Birt-Hogg-Dube Syndrome, Renal Cancer
Conditions
Keywords
Overall Response Rate, Hereditary Cancer Syndrome, mTOR Therapy Naive
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 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
Detailed description
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.
Interventions
DRUGEverolimus
Everolimus is a commercial agent and is supplied by Novartis.
Sponsors
National Cancer Institute (NCI)
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 100 Years
Healthy volunteers
No
Inclusion 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate With Everolimus Treatment. | End of treatment: every 12 weeks up to 1 year | Overall best response is defined as the best response recorded from the start of the treatment until disease progression/recurrence (taking as reference for progressive disease the smallest measurements recorded since the treatment started). Response was assessed by the Response Evaluation in Solid Tumors (RECIST) criteria v1.1. Progressive disease is at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes baseline sum if that is the smallest on study). The sum must also demonstrate an absolute increase of at least 5mm. Note: the appearance of one or more new lesions is also progression. Complete response is disappearance of all target lesions. Partial response is at least a 30% decrease in the sum of the diameters of target lesions. Stable disease is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum of diameters while on study. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival (PFS) | median follow-up time: 9 months | Progression-free survival is defined as the time interval from start of treatment to documented evidence of disease progression. Progression is at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes baseline sum if that is the smallest on study). The sum must also demonstrate an absolute increase of at least 5mm. Note: the appearance of one or more new lesions is also progression. Progressive disease was assessed by the Response Evaluation in Solid Tumors (RECIST) criteria v1.1. |
| Overall Survival (OS) | From the first day of treatment to the day of death, up to 1 year | Overall Survival is defined as the time between the first day of treatment to the day of death. |
| Count of Participants With Non-serious Adverse Events Assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0) | Date treatment consent signed to date off study, approximately 8 months and 28 days. | Here is the count of participants with non-serious adverse events assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0). A non-serious adverse event is any untoward medical occurrence. |
Countries
United States
Participant flow
Pre-assignment details
The Sporadic chromophobe renal tumors arm/group is not included here and throughout because the protocol was amended to remove the Sporadic chromophobe renal tumors arm/group. The study was unable to enroll participants with this disease.
Participants by arm
| Arm | Count |
|---|---|
| Birt-Hogg-Dube Syndrome Birt-Hogg-Dube Syndrome (BHD)-associated renal tumors
Everolimus: Everolimus is a commercial agent and is supplied by Novartis. | 3 |
| Total | 3 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse event-pneumonitis | 2 |
Baseline characteristics
| Characteristic | Birt-Hogg-Dube Syndrome |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 3 Participants |
| Age, Continuous | 56 years STANDARD_DEVIATION 10.75 |
| Race/Ethnicity, Customized A person not meeting definition of Hispanic/Latino | 3 Participants |
| Race/Ethnicity, Customized Asian | 1 Participants |
| Race/Ethnicity, Customized White | 2 Participants |
| Region of Enrollment United States | 3 Participants |
| Sex: Female, Male Female | 1 Participants |
| Sex: Female, Male Male | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 3 |
| other Total, other adverse events | 3 / 3 |
| serious Total, serious adverse events | 0 / 3 |
Outcome results
Primary
Overall Response Rate With Everolimus Treatment.
Overall best response is defined as the best response recorded from the start of the treatment until disease progression/recurrence (taking as reference for progressive disease the smallest measurements recorded since the treatment started). Response was assessed by the Response Evaluation in Solid Tumors (RECIST) criteria v1.1. Progressive disease is at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes baseline sum if that is the smallest on study). The sum must also demonstrate an absolute increase of at least 5mm. Note: the appearance of one or more new lesions is also progression. Complete response is disappearance of all target lesions. Partial response is at least a 30% decrease in the sum of the diameters of target lesions. Stable disease is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum of diameters while on study.
Time frame: End of treatment: every 12 weeks up to 1 year
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Birt-Hogg-Dube Syndrome | Overall Response Rate With Everolimus Treatment. | Complete Response | 0 Participants |
| Birt-Hogg-Dube Syndrome | Overall Response Rate With Everolimus Treatment. | Partial Response | 0 Participants |
| Birt-Hogg-Dube Syndrome | Overall Response Rate With Everolimus Treatment. | Stable Disease | 3 Participants |
| Birt-Hogg-Dube Syndrome | Overall Response Rate With Everolimus Treatment. | Progressive Disease | 0 Participants |
Secondary
Count of Participants With Non-serious Adverse Events Assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0)
Here is the count of participants with non-serious adverse events assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0). A non-serious adverse event is any untoward medical occurrence.
Time frame: Date treatment consent signed to date off study, approximately 8 months and 28 days.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Birt-Hogg-Dube Syndrome | Count of Participants With Non-serious Adverse Events Assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0) | 3 Participants |
Secondary
Overall Survival (OS)
Overall Survival is defined as the time between the first day of treatment to the day of death.
Time frame: From the first day of treatment to the day of death, up to 1 year
Population: Because all the 3 patients were alive as of date of off study, their median time to death is unknown.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Birt-Hogg-Dube Syndrome | Overall Survival (OS) | NA Months |
Secondary
Progression-free Survival (PFS)
Progression-free survival is defined as the time interval from start of treatment to documented evidence of disease progression. Progression is at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes baseline sum if that is the smallest on study). The sum must also demonstrate an absolute increase of at least 5mm. Note: the appearance of one or more new lesions is also progression. Progressive disease was assessed by the Response Evaluation in Solid Tumors (RECIST) criteria v1.1.
Time frame: median follow-up time: 9 months
Population: Because all the 3 patients were alive without progression as of date of off study their median time to progression cannot be determined.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Birt-Hogg-Dube Syndrome | Progression-free Survival (PFS) | NA Months |