Phase 1, Open-Label, Multicenter Study of Intramuscular PRL-02 Depot in Patients With Advanced Prostate Cancer
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 174
- 试验地点
- 48
- 主要终点
- Number of Participants with physical exam abnormalities and/or AEs
研究概览
简要总结
Medicines that reduce the amount of testosterone in the body are commonly used to treat prostate cancer. PRL-02 depot is a potential treatment for men with advanced prostate cancer. It is given by an injection into the muscle. Men with advanced prostate cancer can take part in this study. Their cancer has come back after previous cancer treatment, or the previous cancer treatment they had didn't work.
The main aims of the study are:
- to check the safety of PRL-02 depot given with and without another medicine called enzalutamide.
- to check if the men can tolerate PRL-02 depot given with or without enzalutamide.
- to find a suitable dose of PRL-02 depot.
This study will be in 2 parts.
In the first part, different small groups of men will receive lower to higher doses of PRL-02 depot together with other medicines.
In the second part of the study, men who have previously taken a hormone therapy called abiraterone acetate or have previously taken 1 specific hormone therapy as part of their prostate cancer treatment can take part.
Men in both parts of the study will receive injections of PRL-02 depot into a muscle once every 12 weeks. They will also take dexamethasone or prednisone, or enzalutamide once a day. The other medicines they take depend on which group and which part of the study they are in.
During the study, the men will visit the clinic several times for health checks and scans.
After the final visit, men whose cancer has not become worse will continue to have health checks and scans every few months.
详细描述
Phase 1/2a, open-label, multicenter study of intramuscular (i.m.) PRL-02 depot in participants with castration-sensitive prostate cancer (CSPC) and metastatic castration-resistant prostate cancer (mCRPC). In Phase 1 (Dose Escalation), participants will receive escalating doses of i.m. PRL-02 in 84-day treatment cycles combined with daily oral steroid.
In Phase 2a (Dose Expansion), participants with metastatic castration-sensitive prostate cancer (mCSPC) and mCRPC will receive i.m. PRL-02 at one or more recommended Phase 2 doses (RP2Ds) selected from Phase 1 in 84-day treatment cycles in combination with dexamethasone and docetaxel (Group F1) or in combination with dexamethasone (Groups F2, G). In both phases, participants will undergo scheduled periodic assessments of prostate specific antigen (PSA), testosterone and progesterone levels in the blood.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- Male
- 接受健康志愿者
- 否
入选标准
- •Histological evidence of adenocarcinoma of the prostate
- •Phase 1a Dose Escalation Groups A and B: participants must have one of the following documented conditions:
- •mCSPC (must have documentation by positive bone scan [for bone disease] or metastatic lesions on computed tomography [CT] or magnetic resonance imaging [MRI] scan [for soft tissue])
- •nmCSPC with biochemical relapse of prostate cancer
- •mCSPC with oligometastatic prostate cancer (e.g., positron emission tomography positive)
- •mCRPC (must have documentation by positive bone scan [for bone disease] or metastatic lesions on CT or MRI scan [for soft tissue])
- •NOTE: For participants in the Dose Escalation Cohorts (including backfill) at each of the dose levels up to approximately 10 participants with ARPI-naïve mCRPC who have not received prior treatment with an ARPI (e.g., abiraterone acetate, enzalutamide, apalutamide, darolutamide) will be enrolled.
- •Phase 1a Dose Escalation Groups A and B: participants with mCRPC must have evidence of disease progression defined as one or more of the following:
- •Evidence of radiographic progression of disease following the most recent prostate cancer treatment, defined as progressive disease on CT/MRI per RECIST v1.1 or on a bone scan per PCWG
- •PSA progression defined as the following:
- •PSA nadir is defined as the lowest PSA during or after the most recent treatment. PSA progression is defined as an increased PSA of at least 25% and ≥1 ng/mL above the nadir confirmed by at least 2 measurements with a minimum of 1 week apart, and with at least 1 of the measurements within 90 days prior to screening.
- •Participants with nmCSPC and biochemical recurrence, who had a radical prostatectomy (with or without radiotherapy) as the primary treatment for prostate cancer, must have a screening PSA ≥1 ng/mL. Participants with nmCSPC and biochemical recurrence who had radiotherapy only, as primary treatment for prostate cancer, must have a screening PSA ≥2 ng/mL above the nadir.
- •Phase 1b Expansion Groups D and E: participants must have mCRPC Participants in Group D must have received prior treatment with abiraterone acetate, but must not have received treatment with other ARPIs (enzalutamide, apalutamide or darolutamide). Participants in Group E must have received prior treatment with only 1 of the following ARPIs: enzalutamide, apalutamide or darolutamide. Participants in both Groups D and E must have documented evidence of progression with one or more of the following:
- •Evidence of radiographic progression of disease following the most recent prostate cancer treatment, defined as progressive disease on CT/MRI per RECIST v1.1 or on a bone scan per PCWG
- •Disease spread that is limited to the regional pelvic lymph nodes does not qualify as radiographic progression.
- •PSA progression defined as the following:
- •PSA nadir is defined as the lowest PSA during or after the most recent treatment. PSA progression is defined as an increased PSA of at least 25% and ≥1 ng/mL above the nadir confirmed by at least 2 measurements with a minimum of 1 week apart, and with at least 1 of the measurements within 90 days prior to screening.
- •Participants with mCRPC must have undergone bilateral orchiectomy or received concurrent GnRH agonist or antagonist therapy for at least 6 weeks prior to the first dose of study drug.
- •Participants with mCSPC or nmCSPC with biochemical recurrence should have received <6 months of ADT with a GnRH agonist or antagonist or have a history of bilateral orchiectomy (i.e., surgical or medical castration) within 6 months prior to Day
- •Castration therapy (i.e., medical or surgical) must have been started at least 14 days prior to Cycle 1 Day 1 and participants should have no radiographic evidence of disease progression or rising PSA levels after starting ADT and prior to Cycle 1 Day
- •A serum testosterone level <50 ng/dL at screening (for mCRPC participants only)
- •Adequate muscle mass for an i.m. injection
- •An ECOG PS of 0 or 1
- •Adequate bone marrow reserve defined as:
- •Absolute neutrophil count (ANC) ≥1500/µL
- •Platelet count ≥100,000/µL
- •Hemoglobin ≥9 gm/dL
- •Adequate renal function defined as a serum creatinine ≤1.5 × upper limit of normal (ULN) for the reference laboratory or a calculated creatinine clearance ≥50 mL/min as determined by a validated algorithm for calculating creatinine clearance
- •Adequate hepatic function, defined as alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 × ULN and total bilirubin ≤1.5 × ULN. Exception for elevated bilirubin secondary to Gilbert's disease. Confirmation of Gilbert's diagnosis requires: elevated unconjugated (indirect) bilirubin values; normal complete blood count in previous 12 months, blood smear, and reticulocyte count; normal aminotransferases and alkaline phosphatase in previous 12 months.
- •Serum albumin ≥3 gm/dL and serum potassium ≥3.5 mEq/L
- •Participants who are non-sterile and who are heterosexually active with a female partner of childbearing potential must be willing to use a highly effective means of contraception, such as a male condom plus spermicide, from the time of screening, throughout the total duration of the drug treatment, and until 12 weeks after the final dose of PRL-02 or enzalutamide (Group H).
- •Participant is able to comply with study requirements throughout the study.
- •The Following Inclusion Criteria Apply to Dose Escalation Group H Only
- •Participants must have one of the following documented conditions:
- •mCSPC (must have documentation of a positive PMSA-PET or positive bone scan [for bone disease] or metastatic lesions on CT or MRI scan [for soft tissue])
- •mCRPC (must have documentation of a positive PMSA-PET or positive bone scan [for bone disease] or metastatic lesions on CT or MRI scan [for soft tissue])
- •NOTE: For participants in the Dose Escalation Cohorts (including backfill) at each of the dose levels, the Sponsor may elect to enroll up to 10 participants with ARPI-naïve mCRPC who have not received prior treatment with an ARPI (e.g., abiraterone acetate, enzalutamide, apalutamide, darolutamide).
- •Participants with mCRPC must have evidence of disease progression defined as one or more of the following:
- •Evidence of radiographic progression of disease following the most recent prostate cancer treatment, defined as progressive disease on CT/MRI per RECIST v1.1 or on a bone scan per PCWG
- •PSA progression defined as the following:
- •PSA nadir is defined as the lowest PSA during or after the most recent treatment. PSA progression is defined as an increased PSA of at least 25% and ≥1 ng/mL above the nadir confirmed by at least 2 measurements with a minimum of 1 week apart, and with at least 1 of the measurements within 90 days prior to screening.
- •Participant is able to swallow enzalutamide capsules whole.
排除标准
- •Known active central nervous system (CNS) metastases. Note: Participants with CNS metastases that have been treated with surgery and/or radiation therapy, who are off pharmacologic doses of glucocorticoids, and who are neurologically stable are eligible.
- •Impending bone fracture due to bone metastases
- •Has a known additional malignancy beyond prostate cancer that required active treatment with the exception of any of the following:
- •Adequately treated basal cell carcinoma, squamous cell carcinoma of the skin, or in situ carcinoma of any type
- •Adequately treated Stage I cancer from which the participant is currently in remission and has been in remission for ≥2 years
- •Any other cancer from which the participant has been disease-free for ≥5 years
- •Clinically significant cardiac disease, defined as any of the following:
- •Clinically significant cardiac arrhythmias including bradyarrhythmia which are poorly controlled.
- •Congenital long QT syndrome
- •QT interval corrected by Fridericia's formula (QTcF) ≥450 msec at screening (based on average of triplicate ECGs at baseline). If the QT interval corrected for heart rate intervals (QTc) is prolonged in a participant with a pacemaker or bundle branch block, the participant may be enrolled in the study if confirmed by the Medical Monitor.
- •History of clinically significant cardiac disease or congestive heart failure greater than New York Heart Association (NYHA) Class II or left ventricular ejection fraction measurement of <50% at baseline. Participants must not have unstable angina (symptoms at rest) or new-onset angina within the last 3 months or myocardial infarction within the past 6 months [NYHA Classification 2014].
- •Uncontrolled hypertension, defined as systolic blood pressure (BP) >160 mmHg or diastolic BP >100 mmHg which has been confirmed by 2 successive measurements despite optimal medical management.
- •Arterial or venous thrombotic or embolic events such as cerebrovascular accident (including transient ischemic attacks), deep vein thrombosis, or pulmonary embolism within the 3 months before start of study medication (except for adequately treated catheter-related venous thrombosis occurring >1 month before the start of study medication).
- •Received an investigational drug within 4 weeks or 5 half-lives (whichever is shorter) of the first dose of study drug.
- •Received chemotherapy within 2 weeks or 5 half-lives (whichever is shorter) of the first dose of study drug.
- •Additional criteria: ARPI-naïve mCRPC participants enrolled in the Dose Escalation Cohorts (including backfill) must not have received prior chemotherapy in the mCRPC setting (prior receipt of chemotherapy in the mCSPC setting is allowed, if received at least 2 weeks or 5 half-lives prior to the first dose of study drug).
- •Any unresolved NCI CTCAE criteria v5.0 Grade >2 toxicity from previous anticancer therapy at the Screening visit. Note: Participants receiving ongoing hormone replacement therapy for endocrine immune-related AEs without clinical symptoms will not be excluded.
- •Has not recovered from recent major surgery or trauma
- •Received a blood transfusion within 2 weeks of the first dose of study drug
- •History of impaired pituitary or adrenal gland function (e.g., Addison's disease, Cushing's syndrome)
- •Prior treatment with abiraterone acetate, orteronel. Exception: participants in Phase 1b Expansion Group D will have received prior abiraterone acetate, and participants in Group H may have received prior treatment with abiraterone acetate.
- •Current treatment with systemic ketoconazole or any other CYP17 inhibitor. Participants who have received systemic ketoconazole or any other CYP17 inhibitor must have discontinued these agents ≥4 weeks prior to the first dose of study drug.
- •Prior systemic treatment with an azole drug (e.g., fluconazole, itraconazole) within 4 weeks of first dose of study drug.
- •Prior treatment with estrogens within 12 weeks of the first dose of study drug
- •Need for systemic glucocorticoids greater than replacement doses; the use of topical, intraocular, inhalational, intranasal, or intra-articular glucocorticoids is permitted.
- •Prior use of any herbal products that could decrease PSA levels (e.g., saw palmetto) within 4 weeks of the first dose of study drug. Participants must agree not to use such herbal products during study participation.
- •Use of biotin (i.e., vitamin B7) or supplements containing biotin higher than the daily adequate intake of 30 µg [NIH-ODS 2022]. Note: Participants who switch from a high dose to a dose of 30 µg/day or less prior to first dose of study drug are eligible for study entry.
- •Required concomitant use of strong inducers of CYP3A4, except for enzalutamide given as study drug in Group H
- •Known hypersensitivity to PRL-02, abiraterone, abiraterone decanoate, prednisone, or dexamethasone or any of their excipients or components.
- •Has jaundice or known current active liver disease from any cause, including hepatitis A (hepatitis A virus immunoglobulin M [IgM] positive), hepatitis B (hepatitis B virus surface antigen [HBsAg] positive, confirmed by polymerase chain reaction [PCR]), or hepatitis C (hepatitis C virus [HCV] antibody positive, confirmed by HCV ribonucleic acid)
- •Hemoglobin A1c (HbA1c) >10% in participants previously diagnosed with diabetes mellitus. HbA1c >8% in participants whose diabetes mellitus is previously undiagnosed. (Excluded participants may be rescreened after referral and evidence of improved control of their condition).
- •Uncontrolled infection with human immunodeficiency virus (HIV)+. Exception: participants with well-controlled HIV (e.g., CD4 >350/mm3 and undetectable viral load) are eligible.
- •Body mass index >40 kg/m2
- •The Following Exclusion Criteria Apply to Dose Escalation Group H Only
- •Clinically significant cardiac disease, defined as any of the following:
- •NYHA class III or IV congestive heart failure or a history of NYHA class III or IV congestive heart failure, unless a screening echocardiogram or multigated acquisition scan performed within 3 months before the randomization date demonstrates a left ventricular ejection fraction of ≥45%
- •History of Mobitz II second-degree or third-degree heart block without a permanent pacemaker in place
- •Hypotension as indicated by systolic BP <86 mm Hg at screening
- •Bradycardia as indicated by a heart rate of ≤45 beats per minute on the screening ECG
- •Participant has a history of seizure or any condition that may predispose to seizure.
- •Use or required use of any prohibited medication.
- •Participant has a gastrointestinal disorder affecting absorption.
- •Participant has shown hypersensitivity reaction to the active pharmaceutical ingredient or any of the study capsule components, including Labrasol®, butylated hydroxyanisole, and butylated hydroxytoluene.
研究组 & 干预措施
Phase 1a Dose Escalation: Group A
Participants with metastatic castration-sensitive prostate cancer (mCSPC), nonmetastatic castration-sensitive prostate cancer (nmCSPC) with biochemical relapse, or metastatic castration-resistant prostate cancer (mCRPC) will receive escalating doses of PRL-02 + prednisone.
干预措施: PRL-02 injection (Drug)
Phase 1b Dose Expansion: Group D
Participants with mCRPC with prior treatment with abiraterone acetate will receive escalating doses of PRL-02 + dexamethasone.
干预措施: PRL-02 injection (Drug)
Phase 1a Dose Escalation: Group B
Participants with mCSPC, nmCSPC with biochemical relapse, or mCRPC will receive escalating doses of PRL-02 + dexamethasone.
干预措施: PRL-02 injection (Drug)
Phase 1a Dose Escalation: Group H
Participants with mCSPC or mCRPC will receive escalating doses of PRL-02 + dexamethasone + enzalutamide.
干预措施: PRL-02 injection (Drug)
Phase 1b Dose Expansion: Group E
Participants with mCRPC with prior treatment with 1 of the following androgen receptor pathway inhibitor (ARPIs) (enzalutamide, apalutamide, and/or darolutamide) will receive escalating doses of PRL-02 + dexamethasone.
干预措施: PRL-02 injection (Drug)
Phase 1b Dose Expansion: Group D
Participants with mCRPC with prior treatment with abiraterone acetate will receive escalating doses of PRL-02 + dexamethasone.
干预措施: dexamethasone (Drug)
Phase 1a Dose Escalation: Group B
Participants with mCSPC, nmCSPC with biochemical relapse, or mCRPC will receive escalating doses of PRL-02 + dexamethasone.
干预措施: dexamethasone (Drug)
Phase 1a Dose Escalation: Group H
Participants with mCSPC or mCRPC will receive escalating doses of PRL-02 + dexamethasone + enzalutamide.
干预措施: dexamethasone (Drug)
Phase 1a Dose Escalation: Group H
Participants with mCSPC or mCRPC will receive escalating doses of PRL-02 + dexamethasone + enzalutamide.
干预措施: enzalutamide (Drug)
Phase 1b Dose Expansion: Group E
Participants with mCRPC with prior treatment with 1 of the following androgen receptor pathway inhibitor (ARPIs) (enzalutamide, apalutamide, and/or darolutamide) will receive escalating doses of PRL-02 + dexamethasone.
干预措施: dexamethasone (Drug)
Phase 1a Dose Escalation: Group A
Participants with metastatic castration-sensitive prostate cancer (mCSPC), nonmetastatic castration-sensitive prostate cancer (nmCSPC) with biochemical relapse, or metastatic castration-resistant prostate cancer (mCRPC) will receive escalating doses of PRL-02 + prednisone.
干预措施: prednisone (Drug)
结局指标
主要结局
Number of Participants with physical exam abnormalities and/or AEs
时间窗: Up to 4 years
Number of participants with potentially clinically significant physical exam values or symptoms.
Incidence of Dose Limiting Toxicities (DLTs)
时间窗: Up to 28 days
A DLT is defined as any event meeting the DLT criteria during the first 28 days of each Dose Escalation treatment regardless of attribution to the study drug unless due to underlying disease or extraneous causes.
Number of Participants with Adverse Events (AEs)
时间窗: Up to 4 years
An AE is defined as any untoward medical occurrence in a patient or clinical investigation patient administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment.
Number of Participants with Serious Adverse Events (SAEs)
时间窗: Up to 4 years
An SAE is defined as any untoward medical occurrence that, at any dose: results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, or other medically important events.
Number of Participants with laboratory value abnormalities and/or AEs
时间窗: Up to 4 years
Number of participants with potentially clinically significant laboratory values.
Number of Participants with electrocardiogram (ECG) abnormalities and/or AEs
时间窗: Up to 4 years
Number of participants with potentially clinically significant ECG values.
Number of Participants with vital sign abnormalities and/or AEs
时间窗: Up to 4 years
Number of participants with potentially clinically significant vital sign values.
Number of Participants with Eastern Cooperative Oncology Group (ECOG) performance status score
时间窗: Up to 4 years
The ECOG scale will be used to assess performance status. Grades range from 0 (fully active) to 5 (dead). Negative change scores indicate an improvement. Positive scores indicate a decline in performance.
Testosterone Suppression of Participants as Assessed by Testosterone Levels
时间窗: Up to 4 years
Reduction in testosterone will be summarized by group and dose level.
次要结局
- PK of Abiraterone Decanoate in plasma: t1/2(Up to 455 days)
- PK of Abiraterone in plasma: area under the curve from time 0 to the time of the last measurable concentration (AUClast)(Up to 455 days)
- Pharmacokinetics (PK) of Abiraterone in plasma: Maximum Concentration (Cmax)(Up to 455 days)
- PK of Abiraterone Decanoate in plasma: Cmax(Up to 455 days)
- PK of Abiraterone Metabolite in plasma: Cmax(Up to 455 days)
- PK of Abiraterone in plasma: Minimum Concentration (Cmin)(Up to 455 days)
- PK of Abiraterone Decanoate in plasma: Cmin(Up to 455 days)
- PK of Abiraterone Metabolite in plasma: Cmin(Up to 455 days)
- PK of Abiraterone in plasma: Time of maximum concentration (tmax)(Up to 455 days)
- PK of Abiraterone Decanoate in plasma: tmax(Up to 455 days)
- PK of Abiraterone Metabolite in plasma: tmax(Up to 455 days)
- PK of Abiraterone in plasma: apparent volume of distribution (Vd/F)(Up to 455 days)
- PK of Abiraterone Decanoate in plasma: Vd/F(Up to 455 days)
- PK of Abiraterone Metabolite in plasma: Vd/F(Up to 455 days)
- PK of Abiraterone in plasma: oral clearance (CL/F)(Up to 455 days)
- PK of Abiraterone Decanoate in plasma: CL/F(Up to 455 days)
- PK of Abiraterone Metabolite in plasma: CL/F(Up to 455 days)
- PK of Abiraterone Decanoate in plasma: AUClast(Up to 455 days)
- PK of Abiraterone Metabolite in plasma: AUClast(Up to 455 days)
- PK of Abiraterone in plasma: Area Under the Concentration-time Curve from the Time of Dosing Extrapolated to Time Infinity (AUCinf)(Up to 455 days)
- PK of Abiraterone Decanoate in plasma: AUCinf(Up to 455 days)
- PK of Abiraterone Metabolite in plasma: AUCinf(Up to 455 days)
- PK of Abiraterone in plasma: area under the plasma concentration-time curve during a dosage interval (AUCtau)(Up to 455 days)
- PK of Abiraterone Decanoate in plasma: AUCtau(Up to 455 days)
- PK of Abiraterone Metabolite in plasma: AUCtau(Up to 455 days)
- PK of Abiraterone in plasma: Terminal Elimination Half-life (t1/2)(Up to 455 days)
- PK of Abiraterone Metabolite in plasma: t1/2(Up to 455 days)
- Composite Response Rate(Up to 4 years)
- Best overall response (BOR) per RECIST v1.1(Up to 4 years)
- PSA decline of ≥50% response from baseline (PSA50)(Up to 4 years)
- PSA decline of ≥90% response from baseline (PSA90)(Up to 4 years)
- Percentage of participants achieving a PSA level <0.2 ng/mL(Up to 4 years)
- Duration of response (DOR)(Up to 4 years)
- Radiographic progression-free survival (rPFS)(Up to 4 years)
- Overall response rate (ORR) using RECIST v1.1(Up to 4 years)
- Time to PSA progression(Up to 4 years)
- Overall survival (OS)(Up to 4 years)
- Time to first symptomatic skeletal-related event (SSRE)(Up to 4 years)