- Research has shown that the drug everolimus can stop cancer cells from growing. It is
approved for people with advanced kidney cancer. Researchers want to see if it also helps
people with two other types of kidney cancer.
- To see if everolimus is safe and effective in people with Birt-Hogg-Dube Syndrome
(BHD)-associated kidney cancer or sporadic (nonfamilial) chromophobe renal cancer.
- People ages 18 and over with BHD-associated kidney cancer or advanced sporadic chromophobe
- Participants will be screened with:
- Medical history, physical exam, and blood and urine tests.
- Computed tomography (CT) scan or magnetic resonance imaging (MRI) scan. They will lie
in a machine that takes pictures of their chest/abdomen/pelvis.
- They may also be screened with:
- Another scan, of the brain or neck.
- Bone scan.
- Positron emission tomography scan with fludeoxyglucose (FDG-PET).
- Heart and lung tests.
- Tests for hepatitis.
- Participants will take a tablet once a day by mouth for up to a year. They will keep a
diary of when they take the tablet and any symptoms.
- During the study, participants will have physical exams and urine and blood tests. They
will have scans of the chest/abdomen/pelvis. They may have FDG-PET and bone scans.
- Participants will have tests for hepatitis and may have a tumor sample taken.
- Participants will have a follow-up visit 4 5 weeks finishing taking the drug. They will
have a physical exam and blood tests. They may have scans and/or hepatitis tests.
- Participants will be called about every 3 6 months after the study ends to see how they
- 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.
- Chromophobe renal tumors can occur sporadically and account for roughly 7% of all newly
diagnosed kidney cancers. Histologically, the tumor can look identical to the
chromophobe tumors associated with BHD. Currently there are no effective treatments for
advanced chromophobe RCC but recent case reports suggest that these tumors may respond
to mTOR therapy.
- 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. The
genetic and biochemical changes accompanying sporadic chromophobe tumors are not fully
understood yet. However, they appear histologically identical to BHD-associated
chromophobe tumors and may share some common underlying genetic and biochemical
- BHD is in the family of harmatomaous disorders similar to TSC and Cowden Syndrome, and
studies have found activation of the PI3K/mTOR pathway in BHD renal tumors. FLCN is
believed be part of a complex that interacts with AMPK and is involved with regulation
of mTOR activity. In vitro and in vivo models of FLCN loss demonstrate activation of
both mTORC1 and 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 or sporadically occurring chromophobe renal tumors.
-To determine the overall response rate with everolimus treatment in subjects with 1)
BHD-associated renal tumors 2) sporadic chromophobe renal tumors.
-Patients with renal cell carcinoma (RCC) associated with 1) Birt-Hogg-Dube Syndrome (BHD)
or 2) advanced sporadic chromophobe kidney tumors.
- This is an open label, phase II study to evaluate the efficacy and safety of everolimus
therapy in patients with BHD (cohort 1) or sporadic chromophobe renal tumors (cohort
2). Up to 16 evaluable patients will be enrolled in each cohort.
- Tumor response rate by will be measured by RECIST for BHD-associated and sporadic
chromophobe renal tumors; efficacy analysis will be done independently in the two
- Secondary endpoints will evaluate growth rates (cm/year) while on therapy.
- Additionally, reduction in the size of lung cysts and cutaneous fibrofolliculomas will
- INCLUSION CRITERIA:
- Patients must have a clinical diagnosis of Birt-Hogg-Dub(SqrRoot)(Copyright) Syndrome
(clinical features consistent with BHD and /or a germline FLCN mutation) and the
presence of localized, locally advanced or advanced, renal tumor(s) (cohort 1) or
sporadic locally advanced, or metastatic renal tumor of chromophobe histology
confirmed by histopathologic evaluation (cohort 2).
- Patients must have measurable disease, as defined by RECIST 1.1
- Age greater than or equal to 18 years.
- ECOG performance status less than or equal to 1 (Karnofsky greater than or equal to
- 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
AST(SGOT)/ALT(SGPT) greater than or equal to 2.5 times institutional upper limit of normal
(greater than or equal to 5 times ULN in patients with liver metastases)
creatinine less than or equal to 2.0 times ULN
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
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, GI perforation,
cerebrovascular accidents or other significant illness.
- Recovery from acute toxicity of prior treatment for RCC (to less than or equal to
grade 1 the active version of 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
- 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.
- 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 IV antibiotics, invasive fungal infection, cardiac arrhythmia, or
psychiatric illness/social situations that would limit compliance with study
- 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 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
2. Symptomatic congestive heart failure of New York heart Association Class III or
3. known severely impaired lung function (spirometry and DLCO 50% or less of normal
and 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, BCG, yellow fever, varicella and TY21a typhoid
- 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
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
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
- 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 HBV-DNA or HBsAg +) or Hepatitis C
infection (detectable HCV RNA by PCR)
- Patients who are currently on or have used potent or moderate inhibitors or strong
inducers CYP3A4 or PgP inhibitors in the past 2 weeks
Minimum Eligible Age: 18 Years
Maximum Eligible Age: N/A
Eligible Gender: Both