Everolimus Therapy in People With Birt-Hogg-Dube Syndrome (BHD)-Associated Kidney Cancer or Sporadic Chromophobe Renal Cancer

Background:

- Birt-Hogg-Dube (BHD) is a hereditary cancer syndrome with clinical manifestations
including cutaneous fibrofolliculomas, lung cysts/pneumothorax, and renal cell carcinoma
(RCC). RCC occurs in approximately 30% of patients with BHD. It presents at an early age
of onset and is commonly bilateral and multifocal.

- Tumors associated with BHD can have variable histology, however approximately 85% of
these tumors have a chromophobe component (either alone or part of a hybrid tumor mixed
with elements of oncocytoma).

- The current management includes surgical resection with partial nephrectomy when tumors
reach 3 cm. While significant morbidity can be associated with repeat, partial
nephrectomy with this approach, most patients can maintain renal function and do not
develop systemic disease. There are no proven systemic therapy options for BHD to date.

- Germline mutations in the gene Folliculin (FLCN) are the genetic hallmark of BHD and can
be found in greater than 90% of patients. FLCN is believed to function like a classic
tumor suppressor gene with a second hit in the wild type allele (somatic mutation or
loss of heterozygosity) occurring in the majority of renal tumors.

- BHD is in the family of hamartomatous disorders similar to Tuberous Sclerosis Complex
(TSC) and Cowden Syndrome, and studies have found activation of the phosphoinositide
3-kinase (PI3K)/mTOR pathway in BHD renal tumors. FLCN is believed be part of a complex
that interacts with 5' AMP-activated protein kinase (AMPK) and is involved with
regulation of mTOR activity. In vitro and in vivo models of FLCN loss demonstrate
activation of both mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2).

- Preclinical data from conditional FLCN knockout mice demonstrate that treatment with
sirolimus can reverse renal manifestations.

- We hypothesize that mTOR inhibition with everolimus treatment will be clinically active
in BHD associated RCC.

Objectives:

-To determine the overall response rate with everolimus treatment in subjects with
BHD-associated renal tumors.

Eligibility:

-Patients with renal cell carcinoma (RCC) associated with Birt-Hogg-Dube Syndrome (BHD).

Design:

- This is an open label, phase II study to evaluate the efficacy and safety of everolimus
therapy in patients with BHD associated renal tumors. Up to 16 evaluable patients will
be enrolled.

- Tumor response rate will be measured by Response Evaluation Criteria in Solid Tumors
(RECIST) and efficacy analysis will be done.

- Secondary endpoints will evaluate growth rates (cm/year) while on therapy.

- Additionally, reduction in the size of lung cysts and cutaneous fibrofolliculomas will
be evaluated.

- INCLUSION CRITERIA:

- Patients must have a clinical diagnosis of Birt-Hogg-Dub (Copyright) Syndrome
(clinical features consistent with BHD and /or a germline Folliculin (FLCN) mutation)
and the presence of localized, locally advanced or advanced, renal tumor(s).

- Patients must have measurable disease, as defined by Response Evaluation Criteria in
Solid Tumors (RECIST) 1.1

- Age greater than or equal to 18 years.

- Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 1
(Karnofsky greater than or equal to 70%).

- Patients must have normal organ and marrow function as defined below:

leukocytes greater than or equal to 3,000/mcL

absolute neutrophil count greater than or equal to 1,500/mcL

platelets greater than or equal to 100,000/mcL

total bilirubin less than or equal to 2mg/dL

Aspartate aminotransferase (AST) Serum glutamic oxaloacetic transaminase(SGOT)/Alanine
aminotransferase (ALT) Serum glutamic pyruvic transaminase(SGPT) greater than or equal to
2.5 times institutional upper limit of normal (ULN) (greater than or equal to 5 times ULN
in patients with liver metastases)

creatinine less than or equal to 2.0 times ULN

OR

creatinine clearance greater than or equal to 30 mL/min/1.73 m(2)

fasting serum cholesterol less than or equal to 300 mg/dL OR less than or equal to 7.75
mmol/L

AND

fasting triglycerides less than or equal to 2.5 times ULN

NOTE: In case one or both of these thresholds (for fasting serum cholesterol or
triglyceride) are exceeded, the patient can only be included after initiation of
appropriate lipid lowering medication.

- No history of major bleeding, recent or active myocardial ischemia, gastrointestinal
(GI) perforation, cerebrovascular accidents or other significant illness.

- Recovery from acute toxicity of prior treatment for renal cell carcinoma (RCC) (to
less than or equal to grade 1 the active version of Common Terminology Criteria for
Adverse Events (CTCAE) or to a level permitted under other sections of Inclusion/
Exclusion criteria). Additionally, in patients who have received standard or
experimental treatments for their RCC at least approximately 5 half-lives should have
elapsed from the last dose at the time of study entry.

- No prior therapy with an mTOR-pathway inhibitor.

- Ability of subject to understand and the willingness to sign a written informed
consent document.

EXCLUSION CRITERIA:

- Patients currently receiving anticancer therapies (including chemotherapy, radiation
therapy, antibody based therapy, etc.).

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

- Patients with known brain metastases unless treated with an appropriate modality with
no evidence of progression/recurrence for >3months

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection requiring intravenous (IV) antibiotics, invasive fungal infection, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements.

- Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral
therapy are ineligible because of the potential for pharmacokinetic interactions with
everolimus. Known impairment of gastrointestinal (GI) function or GI disease that may
significantly alter the absorption of oral everolimus.

- Uncontrolled diabetes mellitus as defined by hemoglobin A1c (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:

1. unstable angina pectoris, symptomatic congestive heart failure, myocardial
infarction less than or equal to 6 months prior to start of everolimus, serious
uncontrolled cardiac arrhythmia, or any other clinically significant cardiac
disease.

2. Symptomatic congestive heart failure of New York heart Association Class III or
IV.

3. known severely impaired lung function (spirometry and diffusing capacity of the
lung for carbon monoxide (DLCO) 50% or less of normal and oxygen (O2) saturation
88% or less at rest on room air).

4. active, bleeding diathesis.

- Chronic (treatment > 1 month) or ongoing treatment with corticosteroids or other
immunosuppressive agents. Topical or inhaled corticosteroids are allowed.

- Patients who have received live attenuated vaccines within 1 week of start of
everolimus Examples of live attenuated vaccines include intranasal influenza, measles,
mumps, rubella, oral polio, Bacillus Calmette-Guerin (BCG), yellow fever, varicella
and typhoid vaccine) TY21a typhoid vaccines.

- Patients, who in the opinion of the investigator, are unlikely to comply with
follow-up visits or other study requirements. 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, who do not agree to 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:

1. Use of oral, injected or implanted hormonal methods of contraception or;

2. Placement of an intrauterine device (IUD) or intrauterine system (IUS);

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

4. Total abstinence or;

5. 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.

- Prior invasive malignancy of other histology currently requiring treatment.

- Patients with active Hepatitis B (detectable hepatitis B virus-deoxyribonucleic acid
(HBV-DNA) or hepatitis B virus surface antigen (HBsAg +) or Hepatitis C infection
(detectable hepatitis C virus ribonucleic acid (HCV RNA) by polymerase chain reaction
(PCR)

- Patients who are currently on or have used potent or moderate inhibitors or strong
inducers Cytochrome P450 3A4 (CYP3A4) or P-glycoprotein (PgP) inhibitors in the past 2
weeks