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
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.
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.
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
- 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
- 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
- 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.