Phase IB/II Study of Enzalutamide With Ribociclib in Patients With Metastatic Castrate Resistant, Chemotherapy Naïve Prostate Cancer That Retains RB Expression
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 入组人数
- 52
- 试验地点
- 7
- 主要终点
- Incidence of dose limiting toxicity of ribociclib (Phase IB)
研究概览
简要总结
This phase Ib/II trial studies the safety, side effects, best dose, and effectiveness of ribociclib when given with enzalutamide in treating patients with castrate-resistant prostate cancer that has spread from the primary site (place where it started) to other places in the body (metastatic), is chemotherapy naive, and retains retinoblastoma expression. Testosterone can cause the growth of prostate cancer cells. Hormone therapy using enzalutamide may fight prostate cancer by blocking the use of testosterone by the tumor cells. Ribociclib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Enzalutamide with ribociclib may be safe, tolerable and/or effective in treating metastatic, castrate-resistant, chemotherapy naive prostate cancer that retains retinoblastoma expression.
详细描述
PRIMARY OBJECTIVES:
I. To determine the maximum tolerated dose of ribociclib in combination with 160 mg of enzalutamide. (Phase Ib) II. To determine efficacy with respect to the proportion of subjects that achieve a >= 50% reduction in prostate-specific antigen (PSA) at 12 weeks. (Phase II)
SECONDARY OBJECTIVES:
I. PSA progression-free survival. II. Radiographic progression-free survival (rPFS). III. Safety. IV. Pharmacokinetics.
CORRELATIVE/EXPLORATORY/TERTIARY OBJECTIVES:
研究设计
- 研究类型
- Interventional
- 分配方式
- 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 —（Adult, Older Adult）
- 性别
- Male
- 接受健康志愿者
- 否
入选标准
- •Willing and able to provide written informed consent and Health Insurance Portability and Accountability Act (HIPAA) authorization for the release of personal health information; NOTE: HIPAA authorization may be either included in the informed consent or obtained separately; consent and HIPPA authorization must be obtained prior to any screening procedures
- •Histological or cytological proof of prostate cancer
- •Documented progressive metastatic (m)CRPC based on at least one of the following criteria:
- •PSA progression defined as 25% increase over baseline value with an increase in the absolute value of at least 2 ng/mL that is confirmed by another PSA level with a minimum of a 1 week interval and a minimum PSA of 2 ng/mL
- •Soft-tissue progression defined as an increase >= 20% in the sum of the longest diameter (LD) of all target lesions based on the smallest sum LD since treatment started or the appearance of one or more new lesions
- •Progression of bone disease (evaluable disease) or (new bone lesion[s]) by bone scan
- •Have testosterone < 50 ng/dL; patients must continue primary androgen deprivation with an luteinizing hormone-releasing hormone (LHRH) analogue (agonist or antagonist) if they have not undergone orchiectomy
- •Eastern Cooperative Oncology Group (ECOG) performance status of 0-1
- •Patients on long term (> 6 months) anti-androgen therapy (e.g., flutamide, bicalutamide, nilutamide) will need to be off anti-androgen for 4 weeks (wash out period) and show evidence of disease progression off the anti-androgen; patients that have been on an anti-androgen 6 months or less will need to discontinue anti-androgen therapy prior to treatment start (no wash out period required)
- •Absolute neutrophil count >= 1.5 × 10^9/L (obtained within 14 days prior to treatment start)
- •Platelets (UNVPLT) >= 100 x 10^9/L (obtained within 14 days prior to treatment start)
- •Hemoglobin (HGB) >= 9 g/dl (obtained within 14 days prior to treatment start)
- •Potassium (K) within normal limits for the institution or corrected to within normal limits with supplements before first dose of study medication (obtained within 14 days prior to treatment start)
- •Total calcium (CA) (corrected for serum albumin) within normal limits for the institution or corrected to within normal limits with supplements before first dose of study medication (obtained within 14 days prior to treatment start)
- •Magnesium within normal limits for the institution or corrected to within normal limits with supplements before first dose of study medication (obtained within 14 days prior to treatment start)
- •Phosphorus within normal limits for the institution or corrected to within normal limits with supplements before first dose of study medication (obtained within 14 days prior to treatment start)
- •International normalized ratio (INR) =< 1.5 (obtained within 14 days prior to treatment start)
- •Serum creatinine (CREAT) =< 1.5 mg/dL or creatinine clearance >= 50 mL/min (obtained within 14 days prior to treatment start)
- •Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 2.5 x upper limit of normal (ULN); if the patient has liver metastases, ALT and AST must still be =< 2.5 x ULN; patients with liver metastases and AST/ALT above this limit will not be enrolled (obtained within 14 days prior to treatment start)
- •Total serum bilirubin =< 1.5 x ULN; or total bilirubin (TBILI) =< 3.0 x ULN with direct bilirubin within normal range in patients with well documented Gilbert's syndrome (obtained within 14 days prior to treatment start)
- •Men must agree to use adequate contraception prior to enrollment, for the duration of study participation and for at least 3 months thereafter
- •Must be able to take oral medication without crushing, dissolving or chewing tablets
排除标准
- •Prior exposure to abiraterone acetate or other specific cytochrome P450 (CYP)-17 inhibitors; abiraterone acetate given in the castration-sensitive setting is permissible if stopped at least 6 months prior to initial protocol treatment
- •Prior exposure to enzalutamide, apalutamide, or other investigational AR directed therapy
- •Prior chemotherapy for castration resistant disease; chemotherapy given in the castration-sensitive setting is permissible if stopped at least 4 weeks prior to treatment start
- •Prior isotope therapy with strontium-89, samarium or radium-223 within 12 weeks of treatment start
- •Administration of antifungal agents (itraconazole, fluconazole, etc) within 4 weeks of treatment start or unrecovered adverse events (AEs) due to agents administered more than 4 weeks of treatment start
- •History of pituitary or adrenal dysfunction, active or symptomatic viral hepatitis or chronic liver disease
- •Known symptomatic brain metastases
- •Use of any prohibited concomitant medications: immunotherapy, 5 alpha reductase inhibitors, spironolactone, diethystilbestrol (DES), ketoconazole, newer medications targeting ARs; NOTE: the concurrent use of all other drugs, over-the-counter medications, or alternative therapies must be documented; the principal investigator should be alerted if the patient is taking any agent that interacts with CYP450 system
- •Treatment-related toxicity from prior therapy > grade 2
- •Peripheral neuropathy >= 2
- •History of hypersensitivity to ribociclib or compounds of similar chemical or biologic composition to ribociclib including to peanut and soy or other drugs formulated with polysorbate 80; or enzalutamide
- •Currently taking any herbal, alternative or food supplements (i.e., prostate cancer [PC]-Spes, saw palmetto, St John wort, etc.); all herbal, alternative and food supplements must be discontinued prior to treatment start; patients may continue on a daily multi-vitamin, calcium and vitamin D
- •Planned surgery or radiation therapy during protocol treatment
- •Hormonal-acting agents (including DES, aldosterone, and spironolactone but not including gonadotropin-releasing hormone [GnRH] agonists or antagonists) are forbidden during the trial and must be stopped prior to treatment start; no washout period will be required for any of these agents
- •Initiation of bisphosphonate/denosumab therapy during protocol treatment; patients on stable doses of bisphosphonates or denosumab which have been started no less than 4 weeks prior to treatment start may continue on this medication; NOTE: initiation of bisphosphonate/denosumab therapy will be allowed for the treatment of osteoporosis or prevention of skeletal-related events (SRE) during protocol treatment
- •Patient has a concurrent malignancy or malignancy within 3 years of treatment start, with the exception of adequately treated, basal or squamous cell carcinoma, non-melanomatous skin cancer or curatively resected cervical cancer
- •Patient has impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of the study drugs (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection)
- •Patient has a known history of human immunodeficiency virus (HIV) infection (testing not mandatory)
- •Patient has any other concurrent severe and/or uncontrolled medical condition that would, in the investigator's judgment, cause unacceptable safety risks, contraindicate patient participation in the clinical study or compromise compliance with the protocol (e.g., chronic pancreatitis, chronic active hepatitis, active untreated or uncontrolled fungal, bacterial or viral infections, etc.)
- •Patient has clinically significant, uncontrolled heart disease and/or recent events including any of the following:
- •History of acute coronary syndromes (including myocardial infarction, unstable angina, coronary artery bypass grafting, coronary angioplasty, or stenting) or symptomatic pericarditis within 12 months prior to treatment start
- •History of documented congestive heart failure (New York Heart Association functional classification III-IV)
- •Documented cardiomyopathy
- •Patient has a left ventricular ejection fraction (LVEF) < 50% as determined by multiple gated acquisition (MUGA) scan or echocardiogram (ECHO) at screening
- •History of any cardiac arrhythmias, eg., ventricular, supraventricular, nodal arrhythmias, or conduction abnormality within 12 months prior to treatment start
- •Family history of corrected QT interval (QTc) prolongation or of unexplainable sudden death at < 50 years of age
- •On screening 12 lead electrocardiogram (ECG), any of the following cardiac parameters: bradycardia (heart rate < 50 at rest), tachycardia (heart rate > 90 at rest), PR interval > 220 msec, QRS interval > 109 msec, or Fridericia corrected QT (QTcF) > 450 msec; congenital long QT syndrome or family history of long QT syndrome
- •Systolic blood pressure (SBP) > 160 mmHg or < 90 mmHg
- •Bradycardia (heart rate < 50 at rest), by ECG or pulse, at screening
- •On screening, inability to determine the QTcF interval on the ECG (i.e.: unreadable or not interpretable) or QTcF > 450 msec (using Fridericia's correction); all as determined by screening ECG (mean of triplicate ECGs)
- •Patient is currently receiving any of the following medications and cannot be discontinued 7 days prior to treatment start:
- •Known strong inducers or inhibitors of cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4)/cytochrome P450, family 3, subfamily A, polypeptide 4 (5), including grapefruit, grapefruit hybrids, pummelos, star-fruit, and Seville oranges
- •That have a narrow therapeutic window and are predominantly metabolized through CYP3A4/5
- •That have a known risk to prolong the QT interval or induce Torsades de Pointes
- •Herbal preparations/medications, dietary supplements
- •Patient is currently receiving or has received systemic corticosteroids within < 2 weeks prior to treatment start, or who have not fully recovered from side effects of such treatment
- •* The following uses of corticosteroids are permitted: a short duration (< 5 days) of systemic corticosteroids; any duration of topical applications (e.g. for rash), inhaled sprays (e.g., for obstructive airways diseases), eye drops or local injections (e.g., intra-articular)
- •Patient is currently receiving warfarin or other coumarin-derived anticoagulant for treatment, prophylaxis or otherwise; therapy with heparin, low molecular weight heparin (LMWH) or fondaparinux is allowed
- •PatientParticipation in other studies involving investigational drug(s) within 30 days prior to randomization or within 5 half-lives of the investigational product (whichever is longer) or participation in any other type of medical research judged not to be scientifically or medically compatible with this study. If the patient is enrolled or planned to be enrolled in another study that does not involve an investigational drug, the agreement of the Novartis study medical lead is required to establish eligibility
- •Patient who has received radiotherapy =< 4 weeks or limited field radiation for palliation =< 2 weeks prior to treatment start, and who has not recovered to grade 1 or better from related side effects of such therapy (exceptions include alopecia) and/or in whom >= 30% of the bone marrow was irradiated
- •Patients with central nervous system (CNS) involvement unless they meet ALL of the following criteria:
- •At least 4 weeks from prior therapy completion (including radiation and/or surgery) to treatment start
- •Clinically stable CNS tumor at the time of screening and not receiving steroids and/or enzyme-inducing anti-epileptic medications for brain metastases
- •Patient has had major surgery within 14 days prior to treatment start or has not recovered from major side effects (tumor biopsy is not considered as major surgery)
- •Patient has not recovered from all toxicities related to prior anticancer therapies to National Cancer Institute (NCI)-Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 grade < 1 (exception to this criterion: patients with grade 1 taxane-induced neuropathy, any grade of alopecia, amenorrhea or other toxicities not considered a safety risk for the patient as per investigator's discretion, are allowed to enter the study)
- •Patient with a Child-Pugh score B or C
- •Patient has a history of non-compliance to medical regimen or inability to grant consent
- •Sexually active males unless they use a condom during intercourse while taking the drug and for 30 days after stopping treatment and should not father a child in this period; a condom is required to be used by vasectomized men in order to prevent delivery of the drug via seminal fluid
研究组 & 干预措施
Phase I: 200 mg Ribociclib + Enzalutamide
Enzalutamide will be administered at a dose of 160 mg (40 mg X 4 pills) once daily. 200 mg Ribociclib will be given daily for 21 out of 28 days. The phase I portion of this study will follow a traditional 3+3 design, escalating to the next higher dose cohort if 3 patients are treated and no DLTs are observed in the first cycle of therapy.
干预措施: Enzalutamide (Drug)
Phase I: 200 mg Ribociclib + Enzalutamide
Enzalutamide will be administered at a dose of 160 mg (40 mg X 4 pills) once daily. 200 mg Ribociclib will be given daily for 21 out of 28 days. The phase I portion of this study will follow a traditional 3+3 design, escalating to the next higher dose cohort if 3 patients are treated and no DLTs are observed in the first cycle of therapy.
干预措施: Ribociclib (Drug)
Phase I: 400 mg Ribociclib + Enzalutamide
Enzalutamide will be administered at a dose of 160 mg (40 mg X 4 pills) once daily. 400 mg Ribociclib will be given daily for 21 out of 28 days. The phase I portion of this study will follow a traditional 3+3 design, escalating to the next higher dose cohort if 3 patients are treated and no DLTs are observed in the first cycle of therapy.
干预措施: Enzalutamide (Drug)
Phase I: 200 mg Ribociclib + Enzalutamide
Enzalutamide will be administered at a dose of 160 mg (40 mg X 4 pills) once daily. 200 mg Ribociclib will be given daily for 21 out of 28 days. The phase I portion of this study will follow a traditional 3+3 design, escalating to the next higher dose cohort if 3 patients are treated and no DLTs are observed in the first cycle of therapy.
干预措施: Laboratory Biomarker Analysis (Other)
Phase I: 200 mg Ribociclib + Enzalutamide
Enzalutamide will be administered at a dose of 160 mg (40 mg X 4 pills) once daily. 200 mg Ribociclib will be given daily for 21 out of 28 days. The phase I portion of this study will follow a traditional 3+3 design, escalating to the next higher dose cohort if 3 patients are treated and no DLTs are observed in the first cycle of therapy.
干预措施: Pharmacological Study (Other)
Phase I: 200 mg Ribociclib + Enzalutamide
Enzalutamide will be administered at a dose of 160 mg (40 mg X 4 pills) once daily. 200 mg Ribociclib will be given daily for 21 out of 28 days. The phase I portion of this study will follow a traditional 3+3 design, escalating to the next higher dose cohort if 3 patients are treated and no DLTs are observed in the first cycle of therapy.
干预措施: Biospecimen Collection (Procedure)
Phase I: 200 mg Ribociclib + Enzalutamide
Enzalutamide will be administered at a dose of 160 mg (40 mg X 4 pills) once daily. 200 mg Ribociclib will be given daily for 21 out of 28 days. The phase I portion of this study will follow a traditional 3+3 design, escalating to the next higher dose cohort if 3 patients are treated and no DLTs are observed in the first cycle of therapy.
干预措施: Biopsy (Procedure)
Phase I: 200 mg Ribociclib + Enzalutamide
Enzalutamide will be administered at a dose of 160 mg (40 mg X 4 pills) once daily. 200 mg Ribociclib will be given daily for 21 out of 28 days. The phase I portion of this study will follow a traditional 3+3 design, escalating to the next higher dose cohort if 3 patients are treated and no DLTs are observed in the first cycle of therapy.
干预措施: Echocardiography (Procedure)
Phase I: 200 mg Ribociclib + Enzalutamide
Enzalutamide will be administered at a dose of 160 mg (40 mg X 4 pills) once daily. 200 mg Ribociclib will be given daily for 21 out of 28 days. The phase I portion of this study will follow a traditional 3+3 design, escalating to the next higher dose cohort if 3 patients are treated and no DLTs are observed in the first cycle of therapy.
干预措施: Multigated Acquisition Scan (Procedure)
Phase I: 200 mg Ribociclib + Enzalutamide
Enzalutamide will be administered at a dose of 160 mg (40 mg X 4 pills) once daily. 200 mg Ribociclib will be given daily for 21 out of 28 days. The phase I portion of this study will follow a traditional 3+3 design, escalating to the next higher dose cohort if 3 patients are treated and no DLTs are observed in the first cycle of therapy.
干预措施: Bone Scan (Procedure)
Phase I: 200 mg Ribociclib + Enzalutamide
Enzalutamide will be administered at a dose of 160 mg (40 mg X 4 pills) once daily. 200 mg Ribociclib will be given daily for 21 out of 28 days. The phase I portion of this study will follow a traditional 3+3 design, escalating to the next higher dose cohort if 3 patients are treated and no DLTs are observed in the first cycle of therapy.
干预措施: Computed Tomography (Procedure)
Phase I: 200 mg Ribociclib + Enzalutamide
Enzalutamide will be administered at a dose of 160 mg (40 mg X 4 pills) once daily. 200 mg Ribociclib will be given daily for 21 out of 28 days. The phase I portion of this study will follow a traditional 3+3 design, escalating to the next higher dose cohort if 3 patients are treated and no DLTs are observed in the first cycle of therapy.
干预措施: Magnetic Resonance Imaging (Procedure)
Phase I: 400 mg Ribociclib + Enzalutamide
Enzalutamide will be administered at a dose of 160 mg (40 mg X 4 pills) once daily. 400 mg Ribociclib will be given daily for 21 out of 28 days. The phase I portion of this study will follow a traditional 3+3 design, escalating to the next higher dose cohort if 3 patients are treated and no DLTs are observed in the first cycle of therapy.
干预措施: Laboratory Biomarker Analysis (Other)
Phase I: 400 mg Ribociclib + Enzalutamide
Enzalutamide will be administered at a dose of 160 mg (40 mg X 4 pills) once daily. 400 mg Ribociclib will be given daily for 21 out of 28 days. The phase I portion of this study will follow a traditional 3+3 design, escalating to the next higher dose cohort if 3 patients are treated and no DLTs are observed in the first cycle of therapy.
干预措施: Pharmacological Study (Other)
Phase I: 400 mg Ribociclib + Enzalutamide
Enzalutamide will be administered at a dose of 160 mg (40 mg X 4 pills) once daily. 400 mg Ribociclib will be given daily for 21 out of 28 days. The phase I portion of this study will follow a traditional 3+3 design, escalating to the next higher dose cohort if 3 patients are treated and no DLTs are observed in the first cycle of therapy.
干预措施: Biospecimen Collection (Procedure)
Phase I: 400 mg Ribociclib + Enzalutamide
Enzalutamide will be administered at a dose of 160 mg (40 mg X 4 pills) once daily. 400 mg Ribociclib will be given daily for 21 out of 28 days. The phase I portion of this study will follow a traditional 3+3 design, escalating to the next higher dose cohort if 3 patients are treated and no DLTs are observed in the first cycle of therapy.
干预措施: Biopsy (Procedure)
Phase I: 400 mg Ribociclib + Enzalutamide
Enzalutamide will be administered at a dose of 160 mg (40 mg X 4 pills) once daily. 400 mg Ribociclib will be given daily for 21 out of 28 days. The phase I portion of this study will follow a traditional 3+3 design, escalating to the next higher dose cohort if 3 patients are treated and no DLTs are observed in the first cycle of therapy.
干预措施: Echocardiography (Procedure)
Phase I: 400 mg Ribociclib + Enzalutamide
Enzalutamide will be administered at a dose of 160 mg (40 mg X 4 pills) once daily. 400 mg Ribociclib will be given daily for 21 out of 28 days. The phase I portion of this study will follow a traditional 3+3 design, escalating to the next higher dose cohort if 3 patients are treated and no DLTs are observed in the first cycle of therapy.
干预措施: Multigated Acquisition Scan (Procedure)
Phase I: 400 mg Ribociclib + Enzalutamide
Enzalutamide will be administered at a dose of 160 mg (40 mg X 4 pills) once daily. 400 mg Ribociclib will be given daily for 21 out of 28 days. The phase I portion of this study will follow a traditional 3+3 design, escalating to the next higher dose cohort if 3 patients are treated and no DLTs are observed in the first cycle of therapy.
干预措施: Bone Scan (Procedure)
Phase I: 400 mg Ribociclib + Enzalutamide
Enzalutamide will be administered at a dose of 160 mg (40 mg X 4 pills) once daily. 400 mg Ribociclib will be given daily for 21 out of 28 days. The phase I portion of this study will follow a traditional 3+3 design, escalating to the next higher dose cohort if 3 patients are treated and no DLTs are observed in the first cycle of therapy.
干预措施: Computed Tomography (Procedure)
Phase I: 400 mg Ribociclib + Enzalutamide
Enzalutamide will be administered at a dose of 160 mg (40 mg X 4 pills) once daily. 400 mg Ribociclib will be given daily for 21 out of 28 days. The phase I portion of this study will follow a traditional 3+3 design, escalating to the next higher dose cohort if 3 patients are treated and no DLTs are observed in the first cycle of therapy.
干预措施: Magnetic Resonance Imaging (Procedure)
Phase I: 600 mg Ribociclib + Enzalutamide
Enzalutamide will be administered at a dose of 160 mg (40 mg X 4 pills) once daily. 600 mg Ribociclib will be given daily for 21 out of 28 days. The phase I portion of this study will follow a traditional 3+3 design, escalating to the next higher dose cohort if 3 patients are treated and no DLTs are observed in the first cycle of therapy.
干预措施: Laboratory Biomarker Analysis (Other)
Phase I: 600 mg Ribociclib + Enzalutamide
Enzalutamide will be administered at a dose of 160 mg (40 mg X 4 pills) once daily. 600 mg Ribociclib will be given daily for 21 out of 28 days. The phase I portion of this study will follow a traditional 3+3 design, escalating to the next higher dose cohort if 3 patients are treated and no DLTs are observed in the first cycle of therapy.
干预措施: Pharmacological Study (Other)
Phase I: 600 mg Ribociclib + Enzalutamide
Enzalutamide will be administered at a dose of 160 mg (40 mg X 4 pills) once daily. 600 mg Ribociclib will be given daily for 21 out of 28 days. The phase I portion of this study will follow a traditional 3+3 design, escalating to the next higher dose cohort if 3 patients are treated and no DLTs are observed in the first cycle of therapy.
干预措施: Biospecimen Collection (Procedure)
Phase I: 600 mg Ribociclib + Enzalutamide
Enzalutamide will be administered at a dose of 160 mg (40 mg X 4 pills) once daily. 600 mg Ribociclib will be given daily for 21 out of 28 days. The phase I portion of this study will follow a traditional 3+3 design, escalating to the next higher dose cohort if 3 patients are treated and no DLTs are observed in the first cycle of therapy.
干预措施: Biopsy (Procedure)
Phase I: 600 mg Ribociclib + Enzalutamide
Enzalutamide will be administered at a dose of 160 mg (40 mg X 4 pills) once daily. 600 mg Ribociclib will be given daily for 21 out of 28 days. The phase I portion of this study will follow a traditional 3+3 design, escalating to the next higher dose cohort if 3 patients are treated and no DLTs are observed in the first cycle of therapy.
干预措施: Echocardiography (Procedure)
Phase I: 600 mg Ribociclib + Enzalutamide
Enzalutamide will be administered at a dose of 160 mg (40 mg X 4 pills) once daily. 600 mg Ribociclib will be given daily for 21 out of 28 days. The phase I portion of this study will follow a traditional 3+3 design, escalating to the next higher dose cohort if 3 patients are treated and no DLTs are observed in the first cycle of therapy.
干预措施: Multigated Acquisition Scan (Procedure)
Phase I: 600 mg Ribociclib + Enzalutamide
Enzalutamide will be administered at a dose of 160 mg (40 mg X 4 pills) once daily. 600 mg Ribociclib will be given daily for 21 out of 28 days. The phase I portion of this study will follow a traditional 3+3 design, escalating to the next higher dose cohort if 3 patients are treated and no DLTs are observed in the first cycle of therapy.
干预措施: Bone Scan (Procedure)
Phase I: 600 mg Ribociclib + Enzalutamide
Enzalutamide will be administered at a dose of 160 mg (40 mg X 4 pills) once daily. 600 mg Ribociclib will be given daily for 21 out of 28 days. The phase I portion of this study will follow a traditional 3+3 design, escalating to the next higher dose cohort if 3 patients are treated and no DLTs are observed in the first cycle of therapy.
干预措施: Computed Tomography (Procedure)
Phase I: 600 mg Ribociclib + Enzalutamide
Enzalutamide will be administered at a dose of 160 mg (40 mg X 4 pills) once daily. 600 mg Ribociclib will be given daily for 21 out of 28 days. The phase I portion of this study will follow a traditional 3+3 design, escalating to the next higher dose cohort if 3 patients are treated and no DLTs are observed in the first cycle of therapy.
干预措施: Magnetic Resonance Imaging (Procedure)
Phase II: Enzalutamide Only
Patients receive Enzalutamide 160mg PO QD once daily on Days 1-28 of each 28-day cycle. This is one of two randomized arms in the Phase II portion. Treatment continues until disease progression or unacceptable toxicity. Patients also undergo blood sample collection, tumor biopsy, ECHO or MUGA, bone scan, and CT or MRI on study.
干预措施: Laboratory Biomarker Analysis (Other)
Phase II: Enzalutamide Only
Patients receive Enzalutamide 160mg PO QD once daily on Days 1-28 of each 28-day cycle. This is one of two randomized arms in the Phase II portion. Treatment continues until disease progression or unacceptable toxicity. Patients also undergo blood sample collection, tumor biopsy, ECHO or MUGA, bone scan, and CT or MRI on study.
干预措施: Pharmacological Study (Other)
Phase II: Enzalutamide Only
Patients receive Enzalutamide 160mg PO QD once daily on Days 1-28 of each 28-day cycle. This is one of two randomized arms in the Phase II portion. Treatment continues until disease progression or unacceptable toxicity. Patients also undergo blood sample collection, tumor biopsy, ECHO or MUGA, bone scan, and CT or MRI on study.
干预措施: Biospecimen Collection (Procedure)
Phase II: Enzalutamide Only
Patients receive Enzalutamide 160mg PO QD once daily on Days 1-28 of each 28-day cycle. This is one of two randomized arms in the Phase II portion. Treatment continues until disease progression or unacceptable toxicity. Patients also undergo blood sample collection, tumor biopsy, ECHO or MUGA, bone scan, and CT or MRI on study.
干预措施: Biopsy (Procedure)
Phase II: Enzalutamide Only
Patients receive Enzalutamide 160mg PO QD once daily on Days 1-28 of each 28-day cycle. This is one of two randomized arms in the Phase II portion. Treatment continues until disease progression or unacceptable toxicity. Patients also undergo blood sample collection, tumor biopsy, ECHO or MUGA, bone scan, and CT or MRI on study.
干预措施: Echocardiography (Procedure)
Phase II: Enzalutamide Only
Patients receive Enzalutamide 160mg PO QD once daily on Days 1-28 of each 28-day cycle. This is one of two randomized arms in the Phase II portion. Treatment continues until disease progression or unacceptable toxicity. Patients also undergo blood sample collection, tumor biopsy, ECHO or MUGA, bone scan, and CT or MRI on study.
干预措施: Multigated Acquisition Scan (Procedure)
Phase II: Enzalutamide Only
Patients receive Enzalutamide 160mg PO QD once daily on Days 1-28 of each 28-day cycle. This is one of two randomized arms in the Phase II portion. Treatment continues until disease progression or unacceptable toxicity. Patients also undergo blood sample collection, tumor biopsy, ECHO or MUGA, bone scan, and CT or MRI on study.
干预措施: Bone Scan (Procedure)
Phase II: Enzalutamide Only
Patients receive Enzalutamide 160mg PO QD once daily on Days 1-28 of each 28-day cycle. This is one of two randomized arms in the Phase II portion. Treatment continues until disease progression or unacceptable toxicity. Patients also undergo blood sample collection, tumor biopsy, ECHO or MUGA, bone scan, and CT or MRI on study.
干预措施: Computed Tomography (Procedure)
Phase II: Enzalutamide Only
Patients receive Enzalutamide 160mg PO QD once daily on Days 1-28 of each 28-day cycle. This is one of two randomized arms in the Phase II portion. Treatment continues until disease progression or unacceptable toxicity. Patients also undergo blood sample collection, tumor biopsy, ECHO or MUGA, bone scan, and CT or MRI on study.
干预措施: Magnetic Resonance Imaging (Procedure)
Ribociclib at RP2D + Enzalutamide
Patients receive Ribociclib 600mg PO QD once daily on Days 1-21 of each 28-day cycle in combination with Enzalutamide 160mg PO QD once daily. This is one of two randomized arms in the Phase II portion. Patients will continue treatment until disease progression or unacceptable toxicity. Patients also undergo blood sample collection, tumor biopsy, ECHO or MUGA, bone scan, and CT or MRI on study.
干预措施: Laboratory Biomarker Analysis (Other)
Ribociclib at RP2D + Enzalutamide
Patients receive Ribociclib 600mg PO QD once daily on Days 1-21 of each 28-day cycle in combination with Enzalutamide 160mg PO QD once daily. This is one of two randomized arms in the Phase II portion. Patients will continue treatment until disease progression or unacceptable toxicity. Patients also undergo blood sample collection, tumor biopsy, ECHO or MUGA, bone scan, and CT or MRI on study.
干预措施: Pharmacological Study (Other)
Ribociclib at RP2D + Enzalutamide
Patients receive Ribociclib 600mg PO QD once daily on Days 1-21 of each 28-day cycle in combination with Enzalutamide 160mg PO QD once daily. This is one of two randomized arms in the Phase II portion. Patients will continue treatment until disease progression or unacceptable toxicity. Patients also undergo blood sample collection, tumor biopsy, ECHO or MUGA, bone scan, and CT or MRI on study.
干预措施: Biospecimen Collection (Procedure)
Ribociclib at RP2D + Enzalutamide
Patients receive Ribociclib 600mg PO QD once daily on Days 1-21 of each 28-day cycle in combination with Enzalutamide 160mg PO QD once daily. This is one of two randomized arms in the Phase II portion. Patients will continue treatment until disease progression or unacceptable toxicity. Patients also undergo blood sample collection, tumor biopsy, ECHO or MUGA, bone scan, and CT or MRI on study.
干预措施: Biopsy (Procedure)
Ribociclib at RP2D + Enzalutamide
Patients receive Ribociclib 600mg PO QD once daily on Days 1-21 of each 28-day cycle in combination with Enzalutamide 160mg PO QD once daily. This is one of two randomized arms in the Phase II portion. Patients will continue treatment until disease progression or unacceptable toxicity. Patients also undergo blood sample collection, tumor biopsy, ECHO or MUGA, bone scan, and CT or MRI on study.
干预措施: Echocardiography (Procedure)
Ribociclib at RP2D + Enzalutamide
Patients receive Ribociclib 600mg PO QD once daily on Days 1-21 of each 28-day cycle in combination with Enzalutamide 160mg PO QD once daily. This is one of two randomized arms in the Phase II portion. Patients will continue treatment until disease progression or unacceptable toxicity. Patients also undergo blood sample collection, tumor biopsy, ECHO or MUGA, bone scan, and CT or MRI on study.
干预措施: Multigated Acquisition Scan (Procedure)
Ribociclib at RP2D + Enzalutamide
Patients receive Ribociclib 600mg PO QD once daily on Days 1-21 of each 28-day cycle in combination with Enzalutamide 160mg PO QD once daily. This is one of two randomized arms in the Phase II portion. Patients will continue treatment until disease progression or unacceptable toxicity. Patients also undergo blood sample collection, tumor biopsy, ECHO or MUGA, bone scan, and CT or MRI on study.
干预措施: Bone Scan (Procedure)
Ribociclib at RP2D + Enzalutamide
Patients receive Ribociclib 600mg PO QD once daily on Days 1-21 of each 28-day cycle in combination with Enzalutamide 160mg PO QD once daily. This is one of two randomized arms in the Phase II portion. Patients will continue treatment until disease progression or unacceptable toxicity. Patients also undergo blood sample collection, tumor biopsy, ECHO or MUGA, bone scan, and CT or MRI on study.
干预措施: Computed Tomography (Procedure)
Ribociclib at RP2D + Enzalutamide
Patients receive Ribociclib 600mg PO QD once daily on Days 1-21 of each 28-day cycle in combination with Enzalutamide 160mg PO QD once daily. This is one of two randomized arms in the Phase II portion. Patients will continue treatment until disease progression or unacceptable toxicity. Patients also undergo blood sample collection, tumor biopsy, ECHO or MUGA, bone scan, and CT or MRI on study.
干预措施: Magnetic Resonance Imaging (Procedure)
Phase I: 400 mg Ribociclib + Enzalutamide
Enzalutamide will be administered at a dose of 160 mg (40 mg X 4 pills) once daily. 400 mg Ribociclib will be given daily for 21 out of 28 days. The phase I portion of this study will follow a traditional 3+3 design, escalating to the next higher dose cohort if 3 patients are treated and no DLTs are observed in the first cycle of therapy.
干预措施: Ribociclib (Drug)
Phase I: 600 mg Ribociclib + Enzalutamide
Enzalutamide will be administered at a dose of 160 mg (40 mg X 4 pills) once daily. 600 mg Ribociclib will be given daily for 21 out of 28 days. The phase I portion of this study will follow a traditional 3+3 design, escalating to the next higher dose cohort if 3 patients are treated and no DLTs are observed in the first cycle of therapy.
干预措施: Enzalutamide (Drug)
Phase I: 600 mg Ribociclib + Enzalutamide
Enzalutamide will be administered at a dose of 160 mg (40 mg X 4 pills) once daily. 600 mg Ribociclib will be given daily for 21 out of 28 days. The phase I portion of this study will follow a traditional 3+3 design, escalating to the next higher dose cohort if 3 patients are treated and no DLTs are observed in the first cycle of therapy.
干预措施: Ribociclib (Drug)
Phase II: Enzalutamide Only
Patients receive Enzalutamide 160mg PO QD once daily on Days 1-28 of each 28-day cycle. This is one of two randomized arms in the Phase II portion. Treatment continues until disease progression or unacceptable toxicity. Patients also undergo blood sample collection, tumor biopsy, ECHO or MUGA, bone scan, and CT or MRI on study.
干预措施: Enzalutamide (Drug)
Ribociclib at RP2D + Enzalutamide
Patients receive Ribociclib 600mg PO QD once daily on Days 1-21 of each 28-day cycle in combination with Enzalutamide 160mg PO QD once daily. This is one of two randomized arms in the Phase II portion. Patients will continue treatment until disease progression or unacceptable toxicity. Patients also undergo blood sample collection, tumor biopsy, ECHO or MUGA, bone scan, and CT or MRI on study.
干预措施: Enzalutamide (Drug)
Ribociclib at RP2D + Enzalutamide
Patients receive Ribociclib 600mg PO QD once daily on Days 1-21 of each 28-day cycle in combination with Enzalutamide 160mg PO QD once daily. This is one of two randomized arms in the Phase II portion. Patients will continue treatment until disease progression or unacceptable toxicity. Patients also undergo blood sample collection, tumor biopsy, ECHO or MUGA, bone scan, and CT or MRI on study.
干预措施: Ribociclib (Drug)
结局指标
主要结局
Incidence of dose limiting toxicity of ribociclib (Phase IB)
时间窗: 28 days
Will be defined as an adverse event or clinically significant abnormal laboratory value assessed as unrelated to disease, disease progression, inter-current illness, or concomitant medications. All analysis will be descriptive.
Proportion of patients with a >= 50% reduction in prostate specific antigen (PSA) (Phase II)
时间窗: 12 weeks
A Simon two-stage design for a 12 week PSA50 endpoint with a null hypothesis of 78%, an alternative hypothesis of 93%, alpha of 0.10, power of 90% and 11 subjects treated at the first stage will be used.
Number of Dose Limiting Toxicity of Ribociclib (Phase IB)
时间窗: 28 days
Will be defined as an adverse event or clinically significant abnormal laboratory value assessed as unrelated to disease, disease progression, inter-current illness, or concomitant medications. All analysis will be descriptive.
Number of Patients With a >= 50% Reduction in Prostate Specific Antigen (PSA) (Phase II)
时间窗: 12 weeks
The primary objective for the phase II component of this study is to determine efficacy with respect to the proportion of subjects that achieve a ≥ 50% reduction in PSA at 12 weeks.
次要结局
- Radiographic PFS (rPFS)(Time from treatment start to disease progression in bone or soft-tissue, or death, whichever occurs first, assessed up to 2 years)
- Overall survival(Up to 2 years)
- PSA progression free survival (PFS)(Time of first dose until progression (25% increase in PSA from nadir) or death, assessed up to 2 years)
- PSA Progression Free Survival (PFS)(Time of first dose until progression (25% increase in PSA from nadir) or death, assessed up to 2 years)
- Radiographic PFS (rPFS)(From first dose to disease progression in bone or soft-tissue, or death, whichever occurs first, assessed up to 40 months)
- Overall Survival(From first dose until death from any cause, assessed up to 60 months)