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

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 LEE011 (ribociclib) and gemcitabine
(gemcitabine hydrochloride) in patients with advanced solid tumors or lymphoma.

SECONDARY OBJECTIVES:

I. To describe the safety and tolerability of the combination of LEE011 and gemcitabine.

II. To describe the pharmacokinetic (PK) of LEE011 in combination with gemcitabine.

III. To describe preliminary evidence of efficacy of the combination of LEE011 and
gemcitabine.

IV. To evaluate the correlation of cyclin-dependent kinase (CDK) amplification (testing by
fluorescence in situ hybridization [FISH]), retinoblastoma (RB) and P16 expression (by
immunohistochemistry) in archived and biopsied tumor tissue with treatment response.

OUTLINE: This is a dose-escalation study.

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

After completion of study treatment, patients are followed up at 30 days.

Inclusion Criteria:

- Patients must have advanced/metastatic solid malignancy or lymphoma for which no
standard treatment option exists that will confer clinical benefit

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

- Patients enrolled in the dose expansion phase must have at least one measurable
lesion as defined by Response Evaluation Criteria in Solid Tumors (RECIST) criteria
for solid tumors or measurable nodal disease at baseline as defined by Cheson
criteria for lymphoma

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

- Life expectancy of >= 12 weeks

- Absolute neutrophil count >= 1.5 × 10^9/L

- Platelets >= 100 × 10^9/L

- Hemoglobin >= 9 g/dL

- Potassium above lower limit normal range for the institution; supplementation may be
given before the first dose of study medication

- Total calcium (corrected for serum albumin if albumin abnormal) above lower limit
normal range for the institution; supplementation may be given before the first dose
of study medication

- Magnesium above lower limit normal range for the institution; supplementation may be
given before the first dose of study medication

- Sodium above lower limit normal range for the institution; supplementation may be
given before the first dose of study medication

- Phosphorus above lower limit normal range for the institution; 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 upper
limit of normal (ULN) or =< 5 x ULN if liver metastases are present

- Total bilirubin =< ULN; or total bilirubin =< 3.0 x ULN with direct bilirubin =< 1.5
ULN n patients with well documented Gilbert's syndrome

- Women of childbearing potential must have a negative pregnancy test performed within
7 days prior to the start of study drug

- Must be able to swallow ribociclib capsules

Exclusion Criteria:

- Previous anti-cancer chemotherapy, immunotherapy or investigational agents < 4 weeks
prior to the first day of study defined treatment

- 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 had 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)

- Active clinically serious infections or other serious uncontrolled medical conditions

- 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 baseline neuropathy of > grade 2

- Patient has known hypersensitivity to any of the excipients of ribociclib

- Patient has a known history of human immunodeficiency virus (HIV) infection (testing
not mandatory)

- 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

- Clinically significant, uncontrolled heart disease and/ or a history of cardiac
dysfunction including any of the following:

- History of unstable angina pectoris, symptomatic pericarditis, myocardial
infarction, coronary artery bypass grafting or coronary angioplasty within 12
months prior to study entry

- 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)

- History of clinically significant ventricular arrhythmia and/or conduction
delays within 12 months of screening

- Systolic blood pressure > 160 mmHg or < 90 mmHg

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

- Bradycardia (heart rate < 50 at rest) by electrocardiogram (ECG) or pulse at
screening.

- On screening, inability to determine the Fridericia corrected QT interval (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 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 is currently receiving any of the following medications and cannot be
discontinued 7 days prior to starting study drug (for details):

- Known strong inducers or inhibitors of cytochrome P450, family 3, subfamily A,
polypeptide 4/5 (CYP3A4/5) including grapefruit, grapefruit hybrids, pummelos,
star-fruit, and Seville oranges

- Those have a narrow therapeutic window and are predominantly metabolized through
CYP3A4

- Those have a known strong risk to prolong the QT interval or induce Torsades de
Pointes

- Herbal preparations

- Patient is currently receiving or has received systemic corticosteroids (=< 2 weeks
prior to starting study drug, 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)

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

- 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

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

- Patient has not recovered from all toxicities related to prior anticancer therapies
to grade 1 per National Cancer Institute (NCI)-Common Terminology Criteria for
Adverse Events (CTCAE) version 4.03 (exception to this criterion: patients with any
grade of alopecia are allowed to enter the study)

- Patient with a 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) 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); for female patients
on the study, the vasectomized male partner should be the sole partner for that
patient

- Combination of any of the 2 following (a+b or a+c or b+c)

- a. Use of oral, injected or implanted hormonal methods of contraception or
other forms of hormonal contraception that have comparable efficacy
(failure rate < 1%), for example hormone vaginal ring or transdermal
hormone contraception

- b. Placement of an intrauterine device (IUD) or intrauterine system (IUS)

- c. Barrier methods of contraception: condom or occlusive cap (diaphragm or
cervical/vault caps) with spermicidal foam/gel/film/cream/ vaginal
suppository

- In case of use of oral contraception, women should have been stable on
the same pill before taking study treatment

- Note: oral contraceptives are allowed but should be used in
conjunction with a barrier method of contraception

- 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) or have had surgical bilateral
oophorectomy (with or without hysterectomy) or tubal ligation at least
six weeks ago; in the case of oophorectomy alone, only when the
reproductive status of the woman has been confirmed by follow up
hormone level assessment 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; a condom is required to be used also by vasectomized men