LEE011 (Ribociclib) in Combination With Docetaxel Plus Prednisone in mCRPC

Inclusion Criteria:

- Histologically confirmed prostate cancer. Small cell/neuroendocrine differentiated
allowed but not required for study participation.

- Progressive metastatic prostate cancer (as defined below in Item #5) despite castrate
levels of testosterone (< 50 ng/dL).

- Metastatic lesion amenable to biopsy in the judgment of Study Investigator and
Interventional Radiology (Phase 2 only)

- Patients may have either non-measurable disease OR measurable disease

- Progressive disease during (or within 4 weeks of completion) with abiraterone,
enzalutamide, and/or ARN-509 based on any one of the following:

- For patients with measurable disease, progression by the RECIST criteria.13

- PSA evidence for progressive prostate cancer consists of a PSA level of at least 2
ng/ml which has risen on at least 2 successive occasions, at least one week apart. If
the confirmatory PSA (#3) value is less (i.e., #3b) than the screening PSA (#2) value,
then an additional test for rising PSA (#4) will be required to document progression
for the purposes of eligibility.

- Radionuclide bone scan: At least two new foci consistent with metastatic lesions

- Testosterone < 50 ng/dL. Patients must continue primary androgen deprivation with an
LHRH analogue if they have not undergone orchiectomy.

- Patients treated with first generation anti-androgen as most recent systemic therapy
(bicalutamide, nilutamide) must have at least 4 weeks elapsed from treatment
discontinuation to start of protocol therapy with evidence of disease progression by
PCWG2 criteria following discontinuation of prior anti-androgen.

- ECOG Performance Status 0 or 1.

- Patient has adequate bone marrow and organ function as defined by the following
laboratory values:

- Absolute neutrophil count ≥ 1.5 × 109/L.

- Platelets ≥ 100 × 109/L.

- Hemoglobin ≥ 9 g/dl.

- Potassium, total calcium (corrected for serum albumin), magnesium, sodium and
phosphorus within normal limits for the institution or corrected to within normal
limits before first dose of study medication.

- INR ≤ 1.5 unless on direct thrombin inhibitor at time of study entry.

- Serum creatinine ≤ 1.5mg/dL or estimated creatinine clearance ≥ 50 ml/min

- In the absence of liver metastases, alanine aminotransferase (ALT) and aspartate
aminotransferase (AST) <2.5 x ULN. If the patient has liver metastases, ALT and AST <5
x ULN

- Total bilirubin < ULN; or total bilirubin ≤3.0 x ULN or direct bilirubin ≤1.5 x ULN in
patients with well-documented Gilbert's Syndrome.

- No other systemic therapies for prostate cancer within 28 days or 5 half-lives,
whichever is shorter, prior to day 1 of study therapy.

- Sexually active males must 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 also by vasectomized men in order to prevent delivery of
the drug via seminal fluid. Fertile males must use a condom with spermicide (double
barrier method).

- Age ≥ 18 years

- Written informed consent must be obtained prior to any screening procedures and
according to local guidelines.

Exclusion Criteria:

- Patient has a known hypersensitivity to ribociclib or any of its excipients, or prior
treatment with CDK 4/6 inhibitor.

- Prior chemotherapy for metastatic castration-resistant prostate cancer. Chemotherapy
administered in the castration-sensitive setting is allowed provided last dose of
chemotherapy was greater than 6 months prior to study entry

- Patient has a concurrent malignancy or malignancy within 3 years of randomization,
with the exception of adequately treated, basal cell skin cancer, squamous cell
carcinoma, non-melanomatous skin cancer or curatively resected cervical cancer.

- 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
starting the study treatment

- Clinically stable CNS tumor at the time of screening and not receiving steroids and/or
enzyme-inducing anti-epileptic medications for brain metastases.

- Baseline screening for CNS metastases is not required unless presence of signs and/or
symptoms of involvement

- Patient is not able to swallow oral medication and/or 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 significant small bowel resection).

- 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 screening

- History of documented congestive heart failure (New York Heart Association functional
classification III-IV)

- Patient has a left ventricular ejection fraction (LVEF) < 50% as determined by
Multiple Gated acquisition (MUGA) scan or echocardiogram (ECHO) obtained during
Screening.

- History of any cardiac arrhythmias, e.g., ventricular, supraventricular, nodal
arrhythmias, or conduction abnormality within 12 months of screening. Patients with
rate-controlled atrial fibrillation or flutter are permitted.

- Bradycardia (heart rate < 50 bpm at rest), by ECG or pulse, at screening

- Congenital long QT syndrome or family history of long QT syndrome

- Any of the following abnormalities on screening 12-lead ECG:

- QTcF > 450 msec

- Bradycardia (heart rate < 50 bpm at rest)

- Tachycardia (heart rate > 100 bpm at rest)

- PR interval > 220msec,

- QRS interval >109 msec

- Documented cardiomyopathy

- Systolic blood pressure >160 mmHg or <90 mmHg at screening

- AST and/or ALT > 1.5 x ULN with concomitant alkaline phosphatase > 2.5 x ULN

- Patient receiving any of the following medications within 7 days of day 1 of study
treatment.

- 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

- Patient is currently receiving or has received systemic corticosteroids ≤2 weeks prior
to starting study drug at a dose greater than the equivalent of 10 mg prednisone/day,
or who have not fully recovered from the 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, direct thrombin inhibitors,
low molecular weight heparin (LMWH) or fondaparinux is allowed.

- Participation in a prior investigational study within 30 days prior to enrollment or
within 5 half-lives of the investigational product, whichever is longer

- Major surgery within 14 days prior to starting study drug or has not recovered from
major side effects (tumor biopsy is not considered as major surgery).

- Patient who has received radiotherapy ≤4 weeks or limited field radiation for
palliation ≤2 weeks prior to starting study drug, and who has not recovered to grade 1
or better from related side effects of such therapy (exceptions include alopecia),
and/or in whom ≥25% of the bone marrow was irradiated.

- Patient has a known history of HIV infection (testing not required)

- Patient has not recovered from all toxicities related to prior anticancer therapies to
NCI-CTCAE version 4.03 to less than or equal to Grade 1 (Exception to this criterion:
patients with any grade of alopecia are allowed to enter the study).

- Patients with chronic liver disease with a Child-Pugh score B or C.

- Patients with serious intercurrent infections, or nonmalignant medical illnesses that
are uncontrolled or whose control may be jeopardized by the complications of this
therapy.

- Patients with severe psychiatric illness/social situations that would limit compliance
with study requirements in the judgment of study investigator.

- History of bleeding diathesis. Patients receiving anti-coagulation must be able safely
interrupt treatment for tumor biopsy (Phase 2 only)

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