Intervention: Everolimus
Trial phase: Phase 2
ATC code: L01EG02 | L04AA18
SMILES: COC1CC2CCC(C)C(O)(O2)C(=O)C(=O)N2CCCCC2C(=O)OC(C(C)CC2CCC(OCCO)C(OC)C2)CC(=O)C(C)C=C(C)C(O)C(OC)C(=O)C(C)CC(C)C=CC=CC=C1C
Sex: All
Age groups: Adult | Older Adult
Healthy volunteers: No
Participants at risk: 3
Group description: Birt-Hogg-Dube Syndrome (BHD)-associated renal tumors

Everolimus: Everolimus is a commercial agent and is supplied by Novartis.
Eligibility criteria:
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:

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

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