Everolimus Therapy in People With Birt-Hogg-Dube Syndrome (BHD)-Associated Kidney Cancer or Sporadic Chromophobe Renal Cancer
Condition: Renal Cancer; Birt-Hogg-Dube Syndrome
MeSH terms: Kidney Neoplasms; Carcinoma, Renal Cell; Birt-Hogg-Dube Syndrome; Syndrome
Intervention: Everolimus
Intervention description: Everolimus is a commercial agent and is supplied by Novartis.
Intervention MeSH terms: Everolimus
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 3.0
Sex: All
Minimum age: 18 Years
Maximum age: 100 Years
Healthy volunteers: No
Keywords: Overall Response Rate; Hereditary Cancer Syndrome; mTOR Therapy Naive

Summary:

      Background:

      - 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.

      Objective:

      - 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.

      Eligibility:

      - People ages 18 and over with BHD-associated kidney cancer or advanced sporadic chromophobe
      renal cancer.

      Design:

        -  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
           are doing
    

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:

               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