Pharmacokinetically Guided Everolimus in Patients With Breast Cancer, Pancreatic Neuroendocrine Tumors, or Kidney Cancer

PRIMARY OBJECTIVE:

To determine frequency of any grade of stomatitis at day 29 (cycle 2, day 1) in patients
receiving dose-adjusted everolimus.

SECONDARY OBJECTIVES:

1. Progression-free survival rates at 6 months.

2. Pharmacodynamic (PD)-inhibition of downstream mammalian target of rapamycin (mTOR)
effectors in peripheral blood.

3. Number of dose adjustments required.

4. Percentage of days on therapy.

5. Average minimum concentration (Cmin) values.

6. Frequency and type of treatments for stomatitis.

7. Genetic predictors of stomatitis development in selected outlier patients.

OUTLINE:

Patients receive everolimus orally (PO) daily on days 1-28. Treatment repeats every 28 days
for up to 6 courses in the absence of disease progression or unacceptable toxicity. Patients
also undergo real-time pharmacokinetic therapeutic drug monitoring (TDM) on days 4, 8, and
15 of course 1. Dosing adjustments of everolimus will be performed on day 8, if necessary.
If the everolimus dose is adjusted, patients will continue to undergo real-time
pharmacokinetic TDM weekly until goal concentrations are achieved on 2 consecutive measures.
Patients whose everolimus dose is not adjusted undergo real-time pharmacokinetic TDM on day
1 of courses 2-6.

After completion of study treatment, patients are followed up every 12 weeks.

Inclusion Criteria:

- Eastern Cooperative Oncology Group (ECOG) performance status 0-2

- Confirmed diagnosis of:

- Postmenopausal advanced hormone receptor-positive, human epidermal growth factor
receptor 2 (HER2)-negative breast cancer after failure of treatment with
letrozole or anastrozole

- Progressive neuroendocrine tumors of pancreatic origin (PNET) that is
unresectable, locally advanced or metastatic

- Advanced renal cell carcinoma (RCC) after failure of treatment with sunitinib or
sorafenib

- Histologically confirmed, measurable or evaluable disease. Patients should have at
least one measurable lesion.

- Adequate bone marrow function as indicated by the following:

- Absolute neutrophil count (ANC) > 1,500/μL

- Platelets ≥ 100,000/μL

- Hemoglobin > 10 g/dL

- Adequate renal function, as indicated by creatinine clearance > 30 mL/min

- Adequate liver function, as indicated by:

- Bilirubin ≤ 1.5 x upper limit of normal (ULN)

- International normalized ratio (INR) ≤ 2

- Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) < 2 x ULN
unless related to primary disease

- Signed informed consent

- Adequate birth control when appropriate

- Fasting serum cholesterol ≤ 300 mg/dL OR ≤ 7.75 mmol/L AND fasting triglycerides ≤
2.5 x ULN. NOTE: in case one or both of these thresholds are exceeded, the patient
can only be included after initiation of appropriate lipid lowering medication.

Exclusion Criteria:

- Patients currently receiving anticancer therapies or who have received anticancer
therapies within 4 weeks of the start of everolimus (including chemotherapy,
radiation therapy, antibody based therapy, etc., but not including somatostatin
analogues, e.g., octreotide)

- Known intolerance or hypersensitivity to everolimus or other rapamycin analogs (e.g.
sirolimus, temsirolimus)

- Known impairment of gastrointestinal (GI) function or GI disease that may
significantly alter the absorption of oral everolimus

- Uncontrolled diabetes mellitus as defined by HbA1c >8% despite adequate therapy.
Patients with a known history of impaired fasting glucose or diabetes mellitus (DM)
may be included, however blood glucose and antidiabetic treatment must be monitored
closely throughout the trial and adjusted as necessary.

- Patients who have any severe and/or uncontrolled medical conditions such as:

- Unstable angina pectoris, symptomatic congestive heart failure, myocardial
infarction ≤ 6 months prior to start of everolimus, serious uncontrolled cardiac
arrhythmia, or any other clinically significant cardiac disease

- Symptomatic congestive heart failure of New York Heart Association Class III or
IV

- Active (acute or chronic) or uncontrolled severe infection, liver disease such
as cirrhosis, decompensated liver disease, and active and chronic hepatitis
(i.e. quantifiable hepatitis B virus [HBV]-DNA and/or positive HbsAg,
quantifiable hepatitis C virus [HCV]-RNA)

- Known severely impaired lung function (spirometry and diffusing capacity of the
lung for carbon monoxide [DLCO] 50% or less of normal and O2 saturation 88% or
less at rest on room air)

- Active, bleeding diathesis

- Chronic treatment with corticosteroids or other immunosuppressive agents. Topical or
inhaled corticosteroids are allowed.

- Known history of HIV seropositivity

- Patients who have received live attenuated vaccines within 1 week of start of
everolimus and during the study. Patient should also avoid close contact with others
who have received live attenuated vaccines. Examples of live attenuated vaccines
include intranasal influenza, measles, mumps, rubella, oral polio, Bacillus
Calmette-Guérin (BCG), yellow fever, varicella and TY21a typhoid vaccines.

- Patients who have a history of another primary malignancy, with the exceptions of:
nonmelanoma skin cancer, and carcinoma in situ of the cervix, uteri, or breast from
which the patient has been disease free for ≥3 years

- Patients with a history of non-compliance to medical regimens or who are considered
potentially unreliable or will not be able to complete the entire study

- Patients who are currently part of or have participated in any clinical investigation
with an investigational drug within 1 month prior to dosing

- Pregnant or nursing (lactating) women

- Women of child-bearing potential (WOCBP), defined as all women physiologically
capable of becoming pregnant, must use highly effective methods of contraception
during the study and 8 weeks after. Highly effective contraception methods include
combination of any two of the following:

- Use of oral, injected or implanted hormonal methods of contraception

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

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

- Total abstinence

- Male/female sterilization

- 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 prior to randomization. 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.

- Male patients whose sexual partner(s) are WOCBP who are not willing to use adequate
contraception, during the study and for 8 weeks after the end of treatment