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

This study is currently recruiting participants. (see Contacts and Locations)
Verified March 2017 by Washington University School of Medicine
Information provided by (Responsible Party):
Washington University School of Medicine Identifier:
First received: January 28, 2015
Last updated: March 31, 2017
Last verified: March 2017
The purpose of this research study is to look at participants with solid tumor malignancies and specific mutations respond to treatment with everolimus.

Condition Intervention Phase
Solid Malignancy
Solid Tumor
Drug: Everolimus
Phase 2

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: No masking
Primary Purpose: Treatment
Official Title: Phase II Study of Everolimus in Patients With Advanced Solid Malignancies With TSC1, TSC2, NF1, NF2, or STK11 Mutations

Resource links provided by NLM:

Further study details as provided by Washington University School of Medicine:

Primary Outcome Measures:
  • 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).

Secondary Outcome Measures:
  • 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.

Estimated Enrollment: 12
Actual Study Start Date: October 7, 2015
Estimated Study Completion Date: January 31, 2018
Estimated Primary Completion Date: January 31, 2018 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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.
Drug: Everolimus
Other Names:
  • RAD001
  • Afinitor
  • Votubia

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.

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its identifier: NCT02352844

Contact: Saiama Waqar, M.D. (314) 362-5737

United States, Missouri
Washington University School of Medicine Recruiting
St. Louis, Missouri, United States, 63110
Contact: Saiama Waqar, M.D.    314-362-5737   
Principal Investigator: Saiama Waqar, M.D.         
Sub-Investigator: Maria Baggstrom, M.D.         
Sub-Investigator: Daniel Morgensztern, M.D.         
Sub-Investigator: Ramaswamy Govindan, M.D.         
Sponsors and Collaborators
Washington University School of Medicine
Principal Investigator: Saiama Waqar, M.D. Washington University School of Medicine
  More Information

Additional Information:
Responsible Party: Washington University School of Medicine Identifier: NCT02352844     History of Changes
Other Study ID Numbers: 201502067
Study First Received: January 28, 2015
Last Updated: March 31, 2017
Individual Participant Data  
Plan to Share IPD: No

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

Additional relevant MeSH terms:
Antineoplastic Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Anti-Bacterial Agents
Anti-Infective Agents
Antibiotics, Antineoplastic
Antifungal Agents processed this record on May 22, 2017