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

Study Status: Recruiting
Recruit Status: Recruiting
Study Type: Interventional

Official Title: Phase 2 Study of Everolimus Therapy in Patients With Birt-Hogg-Dube Syndrome (BHD)-Associated Kidney Cancer or Sporadic Chromophobe Renal Cancer

Brief 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

    Detailed Summary:

    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 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.
      • Sponsor: National Cancer Institute (NCI)

      Current Primary Outcome: Overall response rate with everolimus treatment in subjects with 1) BHD-associated renal tumors 2) sporadic chromophobe renal tumors. [ Time Frame: End of treatment ]

      Original Primary Outcome: Same as current

      Current Secondary Outcome:

      • Assess changes in tumor growth rates and ability to delay surgical management in BHD patients. [ Time Frame: 3-4 years ]
      • Assess progression-free survival (PFS) and overall survival (OS). [ Time Frame: 3-4 years ]
      • Evaluate the prevalence of cytogenetic changes, somatic FLCN alterations, and PI3K/mTOR pathway activity in patients with sporadic chromophobe RCC (from initial biopsy or archived tumortissue). [ Time Frame: 3-4 years ]
      • Evaluate the effect of everolimus on mTOR activity inrenal tumors (using pre- and on-treatment biopsies when available). [ Time Frame: 3-4 years ]
      • Assess the effect of therapy on BHD associated lung cysts and cutaneous fibrofolliculomas. [ Time Frame: 3-4 years ]
      • Safety and totlerability of everolimus in patients with BHD-associated localized renal tumors. [ Time Frame: 3-4 years ]


      Original Secondary Outcome:

      Information By: National Institutes of Health Clinical Center (CC)

      Dates:
      Date Received: July 21, 2015
      Date Started: July 10, 2015
      Date Completion: June 1, 2020
      Last Updated: May 12, 2017
      Last Verified: April 26, 2017