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Everolimus in Patients With Advanced Solid Malignancies With TSC1, TSC2, NF1, NF2, or STK11 Mutations

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ClinicalTrials.gov Identifier: NCT02352844
Recruitment Status : Completed
First Posted : February 2, 2015
Results First Posted : October 2, 2018
Last Update Posted : October 2, 2018
Sponsor:
Information provided by (Responsible Party):
Washington University School of Medicine

Tracking Information
First Submitted Date  ICMJE January 28, 2015
First Posted Date  ICMJE February 2, 2015
Results First Submitted Date  ICMJE July 18, 2018
Results First Posted Date  ICMJE October 2, 2018
Last Update Posted Date October 2, 2018
Actual Study Start Date  ICMJE October 7, 2015
Actual Primary Completion Date August 15, 2017   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 28, 2015)
Response Rate (RR) [ Time Frame: Completion of treatment (estimated average of 6 months) ]
The primary endpoint will be to describe the response rate using RECIST 1.1. Response rate will be defined as complete response (disappearance of all target lesion) plus partial response (a least a 30% decrease in the sum of diameters of target lesions).
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT02352844 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: September 5, 2018)
  • Mutations Associated With Therapeutic Response [ Time Frame: Completion of treatment (estimated average of 6 months) ]
    -To correlate mutations in the mTOR pathway with therapeutic response with everolimus
  • Genetic Changes Associated With Disease Progression [ Time Frame: Completion of treatment (estimated average of 6 months) ]
    -To investigate the genetic changes associated with disease progression following treatment with everolimus.
Original Secondary Outcome Measures  ICMJE
 (submitted: January 28, 2015)
  • Mutations Associated With Therapeutic Response [ Time Frame: Completion of treatment (estimated average of 6 months) ]
    -Secondary endpoint will be to further evaluate molecular markers of response or resistance using exome sequencing and transcriptome sequencing when feasible. -. If possible, permutation tests will also be performed to compare the differences of secondary endpoints between responders and non-responders.
  • Genetic Changes Associated With Disease Progression [ Time Frame: Completion of treatment (estimated average of 6 months) ]
    -Secondary endpoint will be to further evaluate molecular markers of response or resistance using exome sequencing and transcriptome sequencing when feasible. -. If possible, permutation tests will also be performed to compare the differences of secondary endpoints between responders and non-responders.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Everolimus in Patients With Advanced Solid Malignancies With TSC1, TSC2, NF1, NF2, or STK11 Mutations
Official Title  ICMJE Phase II Study of Everolimus in Patients With Advanced Solid Malignancies With TSC1, TSC2, NF1, NF2, or STK11 Mutations
Brief Summary The purpose of this research study is to look at participants with solid tumor malignancies and specific mutations respond to treatment with everolimus.
Detailed Description Cancer is a molecularly heterogeneous disease comprised of complex genomic alterations in common and overlapping pathways. Somatic inactivating mutations in tuberous sclerosis complex 1 (TSC1) gene were recently identified as potential markers of response to mTOR therapy. Everolimus is an oral derivative of rapamycin. At the cellular and molecular level, everolimus acts as a signal transduction inhibitor, and selectively inhibits mTOR. We hypothesize that everolimus will exhibit clinical activity in solid malignancies harboring TSC1, TSC2, NF1, NF2, or STK11 mutations.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Solid Malignancy
  • Solid Tumor
Intervention  ICMJE Drug: Everolimus
Other Names:
  • RAD001
  • Afinitor
  • Votubia
Study Arms  ICMJE Experimental: Arm 1 (everolimus)
Everolimus is an oral drug which will be administered on an outpatient basis at a dose of 10 mg daily on a 28-day cycle.
Intervention: Drug: Everolimus
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: March 31, 2017)
12
Original Estimated Enrollment  ICMJE
 (submitted: January 28, 2015)
10
Actual Study Completion Date  ICMJE August 15, 2017
Actual Primary Completion Date August 15, 2017   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Histologically confirmed diagnosis of advanced (metastatic, recurrent, or unresectable) cancer with mutations in any of the following genes: TSC1, TSC2, NF1, NF2 or STK11.
  • Must have failed at least 1 standard of care systemic therapy for their malignancy
  • Measurable disease defined as lesions that can be accurately measured in at least one dimension (longest diameter to be recorded) as >10 mm with CT scan, as >20 mm by chest x-ray, or >10 mm with calipers by clinical exam.
  • Prior therapy (chemotherapy, radiation therapy, and surgery) is allowed if completed at least 2 weeks prior to registration and if all treatment-related toxicities are resolved to ≤ CTCAE grade 1, with the exception of alopecia and hematologic values otherwise meeting the bone marrow function criteria specified below.
  • At least 18 years of age.
  • ECOG performance status ≤ 2
  • Normal bone marrow and organ function as defined below:

    • Leukocytes > 3,000/mcL
    • Absolute neutrophil count > 1,500/mcL
    • Platelets > 100,000/mcL
    • Hemoglobin > 9.0 g/dL
    • Total serum bilirubin ≤ 2.0 x IULN
    • AST(SGOT)/ALT(SGPT) ≤ 2.5 x IULN (≤ 5.0 x IULN in patients with liver metastases)
    • Serum creatinine ≤ 1.5 x IULN OR creatinine clearance > 45 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal
    • Fasting cholesterol ≤ 300 mg/dL OR ≤ 7.75 mmol/L AND fasting triglycerides ≤ 2.5 x IULN. NOTE: In case one or both of these thresholds are exceeded, the patient can only be included after initiation of appropriate lipid lowering medication
  • Able to swallow tablets.
  • Women of childbearing potential, defined as all women physiologically capable of becoming pregnant, must use highly effective methods of contraception during the study and for 8 weeks after. Women are considered post-menopausal and not of childbearing 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 childbearing potential.
  • Male patients whose sexual partner(s) are women of childbearing potential must agree to use adequate contraception during the study and for 8 weeks after the end of treatment.
  • Able to understand and willing to sign an IRB approved written informed consent document (or that of legally authorized representative, if applicable)

Exclusion Criteria:

  • A history of other malignancy ≤ 3 years previous with the exception of basal cell or squamous cell carcinoma of the skin which were treated with local resection only or carcinoma in situ of the cervix.
  • Taking an investigational agent within 4 weeks of initiation of everolimus.
  • Symptomatic brain metastases. Known brain metastases are allowed if asymptomatic and previously treated.
  • A history of allergic reactions attributed to compounds of similar chemical or biologic composition to everolimus or other agents used in the study.
  • Known impairment of GI function or GI disease that may significantly alter the absorption of oral everolimus.
  • Currently taking CYP3A4 inhibitors or inducers (such as the antiepileptic drugs phenytoin, carbamazepine, or phenobarbital; cyclosporine; grapefruit or its juice; Seville oranges; starfruit; or St. John's wort)
  • Chronic treatment with corticosteroids or other immunosuppressive agents. Topical or inhaled corticosteroids are allowed.
  • Received live attenuated vaccine within 1 week of start of everolimus (i.e. intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, and TY21a typhoid vaccines).
  • Uncontrolled diabetes mellitus defined as HbA1c > 8% despite adequate therapy. Patients with a known history of impaired fasting glucose or diabetes mellitus may be included; however, blood glucose and antidiabetic treatment must be monitored closely throughout the trial and adjusted as necessary.
  • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure of NYHA class III or IV, active coronary artery disease, unstable angina pectoris, cardiac arrhythmia, myocardia infraction ≤ 6 months prior to start of everolimus, uncontrolled hypertension (systolic pressure > 150 mmHg or diastolic pressure > 90 mmHg), uncontrolled seizure disorder, liver disease such as cirrhosis, decompensated liver disease, active and chronic hepatitis, known severely impaired lung function (spirometry and DLCO 50% or less of normal and 02 saturation 88% or less at rest on room air), active bleeding diathesis, or psychiatric illness/social situations that would limit compliance with study requirements.
  • Pregnant and/or breastfeeding. Women of childbearing potential must have a negative pregnancy test within 14 days of study entry.
  • Known HIV-positivity on combination antiretroviral therapy because of the potential for pharmacokinetic interactions with everolimus. In addition, these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy. Appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02352844
Other Study ID Numbers  ICMJE 201502067
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Washington University School of Medicine
Study Sponsor  ICMJE Washington University School of Medicine
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Saiama Waqar, M.D. Washington University School of Medicine
PRS Account Washington University School of Medicine
Verification Date September 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP