This is a Phase Ib/II open label clinical trial in patients with metastatic castration
resistant prostate cancer. The objective of the phase Ib portion of the study is to establish
the maximum tolerated dose (MTD) and dose limiting toxicities (DLT) of docetaxel (75 mg/m2 IV
q21 days) and prednisone (5mg orally BID) in combination with ribociclib in escalating oral
daily doses in patients with metastatic castrate resistant prostate cancer (mCRPC) with prior
resistance to abiraterone and/or enzalutamide who have not undergone prior chemotherapy for
metastatic disease. Up to three cohorts will be enrolled to determine the MTD and DLT profile
of this combination during Phase 1b. Dose escalation will follow the standard 3+3 design. The
dosing schedule is being chosen to allow patients to be exposed to the most efficacious
dosing schedule of docetaxel (75 mg/m2 every 3 weeks). If there is excess toxicity observed
with the treatment combination at the first dose level (dose level I), an alternative dosing
schema may be pursued with weekly docetaxel treatment (35 mg/m2 weekly), which has
demonstrated activity in mCRPC and decreased risk of cytopenias compared with every 3 week
The Phase II portion (N = 29) of the study is a single arm, two stage, open-label study of
ribociclib (dosed at the RP2D) in combination with docetaxel and prednisone to determine the
efficacy and further define the safety of the treatment combination. Patients will be treated
with the combination of ribociclib plus docetaxel + prednisone for up to 9 cycles. If there
is no evidence of radiographic or clinical disease progression after 9 cycles of protocol
therapy, patients may continue on single agent maintenance ribociclib until the time of
disease progression. Patients will have the option of starting maintenance ribociclib after 6
cycles of docetaxel if stable disease or better on re-staging scans. The dose of ribociclib
used during maintenance will be the same dose as that immediately preceding cessation of
I. To determine the safety profile, maximally tolerated dose (MTD), and recommended phase 2
dose of ribociclib in combination with docetaxel plus prednisone in patients with metastatic
castration-resistant prostate cancer (mCRPC). (Phase IB) II. To determine the 6-month
radiographic progression-free survival rate with the combination of ribociclib, docetaxel,
and prednisone in patients with mCRPC. (Phase 2)
I. To determine the median radiographic progression-free survival with the combination of
ribociclib, docetaxel, and prednisone in patients with mCRPC.
II. To determine the objective response rate and median duration of response among patients
with measurable disease at baseline.
III. To determine the prostate-specific antigen (PSA) response proportion and time to PSA
IV. To characterize the safety profile of ribociclib in combination with docetaxel.
V. To determine if there is evidence of drug-drug interaction between docetaxel + prednisone
I. To determine whether baseline or percent change from baseline in gallium citrate uptake on
positron emission tomography (PET) scan is associated with clinical outcomes. (For University
of California San Francisco (USCF) Patients Only) II. To determine whether genomic assessment
of MYC pathway activation (MYC amplification or overexpression, Rb1 deletion, cyclin D/E and
CDK 4/6 overexpression) assessed within metastatic tumor tissue, circulating tumor cells
(CTCs), and/or cell-free circulating tumor deoxyribonucleic acid (ctDNA) is predictive of
clinical outcomes with the combination of ribociclib plus docetaxel.
III. To determine whether MYC activation score as determined by validated expression
signature can distinguish those with and without clinical benefit with ribociclib in
combination with docetaxel.
IV. To use an unbiased approach with integration of clinical, genomic, and proteomic data
(differential pathway signature correlation; DiPSC) to define a signature associated with
response to taxane + CDK4/6 inhibition in mCRPC.
OUTLINE: This is a phase Ib, dose-escalation study of ribociclib followed by a phase II
Patients receive docetaxel intravenously (IV) over 1 hour on day 1 or on days 1 and 8,
prednisone orally (PO) twice daily (BID) on days 1-21, and ribociclib PO once daily (QD) on
days 1-4, and 8-15. Treatment repeats every 21 days for 9 cycles in the absence of disease
progression or unacceptable toxicity. Patients achieving stable disease or better on
re-staging scans after 6 cycles and patients without radiographic or clinical disease
progression after 9 cycles of treatment may continue on single agent maintenance ribociclib
PO QD on days 1-14 of every 21 day cycle in the absence of disease progression or
After completion of study treatment, patients are followed up every three months.
- 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).
- 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:
1. For patients with measurable disease, progression by the RECIST criteria.
2. 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.
3. Radionuclide bone scan: At least two new foci consistent with metastatic lesions
- Testosterone < 50 ng/dL. Patients must continue primary androgen deprivation with a
luteinizing hormone-releasing hormone (LHRH) analogue if they have not undergone
- 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.
- Eastern Cooperative Oncology Group (ECOG) Performance Status 0 or 1.
- Patient has adequate bone marrow and organ function as defined by the following
- Absolute neutrophil count ≥ 1.5 × 109/L.
- Platelets ≥ 100 × 109/L.
- Hemoglobin ≥ 9 g/dl.
- Potassium, total calcium (corrected for serum albumin) and magnesium within normal
limits for the institution or corrected to within normal limits before first dose of
- International normalized ratio (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 upper limit of normal (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
- Age ≥ 18 years
- Written informed consent must be obtained prior to any screening procedures and
according to local guidelines.
- Patient has a known hypersensitivity to ribociclib or any of its excipients, or prior
treatment with cyclin-dependent kinase (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
- 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
- Patient has a left ventricular ejection fraction (LVEF) < 50% as determined by
Multiple Gated acquisition (MUGA) scan or echocardiogram (ECHO) obtained during
- 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:
- QT interval with Fridericia's correction (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
- 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
- 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: 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
- 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 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).
- 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
- 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