A Phase 1b Open-Label, Clinical Trial to Evaluate the Safety, Tolerability, and Pharmacokinetics of ARV-110 in Combination With Abiraterone in Patients With Metastatic Prostate Cancer
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 45
- 试验地点
- 19
- 主要终点
- Number of Patients with Adverse Events as a measure of safety and tolerability of ARV-110 in combination with abiraterone
研究概览
简要总结
Phase 1b study to assess the combination of ARV-110 (bavdegalutamide) and abiraterone in participants with metastatic prostate cancer with rising PSA values on abiraterone.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 64 years（Adult, Older Adult）
- 性别
- Male
- 接受健康志愿者
- 否
入选标准
- •Histological, pathological, or cytological confirmed diagnosis of adenocarcinoma of the prostate.
- •Ongoing treatment with stable doses of abiraterone (on an empty stomach) and a concomitant corticosteroid for mCRPC or for metastatic castration sensitive prostate cancer (mCSPC) until Cycle 1, Day 1 (C1D1).
- •Recent Prostate-specific antigen (PSA) values must demonstrate:
- •Rising PSAs at least 16 weeks after initiation of abiraterone
- •At least 2 PSA values that are higher than the PSA nadir on abiraterone, measured at a minimum of 1 week apart . The screening PSA for this study may be used as the 2nd PSA value.
- •No known radiographic evidence of disease progression while receiving abiraterone and clinically benefitting at the time of consent. If there is radiographic disease progression during screening, the participant may be considered eligible if, in the judgement of the investigator, the participant is clinically benefitting from abiraterone.
- •Ongoing androgen deprivation therapy with a gonadotropin-releasing hormone (GnRH) analogue or inhibitor, or orchiectomy (surgical or medical castration).
- •Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
排除标准
- •Previously treated with enzalutamide, apalutamide, darolutamide or experimental therapies (e.g., protein degraders or inhibitors) directed at the androgen receptor.
- •Treatment with any chemotherapy, investigational agents, immunotherapy, or hormonal therapy other than gonadotropin-releasing hormone (GnRH) agonists within 28 days of the start of treatment on protocol.
- •Radiation therapy within 4 weeks of first dose of study drug or prior irradiation to >25% of the bone marrow.
- •Participants taking agents that are either a) sensitive P-glycoprotein (P-gp), breast cancer resistance protein (BCRP) substrates, or Cytochrome P450 3A4 (CYP3A4) substrates, b) P-gp, BCRP, CYP3A4, or CYP2D6 substrates that have a narrow therapeutic index, c) strong CYP3A4 inhibitors or inducers, or d) any other prohibited and/or restricted medications described in the protocol.
- •Major surgery (as judged by the Investigator) within 4 weeks of first dose of study drug.
- •Untreated brain metastases or brain metastases requiring steroids
- •Any other active malignancy within 3 years prior to enrollment, except for adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ.
- •Any of the following in the previous 12 months: myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure (New York Heart Association class II, III or IV), cerebrovascular accident, transient ischemic attack, symptomatic pulmonary embolism, or other clinically significant episode of thromboembolic disease.
- •Any of the following in the previous 6 months: congenital long QT syndrome, Torsade de Pointes, arrhythmias (including sustained ventricular tachyarrhythmia and ventricular fibrillation), left anterior hemiblock (bifascicular block), or ongoing cardiac dysrhythmias of National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Events (CTCAE) Grade ≥2, atrial fibrillation of any grade (Grade ≥2 in the case of asymptomatic lone atrial fibrillation).
- •Hypertension that cannot be controlled by medications (>150/90 millimeters of mercury [mmHg] despite optimal medical therapy).
- •Active, uncontrolled bacterial, fungal, or viral infection, including hepatitis B virus, hepatitis C virus, known human immunodeficiency virus (HIV), or acquired immunodeficiency syndrome (AIDS)-related illness.
- •Active inflammatory gastrointestinal disease, uncontrolled chronic diarrhea, known diverticular disease, or previous gastric resection or lap band surgery. Gastroesophageal reflux disease is allowed except for if under treatment with proton pump inhibitors.
- •Participants with Child Pugh C.
- •Participants with electrolyte imbalances of hypokalemia, hypomagnesemia, and/or hypocalcemia.
- •Participants with QTcF ≥470 millisecond (msec).
研究组 & 干预措施
Bavdegalutamide + Abiraterone (Safety Lead-in)
Male participants received 420 milligrams (mg) bavdegalutamide (3*140 mg tablets) orally once daily with food and continued taking abiraterone orally once daily at the same dose they were taking before enrolling in the study, on an empty stomach (at least 1 hour before or 2 hours after a meal), along with a corticosteroid of the investigator's choice, per the local guidelines or product label in initial safety lead-in phase until disease progression, an adverse event (AE) leading to discontinuation of the study treatment, death, withdrawal of consent, or any criteria were met for discontinuation.
干预措施: Bavdegalutamide (Drug)
Bavdegalutamide + Abiraterone (Safety Lead-in)
Male participants received 420 milligrams (mg) bavdegalutamide (3*140 mg tablets) orally once daily with food and continued taking abiraterone orally once daily at the same dose they were taking before enrolling in the study, on an empty stomach (at least 1 hour before or 2 hours after a meal), along with a corticosteroid of the investigator's choice, per the local guidelines or product label in initial safety lead-in phase until disease progression, an adverse event (AE) leading to discontinuation of the study treatment, death, withdrawal of consent, or any criteria were met for discontinuation.
干预措施: Abiraterone (Drug)
Bavdegalutamide + Abiraterone (Expansion Phase)
After the Recommended Phase 2 Dose (RP2D) was determined, additional male participants were enrolled and participants from safety lead-in phase continued to receive 420 mg bavdegalutamide (3*140 mg tablets) orally once daily with food and continued taking abiraterone orally once daily at the same dose they were taking before enrolling in the study, on an empty stomach (at least 1 hour before or 2 hours after a meal), along with a corticosteroid of the investigator's choice, per the local guidelines or product label until disease progression, an AE leading to discontinuation of the study treatment, death, withdrawal of consent, or any criteria were met for discontinuation.
干预措施: Bavdegalutamide (Drug)
Bavdegalutamide + Abiraterone (Expansion Phase)
After the Recommended Phase 2 Dose (RP2D) was determined, additional male participants were enrolled and participants from safety lead-in phase continued to receive 420 mg bavdegalutamide (3*140 mg tablets) orally once daily with food and continued taking abiraterone orally once daily at the same dose they were taking before enrolling in the study, on an empty stomach (at least 1 hour before or 2 hours after a meal), along with a corticosteroid of the investigator's choice, per the local guidelines or product label until disease progression, an AE leading to discontinuation of the study treatment, death, withdrawal of consent, or any criteria were met for discontinuation.
干预措施: Abiraterone (Drug)
结局指标
主要结局
Number of Patients with Adverse Events as a measure of safety and tolerability of ARV-110 in combination with abiraterone
时间窗: 35 days after subject discontinues study treatment
Adverse events as characterized by type, frequency, severity (as graded by NCI CTCAE version 5.0), timing, seriousness, and relationship to study drug combination
Incidence of dose limiting toxicities of ARV-110 in combination with abiraterone
时间窗: 4 weeks
Dose limiting toxicities in first 4 weeks of the study combination treatment characterized by type, frequency, severity (as graded by NCI CTCAE v 5.0), timing, seriousness, and relationship to study drug
Incidence of laboratory abnormalities as a measure of safety and tolerability of ARV-110 in combination with abiraterone
时间窗: 35 days after subject discontinues study treatment
Laboratory abnormalities as characterized by type, frequency, severity (as graded by NCI CTCAE v 5.0), and timing.
Recommended Phase 2 dose (RP2D)/schedule for the combination
时间窗: 4 weeks
Dose limiting toxicities in first 4 weeks of the study combination treatment will be assessed to determine the dose of ARV-110 and abiraterone associated with acceptable safety and tolerability.
Safety Lead-in: Number of Participants Experiencing Dose Limiting Toxicities (DLTs)
时间窗: Baseline (Day 1) up to Day 28
DLT was defined as: Grade \>=3 hematologic parameters, Grade ≥ 3 neutropenia with infection, Grade 4 neutropenia lasting \> 5 days, Febrile neutropenia, Grade 3 thrombocytopenia with clinically significant bleeding, Grade 4 thrombocytopenia, any toxicity requiring dose interruption for \>=14 days; Grade \>=3 non-hematologic toxicities considered clinically significant and non-clinically significant Grade \>=3 toxicities requiring dose interruption for \>=10 days that determined by the investigator to be clinically relevant. Severity graded according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.
Safety Lead-in: Recommended Phase 2 Dose (RP2D) of Bavdegalutamide
时间窗: Baseline (Day 1) up to Day 28
Dose limiting toxicities in first 4 weeks of the study combination treatment assessed to determine the dose of bavdegalutamide associated with acceptable safety and tolerability.
Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs and Treatment Related TEAEs
时间窗: From Day 1 of study treatment in Safety lead-in up to 30 days after end of study treatment (assessed up to approximately 111.57 weeks)
An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of study drug, whether or not considered related to the study drug. A serious adverse event (SAE) was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. A TEAE is an AE occurring on/after the date of first dose of bavdegalutamide and on-study abiraterone and within 30 days of the last dose of bavdegalutamide and on-study abiraterone. TEAEs included both Serious TEAEs and non-serious TEAEs.
次要结局
- Safety Lead-in: Area Under the Concentration-Time Curve During a Dosing Interval (AUCtau) of Bavdegalutamide and Abiraterone(Pre-dose, 1, 2, 4, 6 and 8 hours post dose on Cycle 1 Day 21 (each cycle is of 28 days))
- Safety Lead-in: Area Under the Concentration-time Curve From Time 0 Through the Last Measurable Concentration (AUClast) of Bavdegalutamide and Abiraterone(Pre-dose, 1, 2, 4, 6 and 8 hours post dose on Cycle 1 Day 21 (each cycle is of 28 days))
- Safety Lead-in: Maximum Observed Plasma Concentration (Cmax) of Bavdegalutamide and Abiraterone(Pre-dose, 1, 2, 4, 6 and 8 hours post dose on Cycle 1 Day 21 (each cycle is of 28 days))
- Safety Lead-in: Minimum Observed Plasma Concentration (Cmin) of Bavdegalutamide and Abiraterone(Pre-dose, 1, 2, 4, 6 and 8 hours post dose on Cycle 1 Day 21 (each cycle is of 28 days))
- Safety Lead-in: Time of Maximum Observed Plasma Concentration (Tmax) of Bavdegalutamide and Abiraterone(Pre-dose, 1, 2, 4, 6 and 8 hours post dose on Cycle 1 Day 21 (each cycle is of 28 days))
- Safety Lead-in: Last Measurable Plasma Concentration (Clast) of Bavdegalutamide and Abiraterone(Pre-dose, 1, 2, 4, 6 and 8 hours post dose on Cycle 1 Day 21 (each cycle is of 28 days))
- Safety Lead-in: Time of Last Measurable Plasma Concentration (Tlast) of Bavdegalutamide and Abiraterone(Pre-dose, 1, 2, 4, 6 and 8 hours post dose on Cycle 1 Day 21 (each cycle is of 28 days))
- Percentage of Participants With Lack of Prostate-Specific Antigen (PSA) Progression(Baseline (Day 1) up to 12 weeks)
- PSA30 Response Rate(Baseline up to approximately 152 weeks)
- PSA50 Response Rate(Baseline up to approximately 152 weeks)
- Duration of PSA30 Response(From the date of the first confirmed PSA30 response up to confirmed PSA progression (assessed up to approximately 152 weeks))
- Duration of PSA50 Response(From the date of the first confirmed PSA50 response up to confirmed PSA progression (assessed up to approximately 152 weeks))
- Time to PSA Progression(From first dose up to date of PSA progression (assessed up to approximately 152 weeks))
- Radiographic Progression-Free Survival (rPFS)(From first dose to the date of first progression (assessed up to approximately 152 weeks))
- Overall Response Rate (ORR) by Modified RECIST v1.1)/PCWG3 Criteria(From first dose up to approximately 152 weeks)
- Duration of Radiographic Response (DOR)(From the date of first documented confirmed response to the date of the first documented tumor progression (assessed up to approximately 152 weeks))
研究者
Clinical Trial Information Desk
Scientific
Arvinas Androgen Receptor Inc.