Everolimus for Cancer With TSC1 or TSC2 Mutation

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Brief Title

Everolimus for Cancer With TSC1 or TSC2 Mutation

Official Title

A Phase II Trial of Everolimus for Cancer Patients With Inactivating Mutations in TSC1 or TSC2 or Activating MTOR Mutations

Brief Summary

      In this research study, the investigators are evaluating the clinical benefit of everolimus
      in cancer patients with inactivating TSC1 or TSC2 mutations or activating MTOR mutations.

      This research study is a Phase II clinical trial, which tests the safety and effectiveness of
      an investigational drug called everolimus to learn whether the drug works in treating a
      specific cancer. "Investigational" means that the drug is being studied. It also means that
      the FDA (the U.S. Food and Drug Administration) has not yet approved everolimus for your type
      of cancer.

      Everolimus is a drug that may stop cancer cells from growing by blocking an important factor
      (mTOR) involved in the growth of cells. This drug has been used in treatment for other
      cancers and is approved by the Food and Drug Administration for treatment of several types of
      cancer, including renal cell carcinoma. Treatment with this drug has been associated with
      responses in some patients whose cancers had mutations in TSC1 or TSC2. The investigators
      think that patients whose tumors have mutations in TSC1 or TSC2 may have a good chance of
      responding to treatment with drugs like everolimus.

Detailed Description

      Patients who fulfill eligibility criteria will be entered into the trial.The participant will
      be given a study drug-dosing calendar for each treatment cycle. Each treatment cycle lasts 28
      days (4 weeks), during which time the participant will be taking the study drug orally (by
      mouth) once daily. The diary will also include special instructions for taking the study
      drug. In addition to the administration of the study drugs the participant will be asked to
      return to the clinic at various time points so that additional exams can be performed. These
      study visits may last as long as 2 hours.

Study Phase

Phase 2

Study Type


Primary Outcome

Objective Response Rate

Secondary Outcome

 Duration of Response





Study Arms / Comparison Groups

Description:  Everolimus
Fixed doses orally once a day per each 28 day cycle
Participants will stay on study as long as they do not progress for a maximum of 24 months.
Tumor assessments will be performed after every 2 cycles for as long as they are on study.


* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information

Recruitment Status


Estimated Enrollment


Start Date

September 2014

Completion Date

June 2019

Primary Completion Date

June 2019

Eligibility Criteria

        Inclusion Criteria: Participants must meet the following criteria on screening examination
        to be eligible to participate in the study:

          -  Participants must have histologically confirmed advanced malignancy that is either
             metastatic and/or unresectable and/or recurrent, with confirmed inactivating mutations
             in TSC1 or TSC2, or activating mutations in MTOR, identified in any CLIA-certified
             laboratory. All genetic findings must be reviewed by the study PI, Dr. David
             Kwiatkowski, prior to study entry.

          -  Biopsy of a primary or metastatic lesion must have been performed within the past two
             years. Sufficient pathologic material must be available to enable whole exome
             sequencing at the time of study entry.

          -  Participants must have measurable disease, defined as at least one lesion that can be
             accurately measured in at least one dimension (longest diameter to be recorded) as ≥
             20 mm with conventional techniques or as ≥10 mm with spiral CT scan. See section 10
             for the evaluation of measureable disease.

          -  Participants may have received any number of prior therapies, from 0 to > 10, but
             prior treatment with PI3-kinase or mTOR inhibitors is not permitted.

          -  Age ≥ 18 years.

          -  ECOG performance status <2 (see Appendix A).

          -  Participants must have normal organ and marrow function as defined below:

               -  Leukocytes ≥3,000/mcL

               -  Absolute neutrophil count ≥1,500/mcL

               -  Platelets ≥100,000/mcL

               -  Hemoglobin ≥9.0 gr/dL

               -  Total bilirubin ≤1.5 ULN

               -  AST (SGOT)/ALT (SGPT) ≤ 2.5 X institutional upper limit of normal. Patients with
                  confirmed liver metastases are permitted to have AST/ALT at levels ≤ 5X the
                  institutional upper limit of normal.

               -  Creatinine ≤ 1.5 X the institutional upper limit of normal.

               -  Total cholesterol < 300 mg/dL

               -  Triglycerides < 250 mg/dL

          -  The effects of everolimus on the developing human fetus are unknown. For this reason
             and because anti-neoplastic agents are known to be teratogenic, women of child-bearing
             potential and men must agree to use adequate contraception (hormonal or barrier method
             of birth control; abstinence) prior to study entry and for the duration of study
             participation. Should a woman become pregnant or suspect she is pregnant while
             participating in this study, she should inform her treating physician immediately.

          -  Ability to understand and the willingness to sign a written informed consent document.

          -  Participants who achieve either a partial response or stable disease ≥ 4 months must
             agree to undergo a tumor biopsy, if safe and feasible, at the time of progressive
             disease while on study drug everolimus.

        Exclusion Criteria:Participants who exhibit any of the following conditions at screening
        will not be eligible for admission into the study.

          -  Participants who have had any of the following:

          -  chemotherapy in the previous 2 weeks (6 weeks for nitrosoureas or mitomycin C)

          -  radiotherapy within 3 weeks

          -  investigational agents within 3 weeks prior to entering the study

          -  patients who have not recovered from significant (in the opinion of the investigator)
             adverse events due to previous agents administered.

          -  Child-Pugh B or C hepatic impairment. Patients with a history of hepatitis or
             significant exposure risk should be tested for hepatitis B and C with serologic
             markers: HBsAg, HBs Ab, HBcoreIgG Ab, HCV Ab. Patients with active hepatitis B or C
             are excluded.

          -  Any prior exposure to any PI3 kinase or mTOR inhibitor agent.

          -  Participants may not be receiving any other research study agents.

          -  Uncontrolled brain or leptomeningeal metastases, including patients who continue to
             require glucocorticoids for brain or leptomeningeal metastases. Asymptomatic or
             treated brain metastases are acceptable.

          -  History of allergic reactions attributed to compounds of similar chemical or biologic
             composition to everolimus.

          -  A list of prohibited medications on study are listed in Section 5.5

          -  Chronic treatment with corticosteroids or other immunosuppressive therapy.

          -  Uncontrolled intercurrent illness including, but not limited to ongoing or active
             infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
             arrhythmia, or psychiatric illness/social situations that would limit compliance with
             study requirements.

          -  Pregnant women are excluded from this study because everolimus has the potential for
             teratogenic or abortifacient effects. Because there is an unknown but potential risk
             of adverse events in nursing infants secondary to treatment of the mother with
             everolimus, breastfeeding should be discontinued if the mother is treated with
             everolimus. These potential risks may also apply to other agents used in this study.

          -  Individuals with a recent history of a different malignancy are ineligible except for
             the following circumstances: 1) Individuals with a history of other malignancies are
             eligible if they have been disease-free for at least 3 years OR are deemed by the
             investigator to be at low risk for recurrence of that malignancy; 2) Individuals with
             the following cancers are eligible if diagnosed and treated within the past 3 years:
             cervical cancer in situ, and basal cell or squamous cell carcinoma of the skin.

          -  Individuals with known HIV infection are excluded from this study as combination
             antiretroviral therapy could potentially result in significant pharmacokinetic
             interactions with everolimus. In addition, these individuals are at increased risk of
             lethal infections due to the immunosuppressive effects of mTOR inhibition.

          -  Patients who have received live attenuated vaccines within 1 week of start of
             Everolimus. Patient should also avoid close contact with others who have received live
             attenuated vaccines. Examples of live attenuated vaccines include intranasal
             influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella and TY21a
             typhoid vaccines.

          -  Uncontrolled diabetes mellitus as defined by 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.




18 Years - N/A

Accepts Healthy Volunteers



David Kwiatkowski, MD, PhD, , 

Location Countries

United States

Location Countries

United States

Administrative Informations



Organization ID


Secondary IDs


Responsible Party

Principal Investigator

Study Sponsor

Dana-Farber Cancer Institute


 Novartis Pharmaceuticals

Study Sponsor

David Kwiatkowski, MD, PhD, Principal Investigator, Dana-Farber Cancer Institute

Verification Date

September 2020