Phase 1/2a Dose-Escalation and Expansion Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of CORT125281 With Enzalutamide in Patients With Metastatic Castration-Resistant Prostate Cancer
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 入组人数
- 39
- 试验地点
- 16
- 主要终点
- Maximum Tolerated Dose
研究概览
简要总结
This study consists of a dose escalation study with an expansion phase to evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD), and preliminary efficacy of exicorilant (CORT125281) in combination with enzalutamide in patients with metastatic castration-resistant prostate cancer (mCRPC) to identify a recommended dose (RD) for Phase 2 studies.
详细描述
Exicorilant is a selective glucocorticoid receptor (GR) antagonist. In this study, exicorilant will be administered orally in combination with enzalutamide to patients with mCRPC to evaluate the safety, tolerability, PK, PD, and preliminary efficacy of the regimen. The study consists of 2 phases: a dose-determination phase and an expansion phase. The dose determination phase is designed to determine dose-limiting toxicities and the RD of exicorilant plus enzalutamide in patients with mCRPC. Once the recommended dosing regimen has been determined, the following expansion cohorts will be enrolled and treated with exicorilant plus enzalutamide at the RD level.
Abiraterone-Resistant Cohort: Patients who have progressed during treatment with abiraterone, and have received no other androgen receptor (AR)-blocking therapies.
AR Antagonist-Resistant Cohort: Patients who have progressed during treatment with enzalutamide or other second-generation AR inhibitors.
The effect of food on exicorilant PK will be assessed in a portion of the patients enrolled in the Expansion Phase. The 2 expansion cohorts will be enrolled in parallel.
In each phase of the study, routine assessments of safety and tolerability will be performed and samples will be collected to determine standard PK parameters for exicorilant, enzalutamide, and their major metabolites. PD, quality of life evaluations and preliminary evaluations of antitumor activity of exicorilant with enzalutamide will be performed throughout the study.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
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
- •Major Inclusion Criteria:
- •Able to understand the purpose and risks of the study; willing and able to adhere to scheduled visits, treatment plans, laboratory tests, and other study evaluations and procedures, and provide written informed consent
- •Males ≥18 years of age at the time of signing consent
- •Histologically confirmed adenocarcinoma of the prostate with metastatic disease
- •Dose-Determination Phase Segment 1 and Expansion Phase: Progressive disease as defined by prostate-specific antigen (PSA) or imaging after most recent prior therapy. PSA ≥1 ng/mL, if a confirmed rise in PSA is the only indication of progression. Progression by PSA requires rising PSA over a previous reference value by at least 2 measurements obtained ≥1 week apart. PSA measurements can be collected during or after the most recent prior therapy.
- •Dose-Determination Phase Segment 2: Currently receiving enzalutamide with a rising PSA as follows:
- •Rising PSA: 25% increase over nadir and an absolute value of >1 ng/mL by at least 2 measurements obtained ≥1 week apart. PSA measurements can be collected during or after the most recent prior therapy.
- •Patients must have received enzalutamide for a minimum of 12 weeks and have been on stable doses of enzalutamide ≥80 mg once daily for at least 4 weeks prior to Cycle 1 Day
- •Patients will continue enzalutamide without interruption during the Screening Period (no wash-out period). This will be the enzalutamide starting dose for combination with exicorilant beginning on Cycle 1 Day
- •M0 disease is allowed
- •Expansion Phase: Patients must have progressed while receiving an androgen-directed therapy as follows:
- •Abiraterone-Resistant Cohort: Patients must have progressed during treatment with abiraterone
- •Androgen Receptor Antagonist-Resistant Cohort: Patients must have progressed during treatment with enzalutamide or second-generation AR-blocking therapies. Patients progressing on enzalutamide immediately prior to enrolling in this study must be on stable doses of enzalutamide. These patients will continue enzalutamide without interruption during the Screening Period (no wash-out period required).
- •Baseline tumor assessment performed within 28 days prior to the first dose of study treatment (exicorilant and/or on-study enzalutamide, whichever is earliest).
- •Prior surgical or chemical castration with serum testosterone <1.7 nmol/L (50 ng/dL). If the method of castration is use of a luteinizing hormone-releasing hormone (LHRH) analogue, there must be a plan to maintain effective LHRH analogue treatment for the duration of the trial.
- •Consent to have all protocol-required pharmacodynamic biomarker samples, including the pretreatment and on treatment paired tumor biopsies (mandatory for a subset of patients)
- •Consent to provide mandatory pharmacogenomic blood sample (Dose-Determination Segment 1 only)
- •Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
- •Adequate baseline organ function within 14 days prior to the first dose of study treatment (on-study enzalutamide and/or exicorilant, whichever is earliest)
- •Patients receiving systemic corticosteroids greater than 2-weeks in duration within 3 months of study entry or with clinical evidence of adrenal insufficiency must have evidence of adequate adrenal function based upon morning plasma cortisol concentration or adrenocorticotrophic hormone (ACTH, cosyntropin) stimulation test
- •If a patient engages in sexual intercourse with a woman of childbearing potential, a condom with spermicide and another form of birth control must be used during and for 100 days after the final dose of study treatment (exicorilant or enzalutamide, whichever is latest). A condom is required during and for 100 days after completing treatment with enzalutamide if a patient is engaged in sexual activity with a pregnant woman. Patients must also agree to avoid sperm donation during the study and for at least 100 days after the final treatment administration.
排除标准
- •Received chemotherapy, non-palliative radiotherapy, immunotherapy, or any investigational cancer therapies within 21 days prior to the first dose of exicorilant, or treatment with such therapies is planned during protocol treatment. Concomitant anticancer therapy is not permitted during the enzalutamide Lead-In Period during Dose-Determination Phase Segment
- •More than 2 prior cytotoxic chemotherapy regimens for the treatment of mCRPC
- •Dose Determination Phase and Expansion Phases will exclude patients for the following:
- •Dose-Determination Phase (Segment 1 only):
- •Progressed during treatment with enzalutamide prior to Cycle 1 Day -28 (only applies to patients receiving enzalutamide Lead-In) or
- •Received prior second-generation anti-androgen and require urgent disease response or stabilization
- •Expansion Phase Abi-Resistant Cohort:
- •Received prior treatment with enzalutamide, or
- •Received prior second-generation anti-androgen and require urgent disease response or stabilization
- •Expansion Phase ARant-Resistant Cohort: Require urgent disease response or stabilization
- •Ongoing or anticipated therapy with hormone therapy (other than LHRH analogue), including any dose of megestrol acetate (Megace), finasteride (Proscar), dutasteride (Avodart) or received abiraterone within 28 days prior to the first dose of exicorilant
- •Contraindication or precaution for enzalutamide
- •Parenchymal brain metastases
- •Any clinically significant uncontrolled condition that may increase the risk to the study patient or that the Investigator considers places the patient at unacceptable risk
- •Received herbal products or alternative therapies that may decrease PSA levels or that may have hormonal anti-prostate cancer activity within 21 days of study treatment initiation or plans to initiate treatment with these products/alternative therapies during the entire duration of the study
- •Received systemic glucocorticoids within 21 days prior to the first dose of exicorilant, or requirement for chronic or frequently used systemic or inhaled glucocorticoids for medical conditions (eg, rheumatoid arthritis, immunosuppression after organ transplantation). Short courses (≤5 days) for non-cancer related reasons are allowed if clinically required (such as prophylaxis for CT)
- •Concurrent therapy with strong inhibitors or inducers of CYP3A4 or CYP2C8 or with sensitive substrates of CYP3A4, CYP2C9, or CYP2C19.
研究组 & 干预措施
Dose Determination Segment 2: Arm B - 240 mg Exicorilant
Patients will receive combination treatment with once-daily exicorilant 240 mg, enzalutamide once daily, and placebo in 28-day dosing cycles.
干预措施: Placebo (Drug)
Dose Determination Segment 1 (Open-label) Cohort 1 - 360 mg Exicorilant
Patients will receive lead-in enzalutamide monotherapy once daily for 28 days. Patients will then receive combination treatment with twice-daily exicorilant 180 mg (total daily dose 360 mg) and enzalutamide once daily in 28-day dosing cycles.
干预措施: Exicorilant (Drug)
Dose Determination Segment 1 (Open-label) Cohort 1 - 360 mg Exicorilant
Patients will receive lead-in enzalutamide monotherapy once daily for 28 days. Patients will then receive combination treatment with twice-daily exicorilant 180 mg (total daily dose 360 mg) and enzalutamide once daily in 28-day dosing cycles.
干预措施: Enzalutamide (Drug)
Dose Expansion - Abi-Resistant Cohort (Open-label)
Patients who have progressed during treatment with abiraterone and no other androgen receptor-blocking therapies will receive exicorilant and enzalutamide.
干预措施: Enzalutamide (Drug)
Dose Expansion - Abi-Resistant Cohort Food Effect (Open-label)
Subcohort (first 10 patients enrolled into Cohort A). Patients enrolled into this subcohort will receive a single dose of exicorilant at Cycle 1 Day -7 and a single dose of exicorilant at Cycle 1 Day 1 30 minutes after a standard breakfast to assess the effect of food on pharmacokinetic (PK)parameters. Patients will then begin exicorilant in combination with enzalutamide on Cycle 1 Day 2 and continue in 28-day dosing cycles.
干预措施: Exicorilant (Drug)
Dose Determination Segment 1 (Open-label) Cohort 2 - 280 mg Exicorilant
Patients will receive lead-in enzalutamide monotherapy once daily for 28 days. Patients will then receive combination treatment with twice-daily exicorilant 140 mg (total daily dose 280 mg) and enzalutamide once daily in 28-day dosing cycles.
干预措施: Exicorilant (Drug)
Dose Determination Segment 1 (Open-label) Cohort 2 - 280 mg Exicorilant
Patients will receive lead-in enzalutamide monotherapy once daily for 28 days. Patients will then receive combination treatment with twice-daily exicorilant 140 mg (total daily dose 280 mg) and enzalutamide once daily in 28-day dosing cycles.
干预措施: Enzalutamide (Drug)
Dose Determination Segment 1 (Open-label) Cohort 3 - 280 mg Exicorilant
Patients will not receive lead-in enzalutamide monotherapy. Patients will receive combination treatment with twice-daily exicorilant 140 mg (total daily dose 280 mg) and enzalutamide once daily in 28-day dosing cycles.
干预措施: Exicorilant (Drug)
Dose Determination Segment 1 (Open-label) Cohort 3 - 280 mg Exicorilant
Patients will not receive lead-in enzalutamide monotherapy. Patients will receive combination treatment with twice-daily exicorilant 140 mg (total daily dose 280 mg) and enzalutamide once daily in 28-day dosing cycles.
干预措施: Enzalutamide (Drug)
Dose Determination Segment 2: Arm A - Maximum Dose 240 mg Exicorilant
Patients will receive treatment with once-daily exicorilant starting at 240 mg and titrating to 280 mg and then to 320 mg at 2-week intervals, as tolerated, in combination with enzalutamide once daily in 28-day dosing cycles. Patients in this arm are reported at the highest titrated dose of exicorilant achieved: 240 mg exicorilant.
干预措施: Exicorilant (Drug)
Dose Determination Segment 2: Arm A - Maximum Dose 240 mg Exicorilant
Patients will receive treatment with once-daily exicorilant starting at 240 mg and titrating to 280 mg and then to 320 mg at 2-week intervals, as tolerated, in combination with enzalutamide once daily in 28-day dosing cycles. Patients in this arm are reported at the highest titrated dose of exicorilant achieved: 240 mg exicorilant.
干预措施: Enzalutamide (Drug)
Dose Determination Segment 2: Arm A - Maximum Dose 280 mg Exicorilant
Patients will receive treatment with once-daily exicorilant starting at 240 mg and titrating to 280 mg and then to 320 mg at 2-week intervals, as tolerated, in combination with enzalutamide once daily in 28-day dosing cycles. Patients in this arm are reported at the highest titrated dose of exicorilant achieved: 280 mg exicorilant.
干预措施: Exicorilant (Drug)
Dose Determination Segment 2: Arm A - Maximum Dose 280 mg Exicorilant
Patients will receive treatment with once-daily exicorilant starting at 240 mg and titrating to 280 mg and then to 320 mg at 2-week intervals, as tolerated, in combination with enzalutamide once daily in 28-day dosing cycles. Patients in this arm are reported at the highest titrated dose of exicorilant achieved: 280 mg exicorilant.
干预措施: Enzalutamide (Drug)
Dose Determination Segment 2: Arm A - Maximum Dose 320 mg Exicorilant
Patients will receive treatment with once-daily exicorilant starting at 240 mg and titrating to 280 mg and then to 320 mg at 2-week intervals, as tolerated, in combination with enzalutamide once daily in 28-day dosing cycles. Patients in this arm are reported at the highest titrated dose of exicorilant achieved: 320 mg exicorilant.
干预措施: Exicorilant (Drug)
Dose Determination Segment 2: Arm A - Maximum Dose 320 mg Exicorilant
Patients will receive treatment with once-daily exicorilant starting at 240 mg and titrating to 280 mg and then to 320 mg at 2-week intervals, as tolerated, in combination with enzalutamide once daily in 28-day dosing cycles. Patients in this arm are reported at the highest titrated dose of exicorilant achieved: 320 mg exicorilant.
干预措施: Enzalutamide (Drug)
Dose Determination Segment 2: Arm B - 240 mg Exicorilant
Patients will receive combination treatment with once-daily exicorilant 240 mg, enzalutamide once daily, and placebo in 28-day dosing cycles.
干预措施: Exicorilant (Drug)
Dose Determination Segment 2: Arm B - 240 mg Exicorilant
Patients will receive combination treatment with once-daily exicorilant 240 mg, enzalutamide once daily, and placebo in 28-day dosing cycles.
干预措施: Enzalutamide (Drug)
Dose Expansion - Abi-Resistant Cohort (Open-label)
Patients who have progressed during treatment with abiraterone and no other androgen receptor-blocking therapies will receive exicorilant and enzalutamide.
干预措施: Exicorilant (Drug)
Dose Expansion - Abi-Resistant Cohort Food Effect (Open-label)
Subcohort (first 10 patients enrolled into Cohort A). Patients enrolled into this subcohort will receive a single dose of exicorilant at Cycle 1 Day -7 and a single dose of exicorilant at Cycle 1 Day 1 30 minutes after a standard breakfast to assess the effect of food on pharmacokinetic (PK)parameters. Patients will then begin exicorilant in combination with enzalutamide on Cycle 1 Day 2 and continue in 28-day dosing cycles.
干预措施: Enzalutamide (Drug)
Dose Expansion - ARant-Resistant Cohort (Open-label)
Patients who progressed during treatment with enzalutamide or second-generation androgen receptor-blocking (ARant) therapies will receive a daily dose of exicorilant and enzalutamide.
干预措施: Exicorilant (Drug)
Dose Expansion - ARant-Resistant Cohort (Open-label)
Patients who progressed during treatment with enzalutamide or second-generation androgen receptor-blocking (ARant) therapies will receive a daily dose of exicorilant and enzalutamide.
干预措施: Enzalutamide (Drug)
结局指标
主要结局
Maximum Tolerated Dose
时间窗: 10 months
Determine the maximum tolerated dose (MTD) and/or biologically active doses of CORT125281 in combination with enzalutamide to identify the recommended dose (RD) for Phase 2 studies based on the number of patients with dose limiting toxicities (DLTs) of CORT125281 in combination with enzalutamide
Number of Patients With One or More Dose-Limiting Toxicity (DLT)
时间窗: From first dose of exicorilant through completion of Cycle 1 (up to 28 days) for Segment 1 and from first dose of exicorilant through completion of Cycle 3 (up to 84 days) for Segment 2
Assess the maximum tolerated dose (MTD) and/or biologically active doses of exicorilant in combination with enzalutamide to identify the recommended dose (RD) for Phase 2 studies based on the number of patients who experienced a DLT while receiving exicorilant in combination with enzalutamide. DLTs were defined as any of the protocol-specified toxicities that the Investigator considered possibly or probably related to study drug that occurred during the DLT-evaluation period. The MTD is defined as the highest dose at which the DLT rate was \<33%.
次要结局
- Number of participants with treatment-related adverse events as assessed by CTCAE v4.0(24 months)
- Cmax PK parameter(Cycle 1 Day 1 through Cycle 3 Day 1)
- AUC 0-24hr PK parameter(Cycle 1 Day 1 through Cycle 3 Day 1)
- Tmax PK parameter(Cycle 1 Day 1 through Cycle 3 Day 1)
- Effect of food on the AUCinf PK of CORT125281(Cycle 1 Day -7)
- Objective Response Rate (ORR)(12 months from the enrollment of the final subject)
- Time to symptomatic skeletal event (SSE)(12 months from the enrollment of the final subject)
- Time to clinical progression(Baseline to 12 months)
- CL/F PK parameter(Cycle 1 Day 1 through Cycle 3 Day 1)
- Effect of food on the AUC0-t PK of CORT125281(Cycle 1 Day -7)
- Reduction in prostate-specific antigen (PSA)(12 months from the enrollment of the final subject)
- Radiographic progression-free survival (rPFS)(Baseline to 12 months)
- AUC 0-last Pharmacokinetic (PK) parameter(Cycle 1 Day 1 through Cycle 3 Day 1)
- Duration of Response (DOR)(12 months from the enrollment of the final subject)
- Overall Survival (OS)(12 months from the enrollment of the final subject)
- AUC 0-infinity PK parameter(Cycle 1 Day 1 through Cycle 3 Day 1)
- Cmin,ss PK parameter(Cycle 1 Day 1 through Cycle 3 Day 1)
- λz PK parameter(Cycle 1 Day 1 through Cycle 3 Day 1)
- Effect of food on the Cmax PK of CORT125281(Cycle 1 Day -7)
- Time to prostate-specific antigen (PSA) progression(Baseline to 12 months)
- AUC of Plasma Enzalutamide: Segment 1(Predose and at time intervals up to 24 hours postdose on Cycle 1 Day -1, Cycle 1 Day 1, and Cycle 2 Day 1)
- Cmax of Plasma Enzalutamide: Segment 1(Predose and at time intervals up to 24 hours postdose on Cycle 1 Day -1, Cycle 1 Day 1, and Cycle 2 Day 1)
- AUC of Plasma N-Desmethyl Enzalutamide: Segment 1(Predose and at time intervals up to 24 hours postdose on Cycle 1 Day -1, Cycle 1 Day 1, and Cycle 2 Day 1)
- Cmax of Plasma N-Desmethyl Enzalutamide: Segment 1(Predose and at time intervals up to 24 hours postdose on Cycle 1 Day -1, Cycle 1 Day 1, and Cycle 2 Day 1)
- AUC of Plasma Enzalutamide Carboxylic Acid: Segment 1(Predose and at time intervals up to 24 hours postdose on Cycle 1 Day -1, Cycle 1 Day 1, and Cycle 2 Day 1)
- Cmax of Plasma Enzalutamide Carboxylic Acid: Segment 1(Predose and at time intervals up to 24 hours postdose on Cycle 1 Day -1, Cycle 1 Day 1, and Cycle 2 Day 1)
- AUC of Plasma Exicorilant: Segment 2(Predose and at time intervals up to 6 hours on Cycle 1 Day 15 (before dose escalation), and at 2 weeks after each dose escalation (Week 4 for escalation from 240 mg to 280 mg exicorilant and Week 6 for escalation from 280 mg to 320 mg exicorilant).)
- Cmax of Plasma Exicorilant: Segment 2(Predose and at time intervals up to 6 hours on Cycle 1 Day 15 (before dose escalation), and at 2 weeks after each dose escalation (Week 4 for escalation from 240 mg to 280 mg exicorilant and Week 6 for escalation from 280 mg to 320 mg exicorilant).)
- AUC of Plasma Enzalutamide: Segment 2(Predose and at time intervals up to 6 hours on Cycle 1 Day 15 (before dose escalation), and at 2 weeks after each dose escalation (Week 4 for escalation from 240 mg to 280 mg exicorilant and Week 6 for escalation from 280 mg to 320 mg exicorilant).)
- Cmax of Plasma Enzalutamide: Segment 2(Predose and at time intervals up to 6 hours on Cycle 1 Day 15 (before dose escalation), and at 2 weeks after each dose escalation (Week 4 for escalation from 240 mg to 280 mg exicorilant and Week 6 for escalation from 280 mg to 320 mg exicorilant).)
- AUC of Plasma N-Desmethyl Enzalutamide: Segment 2(Predose and at time intervals up to 6 hours on Cycle 1 Day 15 (before dose escalation), and at 2 weeks after each dose escalation (Week 4 for escalation from 240 mg to 280 mg exicorilant and Week 6 for escalation from 280 mg to 320 mg exicorilant).)
- Cmax of Plasma N-Desmethyl Enzalutamide: Segment 2(Predose and at time intervals up to 6 hours on Cycle 1 Day 15 (before dose escalation), and at 2 weeks after each dose escalation (Week 4 for escalation from 240 mg to 280 mg exicorilant and Week 6 for escalation from 280 mg to 320 mg exicorilant).)
- AUC of Plasma Enzalutamide Carboxylic Acid: Segment 2(Predose and at time intervals up to 6 hours on Cycle 1 Day 15 (before dose escalation), and at 2 weeks after each dose escalation (Week 4 for escalation from 240 mg to 280 mg exicorilant and Week 6 for escalation from 280 mg to 320 mg exicorilant).)
- Number of Patients With One or More Treatment-Emergent Adverse Events(Up to 27 months for Segment 1 and up to 19 months for Segment 2)
- Area Under the Concentration Versus Time Curve (AUC) of Plasma Exicorilant: Segment 1(Predose and at time intervals up to 12 hours postdose on Cycle 1 Day 1 and Cycle 2 Day 1)
- Maximum Observed Concentration (Cmax) of Plasma Exicorilant: Segment 1(Predose and at time intervals up to 12 hours postdose on Cycle 1 Day 1 and Cycle 2 Day 1)
- Cmax of Plasma Enzalutamide Carboxylic Acid: Segment 2(Predose and at time intervals up to 6 hours on Cycle 1 Day 15 (before dose escalation), and at 2 weeks after each dose escalation (Week 4 for escalation from 240 mg to 280 mg exicorilant and Week 6 for escalation from 280 mg to 320 mg exicorilant).)
- Objective Response Rate (ORR)(Up to 22 months)
- Number of Patients With ≥50% Reduction in Prostate-Specific Antigen (PSA)(Up to 39 months)
- Time to PSA Progression(Up to 39 months)
- Percentage of Patients Who Are Progression-Free by PSA Criteria at 4, 6, and 12 Months(4, 6, and 12 months)
- Time to First Symptomatic Skeletal Event (SSE)(Up to 39 months)
- Time to Progression by Radiographic Criteria(Up to 22 months)
- Percentage of Patients Who Are Progression-Free by Radiographic Criteria at 4, 6, and 12 Months(4, 6, and 12 months)
- Time to Progression by Clinical or Radiographic Criteria(Up to 22 months)
- Percentage of Patients Who Are Progression-Free by Clinical or Radiographic Criteria at 4, 6, and 12 Months(4, 6, and 12 months)
- Time to Progression by Clinical or Biochemical Criteria(Up to 33 months)
- Percentage of Patients Who Are Progression-Free by Clinical or Biochemical Criteria at 4, 6, and 12 Months(4, 6, and 12 months)
- Duration of Response (DOR)(Up to 11 months)
- Overall Survival (OS)(Up to 52 months)