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

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.

Inclusion Criteria:

1. 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.

2. Males 18 years of age and above

3. Histological or cytological proof of prostate cancer

4. 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:

1. 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.

2. Prior exposure to enzalutamide or other investigational AR directed therapy

3. Prior chemotherapy.

4. Prior isotope therapy with strontium-89, samarium or radium-223 within 12 weeks of
enrollment.

5. 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.

6. History of pituitary or adrenal dysfunction, active or symptomatic viral hepatitis or
chronic liver disease.

7. Known symptomatic brain metastases.

8. 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.

9. Treatment-related toxicity from prior therapy > Grade 2.

10. Peripheral neuropathy > 2

11. 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.

12. Planned surgery or radiation therapy during protocol treatment,

13. 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.

14. 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.

15. 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.

16. 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).

17. Patient has a known history of HIV infection (testing not mandatory).

18. 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.).

19. 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

20. 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)

21. 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

22. 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)

23. 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.

24. 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.

25. 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.

26. 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

27. 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).

28. 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).

29. Patient with a Child-Pugh score B or C.

30. Patient has a history of non-compliance to medical regimen or inability to grant
consent.

31. 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.