugTake the specified dose (20mg or 30mg) orally twice a day. Take it on an empty stomach in the morning with about 200 mL of warm water.
Enzalutamide
DrugTake orally, 160mg each time, once a day. Take orally with or without meals.
Number of participants who experience one or more adverse events (AEs)
An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention.
Dose Limiting Toxicity (DLT)
Numbers of participants experiencing AEs which are defined as DLTs classfied by CTCAE v5.0.
Maximum tolerated dose（MTD）
To determine the maximum tolerated dose for combination-agent escalation.
Recommended Phase 2 Dose（RP2D）
The RP2D is defined as the dose level chosen for the dose expansion arms, based on safety, tolerability, efficacy collected during the dose escalation portion of the study
Prostate-specific antigen (PSA) response rate
The Prostate-specific Antigen (PSA) response rate is the percentage of participants who had PSA response defined as a reduction in the PSA level from baseline by ≥50%. The reduction in PSA level will be confirmed by an additional PSA evaluation performed ≥3 weeks from the original response per Prostate Cancer Working Group (PCWG) criteria.
Overall survival (OS)
OS is defined as the time from randomization to death due to any cause.
Duration of response (DOR)
DOR is defined as the time from first documented evidence of complete response (CR) or partial response (PR) per PCWG and RECIST 1.1 criteria until progressive disease (PD) or death. PD per RECIST 1.1 is defined as at least a 20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of a least 5 mm. PD per PCWG is the appearance of \>2 new bone lesions on bone scan, that have been confirmed to not represent tumor flare, and are persistent for \>6 weeks.
Objective response rate (ORR)
The ORR is defined as the percentage of participants with complete response (CR: disappearance of all target lesions per Response Criteria in Solid Tumors version 1.1 (RECIST 1.1); and no evidence of disease (NED) on base scan per Prostate Cancer Working Group (PCWG) or partial response (PR: at least a 30% decrease in the sum of diameters of target lesions per RECIST 1.1; and non-progressive disease, non-evaluable \[NE\], or NED on bone scan or CR with non-progressive disease or NE bone scan per PCWG).
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