Enzalutamide With and Without Ribociclib for Metastatic, Castrate-Resistant, Chemotherapy-Naive Prostate Cancer That Retains RB Expression

Study Overview
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Brief Summary
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This partially randomized phase IB/II trial studies the side effects and best dose of ribociclib when given with enzalutamide and to see how well they work compared to enzalutamide alone in treating patients with prostate cancer that does not respond to treatment with hormones (hormone resistant), has spread from the primary site (place where it started) to other places in the body (metastatic), is chemotherapy naïve, 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. It is not yet known whether enzalutamide works better when given with or without ribociclib in treating patients with prostate cancer.

Detailed Description
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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. III. Safety. IV. Pharmacokinetics. TERTIARY OBJECTIVES: I. To evaluate the expression of retinoblastoma (RB) in circulating tumor cells (CTCs) and tumor tissue. II. To evaluate other mechanisms of castrate resistance (such as androgen receptor [AR]-variant [v]7) in tumor tissue and CTCs. III. To explore resistance mechanisms of cyclin dependent kinase (CDK)4/6 inhibitors in tumor samples in patients that progress on enzalutamide and ribociclib. IV. Explore the use/correlation of circulating deoxyribonucleic acid (DNA)/exosomes in castrate-resistant prostate cancer (CRPC) patients treated with enzalutamide with and without ribociclib. V. Androgen profiles and correlation to clinical outcomes. VI. Development of model explant systems to correlate with the clinical outcome. OUTLINE: This is a phase I, dose-escalation study of ribociclib followed by a phase II study. PHASE Ib: Patients receive enzalutamide orally (PO) once daily (QD) on days 1-28 and ribociclib PO QD on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. PHASE II: Patients are randomized to 1 of 2 treatment arms. ARM A: Patients receive enzalutamide PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. ARM B: Patients receive enzalutamide PO QD on days 1-28 and ribociclib PO QD on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up every 3 months for 24 months.

Official Title
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Randomized Phase IB/II Study of Enzalutamide With and Without Ribociclib in Patients With Metastatic Castrate Resistant, Chemotherapy Naïve Prostate Cancer That Retains RB Expression

Conditions
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Hormone-Resistant Prostate Cancer, Metastatic Prostate Carcinoma, Prostate Carcinoma Metastatic in the Bone, Stage IV Prostate Cancer

Intervention / Treatment
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* Drug: Enzalutamide
* Drug: Ribociclib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Willing and able to provide written informed consent and 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. Males 18 years of age and above Histological or cytological proof of prostate cancer Documented progressive mCRPC 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 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. 7) Have testosterone < 50 ng/dL. Patients must continue primary androgen deprivation with an LHRH analogue (agonist or antagonist) if they have not undergone orchiectomy 8) ECOG performance status of 0-1 9) 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 enrollment (no wash out period required). 10) Patient has adequate bone marrow and organ function as defined by the following laboratory values: Absolute neutrophil count ≥ 1.5 × 109/L. Platelets (UNVPLT) ≥ 100 × 109/L. Hemoglobin (HGB) ≥ 9 g/dl. Potassium (K), total calcium (CA)(corrected for serum albumin), magnesium, sodium (NA) and phosphorus within normal limits for the institution or corrected to within normal limits with supplements before first dose of study medication. INR ≤ 1.5. Serum creatinine (CREAT) ≤ 1.5 mg/dL or creatine clearance > 50 mL/min. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 x 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.. 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. 11) The effects of ribociclib on the developing human fetus at the recommended therapeutic dose are unknown. Men must agree to use adequate contraception prior to enrollment, for the duration of study participation and for at least 3 months thereafter. 12) Must be able to take oral medication without crushing, dissolving or chewing tablets. Exclusion Criteria: Prior exposure to abiraterone acetate or other specific 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 or other investigational AR directed therapy Prior chemotherapy. Prior isotope therapy with strontium-89, samarium or radium-223 within 12 weeks of enrollment. Administration of antifungal agents (itraconazole, fluconazole, etc) within 4 weeks of enrollment or unrecovered AEs due to agents administered more than 4 weeks of enrollment. 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, diethylstilbestrol (DES), ketoconazole, newer medications targeting ARs. NOTE: Because of the potential for drug-drug interaction, 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. All herbal, alternative and food supplements (i.e., PC-Spes, Saw Palmetto, St John Wort, etc.). They must be discontinued prior to enrollment. 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 GnRH agonists or antagonists) are forbidden during the trial and must be stopped prior to enrollment. 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 enrollment 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 enrollment, 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 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 enrollment 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 enrollment. Family history of QTc prolongation or of unexplainable sudden death at <50 years of age. On screening 12 lead 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 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 enrollment: Known strong inducers or inhibitors of CYP3A4/5, 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 enrollment, or who have not fully recovered from side effects of such treatment. The following uses of corticosteroids are permitted: single doses, 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. Patient who has participated in a prior investigational study within 30 days prior to enrollment or within 5 half-lives of the investigational product, whichever is longer. Patient who has received radiotherapy ≤ 4 weeks or limited field radiation for palliation ≤ 2 weeks prior to enrollment, 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 enrollment 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 enrollment 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 NCI-CTCAE version 4.03 Grade <1 (Exception to this criterion: patients with any grade of alopecia 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Enzalutamide<br>Patients receive enzalutamide PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. | Drug: Enzalutamide<br>* Given PO<br>* Other names: MDV3100;|
| Experimental: Enzalutamide + Ribociclib<br>Patients receive enzalutamide PO QD on days 1-28 and ribociclib PO QD on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. | Drug: Enzalutamide<br>* Given PO<br>* Other names: MDV3100;Drug: Ribociclib<br>* Given PO<br>* Other names: LEE011;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose limiting toxicity of Ribociclib (Phase IB) | DLT is 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. | 28 days | 
| Proportion of patients with a >= 50% reduction in PSA (Phase II) | The proportion of subjects with 50% reduction in PSA at 12 weeks will be estimated within each group along with exact 95% binomial confidence intervals. Groups will be compared with respect to the proportion of subjects with a 50% reduction in PSA at 12 weeks using a one-sided Fisher's exact test with alpha=0.10. Summary statistics include the number of observations, mean, standard deviation, median, minimum, and maximum values. A P-value of 0.10 will be used to declare statistical significance for the primary outcome. | 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PSA progression free survival (PFS) | Summarized by treatment arm using Kaplan-Meier plots. Median PFS will be estimated from the Kaplan-Meier analysis. | Time of first dose until progression (25% increase in PSA from nadir) or death, assessed up to 2 years | 
| Radiographic PFS (rPFS) | Summarized by treatment arm using Kaplan-Meier plots. Median rPFS will be estimated from the Kaplan-Meier analysis. | 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 |