| Eligibility |
Inclusion Criteria:
- 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
Exclusion Criteria:
- 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
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