Ribociclib and Gemcitabine Hydrochloride in Treating Patients With Advanced or Metastatic Solid Tumors

PRIMARY OBJECTIVES:

I. To describe the dose-limiting toxicities and identify the maximum tolerated dose (MTD) and
recommended phase II dose of the combination of ribociclib and gemcitabine hydrochloride
(gemcitabine) in patients with advanced solid tumors.

SECONDARY OBJECTIVES:

I. To describe the safety and tolerability of the combination of ribociclib and gemcitabine.

II. To describe the pharmacokinetic (PK) of ribociclib in combination with gemcitabine.

III. To describe preliminary evidence of efficacy of the combination of ribociclib and
gemcitabine.

TERTIARY OBJECTIVES:

I. To evaluate the correlation of CDK4/6, cyclin D1 and cyclin D3 amplification,
retinoblastoma (RB) and P16 expression in archived and biopsied tumor tissue with treatment
response.

OUTLINE: This is a dose-escalation study.

Patients receive gemcitabine hydrochloride intravenously (IV) over 30 minutes on days 1 and 8
and ribociclib orally (PO) once daily (QD) on days 8-14. Courses repeat every 21 days in the
absence of disease progression or unacceptable toxicity.

Inclusion Criteria:

- Diagnosis of advanced/metastatic solid malignancy for which no standard treatment
option exists that will confer clinical benefit

- Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1

- Dose expansion phase only: must have at least one measurable lesion as defined by
Response Evaluation Criteria in Solid Tumors (RECIST) criteria

- Ability to provide written informed consent which must be obtained prior to any
screening procedures and according to local guidelines

- Life expectancy of >= 12 weeks

- Absolute neutrophil count >= 1500/mm^3

- Platelets >= 100,000/mm^3

- Hemoglobin >= 9 g/dL

- Potassium >= lower limit of normal (LLN) range for the institution

- Calcium >= LLN (corrected for serum albumin, if albumin abnormal)

- Magnesium >= LLN

- Sodium >= LLN

- Phosphorus >= LLN; NOTE: Supplementation may be given before the first dose of study
medication

- International normalized ratio (INR) =< 1.5

- Serum creatinine =< 1.5 mg/dL or creatinine clearance >= 50 mL/min (calculated by
Cockcroft Gault equation)

- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 2.5 x upper
limit of normal (ULN) or =< 5 x ULN if liver metastases are present

- Total bilirubin =< 3.0 x ULN; if patient has known Gilbert?s syndrome direct bilirubin
=< 1.5 x ULN

- Standard 12-lead electrocardiography (ECG) with the following parameters at screening
(defined as the mean of the triplicate ECGs):

- Fridericia's correction formula (QTcF) interval at screening < 450 msec (using
Fridericia? s correction)

- Resting heart rate 50 to 100 beats per minute

- Negative pregnancy test performed =< 7 days prior to registration (women of
childbearing potential only)

- Able to swallow ribociclib capsules

- Willingness to return to enrolling institution for follow-up (during the active
monitoring phase of the study)

- Willingness to provide mandatory blood samples for research purposes

Exclusion Criteria:

- Previous anti-cancer chemotherapy, immunotherapy or investigational agents =< 28 days
prior to registration

- Received radiotherapy =< 28 days or limited field radiation for palliation =< 14 days
prior to registration, 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

- Major surgery =< 14 days prior to registration or has not recovered from major side
effects (tumor biopsy is not considered as major surgery)

- Active clinically serious infections or other serious uncontrolled medical conditions

- 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)

- Baseline neuropathy of > grade 2

- Known hypersensitivity to any of the excipients of ribociclib

- Known human immunodeficiency virus (HIV) patients with active and untreated disease

- Central nervous system (CNS) involvement unless they meet ALL of the following
criteria:

- >= 28 days from prior therapy completion (including radiation and/or surgery) to
registration

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

- Clinically significant, uncontrolled heart disease and/ or cardiac repolarization
abnormalities including any of the following:

- History of unstable angina pectoris, symptomatic pericarditis, myocardial
infarction, coronary artery bypass grafting or coronary angioplasty =< 12 months
prior to registration

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

- Documented cardiomyopathy

- Left ventricular ejection fraction (LVEF) < 50% as determined by echocardiogram
(ECHO)

- Clinically significant cardiac arrhythmias ( e.g ventricular tachycardia) , left
bundle branch block, high-grade atrioventricular (AV) block ( e.g bifascucular
block, Mobitz type II and third degree AV block)

- Long QT syndrome or family history of idiopathic sudden death or congenital long
QT syndrome, or any of the following:

- Risk factors for torsades de pointe (TdP) including uncorrected hypokalemia
or hypomagnesemia, history of cardiac failure, or history of clinically
significant/symptomatic bradycardia

- Concomitant use of medication(s) with a known risk to prolong the QT
interval and/or known to cause torsades de pointe that cannot be
discontinued (within 5 half-lives or =< 7 days prior to registration) or
replaced by safe alternative medication

- Inability to determine the QT interval on screening (QTcF, using Fridericia?
s correction)

- Systolic blood pressure > 160 mmHg or < 90 mmHg

- 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.)

- Currently receiving any of the following medications and cannot be discontinued 7 days
prior to starting the study

- Herbal supplements including grapefruit, grapefruit hybrids, pummelos,
star-fruit, Seville oranges or products containing the juice of each; orange
juice is allowed

- Known strong inducers or inhibitors of CYP3A4/5 including grapefruit, grapefruit
hybrids, pomelos, star-fruit, and Seville oranges

- Medications known to have a narrow therapeutic window and are predominantly
metabolized through CYP3A4

- Currently receiving or has received systemic corticosteroids (=< 14 days prior to
registration, or who have not fully recovered from side effects of such treatment);
NOTE: 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)

- History of non-compliance to medical regimen or inability to grant consent

- Currently receiving warfarin or other warfarin-derived anticoagulant for treatment,
prophylaxis or otherwise; Note: Therapy with heparin, direct oral anticoagulants, low
molecular weight heparin (LMWH) or fondaparinux is allowed

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

- Failure to recover from all adverse events/toxicities related to prior anticancer
therapies to grade 1 per National Cancer Institute (NCI)-Common Terminology Criteria
for Adverse Events (CTCAE) version 4.03; NOTE: Exception: patients with any grade of
alopecia are allowed to enter the study

- Child-Pugh score B or C (for cirrhosis patients only)

- Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a
female after conception and until the termination of gestation, confirmed by a
positive human chorionic gonadotropin (hCG) laboratory test

- Women of child-bearing potential, defined as all women physiologically capable of
becoming pregnant, unless they are using highly effective methods of contraception
throughout the study and for 8 weeks after study drug discontinuation; highly
effective contraception methods include:

- Total abstinence when this is in line with the preferred and usual lifestyle of
the patient; periodic abstinence (e.g., calendar, ovulation, symptothermal,
post-ovulation methods) and withdrawal are not acceptable methods of
contraception

- Female sterilization (have had surgical bilateral oophorectomy with or without
hysterectomy), total hysterectomy, or tubal ligation at least 6 weeks before
taking study treatment; in case of oophorectomy alone, only when the reproductive
status of the woman has been confirmed by follow up hormone level assessment

- Male sterilization (at least 6 months prior to screening), the vasectomized male
partner should be the sole partner for that patient

- Use of oral, injected or implanted hormonal methods of contraception or placement
of an intrauterine device (IUD) or intrauterine system (IUS), or other forms of
hormonal contraception that have comparable efficacy (failure rate < 1%), for
example hormone vaginal ring or transdermal hormone contraception

- Note: In case of use of oral contraception, women should have been stable on the
same pill for a minimum of 3 months before taking study treatment; Note: Oral
contraceptives are allowed but should be used in conjunction with a barrier
method of contraception due to unknown effect of drug-drug interaction

- Note: Women are considered post-menopausal and not of child bearing potential if
they have had 12 months of natural (spontaneous) amenorrhea with an appropriate
clinical profile (e.g. age appropriate, history of vasomotor symptoms) is she
considered not of child bearing potential

- Sexually active males unless they use a condom during intercourse while taking the
drug and for 21 days after stopping treatment and should not father a child in this
period; Note: A condom is required to be used also by vasectomized men in order to
prevent delivery of the drug via seminal fluid

- Known standard therapy for the patient?s disease that is potentially curative or
definitely capable of extending life expectancy