Clinical trial NCT02201212
Conditions: TSC1 TSC2 Tuberous Sclerosis Complex MTOR
Keywords: TSC1 TSC2 Tuberous Sclerosis Complex MTOR
Sponsor: Dana-Farber Cancer Institute
Start date: 2014-09-01; Completion date: 2019-06-01
Enrollment: 30 participants; Allocation: NA; Intervention model: SINGLE_GROUP

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.

Arms: arm 1: 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.
Interventions: intervention 1: Everolimus
Intervention descriptions: intervention 1: None

Protocol documents:
Prot_SAP_000.pdf: 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
 
Protocol Version 9.0 Date: 13-March-2017 
 
Local Protocol #:14-229 
 
 
Novartis Study Number: CRAD001MUS217T 
 
Title: A Phase II trial of everolimus for cancer patients with inactivating mutations in 
TSC1 or TSC2 or activating MTOR mutations 
 
Principal Investigator: David J. Kwiatkowski, MD, PhD 
 
 Dana-Farber/Harvard Cancer Center (DF/HCC) 
 
Other Investigators:  Gopakumar V. Iyer, MD 
                                     Memorial Sloan Kettering Cancer Center (MSKCC) 
 
 
Coordinating Center: Dana-Farber/Harvard Cancer Center 
 
Statistician: Suzanne E. Dahlberg, PhD  
 
Study Coordinator: Ketki Bhushan, MPH    
 
Responsible Research Nurse: Cameron Sze, RN, BSN and Julia Hewes RN, BSN 
 
 
Agent(s):  Everolimus 
 
Study Exempt from IND Requirements per 21 CFR 312.2(b). 
 
 
  


Everolimus in TSC1 and TSC2 mutated tumors 
 
 
 13-March-2017 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
 
 
 
 
 
 
 
Patients will stay on study as long as they do not progress. Tumor assessments will be performed 
after every 2 cycles for as long as they are on study.


Everolimus in TSC1 and TSC2 mutated tumors 
13-March-2017 
 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
  
TABLE OF CONTENTS 
1. 
OBJECTIVES .................................................................................................................................................... 4 
1.1 
Study Design .................................................................................................................................................... 4 
1.2 
Primary Objectives .......................................................................................................................................... 4 
1.3 
Secondary Objectives ...................................................................................................................................... 4 
2. 
BACKGROUND ................................................................................................................................................ 4 
2.1 
Study Agent(s) ................................................................................................................................................. 4 
2.2 
Study Disease/Rationale for the Study ............................................................................................................ 6 
2.3 
Correlative Studies Background...................................................................................................................... 7 
3. 
PARTICIPANT SELECTION .......................................................................................................................... 7 
3.1 
Eligibility Criteria ........................................................................................................................................... 7 
3.2 
Exclusion Criteria ........................................................................................................................................ 9 
3.3 
Inclusion of Women, Minorities and Other Underrepresented Populations ................................................. 10 
4. 
REGISTRATION PROCEDURES ................................................................................................................ 10 
4.1 
General Guidelines for DF/HCC and DF/PCC Institutions ......................................................................... 10 
4.2 
Registration Process for DF/HCC and DF/PCC Institutions ................................................................. 11 
4.3 
General Guidelines for Other Participating Institutions ................................................................... 12 
4.4 
Registration Process for Other Participating Institutions ........................................................................... 12 
5. 
TREATMENT PLAN ...................................................................................................................................... 12 
5.1 
Dosing Plan .................................................................................................................................................. 12 
5.2 
Screening Criteria ........................................................................................................................................ 13 
5.3 
Pretreatment Criteria .................................................................................................................................... 14 
5.4 
Agent Administration .............................................................................................................................. 14 
5.5 
General Concomitant Medication and Supportive Care Guidelines ............................................................. 15 
5.6 
Duration of Therapy ....................................................................................................................................... 17 
5.7 
Duration of Follow Up .................................................................................................................................. 18 
5.8 
Criteria for Removal from Study ................................................................................................................... 18 
6. 
EXPECTED TOXICITIES AND DOSING DELAYS/DOSE MODIFICATIONS .................................... 18 
6.1 
Anticipated Toxicities .................................................................................................................................... 19 
6.2 
Toxicity Management .................................................................................................................................... 21 
6.3 
Hepatic Impairment Dose Modifications ...................................................................................................... 28 
7. 
DRUG FORMULATION AND ADMINISTRATION ................................................................................. 29 
7.1 
Everolimus ..................................................................................................................................................... 29 


Everolimus in TSC1 and TSC2 mutated tumors 
13-March-2017 
 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
8. 
CORRELATIVE/SPECIAL STUDIES .......................................................................................................... 31 
8.1 
Pharmacokinetic Studies ............................................................................................................................... 31 
8.2 
Pharmacodynamic Studies ............................................................................................................................ 31 
9. 
STUDY CALENDAR ...................................................................................................................................... 32 
10. 
MEASUREMENT OF EFFECT..................................................................................................................... 33 
11. 
ADVERSE EVENT REPORTING REQUIREMENTS ............................................................................... 41 
11.1 
Definitions ................................................................................................................................................ 41 
11.2 
Procedures for AE and SAE Recording and Reporting ............................................................................ 43 
11.3 
Reporting Requirements ........................................................................................................................... 43 
11.4 
Reporting to the Study Sponsor ................................................................................................................ 44 
11.5 
Reporting to the Institutional Review Board (IRB)................................................................................... 45 
11.6 
Reporting to Novartis Pharmaceuticals ................................................................................................... 45 
11.7 
Reporting to Hospital Risk Management .................................................................................................. 47 
11.8 
Monitoring of Adverse Events and Period of Observation ....................................................................... 47 
12. 
DATA AND SAFETY MONITORING .......................................................................................................... 47 
12.1 
Data Reporting ......................................................................................................................................... 47 
12.2 
Safety Meetings ......................................................................................................................................... 48 
12.3 
Monitoring ................................................................................................................................................ 48 
13. 
REGULATORY CONSIDERATIONS .......................................................................................................... 49 
13.1 
Protocol Review and Amendments ........................................................................................................... 49 
13.2 
Informed Consent ..................................................................................................................................... 49 
13.3 
Ethics and Study Execution ...................................................................................................................... 49 
13.4 
Study Documentation ................................................................................................................................ 50 
13.5 
Records Retention ..................................................................................................................................... 50 
13.6 
Multi-center Guidelines ............................................................................................................................ 50 
14. 
STATISTICAL CONSIDERATIONS ............................................................................................................ 51 
14.1 
Study Design/Endpoints ............................................................................................................................ 51 
14.2 
Consideration of gene and mutation specific response rates ................................................................... 52 
14.3 
Sample Size/Accrual Rate ......................................................................................................................... 52 
15. 
PUBLICATION PLAN .................................................................................................................................... 52 
16. 
REFERENCES ................................................................................................................................................. 53 
17. 
APPENDICES .................................................................................................................................................. 55 


Everolimus in TSC1 and TSC2 mutated tumors 
13-March-2017 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
 
4 
1. OBJECTIVES 
 
1.1 Study Design 
 
This is a single-arm non-randomized phase II study evaluating the mTOR inhibitor everolimus in 
cancer patients who have documented inactivating mutations in TSC1, TSC2, or activating 
MTOR mutations in their cancers. 
 
1.2 Primary Objectives 
 
1) Evaluate the clinical benefit of everolimus, defined as objective response (RECIST 
1.1) in patients with tumors that have been confirmed prior to study entry to have 
TSC1, TSC2, or MTOR mutations. 
 
1.3 Secondary Objectives 
 
1) Perform immunohistochemical analysis and whole exome sequencing on all study 
patients to examine correlations between other genetic and genomic events and 
response. 
2) Assess duration of response, progression-free survival, overall survival, and toxicity. 
 
 
2. BACKGROUND 
 
2.1 Study Agent(s) 
 
2.1.1 Everolimus 
 
Everolimus is a novel derivative of rapamycin. It has been in clinical development 
since 1996 as an immunosuppressant in solid organ transplantation. Everolimus is 
approved in Europe and other global markets (trade name: Certican®) for cardiac and 
renal transplantation, and in the United States (trade name: Zortress®) for the 
prevention of organ rejection of kidney transplantation. 
 
Everolimus was developed in oncology as Afinitor® and was approved for advanced 
renal cell carcinoma (RCC) in 2009. In 2010, Afinitor® received United States (US) 
approval for patients with subependymal giant cell astrocytoma (SEGA) associated 
with tuberous sclerosis (TSC). Everolimus is also available as Votubia® in the 
European Union (EU) for patients with SEGA associated with TSC. Afinitor® was 
approved for “progressive pancreatic neuroendocrine tumor (PNET) in patients with 
unresectable, locally advanced, or metastatic disease” in 2011 in various countries, 
including the US and Europe. In 2012 Afinitor® received approval for the treatment of 
postmenopausal women with advanced hormone receptor-positive, HER2- negative 
breast cancer (advanced HR+ BC) in combination with exemestane, after failure of 
treatment with letrozole or anastrozole. Furthermore, in 2012, Afinitor® received 


Everolimus in TSC1 and TSC2 mutated tumors 
13-March-2017  
 
5
approval for the treatment of adult patients with TSC who have renal angiomyolipoma 
not requiring immediate surgery. 
Approximately 30,582 cancer patients have been treated with everolimus as of 30-Sep-
2013: 
• 16,671 patients in Novartis-sponsored clinical trials 
• 1,911 patients in the individual patient supply program 
• More than 12,000 patients in investigator-sponsored studies. 
 
In addition, healthy volunteer subjects and non-oncology subjects with hepatic 
impairment have participated in clinical pharmacology studies. 
 
Mechanism of Action: 
 
Everolimus is a derivative of rapamycin which acts as a signal transduction inhibitor. 
Everolimus selectively inhibits mTOR (mammalian target of rapamycin), specifically 
targeting the mTOR-raptor signal transduction complex known as mTORC1. mTOR is 
a key serine-threonine kinase in the PI3K/AKT signaling cascade, which is known to be 
dysregulated in a wide spectrum of human cancers (1). 
Everolimus is being investigated as an anticancer agent based on its potential to act 
directly on the tumor cells by inhibiting tumor cell growth and proliferation; and 
indirectly by inhibiting angiogenesis leading to reduced tumor vascularity (via potent 
inhibition of tumor cell VEGF (vascular endothelial growth factor) production and 
VEGF-induced proliferation of endothelial cells). 
 
Rationale for Starting Dose 
 
Everolimus has been approved for the treatment of ER positive/HER2 negative breast 
cancer following failure of aromatase inhibitors, for advanced RCC, for pancreatic 
neuroendocrine tumors and renal angiomyolipoma at a dose of 10 mg daily.  This dose 
will be administered in this study. 
 
Safety Profile 
 
As of September 30th 2011, 18,730 cancer patients have been treated with everolimus.  
The frequency and severity of side effects are available from the prescribing 
information pamphlet for physicians: 
http://www.pharma.us.novartis.com/product/pi/pdf/afinitor.pdf 
 
 
 
 
 


Everolimus in TSC1 and TSC2 mutated tumors 
13-March-2017  
 
6
2.2 Study Disease/Rationale for the Study 
 
At the cellular and molecular level, Everolimus acts as a signal transduction inhibitor. It 
selectively inhibits mTOR (mammalian target of rapamycin), a key protein kinase 
which regulates cell growth, proliferation and survival. The mTOR kinase is mainly 
activated via the phosphatidylinositol 3-kinase (PI3-Kinase) pathway through 
AKT/PKB and the protein complex made of the gene products of the two genes which 
cause tuberous sclerosis complex (TSC1/TSC2). Mutations in these components or in 
PTEN, a negative regulator of PI3-kinase, may result in dysregulation of mTOR. 
Abnormal functioning of various components of this signaling pathway contributes to 
the pathophysiology of numerous human cancers. Various preclinical models have 
confirmed the role of this pathway in tumor development (2). 
The main known functions of mTOR include acting as a sensor of mitogens, growth 
factors and energy and nutrient levels; and it facilitates cell-cycle progression from G1-
S phase in appropriate growth conditions (3).   
The PI3K/mTOR pathway is frequently dysregulated in many human cancers, and 
oncogenic transformation may sensitize tumor cells to mTOR inhibitors.  PI3-kinase 
mutations have been reported in the primary tumor in 10-20% of human colorectal and 
other cancers (4, 5).  The loss of PTEN protein, either through gene deletion or 
functional silencing (promoter hypermethylation), is reported in approximately 60% of 
primary human colorectal cancers and many other cancer types (6).  The mTOR 
pathway is involved in the production of pro-angiogenic factors (i.e., VEGF) and 
inhibition of endothelial cell growth and proliferation.  Through inactivating eukaryotic 
initiation factor 4E binding proteins and activating the 40S ribosomal S6 kinases (i.e., 
p70S6K1), mTOR regulates protein translation, including the HIF-1 proteins. Inhibition 
of mTOR is expected to lead to decreased expression of HIF-1. 
 
Several clinical studies have now been reported in which everolimus has shown clinical 
benefit for patients with cancers with mutations in TSC1 or TSC2.  Randomized 
clinical trials in patients with the genetic disorder Tuberous Sclerosis Complex (TSC) 
who have tumors in the brain, subependymal giant cell astrocytoma, or renal 
angiomyolipoma, have shown benefit in response to everolimus treatment (7, 8).  
PEComas, a sarcoma related to angiomyolipoma, but occurring in non-TSC patients 
and usually due to mutations in TSC2, have also shown benefit including sustained 
complete responses while on everolimus (9, 10).  Finally, a recent report described a 
clinical trial of everolimus for bladder cancer, in which one patient had a sustained 
complete clinical response lasting over 2 years (11).  That patient was shown to have a 
TSC1 inactivating mutation in her cancer.  Notably, other bladder cancer patients on 
that trial whose cancers also had mutations in TSC1 had transient minor responses.  
However, the majority of patients on the trial had no mutations in TSC1, and showed 
progressive disease.  Both TSC1 and TSC2 mutations and mTOR activating mutations 
have been identified in a set of 6 extreme responders to Everolimus out of 300 patients 
with renal cell carcinoma treated at Memorial Sloan Kettering (12).  Furthermore, an 
activating MTOR mutation has been associated with exceptional response to treatment 


Everolimus in TSC1 and TSC2 mutated tumors 
13-March-2017  
 
7
in a bladder cancer patient (13), and multiple, relatively common, activating MTOR 
mutations have been defined through in vitro studies (14). 
  
 
We hypothesize that due to the positioning of TSC1/TSC2 as a key regulator of 
mTORC1, that all cancers with inactivating mutations in TSC1 or TSC2 will have 
sensitivity to everolimus.  The extent of sensitivity will likely depend on other genomic 
events present in these cancers, tissue type, and other unknown factors. Furthermore, 
we similarly hypothesize that cancers bearing MTOR activating mutations will also 
have sensitivity to everolimus. 
 
 
2.3 
Correlative Studies Background 
 
As described above, the TSC1/TSC2 protein complex functions as a key regulator of 
mTORC1 activity, and hence mutation in either gene results in strong activation of 
mTORC1, both in vivo (mouse tumor models, human cancers (e.g. PEComa)) and in 
vitro (multiple cell lines).  Nonetheless, human cancers are often subject to numerous 
mutations and genomic copy number changes throughout the genome.  In the 
publication in which Everolimus was described to cause a complete sustained clinical 
response in a patient with metastatic bladder cancer, the responding patient’s cancer also 
had a mutation in NF2 and other genes.  We hypothesize that other genetic and genomic 
events affect sensitivity to Everolimus, and hence wish to perform whole exome 
sequencing to identify both mutational events and genome-wide copy number changes 
(amplifications and deletions) on cancer samples from patients on this trial.  
Furthermore, in responding patients who subsequently progress, we will also require 
repeat biopsy to permit genetic studies to examine the mechanism of resistance, as long 
as this can be performed without medical risk.  In addition, we will prepare cancer cell 
lines from these patients using either the patient-derived xenograft system, or through 
direct establishment of a cell line using a feeder layer. 
 
3. PARTICIPANT SELECTION 
 
This study will enroll 30 patients with inactivating mutations in TSC1 or TSC2, or activating 
mTOR mutations. 
 
3.1 
Eligibility Criteria 
 
Participants must meet the following criteria on screening examination to be eligible to 
participate in the study: 
 
3.1.1 Participants must have histologically confirmed advanced malignancy that is 
metastatic and/or unresectable and/or recurrent with confirmed inactivating 
mutations in TSC1 or TSC2 or activating MTOR mutations, identified in any 


Everolimus in TSC1 and TSC2 mutated tumors 
13-March-2017  
 
8
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. Patients with biopsy samples older than 2 
years must undergo a fresh tumor biopsy or should receive approval for enrollment 
from the Principal investigator. 
3.1.2 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 for 
non-nodal lesions and short axis for nodal lesions) as ≥20 mm with conventional 
techniques or as ≥10 mm with spiral CT scan, MRI, or calipers by clinical exam.  
See Section 10 for the evaluation of measurable disease. 
 
3.1.3 Participants may have received any number of prior therapies, from 0 to > 10.  Prior 
treatment with PI3-kinase or mTOR inhibitors is not permitted, unless they were 
given as adjuvant therapy without undue toxicity, and without suggestion of 
resistance to therapy. 
 
3.1.4  Age ≥ 18 years.  
 
3.1.5 ECOG performance status <2 (see Appendix A). 
  
3.1.6 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 X the institutional upper limit of normal (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 ≤ 5 X the institutional upper limit of normal (ULN) 
• creatinine ≤ 1.5 X the institutional upper limit of normal (ULN) 
• Total cholesterol < 300 mg/dL 
• Triglycerides < 250 mg/dL 
3.1.7 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 


Everolimus in TSC1 and TSC2 mutated tumors 
13-March-2017  
 
9
she is pregnant while participating in this study, she should inform her treating 
physician immediately. 
 
 
 
3.1.8 Ability to understand and the willingness to sign a written informed consent 
document. 
 
3.1.9 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. 
 
3.2 
Exclusion Criteria 
 
Participants who exhibit any of the following conditions at screening will not be 
eligible for admission into the study. 
 
3.2.1 Participants who have had any of the following: 
3.2.1.1  Chemotherapy in the previous 2 weeks (6 weeks for nitrosoureas or 
mitomycin C) 
3.2.1.2 Radiotherapy within 3 weeks 
3.2.1.3 Investigational agents within 3 weeks prior to entering the study 
3.2.1.4 Patients who have not recovered from significant (in the opinion of the 
investigator) adverse events due to previous agents administered. 
 
3.2.2 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, and HCV Ab.  Patients with active 
hepatitis B or C are excluded. 
 
 
3.2.3 Participants may not be receiving any other research study agents. 
 
3.2.4 Uncontrolled brain or leptomeningeal metastases, including patients who continue 
to require glucocorticoids for brain or leptomeningeal metastases.  Asymptomatic 
or treated brain metastases are acceptable. 
 
3.2.5 History of allergic reactions attributed to compounds of similar chemical or 
biologic composition to everolimus. 
 
3.2.6 A list of prohibited medications on study are listed in Section 5.5 
 
3.2.7 Chronic treatment with corticosteroids or other immunosuppressive therapy 
 


Everolimus in TSC1 and TSC2 mutated tumors 
13-March-2017  
 
10
3.2.8 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. 
 
3.2.9 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.  
 
3.2.10 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. 
 
3.2.11 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. 
 
3.2.12 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. 
 
3.2.13 Uncontrolled diabetes mellitus: HbA1c must be < 8% or there must be 
documentation that control has been good for the week prior to study entry, with 
daily morning glucoses at < 150 mg/dl. 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. 
 
3.3 
Inclusion of Women, Minorities and Other Underrepresented Populations 
 
Both men and women and members of all races and ethnic groups are eligible for this trial. 
 
4. REGISTRATION PROCEDURES 
 
 
4.1 
General Guidelines for DF/HCC and DF/PCC Institutions 


Everolimus in TSC1 and TSC2 mutated tumors 
13-March-2017  
 
11
 
Institutions will register eligible participants with the DF/HCC Office of Data Quality (ODQ) 
central registration system. Registrations must occur prior to the initiation of protocol therapy. 
Any participant not registered to the protocol before protocol therapy begins will be considered 
ineligible and registration will be denied. 
 
An investigator will confirm eligibility criteria and a member of the study team 
will complete the ODQ protocol-specific eligibility checklist. 
 
Following registration, participants may begin protocol therapy. Issues that would 
cause treatment delays should be discussed with the Overall Principal Investigator 
(PI). If a participant does not receive protocol therapy following registration, the 
participant’s registration on the study must be canceled. Notify the ODQ Registrar 
of registration cancellations as soon as possible.  
 
4.2 
Registration Process for DF/HCC and DF/PCC Institutions 
 
The ODQ registration staff is accessible on Monday through Friday, from 8:00 AM to 
5:00 PM Eastern Standard Time. In emergency situations when a participant must begin 
protocol therapy during off-hours or holidays, call the ODQ registration line at 617-632-
3761 and follow the instructions for registering participants after hours. 
 
The registration procedures are as follows: 
 
• Obtain written informed consent from the participant prior to the performance of 
any protocol specific procedures or assessments.  
 
• Complete the ODQ protocol-specific eligibility checklist using the eligibility 
assessment documented in the participant’s medical record and/or research chart. 
To be eligible for registration to the protocol, the participant must meet all 
inclusion and exclusion criterion as described in the protocol and reflected on 
the eligibility checklist. 
 
• Fax the eligibility checklist(s) and all pages of the consent form(s) to the ODQ at 
617-632-2295. For Phase I protocols, attach participant dose level assignment 
confirmation from the sponsor. 
 
• The ODQ Registrar will (a) review the eligibility checklist, (b) register the 
participant on the protocol, and (c) randomize the participant when applicable. 
 
• An email confirmation of the registration and/or randomization will be sent to the 
Overall PI, study coordinator(s) from the Lead Site, treating investigator and 
registering person immediately following the registration and/or randomization. 
 
. 
 


Everolimus in TSC1 and TSC2 mutated tumors 
13-March-2017  
 
12
4.3 General Guidelines for Other Participating Institutions 
 
Eligible participants will be entered on study centrally at the DFCI by staff of the coordinating 
center. Following registration, participants should begin protocol therapy within 5 days. * 
Issues that would cause treatment delays should be discussed with the Overall PI.  If a 
participant does not receive protocol therapy following registration, the participant’s 
registration on the study must be canceled.  The staff at the coordinating center should be 
notified of cancellations as soon as possible. 
 
 
4.4 
Registration Process for Other Participating Institutions 
 
To register a participant on this study, please refer to Appendix C, Data and Safety 
Monitoring Plan (DSMP) Section 3.7. 
 
5. TREATMENT PLAN  
 
Treatment will be administered on an outpatient basis. Expected toxicities and potential risks 
as well as dose modifications for everolimus are described in Section 6 (Expected Toxicities 
and Dosing Delays/Dose Modification). No investigational or commercial agents or therapies 
other than those described below may be administered with the intent to treat the participant’s 
malignancy.  As this is a non-randomized trial, all trial subjects will receive everolimus. 
 
If a patient is deriving clinical benefit, they may continue on treatment beyond progressive 
disease with PI approval. 
 
5.1 
Dosing Plan 
The study drug Everolimus will be self-administered. The investigator will instruct the patient 
to take the study drug exactly as specified in the protocol. Everolimus will be administered 
orally as once daily dose of 10 mg (one 10mg tablet) continuously from study day 1 until 
progression of disease or unacceptable toxicity. Patients will be instructed to take Everolimus 
in the morning, at the same time each day, and to keep a pill diary. A treatment cycle is 
defined as 28 days (4 weeks). 
It is recommended that Everolimus is taken in the morning, one hour prior to breakfast.  
Dietary habits around the time of Everolimus intake should be as consistent as possible 
throughout the study. The tablets should be swallowed whole with a glass of water and should 
not be chewed or crushed. For patients unable to swallow tablets, the tablet(s) should be 
dispersed completely in a glass of water (containing approximately 30 mL) by gently stirring, 
immediately prior to drinking. The glass should be rinsed with the same volume of water and 
the rinse completely swallowed to ensure the entire dose is administered.  
    Doses of everolimus may be administered with or without food, whatever is most convenient  
    for the participants. However, dosing with or without food must be consistent throughout the    
    course of the study. 
If vomiting occurs, no attempt should be made to replace the vomited dose.  


Everolimus in TSC1 and TSC2 mutated tumors 
13-March-2017  
 
13
All dosages prescribed and dispensed to the patient and all dose changes during the study 
must be recorded. 
Medication labels will comply with US legal requirements and be printed in English. They 
will supply no information about the patient. The storage conditions for study drug will be 
described on the medication label. 
Everolimus will be provided by Novartis. Everolimus is formulated as tablets for oral 
administration of 5mg and 10 mg strength. Tablets are blister-packed under aluminum foil, 
which should be opened only at the time of administration as drug is both hygroscopic and 
light-sensitive. Typically, patients will be given a 4-week supply; however, after cycle 2 it 
may be an 8-week supply at the discretion of the investigator.  
 
5.2 
Screening Criteria  
All subjects or their legally acceptable representative and the person who conducted the 
informed consent discussion must personally sign and date the consent form before any study-
specific screening procedures are performed. Procedures that have been performed before 
consent was obtained as part of routine care are not considered study-specific procedures.  
Medical history information to be collected during screening must date back to the original 
diagnosis of cancer. If a subject is referred to the study center, a copy of all applicable reports 
and histological or cytological evidence, confirming the diagnosis must be provided to the 
study center before enrollment. Copies of recent (i.e., within the past 6 months) radiographic 
images confirming disease progression by modified RECIST should be provided to the study 
center.  
All subjects who have signed the IRB approved consent form must be registered as a screened 
subject. At the time of registration, the subject will receive a unique 2 digit subject 
identification number. This number will be used to identify the subject throughout the study 
and must be used on all study documentation related to that subject. The subject identification 
number must remain constant throughout the entire study.  
All screening tests and procedures must be performed and the results available within a 
maximum of 14 days before study day 1 unless otherwise noted.  
Subjects who do not meet eligibility criteria within the 14 day screening period will not be 
eligible for enrollment. However, subjects may be re-screened up to 2 additional times at the 
discretion of the investigator. The subject must be re-consented if more than 28 days have 
elapsed since the date of last informed consent.  
The following screening assessments must be performed: 
• Review of inclusion and exclusion criteria 
• Medical history review, documentation of diagnosis and previous treatment. 
• Physical examination, ECOG performance status, blood pressure, respiratory rate, 
resting pulse, temperature, height and weight. 
•  CT scans (contrast-enhanced) or MRI scan (contrast-enhanced) of areas of known 
disease and that are of acceptable quality as baseline study within 30 days prior to study 
day 1.  


Everolimus in TSC1 and TSC2 mutated tumors 
13-March-2017  
 
14
Laboratory assessment consisting of  
• Hematology 
• Chemistry 
• Urinalysis  
• beta HCG pregnancy test for women of child-bearing potential 
5.3 
Pretreatment Criteria 
The first dose of Everolimus may be administered on the same day as enrollment but no 
more than 10 business days after enrollment. The treatment period begins on the first day 
of treatment with Everolimus. 
If a subject is unable to come into the clinic for a required study visit or if unforeseen 
events occur, the visit procedures may be performed within a one week time frame.  
The following assessments will be performed at each clinic visit according to table 3.4 
throughout the treatment period:  
• Physical examination, 
• ECOG performance status,  
• Blood pressure, respiratory rate, resting pulse, temperature, and weight. 
• Laboratory evaluations: If patients have met trial eligibility within the previous 72 
hours, no specific criteria will need required in order to initiate the protocol unless, 
in the investigator’s opinion, significant medical issues arise which would 
contraindicate starting the study medications. If patients have completed entry 
criteria >72 hours prior to cycle 1 day 1, laboratory values on cycle 1 day 1 should 
be repeated to confirm all eligibility criteria are met. 
• CT scans (contrast-enhanced) or MRI scan (contrast-enhanced) or PET-CT scan of 
areas of known disease every 8 weeks with a 5 business-day time window in case 
unforeseen events occur. Evaluation according to RECIST criteria compared to 
previous scan.  
• beta HCG pregnancy test for women of child-bearing potential  
Documentation of all adverse events will occur at each clinic visit and at any other time 
point when necessary. There are no specific criteria for the initiation of a given cycle 
except for the ones indicated in the dose modification tables 6-2, 6-3 & 6-4.  Study 
subjects may commence with treatment if, in the opinion of the investigator and based 
on the guidance of Section 6, it is safe for the participant to do so.  
 
5.4 Agent Administration  
 
Everolimus will be administered orally daily, either at the starting dose of 10 mg, or at a 
lower dose based on guidance in Section 6. 


Everolimus in TSC1 and TSC2 mutated tumors 
13-March-2017  
 
15
 
5.5 
General Concomitant Medication and Supportive Care Guidelines 
 
Any new medications that patients might start taking while on study need to be reported to 
the study MD first before they start taking it.  At each visit, the investigator will ask the 
patient about any new medications he/she is or has taken after the start of the study drug. 
All Concomitant medications/Significant non-drug therapies taken ≤ 30 days prior to start 
and after start of study drug, including physical therapy and blood transfusions, should be 
recorded. 
The following restrictions apply during the entire duration of the study: 
• No other investigational therapy should be given to patients. 
• No anticancer agents other than the study medication should be given to patients. The 
only exception is that treatment with hormonal agents for either prostate or breast cancer 
may be continued (not added) during this study.  If such agents are required for a patient 
then the patient must first be withdrawn from the study. 
• Growth factors (e.g. G-CSF, GM-CSF, erythropoietin, platelets growth factors etc.) are 
not to be administered prophylactically but may be prescribed by the investigator for 
rescue from severe hematologic events, if this is thought to be appropriate. 
• Concurrent administration of Everolimus and strong CYP3A4 inhibitors (such as 
ketoconazole, itraconazole, ritonavir) and inducers (such as rifampin, rifabutin) should be 
avoided. Provided there is no alternative treatment available, patients should be closely 
monitored for potential toxicities. 
• Concurrent administration of Everolimus and moderate CYP3A4 inhibitors (such as 
erythromycin, fluconazole, calcium channel blockers, benzodiazepines) and moderate 
CYP3A4 inducers (e.g. carbamazepine, phenobarbital, phenytoin) should also be avoided 
if possible, or used subject to caution (e.g. increased frequency of safety monitoring, 
temporary interruption of Everolimus). 
• Competitive inhibition could occur when Everolimus is combined with drugs which are 
also CYP3A4 substrates. Therefore caution should be exercised in such cases. 
• Co-administration with substrates, inducers, or inhibitors of P-glycoprotein should be 
avoided, if possible, or used subject to caution (e.g. increased frequency of safety 
monitoring, temporary interruption of Everolimus).  
• Grapefruit and grapefruit juice affect cytochrome P450 and P-glycoprotein activity and 
should therefore be avoided.  
• In addition, patients should avoid Seville oranges and star fruit, as well as the juice of 
these fruits, which are potent CYP3A4-inhibitors.  
• No chronic treatment with systemic steroids or another immunosuppressive agents. 
Topical or inhaled corticosteroids are allowed. 
• Everolimus may affect the response to vaccinations making the response to the 
vaccination less effective. Live vaccines should be avoided while a patient is treated with 
Everolimus. 


Everolimus in TSC1 and TSC2 mutated tumors 
13-March-2017  
 
16
Oral anticoagulants such as warfarin are CYP2C9 substrates and, as such, no interaction with 
Everolimus is expected. However, drug-drug interaction studies between macrolide 
antibiotics and warfarin have produced mixed outcomes and the disparity in these findings 
has led to the conclusion that multiple factors may alter the clearance of warfarin. The co-
administration of Everolimus and oral anticoagulants is possible but should be subject to 
verification of coagulation (INR) once steady state is reached (after one week’s treatment). 
A comprehensive list of cytochrome P450 isoenzymes and CYP3A4 inhibitors, inducers, and 
substrates can be found at http://medicine.iupui.edu/flockhart.  This website is continually 
revised and should be checked frequently for updates. 
Please refer to Table 5-1 listing relevant inducers and inhibitors of CYP3A and Table 5.2 for 
a list of relevant substrates, inducers, and inhibitors of PgP.  
Table 5-1 clinically relevant drug interactions: inducers, and inhibitors of 
isoenzyme CYP3A 
Inducers 
carbamazepine, glucocorticoids, modafinil, oxcarbazepine, phenobarbital, phenytoin, 
pioglitazone, rifabutin, rifampin, St. John’s wort, troglitazone, efavirenz, nevirapine, 
topiramate, avasimibe, bosentan, etravirine, nafcillin, ritonavir, talviraline (not available in US 
market), tipranavir, amprenavir, aprepitant, armodafinil (R-modafinil), dexamethasone, 
nevirapine, prednisone, pleconaril (not available in US market), rufinamide 
Inhibitors 
Strong inhibitors: 
clarithromycin, conivaptan, indinavir, itraconazole, ketoconazole, lopinavir, mibefradil, 
nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, troleandamycin, voriconazole, 
tipranavir, elvitegravir, Posaconazole (Krishna et al 2009)  
Moderate inhibitors: 
aprepitant, atazanavir, casopitant, cimetidine, ciprofloxacin, darunavir, diltiazem, 
erythromycin, fluconazole, grapefruit juice (citrus parasidi fruit juice), imatinib, tofisopam, 
verapamil, amprenavir, fosamprenavir, dronedarone 
 


Everolimus in TSC1 and TSC2 mutated tumors 
13-March-2017  
 
17
Table 5-2 Clinically relevant drug interactions: substrates, inducers, inhibitors of PgP and 
PgP/CYP3A dual inhibitors 
 
Substrates 
digoxin, fexofenadine, indinavir, vincristine, colchicine, topotecan, paclitaxel 
Inducers 
rifampin, St John’s wort 
PgP Inhibitors and PgP/CYP3A Dual Inhibitors 
amiodarone, captopril, carvedilol, clarithromycin, conivaptan, diltiazem, dronedarone, 
elacridar, erythromycin, felodipine, fexofenadine, ginkgo (ginkgo biloba), indinavir, 
itraconazole, lopinavir, mibefradil, milk thistle (silybum marianum), nifedipine, nitrendipine, 
quercetin, quinidine, ranolazine, ritonavir, saquinavir, Schisandra chinensis, St John’s wort 
(hypericum perforatum), talinolol, telmisartan, tipranavir, valspodar, verapamil 
Reference: Internal Clinical Pharmacology Drug-drug interaction (DDI) memo, updated Oct. 
2, 2011, which summarizes DDI data from three sources including the FDA’s “Guidance for 
Industry, Drug Interaction Studies”, the University of Washington’s Drug Interaction 
Database, and Indiana University School of Medicine's Drug Interaction Table. 
Vaccinations 
Immunosuppressants may affect the response to vaccination and vaccination during treatment 
with Everolimus may therefore be less effective. The use of live vaccines should be avoided 
during treatment with Everolimus Examples of live vaccines are: intranasal influenza, 
measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, and TY21a typhoid 
vaccines. 
 
 
5.6 
Duration of Therapy 
 
Duration of therapy will depend on individual response, evidence of disease 
progression and tolerance. In the absence of treatment delays due to adverse events, 
treatment may continue forever or until one of the following criteria applies: 
• Disease progression, 
• Intercurrent illness that prevents further administration of treatment, 
• Unacceptable adverse event(s), 
• Participant demonstrates an inability or unwillingness to comply with the oral 
medication regimen and/or documentation requirements 
• Participant decides to withdraw from treatment but is willing to be followed, 
• Participants decides to withdraw consent from the study, or 
• General or specific changes in the participant's condition render the participant 
unacceptable for further treatment in the opinion of the treating investigator. 
 
 
 


Everolimus in TSC1 and TSC2 mutated tumors 
13-March-2017  
 
18
 
5.7 
Duration of Follow Up  
 
Participants will be followed until death after removal from treatment. This 
follow-up will be performed by review of the medical record, contact with care 
providers, and/or telephone contact as needed every 3 months. 
  
5.8 
Criteria for Removal from Study  
 
Participants will be removed from treatment when any of the criteria listed in 
Section 5.6 applies. The reason for discontinuation of treatment and the date the 
participant was removed must be documented in the study-specific case report 
form (CRF). Alternative care options will be discussed with the participant. 
 
In the event of unusual or life-threatening complications, participating investigators 
must immediately notify the Principal Investigator. 
 
6. EXPECTED TOXICITIES AND DOSING DELAYS/DOSE MODIFICATIONS  
 
For patients who do not tolerate the protocol-specified dosing schedule, dose adjustments are 
permitted in order to allow the patient to continue the study treatment. Details of study 
treatment schedule adjustments and dose levels are provided in table 6-1: 
 
Table 6-1 Study treatment schedule adjustments and dose levels 
Dose level 
Dose and schedule 
0 (starting dose) 
10 mg daily 
-1 
5 mg daily 
-2 
5 mg every other day 
 
If a patient has already decreased 2 dose levels, no further dose reduction is permitted. 
Patients who need an additional dose reduction will be required to discontinue Everolimus. 
 
Dose delays and modifications will be made using the following recommendations. Toxicity 
assessments will be done using the CTEP Active Version of the NCI Common Terminology 
Criteria for Adverse Events (CTCAE v4.0) which is identified and located on the CTEP 
website at: http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.  
 
If possible, symptoms should be managed symptomatically. In the case of toxicity, 
appropriate medical treatment should be used (including anti-emetics, anti-diarrheals, etc.). 
 
All adverse events experienced by participants will be collected from the time of the first 
dose of study treatment, through the study and until the final study visit. Participants 


Everolimus in TSC1 and TSC2 mutated tumors 
13-March-2017  
 
19
continuing to experience toxicity at the off study visit may be contacted for additional 
assessments until the toxicity has resolved or is deemed irreversible. 
  
 
6.1 
Anticipated Toxicities 
  
A list of the adverse events and potential risks associated with Everolimus appear 
below and will determine whether dose delays and modifications will be made or 
whether the event requires expedited reporting in addition to routine reporting. 
  
Adverse Reactions Significant: 
>10%: 
 
Cardiovascular: Peripheral edema (4% to 45%), hypertension (4% to 30%; 
hypertensive crisis: 1%) 
 
Central nervous system: Fatigue (7% to 45%), fever (15% to 32%), headache (18% to 
30%), seizure (5% to 29%), anxiety/aggression/behavioral disturbance (SEGA: 21%), 
insomnia (6% to 17%), dizziness (7% to 14%) 
 
Dermatologic: Rash (18% to 59%), acneiform dermatitis (3% to 25%), nail disorders 
(5% to 22%), acne (3% to 22%), cellulitis (SEGA: 29%), pruritus (13% to 21%), dry 
skin (9% to 18%), contact dermatitis (14%), excoriation (14%) 
 
Endocrine & metabolic: Hypercholesterolemia (17% to 85%), hyperglycemia (12% to 
75%; grades 3/4: <1% to 17%), hypertriglyceridemia (≤73%), bicarbonate decreased 
(≤56%), hypophosphatemia (9% to 49%), hypocalcemia (17% to 37%), albumin 
decreased (≤33%), hypoglycemia (≤32%), hypokalemia (12% to 29%), hyperlipidemia 
(renal transplant: 21%), hyperkalemia (renal transplant: 18%), amenorrhea (≤17%), 
hyponatremia (≤16%), dyslipidemia (renal transplant: 15%), hypomagnesemia (renal 
transplant: 14%) 
 
Gastrointestinal: Stomatitis (oncology uses: 44% to 86%; grade 3: 4% to 9%; grade 4: 
<1%; renal transplant: 8%), diarrhea (14% to 50%; grade 3: ≤5%; grade 4: <1%), 
constipation (10% to 38%), abdominal pain (3% to 36%), nausea (8% to 32%: grade 3: 
≤2%; grade 4: <1%), appetite decreased (6% to 30%), anorexia (1% to 30%), vomiting 
(15% to 29%; grade 3: ≤2%; grade 4: <1%), weight loss (9% to 28%), taste alteration 
(1% to 22%), gastroenteritis (1% to 18%), xerostomia (8% to 11%) 
 
Genitourinary: Urinary tract infection (5% to 22%), dysuria (renal transplant: 11%) 
 
Hematologic: Anemia (26% to 92%; grades 3/4: ≤15%; grade 4: <1%), PTT increased 
(SEGA: 72%), leukopenia (oncology uses: 26% to 58%; renal transplant 3%), 
lymphocytopenia (20% to 54%; grades 3/4: ≤18%), thrombocytopenia (19% to 54%; 
grade 3: ≤3%; renal transplant <10%), neutropenia (14% to 46%; grades 3/4: ≤9%)  
 


Everolimus in TSC1 and TSC2 mutated tumors 
13-March-2017  
 
20
Hepatic: AST increased (23% to 89%; grade 3: ≤4%; grade 4: <1%), alkaline 
phosphatase increased (32% to 74%), ALT increased (18% to 51%; grade 3: ≤4%; 
grade 4: <1%) 
 
Neuromuscular & skeletal: Weakness (13% to 33%), arthralgia (≤20%), back pain 
(11% to 15%), limb pain (8% to 14%) 
Otic: Otitis (6% to 36%) 
 
Renal: Creatinine increased (11% to 50%), hematuria (renal transplant: 12%)  
 
Respiratory: Upper respiratory infection (11% to 82%), sinusitis (3% to 39%), cough 
(7% to 30%), dyspnea (20% to 24%; grade 3: 2% to 6%; grade 4: ≤1%), epistaxis 
(≤22%), pneumonitis (includes alveolitis, interstitial lung disease, lung infiltrate, 
pulmonary alveolar hemorrhage, pulmonary toxicity; 1% to 19%; grade 3: 3% to 4%; 
grade 4: <1%), nasal congestion (14%), rhinitis (14%), pharyngitis (4% to 11%)  
 
Miscellaneous: Infection (13% to 62%; grade 3: 4% to 7%; grade 4: 1% to 3%)  
 
1% to 10%: 
 
Cardiovascular: Chest pain (5%), tachycardia (3%), heart failure (1%), angina, atrial 
fibrillation, chest discomfort, deep vein thrombosis, edema (generalized), hypotension, 
palpitation, syncope 
 
Central nervous system: Depression (5%), migraine (5%), chills (4%), agitation, 
hallucination, hemiparesis, hypesthesia, malaise, somnolence 
 
Dermatologic: Eczema (10%), alopecia (≤10%), palmar-plantar erythrodysesthesia 
syndrome ([hand-foot syndrome] 5%), papule (5%), erythema 4%, onychoclasis (4%), 
pityriasis rosea (4%), skin lesions (4%), hirsutism, incision complications, 
hyperhydrosis, hypertrichosis 
 
Endocrine & metabolic: Menorrhagia (6% to 10%), menstrual irregularities (6% to 
10%), diabetes mellitus (exacerbation: 2%; new-onset: <10%), dysmenorrhea (6%), 
metrorrhagia (6%), cushingoid syndrome, dehydration, gout, hypercalcemia, 
hyperparathyroidism, hyperphosphatemia, hyperuricemia, iron deficiency, vitamin B12 
deficiency 
 
Gastrointestinal: Gastritis (7%), hemorrhoids (5%), dyspepsia (4%), dysphagia (4%), 
ageusia (1%), abdominal distention, epigastric discomfort, flatulence, gastroesophageal 
reflux, gingival hypertrophy, hematemesis, ileus, peritonitis  
 
Genitourinary: Vaginal hemorrhage (8%), bladder spasm, erectile dysfunction, ovarian 
cysts, pollakiuria, polyuria, pyuria, scrotal edema, urinary retention, urinary urgency  
 
Hematologic: Hemorrhage (3%), leukocytosis, lymphadenopathy, thrombocythemia 


Everolimus in TSC1 and TSC2 mutated tumors 
13-March-2017  
 
21
 
Hepatic: Bilirubin increased (3% to 10%; grades 3/4: ≤1%)  
 
Neuromuscular & skeletal: Muscle spasm (≤10%), tremor (8%), paresthesia (5%), jaw 
pain (3%), joint swelling, musculoskeletal pain, myalgia, osteonecrosis, osteopenia, 
osteoporosis, spondylitis  
 
Ocular: Eyelid edema (4%), ocular hyperemia (4%), conjunctivitis (2%), blurred 
vision, cataract  
Renal: Renal failure (3%), BUN increased, hydronephrosis, interstitial nephritis, 
proteinuria, renal artery thrombosis, renal impairment 
 
Respiratory: Pleural effusion (7%), nasopharyngitis (6%), pneumonia (6%), bronchitis 
(4%), pharyngolaryngeal pain (4%), rhinorrhea (3%), atelectasis, nasal congestion, 
pulmonary edema, sinus congestion, wheezing 
 
Miscellaneous: Hypersensitivity (3%; includes anaphylaxis, dyspnea, flushing, chest 
pain, angioedema), BK virus infection, candidiasis, night sweats  
 
<1% (Limited to important or life-threatening):  
 
Aspergillosis, azoospermia, cardiac arrest, fluid accumulation, graft thrombosis, hepatic 
cholestasis, 
hepatitis 
B 
reactivation, 
lymphoma, 
oligospermia, 
pancreatitis, 
pancytopenia, 
polyoma 
virus 
infection 
(BK 
virus), 
progressive 
multiple 
leukoencephalopathy (PML), pulmonary embolism, respiratory distress, sepsis, skin 
cancer, 
synovitis 
(severe), 
testosterone 
levels 
decreased, 
thrombotic 
microangiopathy/thrombotic thrombocytopenic purpura/hemolytic uremic syndrome 
(TMA/TTP/HUS), wound healing impaired 
 
6.2 
Toxicity Management 
 
 
Table 6-2 and 6-3 list the dosing guidelines for everolimus-related non-hematologic and 
hematologic toxicities.  Table 6-4 provides guidelines for the management of 
everolimus-associated pneumonitis. 
 


Everolimus in TSC1 and TSC2 mutated tumors 
13-March-2017  
 
22
Table 6-2 Dosing guidelines for Everolimus-related non-hematologic toxicities 
Toxicity 
Action 
Non-Infectious Pneumonitis 
Please refer Table 6-4 
Reactivation of HBV or HCV 
flare 
Please refer to Section 6.2.1.7. 
AST or ALT elevation 
Grade 1 (> ULN - 3.0 x ULN) 
Grade 2 (> 3.0 - 5.0 x ULN) 
Maintain current dose level 
AST or ALT elevation 
Grade 3 (> 5.0 - 20.0 ULN) * 
Interrupt Everolimus administration until resolution to ≤ 
grade 1 (or ≤ grade 2 if baseline values were within the 
range of grade 2). If resolution occurs ≤ 7 days, Everolimus 
should be re-started at the dose level prior to interruption. 
If resolution takes > 7 days, or if event recurs within 28 
days, hold Everolimus until recovery to ≤ grade 1 or 
baseline grade / value and reintroduce Everolimus at one 
dose level lower, if available.  If resolution takes > 28 days, 
the patient comes off the study. 
AST or ALT elevation 
Grade 4 (> 20 x ULN) * 
 
 
 
Recurrence of grade 4 after dose 
reduction or toxicity requiring 
Everolimus interruption for > 
28 days 
Interrupt Everolimus administration until resolution to ≤ 
grade 1 (or ≤ grade 2 if baseline values were within the 
range of grade 2). If resolution occurs ≤ 7 days, Everolimus 
should be re-started at one dose level lower. If resolution 
takes > 7 days, discontinue Everolimus. 
Discontinue Everolimus. 
Intolerable grade 2 mucositis, or 
grade 3 AE, except 
hyperglycemia or 
hypertriglyceridemia or 
hypercholesterolemia  
Interrupt Everolimus administration until resolution to ≤ 
grade 1 or baseline grade / value. 
If resolution occurs within ≤ 7 days, Everolimus should be 
re-started at the dose level prior to interruption. 
If resolution takes > 7 days, or if event recurs within 28 
days, hold Everolimus until recovery to ≤ grade 1 or 
baseline grade / value and reintroduce Everolimus at one 
dose level lower, if available. 
Patients will be withdrawn from the study if they fail to 
recover to ≤ grade 1 or baseline grade / value within 28 
days. 


Everolimus in TSC1 and TSC2 mutated tumors 
13-March-2017  
 
23
Toxicity 
Action 
Any other grade 4 toxicity not 
listed here, including those 
involving the cardiac, 
endocrine, GI, metabolism, 
musculoskeletal, CNS, renal, 
respiratory, vascular, and 
cutaneous systems (CTCAE v4)  
Hold Everolimus until recovery to grade ≤ 1 or baseline 
value 
Reintroduce Everolimus at one dose level lower, if 
available.  If resolution takes > 28 days, the patient comes 
off the study. 
Grade 3 or 4 clinical liver 
failure (asterixis or 
encephalopathy/coma) 
Discontinue Everolimus 
Recurrence of intolerable grade 
2 mucositis or grade 3 event 
after dose reduction 
Reduce dose to the next lower dose level, if available. The 
lowest possible dose level of Everolimus is 2.5 mg daily. 
Below this level, Everolimus must be discontinued. 
Recurrence of grade 4 after dose 
reduction 
Discontinue Everolimus 
Any non-hematologic toxicity 
requiring Everolimus 
interruption for > 28 days 
Discontinue Everolimus, take patient off study 
* Should HCV flare be confirmed, the guidelines for flare must take precedence  
 


Everolimus in TSC1 and TSC2 mutated tumors 
13-March-2017  
 
24
Table 6-3 Dosing guidelines for Everolimus-related hematologic toxicities 
Toxicity 
Action 
Grade 2 thrombocytopenia 
(platelets <75, ≥ 50x109/L) 
No action 
 
Grade 3 thrombocytopenia 
(platelets <50, ≥ 25 x109/L) 
Interrupt Everolimus until resolution to grade ≤1  
If resolution occurs ≤ 7 days, reintroduce Everolimus at the 
dose level prior to interruption. 
If resolution occurs > 7 days, or event recurs within 28 days, 
reintroduce Everolimus at one dose level lower, if available. 
If resolution takes > 28 days, the patient comes off the study. 
Grade 4 thrombocytopenia 
(platelets < 25 x109/L) 
Interrupt Everolimus until recovery to grade ≤ 1. Then 
reintroduce Everolimus at one dose level lower, if available. If 
resolution takes > 28 days, the patient comes off the study. 
Grade 3 neutropenia or anemia 
(neutrophil <1, ≥0.5 x109/L) 
Interrupt Everolimus until resolution to grade ≤1 or baseline 
value 
If AE resolution occurs ≤ 7 days, reintroduce Everolimus at the 
same dose level. 
If AE resolution occurs > 7 days, or event recurs within 28 
days, reintroduce Everolimus at one dose level lower, if 
available. 
If resolution takes > 28 days, the patient comes off the study. 
Grade 4 neutropenia or anemia 
Interrupt Everolimus until recovery to grade ≤ 1 or baseline 
value. Reintroduce Everolimus at one dose level lower, if 
available. * If resolution takes > 28 days, the patient comes off 
the study. 
Febrile neutropenia 
Interrupt Everolimus until resolution to grade ≤ 1 (or baseline 
value) and no fever. Reintroduce Everolimus at one dose level 
lower, if available. * If resolution takes > 28 days, the patient 
comes off the study. 
Recurrence of grade 3 toxicity 
after dose reduction 
Reduce dose to the next lower dose level, if available.  
*Recurrence of grade 4 toxicity 
(including febrile neutropenia) 
after dose reduction 
Discontinue Everolimus 
*Any hematologic toxicity 
requiring Everolimus 
interruption for > 28 days 
Discontinue Everolimus 


Everolimus in TSC1 and TSC2 mutated tumors 
13-March-2017  
 
25
Table 6-4 Management of non-infectious pneumonitis 
Grade 
Required investigations 
Management 
of 
pneumonitis 
Everolimus dose 
adjustment 
Grade 1 
CT scans with lung windows. 
No specific 
therapy is 
required 
No dose adjustment 
required.  
Initiate appropriate 
monitoring. 
Grade 2 
CT scan with lung windows. 
Consider pulmonary function 
testing includes: spirometry, 
DLCO, and room air O2 
saturation at rest. Consider a 
bronchoscopy with biopsy 
and/or BAL. Monitoring at 
each visit until return to ≤ 
grade 1. Return to initial 
monitoring frequency if no 
recurrence. 
Symptomatic 
only. Consider 
corticosteroids 
and/or other 
supportive 
therapy if 
symptoms are 
troublesome. 
Rule out infection and 
consider interruption of 
Everolimus until symptoms 
improve to Grade ≤ 1. 
Re-initiate Everolimus at 
one dose level lower.  
Discontinue Everolimus if 
failure to recover within ≤ 
28 days. 
Grade 3 
CT scan with lung windows 
and pulmonary function 
testing includes: spirometry, 
DLCO, and room air O2 
saturation at rest. Monitoring 
at each visit until return to ≤ 
grade 1. Return to initial 
monitoring frequency if no 
recurrence. Bronchoscopy 
with biopsy and/or BAL is 
recommended. 
Consider  
corticosteroids 
if infective 
origin is ruled 
out. Taper as 
medically 
indicated. 
Rule out infection and 
interrupt Everolimus until 
symptoms improve to Grade 
≤ 1. 
Consider re-initiating 
Everolimus at one dose level 
lower at investigator 
discretion.  
Discontinue Everolimus if 
failure to recover within ≤ 
28 days. 
Grade 4 
CT scan with lung windows 
and required pulmonary 
function testing, if possible, 
includes: spirometry, DLCO, 
and room air O2 saturation at 
rest. Monitoring at each visit 
until return to ≤ grade 1. 
Return to initial monitoring 
frequency if no recurrence. 
Bronchoscopy with biopsy 
and/or BAL is recommended 
if possible. 
Consider 
corticosteroids 
if infective 
origin is ruled 
out. Taper as 
medically 
indicated. 
Rule out infection and 
discontinue Everolimus. 
 


Everolimus in TSC1 and TSC2 mutated tumors 
13-March-2017  
 
26
6.2.1 
Management of specific toxicities 
Overall, safety data available from completed, controlled and uncontrolled studies 
indicate that everolimus is generally well tolerated at weekly or daily dose schedules. The 
safety profile is characterized by manageable adverse events (AEs). These AEs are 
generally reversible and non-cumulative. 
Adverse events most frequently observed with everolimus are rash, stomatitis /oral 
mucositis, non-infectious pneumonitis, fatigue, headache, anorexia, nausea, vomiting, 
diarrhea, and infections. Overall, the most frequently observed laboratory abnormalities 
include neutropenia, thrombocytopenia, hypercholesterolemia, and/or 
hypertriglyceridemia. The majority of these AEs have been of mild to moderate severity 
(NCI CTC grade 1-2). Recommendations for dose adjustments, should any of these 
treatment-related adverse events occur, are given in tables 6-2 and 6-3 
6.2.1.1 Management of infections 
Everolimus has immunosuppressive properties and may predispose patients to bacterial, 
fungal, viral or protozoal infections, including infections with opportunistic pathogens. 
Localized and systemic infections, including pneumonia, other bacterial infections, 
invasive fungal infections, such as aspergillosis or candidiasis and viral infections 
including reactivation of hepatitis B virus, have been described in patients taking 
Everolimus. Some of these infections have been severe (e.g. leading to respiratory or 
hepatic failure) and occasionally have had a fatal outcome. 
Physicians and patients should be aware of the increased risk of infection with 
Everolimus. Treat pre-existing infections prior to starting treatment with Everolimus. 
While taking Everolimus, be vigilant for symptoms and signs of infection; if a diagnosis 
of infection is made, institute appropriate treatment promptly and consider interruption or 
discontinuation of Everolimus. 
If a diagnosis of invasive systemic fungal infection is made, discontinue Everolimus and 
treat with appropriate antifungal therapy. 
6.2.1.2 Management of skin toxicity 
For patients with grade 1 toxicity, no specific supportive care is usually needed or 
indicated. Rash must be reported as an AE. Patients with grade 2 or higher toxicity may 
be treated with the following suggested supportive measures at the discretion of the 
investigator: oral minocycline, topical tetracycline, topical clindamycin, topical silver 
sulfadiazine, diphenhydramine, oral prednisolone (short course), topical corticosteroids, 
or pimecrolimus. 
6.2.1.3 Management of stomatitis / oral mucositis / mouth ulcers 
Patients with a clinical history of stomatitis/mucositis/mouth ulcers and those with 
gastrointestinal morbidity associated with mouth/dental infections, irritation of 
esophageal mucosa e.g. gastroesophageal reflux disease (GERD) and pre-existing 
stomatitis/mucositis must be monitored even more closely. Patients should be instructed 
to report the first onset of buccal mucosa irritation/reddening to their study physician 
immediately. 


Everolimus in TSC1 and TSC2 mutated tumors 
13-March-2017  
 
27
Stomatitis/oral mucositis/mouth ulcers due to Everolimus should be treated using local 
supportive care. Please note that investigators in earlier trials have described the oral 
toxicities associated with Everolimus as mouth ulcers, rather than mucositis or stomatitis. 
If your examination reveals mouth ulcers rather than a more general inflammation of the 
mouth, please classify the adverse event as such. Please follow the paradigm below for 
treatment of stomatitis/oral mucositis/mouth ulcers: 
 
1. For mild toxicity (grade 1), use conservative measures such as non-alcoholic mouth 
wash or salt water (0.9%) mouth wash several times a day until resolution. 
2. For more severe toxicity (grade 2 in which case patients have pain but are able to 
maintain adequate oral alimentation, or grade 3 in which case patients cannot maintain 
adequate oral alimentation), the suggested treatments are topical analgesic mouth 
treatments (i.e., local anesthetics such as, benzocaine, butyl aminobenzoate, tetracaine 
hydrochloride, menthol, or phenol) with or without topical corticosteroids, such as 
triamcinolone oral paste 0.1% (Kenalog in Orabase®). 
3. Agents containing alcohol, hydrogen peroxide, iodine, and thyme derivatives may 
tend to worsen mouth ulcers. It is preferable to avoid these agents. 
4. Antifungal agents should be avoided unless a fungal infection is diagnosed. In 
particular, systemic imidazole antifungal agents (ketoconazole, fluconazole, itraconazole, 
etc.) should be avoided in all patients due to their strong inhibition of Everolimus 
metabolism, therefore leading to higher Everolimus exposures. Therefore, topical 
antifungal agents are preferred if an infection is diagnosed. 
6.2.1.4 Management of diarrhea 
Appearance of grade 1-2 diarrhea attributed to study drug toxicity may be treated with 
loperamide. Loperamide is taken 4 mg orally after the first loose stool, then 2 mg after 
each loose stool, not to exceed 16 mg in any 24-hour period. 
 
6.2.1.5 Management of hyperlipidemia and hyperglycemia 
Treatment of hyperlipidemia should take into account the pre-treatment status and dietary 
habits of the patient. Grade 2 or higher hypercholesterolemia (>300 mg/dL or 7.75 
mmol/L) or grade 2 hypertriglyceridemia or higher (>2.5x upper normal limit) should be 
treated with a 3-hydroxy-3-methyl-glutaryl (HMG)-CoA reductase inhibitor (e.g. 
atorvastatin, pravastatin, fluvastatin) or appropriate triglyceride-lowering medication, in 
addition to diet. 
Note: Concomitant therapy with fibrates and an HMG-CoA reductase inhibitor is 
associated with an increased risk of a rare but serious skeletal muscle toxicity manifested 
by rhabdomyolysis, markedly elevated creatine phosphokinase (CPK) levels and 
myoglobinuria, acute renal failure and sometimes death. The risk versus benefit of using 
this therapy should be determined for individual patients based on their risk of 
cardiovascular complications of hyperlipidemia. 


Everolimus in TSC1 and TSC2 mutated tumors 
13-March-2017  
 
28
Hyperglycemia has been reported in clinical trials. Monitoring of fasting serum glucose is 
recommended prior to the start of Everolimus and periodically thereafter. Optimal 
glycemic control should be achieved before starting a patient on Everolimus. 
6.2.1.6 Management of non-infectious pneumonitis 
Non-infectious pneumonitis is a class effect of rapamycin derivatives. Cases of non-
infectious pneumonitis (including interstitial lung disease) have also been described in 
patients taking Everolimus. Some of these have been severe and on rare occasions, a fatal 
outcome was observed. 
 
• A diagnosis of non-infectious pneumonitis should be considered in patients 
presenting with non-specific respiratory signs and symptoms such as hypoxia, 
pleural effusion, cough or dyspnea, and in whom infectious, neoplastic and other 
non-medicinal causes have been excluded by means of appropriate investigations. 
Patients should be advised to report promptly any new or worsening respiratory 
symptoms. 
• Patients who develop radiological changes suggestive of non-infectious pneumonitis 
and have few or no symptoms may continue Everolimus therapy without dose 
alteration. 
Individuals participating in this trial will be routinely questioned as to the presence of 
new or changed pulmonary symptoms consistent with lung toxicity. Moreover, potential 
lung radiological changes can be detected by the chest CT/MRI scans that are performed 
on all patients every 8 weeks for tumor assessment according to the schedule of events. In 
addition, pulmonary function tests (PFTs) will be conducted, if clinically indicated, to 
monitor for pneumonitis. If non-infectious pneumonitis develops, the guidelines in table 
6-4 should be followed. Consultation with a pulmonologist is recommended for any case 
of pneumonitis that develops during the study. 
 
6.2.1.7 Management of Hepatitis B and C Reactivation 
 
Patients with a history of hepatitis or significant exposure to hepatitis will be screened at 
the beginning of the study to assess activity of disease.  Those with active hepatitis B or 
C are excluded from this protocol.  Everolimus has been associated with reactivation of 
both hepatitis B virus (HBV) and hepatitis C virus (HCV).  Patients entered on this study 
who subsequently show evidence of active hepatitis B or C will be withdrawn from the 
study. 
 
 
6.3 
Hepatic Impairment Dose Modifications 
  
•  Mild hepatic impairment (Child-Pugh A) – the recommended dose is 7.5 mg daily. 


Everolimus in TSC1 and TSC2 mutated tumors 
13-March-2017  
 
29
• Moderate hepatic impairment (Child-Pugh B) – the recommended dose is 2.5 mg daily 
(if deterioration in hepatic function is observed on study). 
• Severe hepatic impairment (Child-Pugh C) – not recommended. If the desired benefit 
outweighs the risk, a dose of 2.5 mg daily must not be exceeded. 
• Dose adjustments should be made if a patient’s hepatic (Child-Pugh) status changes 
during treatment. 
Everolimus is not recommended for patients with hepatic impairment who require doses 
below 2.5 mg every other day. 
 
7. DRUG FORMULATION AND ADMINISTRATION  
 
7.1 
Everolimus 
 
7.1.1 Description 
Chemical Name and Structure 
(1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30S,32S,35R)-1,18-dihydroxy-
12-(11)-19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-aza-
tricyclo[30.3.1.04,9]hexatriaconta-16,24, 26,28-tetraene-2,3,10,14,20-pentaone 
 
N
O
OH
C
H3
O
O
CH3
CH3
OH
C
H3
O
O
O
O
H
C
H3
O
CH3
O
C
H3
O
O
CH3
CH3
O
C
H3
 
 
Pharmacokinetics 
 
Absorption: Rapid, but moderate 
Protein binding: ~74% 
Metabolism: Extensively metabolized in the liver via CYP3A4; forms 6 weak 
metabolites 
Bioavailability:  Tablets: ~30%; systemic exposure reduced by 22% with a high-fat 
meal and by 32% with a light-fat meal 


Everolimus in TSC1 and TSC2 mutated tumors 
13-March-2017  
 
30
Half-life elimination: ~30 hours 
Time to peak, plasma: 1-2 hours 
Excretion: Feces (80%, based on solid organ transplant studies); Urine (~5%, based on 
solid organ transplant studies) 
Drug Interactions: Substrate of CYP3A4 (major), P-glycoprotein 
  
7.1.2 Form 
 
Everolimus comes in 2.5 mg, 5 mg, and 10 mg tablets. 
Tablets: It is recommended that Everolimus is taken in the morning, one hour prior to 
breakfast. The tablets should be swallowed whole with a glass of water and should not 
be chewed or crushed. For patients unable to swallow tablets, the tablet(s) should be 
dispersed completely in a glass of water (containing approximately 30 mL) by gently 
stirring, immediately prior to drinking. The glass should be rinsed with the same volume 
of water and the rinse completely swallowed to ensure the entire dose is administered. 
Everolimus missed doses may be taken up to 6 hours after regularly scheduled time; if > 
6 hours, resume at next regularly scheduled time.  
 
7.1.3 Storage and Stability 
 
Everolimus should be stored at room temperature in a dry, dark location. 
 
7.1.4 Compatibility 
 
Not applicable 
7.1.5 Handling 
 
Qualified personnel, familiar with procedures that minimize undue exposure to 
themselves and the environment, should undertake the preparation, handling, and 
safe disposal of the chemotherapeutic agent in a self-contained and protective 
environment.  Avoid contact with broken tablets. 
 
7.1.6 Availability 
 
Everolimus will be supplied free of charge by Novartis for this study. 
 
7.1.7 Preparation 
 
Everolimus will be made available in blister packs of tablets.  No specific 
preparation will be required 
  
7.1.8 Administration 
 


Everolimus in TSC1 and TSC2 mutated tumors 
13-March-2017  
 
31
Everolimus is taken orally once daily. 
 
7.1.9 Ordering 
 
Drug supply will be ordered by pharmacy personnel at each site using the Drug 
Request Form in Appendix B.  
 
7.1.10 Accountability 
 
The investigator, or a responsible party designated by the investigator, must 
maintain a careful record of the inventory and disposition of the agent 
(investigational or free of charge) using the NCI Drug Accountability Record or 
another comparable drug accountability form. (See the CTEP website at 
http://ctep.cancer.gov/protocolDevelopment  for the “Policy and Guidelines for 
Accountability and Storage of Investigational Agents” or to obtain a copy of the 
drug accountability form.) 
 
7.1.11 Destruction and Return 
 
At the end of the study, unused supplies of everolimus should be destroyed 
according to institutional policies. Destruction will be documented in the Drug 
Accountability Record Form. 
 
8. CORRELATIVE/SPECIAL STUDIES  
8.1 
Pharmacokinetic Studies 
 
As everolimus is an approved agent, no pharmacokinetic studies will be performed. 
8.2 
Pharmacodynamic Studies 
8.2.1 Laboratory Correlative Studies 
8.2.1.1 Whole exome sequence analysis of tumor specimen 
 
Paraffin blocks of tumor biopsies or resection specimens will be collected at 
the time of study entry by the Principal Investigator for whole exome 
sequencing analysis. If paraffin blocks are not released by the pathology 
department, unstained slides maximum of 20 and minimum of 5 will be 
requested with each tissue cut measuring a minimum of 4 microns in width.  
These samples will be sent to the research laboratory of the Principal 
Investigator at the following address: David Kwiatkowski, Brigham and 
Women’s Hospital, 20 Shattuck St., Thorn 826C, Boston, MA  02115.  These 
samples will be used for DNA extraction and analysis by whole exome 
sequencing at the Broad Institute.  A paired normal DNA sample is required 


Everolimus in TSC1 and TSC2 mutated tumors 
13-March-2017  
 
32
for this analysis and will be collected as a blood sample on the date of study 
entry.  Whole exome data will be analyzed using standard pipeline tools in use 
at the Broad Institute, including Mutect to identify sequence variants present 
in the cancer and not in the normal DNA sample, and CapSeg to identify 
regions of significant copy number variation across the genome. 
 
 
9.  STUDY CALENDAR 
 
Baseline evaluations are to be conducted within 1-week prior to start of protocol 
therapy. Scans must be done <4 weeks prior to the start of therapy. In the event that the 
participant's condition is deteriorating, laboratory evaluations should be repeated within 
48 hours prior to initiation of the next cycle of therapy. 
All assessments must be performed prior to administration of any study 
medication. All study assessments and medications should be administered within 
one week of the protocol-specified date, unless otherwise noted.  
 


Everolimus in TSC1 and TSC2 mutated tumors 
13-March-2017  
 
33
Action 
Study entry 
(within 14 days of 
day 1 unless 
otherwise noted)) 
Day1 
At clinic visit every 4 weeks* 
(This may be extended to 
every 8 weeks after cycle 2 
upon investigator’s discretion) 
Every 8 weeks for max. 24 
months* 
End 
of 
Study 
Informed consent 
X 
(within 28 days of 
day1) 
 
 
 
 
Medical history and height  
X 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
Vital Signs 
X 
X 
X 
 
X 
ECOG Performance status 
X 
X 
X 
 
X 
Physical examination and weight 
X 
X 
X 
 
X 
AE’s and con-
medications/treatments 
X 
X 
X 
 
X 
Pregnancy test (female subjects 
<50) 
X (in clinic) 
X 
X (in clinic) 
X** 
 
Hematology and blood chemistry 
X 
X*** 
X 
 
X 
Urinalysis 
X 
X (only if abnormal at baseline or 
clinically indicated) 
 
 
CT/MRI chest, abdomen, and 
other disease sites, as 
appropriate 
X 
(within 30 days of 
day 1) 
 
 
Repeat scans of areas of 
known disease or of new 
areas based on clinical 
judgment 
 
Everolimus 
 
Administered daily continuously until removal from study 
 
Cf-DNA blood 
 
X 
 
Archived tumor sample 
Sample must have been acquired no longer than 2 years prior to enrollment in the study 
Tumor biopsy 
Participants who achieved either a partial response or stable disease ≥ 4 months must agree to a 
tumor biopsy upon disease progression, assuming it is judged safe and feasible by treating physician  
 
• 
*+/- one week depending on appointment availability due to holidays or unforeseen events 
• 
**When women of child-bearing age are being seen every two months, it is recommended that they perform home pregnancy testing 
at 1 month between visits.  They should also have an office pregnancy test at every visit. Patients will be contacted by a member of 
the study team via phone to track the pregnancy tests performed at home. 
• 
***Hematology and blood chemistry studies need to be assessed on C1D1 only if screening was performed >72 hours prior. In this 
case laboratory values on cycle 1 day 1 must meet eligibility criteria. 
 
Hematology: hemoglobin, hematocrit, platelets, total white blood cell count (WBC) and differential. 
Chemistry: must include sodium, potassium, chloride, bicarbonate, calcium, glucose, creatinine, blood urea nitrogen, albumin, total protein, 
SGOT (AST), SGPT (ALT), total bilirubin, alkaline phosphatase, uric acid, phosphorus, serum lipid profile (triglycerides, total cholesterol, HDL 
and LDL).  Because accurate serum glucose and lipid measurements are required, patients should be fasting at the time of the blood sampling. 
Urinalysis: Standard urinalysis dipstick assessment (pH, protein, glucose, blood, ketones, and leukocytes) should be performed at baseline. This 
must be supplemented with laboratory quantification of any potentially relevant abnormalities. 
Physical Examination: General appearance, skin, head, neck, lungs, heart, abdomen, lymph nodes, extremities and basic nervous system. 
cf-DNA blood: to be collected pre-dose on day 1 of cycle 1 using Cell- Free DNA BCT (Sterck) tube, 10ml or PAXgene, DNA tubes 8.5 ml . 
Store at room temperature (ambient) for same day shipment 
 
 
 
10. MEASUREMENT OF EFFECT  
For the purposes of this study, participants should be re-evaluated for response every 
8 weeks. In addition to a baseline scan, confirmatory scans should also be obtained 4-


Everolimus in TSC1 and TSC2 mutated tumors 
13-March-2017  
 
34
8 weeks (not less than 4 weeks) following initial documentation of objective 
response. 
Response and progression will be evaluated in this study using the new international 
criteria proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) 
1.1 (Eisenhauer et al., 2009).  Changes in the diameter (unidimensional 
measurement) of the tumor lesions are used in the RECIST 1.1 criteria. 
10.1.1 Definitions 
Evaluable for toxicity: All participants who receive at least one dose of study 
treatment will be evaluable for toxicity from the time of their first treatment. 
Evaluable for objective response: Only those participants who have 
measurable disease present at baseline, have received at least one cycle of 
therapy, and have had their disease re-evaluated will be considered evaluable 
for response. These participants will have their response classified according 
to the definitions stated below. (Note: Participants who exhibit objective 
disease progression or die prior to the end of cycle 1 will also be considered 
evaluable.} 
10.1.2 Disease Parameters 
Measurable disease. Measurable disease is the presence of at least one 
(1) lesion that can be accurately measured in at least one dimension with 
longest diameter >20 millimeters (mm) using conventional techniques (CT, 
MRI, x-ray) or >10 mm with spiral CT scan. Measurable lesions must be at 
least 2 times the slice thickness in mm. All tumor measurements must be 
recorded in millimeters (or decimal fractions of centimeters). 
A lesion in a previously irradiated area is not eligible for measurable disease 
unless there is objective evidence of progression of the lesion prior to study 
enrollment. Lesions in previously irradiated areas must be clearly identified as 
such. 
  
Malignant lymph nodes: To be considered pathologically enlarged and 
measurable, a lymph node must be > 15 mm in short axis when assessed by CT 
scan (CT scan slice thickness recommended to be no greater than 5 mm). At 
baseline and in follow-up, only the short axis will be measured and followed. 
 
Non-measurable disease: All other lesions (or sites of disease), including small 
lesions (longest diameter <10 mm or pathological lymph nodes with > 10 to < 
15mm short axis, are considered non-measurable disease. Bone lesions, 
leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis 
cutis/pulmonis, inflammatory breast disease, abdominal masses identified by 


Everolimus in TSC1 and TSC2 mutated tumors 
13-March-2017  
 
35
physical exam that are not measurable by reproducible imaging techniques, and 
cystic lesions are all considered non-measurable. 
 
Target lesions: All measurable lesions up to a maximum of 2 lesions per 
organ and 5 lesions in total, representative of all involved organs, should be 
identified as target lesions and recorded and measured at baseline. Lesions 
must be accurately measured in 1 dimension with a minimum size of 10 mm 
by CT or MRI (slice thickness no greater than 5 mm), 20 mm by chest x-ray. 
Nodes must have a short axis > 15 mm. The short axis should be included in 
the sum of the lesions in the calculation of response. Nodes that shrink to < 10 
mm are considered normal. Target lesions should be selected on the basis of 
their size, be representative of all the involved organs, and should be lesions 
that can be followed with reproducible repeated measurements.  
Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue 
components, that can be evaluated by cross sectional imaging techniques such as 
CT or MRI can be considered target lesions if the soft tissue component meets 
the definition of measurability as defined above. Cystic lesions thought to 
represent cystic metastases can be considered as target lesions. However, if non-
cystic lesions are present, these are preferred for selection as target lesions. 
Lesions in previously irradiated areas or areas subject to other loco-regional 
therapy are usually not considered measurable unless there has been 
demonstrated progression of that lesion.  
Non-target lesions:  All other lesions, including small lesions < 10 mm or 
pathological lymph nodes measuring > 10 mm to < 15 mm in short axis, as 
well as truly non-measurable lesions, which include leptomeningeal disease, 
ascites, pleural or pericardial effusion, inflammatory breast disease, 
lymphangitic involvement of skin or lung, abdominal masses identified by 
physical exam that are not measurable by reproducible imaging techniques.  
10.1.3 Methods for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation, using a ruler, 
calipers, or digital measurement tool. All baseline evaluations should be performed 
as closely as possible to the beginning of treatment and never more than 4 weeks 
before the beginning of the treatment. 
The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during follow-up. 
Imaging-based evaluation is preferred to evaluation by clinical examination 
when both methods have been used to assess the anti-tumor effect of a 
treatment. 


Everolimus in TSC1 and TSC2 mutated tumors 
13-March-2017  
 
36
Clinical lesions. Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes). For the case of 
skin lesions, documentation by color photography, including a ruler to estimate 
the size of the lesion, is recommended. 
Chest x-ray. Lesions on chest x-ray are acceptable as measurable lesions when 
they are clearly defined and surrounded by aerated lung; however, CT is 
preferable. 
 
Conventional CT and MRI: This guideline has defined measurability of lesions 
on CT scan based on the assumption that CT thickness is 5mm or less. If CT 
scans have slice thickness greater than 5 mm, the minimum size of a measurable 
lesion should be twice the slice thickness. MRI is also acceptable in certain 
situations (e.g. for body scans).   
 
Use of MRI remains a complex issue.  MRI has excellent contrast, spatial, and 
temporal resolution; however, there are many image acquisition variables 
involved in MRI, which greatly impact image quality, lesion conspicuity, and 
measurement.  Furthermore, the availability of MRI is variable globally.  As with 
CT, if an MRI is performed, the technical specifications of the scanning 
sequences used should be optimized for the evaluation of the type and site of 
disease.  Furthermore, as with CT, the modality used at follow-up should be the 
same as was used at baseline and the lesions should be measured/assessed on the 
same pulse sequence.  It is beyond the scope of the RECIST guidelines to 
prescribe specific MRI pulse sequence parameters for all scanners, body parts, 
and diseases.  Ideally, the same type of scanner should be used and the image 
acquisition protocol should be followed as closely as possible to prior scans.  
Body scans should be performed with breath-hold scanning techniques, if 
possible. 
Ultrasound (US): When the primary endpoint of the study is objective 
response evaluation, US should not be used to measure tumor lesions. It is, 
however, a possible alternative to clinical measurements of superficial palpable 
lymph nodes, subcutaneous lesions, and thyroid nodules. US might also be useful 
to confirm the complete disappearance of superficial lesions usually assessed 
by clinical examination. 
FDG PET and PET/CT. The acquisition of FDG PET and FDG PET/CT scans 
should follow the NCI Guidelines for using FDG PET as an indicator of 
therapeutic response (L.K. Shankar, J.M. Hoffman, S. Bacharach, M.M. Graham, 
J. Karp, A.A. Lammertsma, S. Larson, D.A. Mankoff, B.A. Siegel, A. Van den 
Abbeele, J. Yap, D. Sullivan. Consensus recommendations for the use of 18F-
FDG PET as an indicator of therapeutic response in patients in National Cancer 
Institute Trials. J Nucl Med, 47(6):901-903, 2006). Patients should avoid 
strenuous exercise and be on a low carbohydrate diet for 24 hours prior to the 


Everolimus in TSC1 and TSC2 mutated tumors 
13-March-2017  
 
37
scan. Patients should fast for 4 hours or longer prior to the FDG injection and 
should have serum glucose of less than 200 mg/dL at the time of FDG injection. 
A 10-20 mCi dose of FDG should be injected for typical adult patients. For 
longitudinal studies with multiple scans, particular attention should be paid to 
ensure consistent patient preparation and acquisition parameters between the 
follow-up scan and the baseline scan. When designing a study where PET scans 
are going to be utilized as one of the modalities to evaluate efficacy, it is 
important to consult with physicians in nuclear medicine in designing the 
appropriate criteria to be utilized. 
Endoscopy, Laparoscopy: The utilization of these techniques for objective 
tumor evaluation has not yet been fully and widely validated. Their uses in this 
specific context require sophisticated equipment and a high level of expertise 
that may only be available in some centers. Therefore, the utilization of such 
techniques for objective tumor response should be restricted to validation 
purposes in reference centers. However, such techniques may be useful to 
confirm complete pathological response when biopsies are obtained. 
Tumor markers. Tumor markers alone cannot be used to assess response. If 
markers are initially above the upper normal limit, they must normalize for 
a subject to be considered in complete clinical response. Specific additional 
criteria for standardized usage of prostate-specific antigen (PSA) and CA-125 
response in support of clinical trials are being developed. 
Cytology, Histology: These techniques can be used to differentiate between 
partial responses (PR) and complete responses (CR) in rare cases (e.g., residual 
lesions in tumor types, such as germ cell tumors, where known residual 
benign tumors can remain). 
The cytological confirmation of the neoplastic origin of any effusion that 
appears or worsens during treatment when the measurable tumor has met 
criteria for response or stable disease is mandatory to differentiate between 
response or stable disease (an effusion may be a side effect of the treatment) 
and progressive disease. 
10.1.4  Response Criteria  
10.1.4.1 Evaluation of Target Lesions 
 
Complete Response (CR):  
Disappearance of all target lesions: Any pathological lymph node 
must have reduction in short axis to < 10 mm. 
Partial Response (PR):   


Everolimus in TSC1 and TSC2 mutated tumors 
13-March-2017  
 
38
At least a 30% decrease in the sum of the diameters of target lesions, 
taking as reference the baseline sum diameters. 
 
Progressive Disease (PD):  
                At least a 20% increase in the sum of the diameters of target lesions, 
taking as reference the smallest sum with at least 5mm absolute 
increase in the sum of all lesions. The appearance of one or more new 
lesions* denotes disease progression.   
 
  
 
Stable Disease (SD):  
 
Neither sufficient shrinkage to qualify for PR nor sufficient increase 
to qualify for PD, taking as reference the smallest sum diameters 
while on study. 
Unknown (UN): Assessment of target lesions cannot be made due to 
insufficient or unevaluable data. In this case, a concise explanation must 
be given. 
Note: If tumor response data is missing for target lesions, the overall 
assessment must be UN unless there is new disease that would result in 
an overall assessment of PD. However, if there is missing or 
unevaluable data for non-target lesions, but data is available for all 
target lesions, the overall response for that time point will be assigned 
based on the sum LD of all target lesions. Additionally, the assessment 
of CR cannot be made if there is missing or unevaluable data for non-
target lesions. In this case, the overall assessment would be PR. 
*Definition of New Lesion: The finding of a new lesion should be unequivocal 
(i.e. not due to difference in scanning technique, imaging modality, or findings 
thought to represent something other than tumor (ex: new bone lesions may be 
healing or flare of pre-existing lesions). However, a lesion identified on a 
follow-up scan in an anatomical location that was not scanned at baseline is 
considered new and will indicate PD. If a new lesion is equivocal (because of 
small size, etc.), follow-up evaluation will clarify if it truly represents new 
disease and if PD is confirmed, progression should be declared using the date of 
the initial scan on which the lesion was discovered.  
10.1.4.2 Evaluation of Non-Target Lesions 
 
Complete Response (CR): Disappearance of all non-target lesions and 


Everolimus in TSC1 and TSC2 mutated tumors 
13-March-2017  
 
39
normalization of tumor marker level.  All lymph nodes must be non-
pathological in size (< 10 mm short axis).  
Note: If tumor markers are initially above the upper normal limit, 
they must normalize for a subject to be considered in complete 
clinical response. 
Incomplete Response/Stable Disease (SD): Persistence of one or 
more non-target lesions and/or maintenance of tumor marker level 
above the normal limits. 
Progressive Disease (PD): Appearance of one or more new 
lesions* (new lesions must be > slice thickness) and/or 
unequivocal progression of existing non-target lesions.  Overall 
level of substantial worsening that merits discontinuation of 
therapy. A useful test that can be applied when assessing non-
targets for unequivocal progression is to consider if the increase 
in overall disease burden based on the change in non-
measurable disease is comparable in magnitude to the increase 
that would be required to declare PD for measurable disease. 
Unknown (UN): Assessment of non-target lesions cannot be made due 
to insufficient or unevaluable data. In this case, a concise explanation 
must be given. 
*Definition of New Lesion: The finding of a new lesion should be unequivocal 
(i.e. not due to difference in scanning technique, imaging modality, or findings 
thought to represent something other than tumor (ex: new bone lesions may be 
healing or flare of pre-existing lesions). However, a lesion identified on a 
follow-up scan in an anatomical location that was not scanned at baseline is 
considered new and will indicate PD. If a new lesion is equivocal (because of 
small size, etc.), follow-up evaluation will clarify if it truly represents new 
disease and if PD is confirmed, progression should be declared using the date of 
the initial scan on which the lesion was discovered.  
 
10.1.4.3 Evaluation of Best Overall Response 
The best overall response is 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). The participant's best response assignment will 
depend on the achievement of both measurement and confirmation 
criteria. 
 


Everolimus in TSC1 and TSC2 mutated tumors 
13-March-2017  
 
40
For Patients with Measurable Disease (i.e., Target Disease) 
 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response for 
when Confirmation is 
Required: 
CR 
CR 
No 
CR 
>4 wks confirmation 
CR 
Non-CR/Non-PD 
No 
PR 
>4 wks confirmation 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-
PD/Not 
evaluated 
No 
PR 
SD 
Non-CR/Non-
PD/Not 
evaluated 
No 
SD 
Documented at least once 
>4 wks from baseline 
PD 
Any 
Yes, or No 
PD 
No prior SD, PR or CR 
Any 
PD* 
Yes, or No 
PD 
Any 
Any 
Yes 
PD 
* 
In exceptional circumstances, unequivocal progression in non-target lesions may be 
accepted as disease progression. 
 
Note:   Participants with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be 
reported as "symptomatic deterioration". Every effort should be made to document the 
objective progression even after discontinuation of treatment. 
 
 
For Patients with Non-Measurable Disease (i.e., Non-Target Disease) 
 
Non-Target Lesions 
New 
Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
NonCR/non-PD 
Not all evaluated 
No 
Not evaluated 
Unequivocal PD 
Yes, or No 
PD 
Any 
Yes 
PD 
Non-CR/non-PD is preferred over stable disease for non-target disease since SD is 
increasingly used an endpoint for assessment of efficacy in some trials so to assign this 
category when no lesions can be measured is not advised.  
 


Everolimus in TSC1 and TSC2 mutated tumors 
13-March-2017  
 
41
10.1.5 Duration of Response 
Duration of overall response: The duration of overall response is measured 
from the time measurement criteria are met for CR or PR (whichever is first 
recorded) until the first date that recurrence or PD is objectively documented, 
taking as reference for PD the smallest measurements recorded since the 
treatment started. 
Duration of overall complete response: The duration of overall CR is 
measured from the time measurement criteria are first met for CR until the 
first date that recurrent disease is objectively documented. 
Duration of stable disease: Stable disease is measured from the start of the 
treatment until the criteria for progression are met, taking as reference the 
smallest measurements recorded since the treatment started. 
10.1.6 Progression-Free Survival 
Progression-Free Survival (PFS) is defined as the duration of time from study 
registration to the date of documented disease progression or death, whichever 
occurs first. Patients not experiencing an event will be censored at the date of the last 
disease assessment. 
  
11. ADVERSE EVENT REPORTING REQUIREMENTS 
 
11.1 Definitions 
11.1.1 Adverse Event (AE) 
 
An adverse event (AE) is any undesirable sign, symptom or medical condition or 
experience that develops or worsens in severity after starting the first dose of 
study treatment or any procedure specified in the protocol, even if the event is not 
considered to be related to the study.  
 
Abnormal laboratory values or diagnostic test results constitute adverse events 
only if they induce clinical signs or symptoms or require treatment or further 
diagnostic tests.  
11.1.2 Serious adverse event (SAE) 
 
A serious adverse event (SAE) is any adverse event, occurring at any dose and 
regardless of causality that:  
• Results in death 


Everolimus in TSC1 and TSC2 mutated tumors 
13-March-2017  
 
42
• Is life-threatening. Life-threatening means that the person was at 
immediate risk of death from the reaction as it occurred, i.e., it does not 
include a reaction which hypothetically might have caused death had it 
occurred in a more severe form. 
• Requires or prolongs inpatient hospitalization (i.e., the event required at 
least a 24-hour hospitalization or prolonged a hospitalization beyond the 
expected length of stay). Hospitalization admissions and/or surgical 
operations scheduled to occur during the study period, but planned prior to 
study entry are not considered SAEs if the illness or disease existed before 
the person was enrolled in the trial, provided that it did not deteriorate in 
an unexpected manner during the trial (e.g., surgery performed earlier than 
planned). 
• Results in persistent or significant disability/incapacity. Disability is 
defined as a substantial disruption of a person’s ability to conduct normal 
life functions. 
• Is a congenital anomaly or birth defect; or 
• Is an important medical event when, based upon appropriate medical 
judgment, it may jeopardize the participant and require medical or surgical 
intervention to prevent one of the outcomes listed above. Examples of 
such medical events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home; blood dyscrasias or 
convulsions that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse. 
 
Events not considered to be serious adverse events are hospitalizations for: 
• routine treatment or monitoring of the studied indication, not associated 
with any deterioration in condition, or for elective procedures 
• elective or pre-planned treatment for a pre-existing condition that did not 
worsen 
• emergency outpatient treatment for an event not fulfilling the serious 
criteria outlined above and not resulting in inpatient admission 
• respite care 
 
11.1.3 Expectedness 
 
Adverse events can be 'Expected' or 'Unexpected.'  
11.1.3.1 Expected adverse event 
 
Expected adverse events are those that have been previously identified as 
resulting from administration of the agent. For the purposes of this study, 
an adverse event is considered expected when it appears in the current 
adverse event list, the Investigator’s Brochure, the package insert or is 
included in the informed consent document as a potential risk.   
 


Everolimus in TSC1 and TSC2 mutated tumors 
13-March-2017  
 
43
Refer to Section 6.1 for a listing of expected adverse events associated 
with the study agent(s). 
11.1.3.2 Unexpected adverse event 
 
 
For the purposes of this study, an adverse event is considered unexpected 
when it varies in nature, intensity or frequency from information 
provided in the current adverse event list, the Investigator’s Brochure, 
the package insert or when it is not included in the informed consent 
document as a potential risk.   
11.1.4 Attribution 
 
Attribution is the relationship between an adverse event or serious adverse event 
and the study treatment. Attribution will be assigned as follows: 
 
• Definite – The AE is clearly related to the study treatment. 
• Probable – The AE is likely related to the study treatment. 
• Possible – The AE may be related to the study treatment.  
• Unlikely - The AE is doubtfully related to the study treatment. 
• Unrelated - The AE is clearly NOT related to the study treatment. 
11.2 Procedures for AE and SAE Recording and Reporting 
 
Participating investigators will assess the occurrence of AEs and SAEs at all participant 
evaluation time points during the study.  
 
All AEs and SAEs whether reported by the participant, discovered during questioning, 
directly observed, or detected by physical examination, laboratory test or other means, 
will be recorded in the participant’s medical record and on the appropriate study-
specific case report forms.  
 
The descriptions and grading scales found in the revised NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for AE reporting. All 
appropriate treatment areas should have access to a copy of the CTCAE version 4.0. 
A copy of the CTCAE version 4.0 can be downloaded from the CTEP website at: 
 
 http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.  
 
11.3 Reporting Requirements 
 
For multi-site trials where a DF/HCC investigator is serving as the principal investigator, 
each participating investigator is required to abide by the reporting requirements set by 
the DF/HCC. This applies to any medical event equivalent to an unexpected grade 2 or 3 


Everolimus in TSC1 and TSC2 mutated tumors 
13-March-2017  
 
44
with a possible, probable or definite attribution, unexpected grade 4 toxicities, and grade 
5 (death) regardless of study phase or attribution. 
 
The study must be conducted in compliance with FDA regulations, local safety reporting 
requirements, and reporting requirements of the principal investigator.  
 
Each investigative site will be responsible to report SAEs that occur at that institution to 
their respective IRB. It is the responsibility of each participating investigator to report 
serious adverse events to the study sponsor and/or others as described below.  
 
11.4 Reporting to the Study Sponsor 
11.4.1 Serious Adverse Event Reporting 
 
All serious adverse events that occur after the initial dose of study treatment, 
during treatment, or within 30 days of the last dose of treatment must be reported 
to the DF/HCC Overall Principal Investigator on the local institutional SAE form. 
This includes events meeting the criteria outlined in Section 11.1.2, as well as the 
following: 
 
• Grade 2 (moderate) and Grade 3 (severe) Events – Only events that are 
unexpected and possibly, probably or definitely related/associated with the 
intervention. 
 
• All Grade 4 (life-threatening or disabling) Events – Unless expected AND 
specifically listed in the protocol as not requiring reporting. 
 
• All Grade 5 (fatal) Events – When the participant is enrolled and actively 
participating in the trial OR when the event occurs within 30 days of the 
last study intervention.  
 
Note: If the participant is in long term follow up, report the death at the time 
of continuing review.  
 
Participating investigators must report each serious adverse event to the DF/HCC 
Overall Principal Investigator within 1 business day of learning of the occurrence. 
In the event that the participating investigator does not become aware of the 
serious adverse event immediately (e.g., participant sought treatment elsewhere), 
the participating investigator is to report the event within 1 business day after 
learning of it and document the time of his or her first awareness of the adverse 
event. Report serious adverse events by telephone, email or facsimile to: 
 
 
 
 
David Kwiatkowski, MD, PhD 
Phone: (857) 307-0781 


Everolimus in TSC1 and TSC2 mutated tumors 
13-March-2017  
 
45
Fax: (617) 394-2762 
dkwiatkowski@partners.org  
 
 
Within the following 1-2 business days, the participating investigator must 
provide follow-up information on the serious adverse event. Follow-up 
information should describe whether the event has resolved or continues, if and 
how the event was treated, and whether the participant will continue or 
discontinue study participation. 
11.4.2 Non-Serious Adverse Event Reporting  
 
Non-serious adverse events will be reported to the DF/HCC Overall Principal 
Investigator on the toxicity Case Report Forms.   
11.5 Reporting to the Institutional Review Board (IRB) 
 
Investigative sites within DF/HCC will report all serious adverse events directly to the 
DFCI Office for Human Research Studies (OHRS). 
 
Other investigative sites will report SAEs to their respective IRB according to the local 
IRB’s policies and procedures in reporting adverse events. A copy of the submitted 
institutional SAE form should be forwarded to the Overall PI within the timeframes 
detailed in the table below.   
 
 
 
 
Attribution 
DF/HCC Reportable AEs 
Gr. 2 & 3 AE 
Expected 
Gr. 2 & 3 AE 
Unexpected 
Gr. 4 AE Expected 
Gr. 4 AE 
Unexpected 
Gr. 5 AE 
Expected or 
Unexpected 
Unrelated 
Unlikely 
Not required 
Not required 
5 calendar days# 
5 calendar days 
24 hours* 
Possible 
Probable 
Definite 
 
Not required 
 
5 calendar days 
 
5 calendar days# 
 
5 calendar days 
 
24 hours* 
# If listed in protocol as expected and not requiring expedited reporting, event does not need to be reported. 
 
* For participants enrolled and actively participating in the study or for AEs occurring within 30 days of the last 
intervention, the AE should be reported within 24 business hours of learning of the event. 
 
 
The Overall PI will submit SAE reports from outside institutions to the DFCI OHRS 
according to DFCI IRB policies and procedures in reporting adverse events.  
 
11.6 Reporting to Novartis Pharmaceuticals 
 


Everolimus in TSC1 and TSC2 mutated tumors 
13-March-2017  
 
46
The principal investigator has the obligation to report all serious adverse events to the 
IRB, and Novartis Pharmaceuticals Drug Safety and Epidemiology Department 
(DS&E). 
To ensure patient safety, every SAE, regardless of suspected causality, occurring 
• after the patient has provided informed consent and until at least 30 days after the 
patient has stopped study treatment/participation 
• after protocol-specified procedures begin (e.g., placebo run-in, washout period, 
double-blind treatment, etc.) and 30 days after the patient has stopped study 
treatment 
• after the start of any period in which the study protocol interferes with the standard 
medical treatment given to a patient (e.g., treatment withdrawal during washout 
period, change in treatment to a fixed dose of concomitant medication) and until 30 
days after the patient has stopped study treatment 
must be reported to Novartis by each participating study team within 1 business day of 
learning of its occurrence (fax: 877-778-9739). This includes serious, related, labeled 
(expected) and serious, related, unlabeled (unexpected) adverse experiences. All deaths 
during treatment or within 30 days following completion of active protocol therapy 
must be reported within 5 working days. A copy of the report needs to be sent to the 
Protocol Sponsor at the fax number listed in section 11.4.1. 
Any SAEs experienced after this 30 days period should only be reported to Novartis if 
the investigator suspects a causal relationship to the study drug. Recurrent episodes, 
complications, or progression of the initial SAE must be reported as follow-up to the 
original episode within 1 business day of the investigator receiving the follow-up 
information. A SAE occurring at a different time interval or otherwise considered 
completely unrelated to a previously reported one should be reported separately as a 
new event.  The end date of the first event must be provided. 
The original copy of the SAE Report and the fax confirmation sheet must be kept 
within the Trial Master File at the study site. 
Follow-up information is sent to the same fax number as the original SAE Report Form 
was sent, using a new fax cover sheet, stating that this is a follow-up to the previously 
reported SAE, and giving the date of the original report. Each re-occurrence, 
complication, or progression of the original event should be reported as a follow-up to 
that event regardless of when it occurs. The follow-up information should describe 
whether the event has resolved or continues, if and how it was treated, whether the 
blind was broken or not (if applicable), and whether the patient continued or withdrew 
from study participation. 
If the SAE is not previously documented in the Everolimus Investigator Brochure or 
Package Insert (new occurrence) and is thought to be related to the Novartis study drug, 
a DS&E associate may urgently require further information from the investigator for 
Health Authority reporting. Novartis may need to issue an Investigator Notification 
(IN), to inform all investigators involved in any study with the same drug that this SAE 
has been reported. Suspected Unexpected Serious Adverse Reactions (SUSARs) will be 
collected and reported to the competent authorities and relevant ethics committees in 


Everolimus in TSC1 and TSC2 mutated tumors 
13-March-2017  
 
47
accordance with Directive 2001/20/EC or as per national regulatory requirements in 
participating countries. 
11.7 Reporting to Hospital Risk Management 
 
Participating investigators will report to their local Risk Management office any subject 
safety reports or sentinel events that require reporting according to institutional policy. 
11.8 Monitoring of Adverse Events and Period of Observation 
 
All adverse events, both serious and non-serious, and deaths that are encountered from 
initiation of study intervention, throughout the study, and within 30 days of the last 
study intervention should be followed to their resolution, or until the participating 
investigator assesses them as stable, or the participating investigator determines the 
event to be irreversible, or the participant is lost to follow-up. The presence and 
resolution of AEs and SAEs (with dates) should be documented on the appropriate case 
report form and recorded in the participant’s medical record to facilitate source data 
verification.  
 
For some SAEs, the study sponsor or designee may follow-up by telephone, fax, and/or 
monitoring visit to obtain additional case details deemed necessary to appropriately 
evaluate the SAE report (e.g., hospital discharge summary, consultant report, or 
autopsy report).  
 
Participants should be instructed to report any serious post-study event(s) that might 
reasonably be related to participation in this study. Participating investigators should 
notify the DF/HCC Overall Principal Investigator and their respective IRB of any 
unanticipated death or adverse event occurring after a participant has discontinued or 
terminated study participation that may reasonably be related to the study.   
 
12. DATA AND SAFETY MONITORING 
 
12.1 Data Reporting 
12.1.1 Method  
The ODQ will collect, manage, and perform quality checks on the data for 
this study.  
12.1.2 Data Submission  
The schedule for completion and submission of case report forms (paper or 
electronic) to the ODQ is as follows: 
 


Everolimus in TSC1 and TSC2 mutated tumors 
13-March-2017  
 
48
 
Form 
Submission Timeline 
Eligibility Checklist 
Complete prior to registration with ODQ 
On Study Form 
Within 14 days of registration 
Baseline Assessment Form 
Within 14 days of registration 
Treatment Form 
Within 10 days of the last day of the cycle 
Adverse Event Report Form 
Within 10 days of the last day of the cycle 
Response Assessment Form 
Within 10 days of the completion of the cycle 
required for response evaluation 
Off Treatment/Off Study Form Within 14 days of completing treatment or 
being taken off study for any reason 
Follow up/Survival Form 
Within 14 days of the protocol defined follow 
up visit date or call 
 
12.2 Safety Meetings 
 
The DF/HCC Data and Safety Monitoring Committee (DSMC) will review and monitor 
toxicity and accrual data from this study. The committee is composed of clinical 
specialists with experience in oncology and who have no direct relationship with the 
study. Information that raises any questions about participant safety will be addressed 
with the Overall PI and study team. 
 
The DSMC will review each protocol up to four times a year or more often if required 
to review toxicity and accrual data. Information to be provided to the committee may 
include: up-to-date participant accrual; current dose level information; DLT 
information; all grade 2 or higher unexpected adverse events that have been reported; 
summary of all deaths occurring with 30 days of intervention for Phase I or II 
protocols; for gene therapy protocols, summary of all deaths while being treated and 
during active follow-up; any response information; audit results, and a summary 
provided by the study team. Other information (e.g. scans, laboratory values) will be 
provided upon request.  
 
12.3 Monitoring  
 
Involvement in this study as a participating investigator implies acceptance of 
potential audits or inspections, including source data verification, by representatives 
designated by the DF/HCC Overall Principal Investigator (or Protocol Chair) or 


Everolimus in TSC1 and TSC2 mutated tumors 
13-March-2017  
 
49
DF/HCC. The purpose of these audits or inspections is to examine study-related 
activities and documents to determine whether these activities were conducted and 
data were recorded, analyzed, and accurately reported in accordance with the protocol, 
institutional policy, and any applicable regulatory requirements.  
 
All data will be monitored for timeliness of submission, completeness, and adherence 
to protocol requirements. Monitoring will begin at the time of participant registration 
and will continue during protocol performance and completion. For additional 
information, please refer to section 5 of the DSMP (Appendix C). 
 
13. REGULATORY CONSIDERATIONS 
 
13.1 Protocol Review and Amendments 
This protocol, the proposed informed consent and all forms of participant 
information related to the study (e.g., advertisements used to recruit participants) and 
any other necessary documents must be submitted, reviewed and approved by a 
properly constituted IRB governing each study location.  
Any changes made to the protocol must be submitted as amendments and must be 
approved by the IRB prior to implementation. Any changes in study conduct must be 
reported to the IRB. The DF/HCC Overall Principal Investigator (or Protocol Chair) 
will disseminate protocol amendment information to all participating investigators.  
All decisions of the IRB concerning the conduct of the study must be made in 
writing. 
13.2 Informed Consent 
 
All participants must be provided a consent form describing this study and providing 
sufficient information for participants to make an informed decision about their 
participation in this study. The formal consent of a participant, using the IRB 
approved consent form, must be obtained before the participant is involved in any 
study-related procedure. The consent form must be signed and dated by the 
participant or the participant’s legally authorized representative, and by the person 
obtaining the consent. The participant must be given a copy of the signed and dated 
consent document. The original signed copy of the consent document must be 
retained in the medical record or research file.  
13.3 Ethics and Study Execution 
This study is to be conducted according to the following considerations, which 
represent good and sound research practice: 


Everolimus in TSC1 and TSC2 mutated tumors 
13-March-2017  
 
50
• 
US Code of Federal Regulations (CFR) governing clinical study conduct and 
ethical principles that have their origin in the Declaration of Helsinki 
o Title 21 Part 50 – Protection of Human Subjects 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr50_02.html  
o Title 21 Part 54 – Financial Disclosure by Clinical Investigators 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr54_02.html  
o Title 21 Part 56 – Institutional Review Boards 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr56_02.html  
o Title 21 Part 312 – Investigational New Drug Application 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr312_02.html  
• 
State laws 
• 
DF/HCC research policies and procedures        
http://www.dfhcc.harvard.edu/clinical-research-support/clinical-research-unit-
cru/policies-and-procedures/  
It is understood that deviations from the protocol should be avoided, except when 
necessary to eliminate an immediate hazard to a research participant. In such case, 
the deviation must be reported to the IRB according to the local reporting policy.  
13.4 Study Documentation 
 
The investigator must prepare and maintain adequate and accurate case histories 
designed to record all observations and other data pertinent to the study for each 
research participant. This information enables the study to be fully documented and the 
study data to be subsequently verified. 
 
Original source documents supporting entries in the case report forms include but are 
not limited to hospital records, clinical charts, laboratory and pharmacy records, 
recorded data from automated instruments, microfiches, photographic negatives, 
microfilm or magnetic media, and/or x-rays.  
13.5 Records Retention 
 
All study-related documents must be retained for the maximum period required by 
applicable federal regulations and guidelines or institutional policies.  
 
13.6 Multi-center Guidelines   
 
This protocol will adhere to the policies and requirements of the DF/HCC Multi-Center 
Data and Safety Monitoring Plan.  The specific responsibilities of the Overall PI, 


Everolimus in TSC1 and TSC2 mutated tumors 
13-March-2017  
 
51
Coordinating Center, and Participating Institutions and the procedures for auditing are 
presented in Appendix C. 
 
• The Overall PI/Coordinating Center is responsible for distributing all IND Action 
Letters or Safety Reports to all participating institutions for submission to their 
individual IRBs for action as required. 
 
• Mechanisms will be in place to ensure quality assurance, protocol compliance, 
and adverse event reporting at each site. 
 
• Except in very unusual circumstances, each participating institution will order the 
study agent(s) directly from supplier.  A participating site may order the agent(s) 
only after the initial IRB approval for the site has been forwarded to the 
Coordinating Center. 
 
14. STATISTICAL CONSIDERATIONS  
 
This is a single-arm non-randomized phase II study evaluating the mTOR inhibitor 
everolimus in patients who have documented inactivating mutations in either TSC1 or 
TSC2, or activating mutations in MTOR. Preliminary data indicates that TSC1 and 
TSC2 mutations are present in approximately 5-10% of bladder cancer, 10% of 
pancreatic neuroendocrine tumors, 50% of PEComa, 2% of squamous cell lung cancer, 
and 5-10% of anaplastic thyroid cancer.  
14.1 Study Design/Endpoints 
 
The primary objective of this trial is objective response rate according to RECIST 1.1 
criteria.  
 
Secondary objectives include duration of response, progression-free and overall 
survival. Duration of response is defined as the time from RECIST-confirmed response 
(CR+PR) to documented disease progression. Progression-free survival is defined as the 
time from study registration to documented disease progression per RECIST 1.1 or 
death from any cause, whichever occurs first. Patients not experiencing a PFS event will 
be censored at the date of their last disease assessment. Overall survival is defined as 
time from registration to death from any cause, censoring patients thought to be alive at 
the time of final analysis at the last date of follow up. We will also estimate toxicity via 
CTCAE version 4.0, and the association of IHC and whole exome sequencing results 
with patient outcomes and other genetic events. 
 
We will estimate event-time distributions using the Kaplan-Meier method, using 
Greenwood’s formula to estimate the variance and provide 90% confidence intervals for the 
medians, 6-month, and 1-year estimates. Categorical outcomes, such as toxicity and 
response, will be estimated and their corresponding 90% exact binomial confidence 
intervals will be provided.  


Everolimus in TSC1 and TSC2 mutated tumors 
13-March-2017  
 
52
 
For the cohort of patients with TSC1 and TSC2 mutations, we will conduct this study using 
a Simon’s two-stage design. In the first stage we will enroll 21 patients and if a total of at 
least 4 responses (CR + PR) are observed among them, accrual to the second stage will 
open. If 3 or fewer responses are observed among the first 21 patients, the study will 
terminate. In the second stage, an additional 29 patients will be enrolled for a total study 
accrual of 50 patients. After accrual to the second stage is completed, we will declare study 
success if at least 8 responses are observed among the 50 registered patients. This design has 
a probability of stopping early after the first stage of accrual of 85% if the drug is 
ineffective; the overall power of the study to detect the targeted response rate of 30% 
(compared to a null of 10%) is 91% while controlling the type I error at a one-sided level of 
0.07.  
 
For the cohort of 10 patients harboring mTOR mutations, we are somewhat limited in the 
inferences that can be made, however we would consider observing at least 2 responses in 
this cohort worthy of additional study. The maximum half-width of the 90% exact binomial 
confidence interval will be 23.5%. 
14.2 Consideration of gene and mutation specific response rates 
 
 
It is possible that certain combinations of mutation - primary cancer site will not respond to 
Everolimus therapy. Though the distribution of histologic subtypes among patients to be 
enrolled is unknown at this time, it is of interest to conduct exploratory analyses within these 
subgroups (for example, among patients with bladder cancer, PEComas, squamous cell lung 
cancer, etc.) Among a subgroup of 10 patients of any particular histology, there is 0.98 
probability of observing at least 1 response among them, assuming an underlying response 
rate of 30%. Therefore, if 10 patients with TSC1/TSC2 mutations and a single cancer site 
are enrolled and no responses are observed among them, consideration may be given to 
halting enrollment of patients with cancers arising in that specific site.  Since this lack of 
response may vary according to the primary site of cancer, in that instance we will continue 
to enroll patients TSC1/TSC2 mutations and different primary cancer sites. 
14.3 Sample Size/Accrual Rate 
 
We have a planned sample size of 30 patients, with either inactivating TSC1 or TSC2 
mutations, or activating MTOR mutations, so it is estimated that this protocol will complete 
accrual in 48 months, making for an overall accrual rate of approximately 1.25 patients per 
month.  We will be identifying patients for this study from the Oncopanel cancer genotyping 
at DFCI/BWH, the Impact cancer genotyping panel at MSKCC, and CLIA certified 
genotyping laboratories both at other DF/HCC institutions and external sites. 
 
 
 
15. PUBLICATION PLAN 
 


Everolimus in TSC1 and TSC2 mutated tumors 
13-March-2017  
 
53
The results will be made public within 12 months of the end of the last patient’s last visit. The 
initial release of data will be in a peer-reviewed journal or in an abstract that meets the 
requirements of the International Committee of Medical Journal Editors. A full report of 
outcomes will be made public no later than three years after the end of data collection. 
 
 
16. REFERENCES  
 
1. Boulay A, Lane HA. The mammalian target of rapamycin kinase and tumor growth inhibition. 
Recent Results Cancer Res. 2007;172:99-124. 
2. Cohen HT, McGovern FJ. Renal-cell carcinoma. N Engl J Med. 2005;353:2477-90. 
3. Bjornsti MA, Houghton PJ. The TOR pathway: a target for cancer therapy. Nat Rev Cancer. 
2004;4:335-48. 
4. Frattini M, Signoroni S, Pilotti S, Bertario L, Benvenuti S, Zanon C, et al. Phosphatase 
protein homologue to tensin expression and phosphatidylinositol-3 phosphate kinase mutations 
in colorectal cancer. Cancer Res. 2005;65:11227. 
5. Velho S, Oliveira C, Ferreira A, Ferreira AC, Suriano G, Schwartz S, et al. The prevalence of 
PIK3CA mutations in gastric and colon cancer. Eur J Cancer. 2005;41:1649-54. 
6. Goel A, Arnold CN, Niedzwiecki D, Carethers JM, Dowell JM, Wasserman L, et al. Frequent 
inactivation of PTEN by promoter hypermethylation in microsatellite instability-high sporadic 
colorectal cancers. Cancer Res. 2004;64:3014-21. 
7. Bissler JJ, Kingswood JC, Radzikowska E, Zonnenberg BA, Frost M, Belousova E, et al. 
Everolimus for angiomyolipoma associated with tuberous sclerosis complex or sporadic 
lymphangioleiomyomatosis (EXIST-2): a multicentre, randomised, double-blind, placebo-
controlled trial. Lancet. 2013. 
8. Franz DN, Belousova E, Sparagana S, Bebin EM, Frost M, Kuperman R, et al. Efficacy and 
safety of everolimus for subependymal giant cell astrocytomas associated with tuberous sclerosis 
complex (EXIST-1): a multicentre, randomised, placebo-controlled phase 3 trial. Lancet. 
2013;381:125-32. 
9. Dickson MA, Schwartz GK, Antonescu CR, Kwiatkowski DJ, Malinowska IA. Extrarenal 
perivascular epithelioid cell tumors (PEComas) respond to mTOR inhibition: clinical and 
molecular correlates. Int J Cancer. 2013;132:1711-7. 
10. 
Wagner AJ, Malinowska-Kolodziej I, Morgan JA, Qin W, Fletcher CD, Vena N, et al. 
Clinical activity of mTOR inhibition with sirolimus in malignant perivascular epithelioid cell 
tumors: targeting the pathogenic activation of mTORC1 in tumors. J Clin Oncol. 2010;28:835-
40. 
11. 
Iyer G, Hanrahan AJ, Milowsky MI, Al-Ahmadie H, Scott SN, Janakiraman M, Pirun M, 
Sander C, Socci ND, Ostrovnaya I, Viale A, Heguy A, Peng L, Chan TA, Bochner B, Bajorin 
DF, Berger MF, Taylor BS, Solit DB.  Genome sequencing identifies a basis for everolimus 
sensitivity.  Science. 2012 338:221. 
12.  Voss MH, Hakimi AA, R. BA, Scott S, Takeda S, Liu HL, Chen Y, Motzer RJ, Berger MF, 
Hsieh JT. Next-generation sequencing reveals genomic determinants of long-term response to 
mTOR inhibitors in patients with advanced RCC. BJUI 2013 11th International Kidney Cancer 
Symposium Annual Meeting. 
13. Wagle N, Grabiner BC, Van Allen EM, Hodis E, Jacobus S, Supko JG, Stewart M, Choueiri 
TK, Gandhi L, Cleary JM, Elfiky AA, Taplin ME, Stack EC, Signoretti S, Loda M, Shapiro GI, 


Everolimus in TSC1 and TSC2 mutated tumors 
13-March-2017  
 
54
Sabatini DM, Lander ES, Gabriel SB, Kantoff PW, Garraway LA, Rosenberg JE. Activating 
mTOR mutations in a patient with an extraordinary response on a phase I trial of everolimus and 
pazopanib. Cancer Discov. 2014 4:546-53. 
14. Grabiner BC, Nardi V, Birsoy K, Possemato R, Shen K, Sinha S, Jordan A, Beck AH, 
Sabatini DM. A diverse array of cancer-associated MTOR mutations are hyperactivating and can 
predict rapamycin sensitivity. Cancer Discov. 2014 4:554-63.  


Everolimus in TSC1 and TSC2 mutated tumors 
13-March-2017  
 
55
 
17. APPENDICES  
 
Appendix A: Performance Status Criteria 
 
 
ECOG Performance Status Scale 
 
 
Karnofsky Performance Scale 
Grade 
Description 
Percent 
Description 
0 
Normal activity. Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no 
evidence of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of 
disease. 
1 
Symptoms, but ambulatory. 
Restricted in physically strenuous 
activity, but ambulatory and able to 
carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; 
some signs or symptoms of 
disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active 
work. 
2 
In bed < 50% of the time. 
Ambulatory and capable of all self-
care, but unable to carry out any 
work activities. Up and about more 
than 50% of waking hours. 
60 
Requires occasional assistance, 
but is able to care for most of 
his/her needs. 
50 
Requires considerable assistance 
and frequent medical care. 
3 
In bed >50% of the time. Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care 
and assistance. 
30 
Severely disabled, 
hospitalization indicated. Death 
not imminent. 
4 
100% bedridden. Completely 
disabled. Cannot carry on any self-
care. Totally confined to bed or 
chair. 
20 
Very sick, hospitalization 
indicated. Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly.  
5 
Dead. 
0 
Dead. 
 


Everolimus in TSC1 and TSC2 mutated tumors 
13-March-2017  
 
56
 
Appendix B: Drug Order Form 
 
RAD001 
DRUG REQUEST FORM 
Investigational Supply 
 
Please e-mail request to:  maritza.crawford@novartis.com 
 
Date: 
  
Study Title: 
  A Phase II trial of everolimus for cancer patients with  
 
  inactivating mutations in TSC1 or TSC2 
 
 
  
Investigator’s Name: 
 David J. Kwiatkowski, MD, PhD 
Novartis Protocol Number: 
CRAD001 MUS217T 
 
 
Requestor’s Name: 
  
Requestor’s Phone#: 
  
 
 
Institution: 
 Dana-Farber/Harvard Cancer Center 
Shipping Address: 
 David J. Kwiatkowski, MD, PhD 
 
 Attn: Beth Meyers 
 
 450 Brookline Avenue, Yawkey 5 
 
  Boston, MA 02215 
Shipping Phone#: 
617-632-4254 
 
 
Is this Initial Shipment: 
 
Yes           No 
 
 
 
Date by when this shipment is required^: 
 
 
 
 
18. Drug 
Label Strength 
Quantity in boxes*  


Everolimus in TSC1 and TSC2 mutated tumors 
13-March-2017  
 
57
RAD001 
10 mg 
 
RAD001 
5mg 
 
RAD001 
2.5 mg 
 
^Please allow 10-14 days for processing of this request and delivery of the shipment. 
* Tablets are supplied in blister cards in kits/boxes of 28 tabs 
 
If you encounter problems, please email: maritza.crawford@novartis.com 
 
 
 
RAD001 
DRUG REQUEST FORM 
Investigational Supply 
 
Please e-mail request to:  maritza.crawford@novartis.com 
 
Date: 
  
Study Title: 
  A Phase II trial of everolimus for cancer patients with  
 
  inactivating mutations in TSC1 or TSC2 
 
 
  
Investigator’s Name: 
 David J. Kwiatkowski, MD, PhD 
Novartis Protocol Number: 
CRAD001 MUS217T 
 
 
Requestor’s Name: 
  
Requestor’s Phone#: 
  
 
 
Institution: 
MSKCC - Pharmacy 
Shipping Address: 
Gopakumar Viyer 
ATTN:  Gerald O’Neill 


Everolimus in TSC1 and TSC2 mutated tumors 
13-March-2017  
 
58
 
1275 York Ave, C-1087 
 
New York, NY 10065 
 
 
Shipping Phone#: 
 
 
 
Is this Initial Shipment: 
 
Yes           No 
 
 
 
Date by when this shipment is required^: 
 
 
 
 
19. Drug 
Label Strength 
Quantity in boxes*  
RAD001 
10 mg 
 
RAD001 
5mg 
 
RAD001 
2.5 mg 
 
^Please allow 10-14 days for processing of this request and delivery of the shipment. 
* tablets are supplied in blister cards in kits/boxes of 28 tabs 
 
If you encounter problems, please contact maritza.crawford@novartis.com 
 
Appendix C: Data and Safety Monitoring Plan 
 
 
DFCI IRB Protocol #: 14-229 
 
 
 
 
 
APPENDIX C 
 
Dana-Farber/Harvard Cancer Center 


Everolimus in TSC1 and TSC2 mutated tumors 
13-March-2017  
 
59
Multi-Center Data and Safety Monitoring Plan 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Everolimus in TSC1 and TSC2 mutated tumors 
13-March-2017  
 
60
TABLE OF CONTENTS 
1. INTRODUCTION  
1.1 
Purpose  
1.2 
Multi-Center Data and Safety Monitoring Plan Definitions  
2. GENERAL ROLES AND RESPONSIBILITIES  
2.1 
DF/HCC Sponsor  
2.2 
Coordinating Center   
2.3 
Participating Institution   
3. DF/HCC REQUIREMENTS FOR MULTI-CENTER PROTOCOLS  
3.1 
Protocol Distribution  
3.2 
Protocol Revisions and Closures 
 
3.3 
Informed Consent Requirements  
3.4 
IRB Documentation  
3.5 
IRB Re-Approval  
3.6 
Participant Confidentiality and Authorization Statement  
3.7 
DF/HCC Multi-Center Protocol Registration Policy  
3.8 
DF/HCC Protocol Case Number 
 
3.9 
Safety Assessments and Toxicity Monitoring  
3.10 
Data Management 
 
4. REQUISITIONING INVESTIGATIONAL DRUG 
 
5. MONITORING: QUALITY CONTROL 
 
5.1 
Ongoing Monitoring of Protocol Compliance  
5.2 
Monitoring Reports  
5.3 
Accrual Monitoring  
6. AUDITING: QUALITY ASSURANCE  
6.1 
Audit Plan: NCI Sponsored Trials  
6.2 
Audit Plan: DF/HCC Sponsored Trials  
6.3 
Audit Notification  
6.4 
Audit Reports  
6.5 
Participating Institution Performance  
 


Everolimus in TSC1 and TSC2 mutated tumors 
13-March-2017  
 
61
 
1. INTRODUCTION 
 
The Dana-Farber/Harvard Cancer Center Multi-Center Data and Safety Monitoring Plan 
(DF/HCC DSMP) outlines the procedures for conducting a DF/HCC Multi-Center research 
protocol. The DF/HCC DSMP should serve as a reference for any sites external to DF/HCC 
that will be participating in the research protocol. 
 
1.1 
Purpose 
 
To establish standards that will ensure that a Dana-Farber/Harvard Cancer Center Multi-
Center protocol will comply with Federal Regulations, Health Insurance Portability and 
Accountability Act (HIPAA) requirements and applicable DF/HCC Standard Operating 
Procedures.    
 
1.2 
Multi-Center Data and Safety Monitoring Plan Definitions 
 
DF/HCC Multi-Center Protocol:  A research protocol in which one or more outside 
institutions are collaborating with Dana-Farber/Harvard Cancer Center where a DF/HCC 
investigator is the sponsor. DF/HCC includes Dana-Farber/Partners Cancer Care (DF/PCC) 
Network Clinical Trial Affiliates.  
 
Lead Institution:  One of the Dana-Farber/Harvard Cancer Center consortium members 
(Dana-Farber Cancer Institute (DFCI), Massachusetts General Hospital (MGH), Beth 
Israel Deaconess Medical Center (BIDMC), Boston Children’s Hospital (BCH), Brigham 
and Women’s Hospital (BWH)) responsible for the coordination, development, 
submission, and approval of a protocol as well as its subsequent amendments per the 
DFCI IRB and applicable regulatory guidelines (Food and Drug Administration (FDA), 
etc.).  The Lead Institution is typically the home of the DF/HCC Sponsor. The Lead 
Institution also typically serves as the Coordinating Center for the DF/HCC Multi-Center 
Protocol.   
 
DF/HCC Sponsor:  The person sponsoring the submitted Multi-Center protocol.  Within 
DF/HCC, this person is the Overall Principal Investigator who takes responsibility for 
initiation, management and conduct of the protocol at all research locations. In applicable 
protocols, the DF/HCC Sponsor will serve as the single liaison with any regulatory 
agencies. The DF/HCC Sponsor has ultimate authority over the protocol and is responsible 
for the conduct of the study at DF/HCC and all Participating Institutions. In most cases the 
DF/HCC Sponsor is the same person as the DF/HCC Overall Principal Investigator; 
however, both roles can be filled by two different people.  
 
Participating Institution:  An institution that is outside the DF/HCC and DF/PCC 
consortium that is collaborating with DF/HCC on a protocol where the sponsor is a 
DF/HCC Investigator.  The Participating Institution acknowledges the DF/HCC Sponsor 
as having the ultimate authority and responsibility for the overall conduct of the study.    
Coordinating Center: The entity (i.e. Lead Institution, Medical Monitor, Contract 
Research Organization (CRO), etc) that provides administrative support to the DF/HCC 


Everolimus in TSC1 and TSC2 mutated tumors 
13-March-2017  
 
62
Sponsor in order that he/she may fulfill the responsibilities outlined in the protocol document and DSMP, 
and as specified in applicable regulatory guidelines (i.e. Multi-Center Guidelines). In general, the Lead 
Institution is the Coordinating Center for the DF/HCC Multi-Center Protocol. Should the DF/HCC Sponsor 
decide to use a CRO, the CRO will be deemed the Coordinating Center.   
 
DF/HCC Quality Assurance Office for Clinical Trials: A group within DF/HCC responsible 
for registering human subjects for trials, ensuring high-quality standards are used for data collection and the 
ongoing management of clinical trials, auditing, and data and safety monitoring. ODQ also coordinates 
quality assurance efforts related to multi-center clinical research. 
 
2. GENERAL ROLES AND RESPONSIBILITIES 
 
For DF/HCC Multi-Center Protocols, the DF/HCC Sponsor, the Coordinating Center, and 
the Participating Institutions are expected to adhere to the following general 
responsibilities:  
 
2.1 
DF/HCC Sponsor 
 
The DF/HCC Sponsor, David Kwiatkowski, MD, Ph.D. will accept responsibility for all 
aspects of conducting a DF/HCC Multi-Center protocol which includes but is not limited 
to:  
• Oversee the coordination, development, submission, and approval of the protocol as 
well as subsequent amendments.  
• Ensure that the investigators, study team members, and Participating Institutions are 
qualified and appropriately resourced to conduct the protocol.   
• Include the Multi-Center Data and Safety Monitoring Plan as an appendix to the 
protocol. 
• Ensure all Participating Institutions are using the correct version of the protocol. 
• Ensure that each participating investigator and study team member receives adequate 
protocol training and/or a Site Initiation Visit prior to enrolling participants and 
throughout trial’s conduct as needed. 
• Ensure the protocol will be provided to each participating site in a language 
understandable to all applicable site personnel when English is not the primary 
language.  
• Monitor progress and overall conduct of the study at all Participating Institutions.  
• Ensure all DFCI Institutional Review Board (IRB), DF/HCC and other applicable 
reporting requirements are met.  
• Review data and maintain timely submission of data for study analysis.  
• Ensure compliance with all requirements as set forth in the Code of Federal 
Regulations, applicable DF/HCC requirements, HIPAA requirements, and the 
approved protocol. 
• Commit to the provision that the protocol will not be rewritten or modified by 
anyone other than the DF/HCC Sponsor. 
• Identify and qualify Participating Institutions and obtain accrual commitments prior 
to extending the protocol to that site. 
• Monitor accrual and address Participating Institutions that are not meeting their 
accrual requirements.  


Everolimus in TSC1 and TSC2 mutated tumors 
13-March-2017  
 
63
 
2.2 
Coordinating Center  
 
The general responsibilities of the Coordinating Center may include but are not limited to: 
• Assist in protocol development. 
• Review registration materials for eligibility and register participants from 
Participating Institutions with DF/HCCODQ. 
• Distribute protocol and informed consent document updates to Participating 
Institutions as needed. 
• Oversee the data collection process from Participating Institutions. 
• Maintain documentation of Serious Adverse Event (SAE) reports and 
deviations/violation submitted by Participating Institutions and provide to the 
DF/HCC Sponsor for timely review.   
• Distribute serious adverse events reported to the DF/HCC Sponsor that fall under 
the DFCI IRB Adverse Event Reporting Policy to all Participating Institutions. 
• Provide 
Participating 
Institutions 
with 
information 
regarding 
DF/HCC 
requirements that they will be expected to comply with. 
 
• Carry out plan to monitor Participating Institutions either by on-site or remote 
monitoring.  
• Maintain Regulatory documents of all Participating Institutions which includes but 
is not limited to the following: local IRB approvals/notifications from all 
Participating Institutions, confirmation of Federal Wide Assurances (FWAs) for all 
sites, all SAE submissions, Screening Logs for all sites, IRB approved consents for 
all sites 
• Conduct regular communications with all Participating Institutions (conference 
calls, emails, etc) and maintain documentation all relevant communications. 
 
2.2.1 Coordinating Center Contact Information  
 
The DF/HCC Coordinating Center will consist of designees from the Early Drug 
Development Center (Phase I).  Responsibilities are specified below, although may 
be updated based on the DF/HCC Sponsor discretion. 
 
Central email address to be used for general site questions and regulatory 
functions: dfcieddc_regulatory@dfci.harvard.edu 
 
Teleconferences, INDSR and SAE review and circulation, overall coordination of 
accrual, etc.:  
Ketki Bhushan (Study Coordinator) 
 
Phone: (617) 632-4270 
 
Email:  kbhushan@partners.org 
 
2.3 
Participating Institution 
 
Each Participating Institution is expected to comply with all applicable federal regulations 
and DF/HCC requirements, the protocol and HIPAA requirements.  


Everolimus in TSC1 and TSC2 mutated tumors 
13-March-2017  
 
64
 
The general responsibilities for each Participating Institution may include but are not 
limited to: 
• Document the delegation of research specific activities to study personnel. 
• Commit to the accrual of participants to the protocol. 
• Submit protocol and/or amendments to their local IRB. 
• Maintain regulatory files as per sponsor requirements. 
• Provide the Coordinating Center with regulatory documents or source documents 
as requested. 
• Participate in protocol training prior to enrolling participants and throughout the 
trial as required (i.e. teleconferences). 
• Update Coordinating Center with research staff changes on a timely basis. 
• Register participants through the Coordinating Center prior to beginning research 
related activities.  
• Submit Serious Adverse Event (SAE) reports to local IRB per local requirements 
and to the Coordinating Center, in accordance with DF/HCC requirements. Submit 
protocol deviations and violations to local IRB per local requirements and to the 
DF/HCC Sponsor in accordance with DF/HCC requirements. 
• Order, store and dispense investigational agents and/or other protocol mandated 
drugs per federal guidelines and protocol requirements. 
• Have office space, office equipment, and internet access that meet HIPAA 
standards. 
• Participate in any quality assurance activities and meet with monitors or auditors at 
the conclusion of a visit to review findings. 
• Promptly provide follow-up and/or corrective action plans for any monitoring 
queries or audit findings. 
 
3. DF/HCC REQUIREMENTS FOR MULTI-CENTER PROTOCOLS 
 
The following section will clarify DF/HCC Requirements and further detail the 
expectations for participating in a DF/HCC Multi-Center protocol.  
 
3.1 Protocol Distribution 
 
The Coordinating Center will distribute the final DFCI IRB approved protocol and any 
subsequent amended protocols to all Participating Institutions.    
 
3.2 Protocol Revisions and Closures 
 
The Participating Institutions will receive notification of protocol revisions and closures 
from the Coordinating Center.  It is the individual Participating Institution’s 
responsibility to notify its IRB of these revisions. 
 
• Non life-threatening revisions: Participating Institutions will receive written 
notification of protocol revisions regarding non life-threatening events from the 


Everolimus in TSC1 and TSC2 mutated tumors 
13-March-2017  
 
65
Coordinating Center. Non-life-threatening protocol revisions must be IRB 
approved and implemented within 90 days from receipt of the notification. 
 
• Revisions for life-threatening causes: Participating Institutions will receive 
immediate notification from the Coordinating Center concerning protocol revisions 
required to protect lives with follow-up by fax, mail, e-mail, etc.  Life-threatening 
protocol revisions will be implemented immediately followed by IRB request for 
approval. 
 
• Protocol closures and temporary holds: Participating Institutions will receive 
notification of protocol closures and temporary holds from the Coordinating 
Center. Closures and holds will be effective immediately.  In addition, the 
Coordinating Center, will update the Participating Institutions on an ongoing basis 
about protocol accrual data so that they will be aware of imminent protocol 
closures. 
 
3.3 Informed Consent Requirements 
 
The DF/HCC approved informed consent document will serve as a template for the 
informed consent for Participating Institutions. The Participating Institution consent form 
must follow the consent template as closely as possible and should adhere to 
specifications outlined in the DF/HCC Guidance Document on Model Consent Language 
for PI-Initiated Multi-Center Protocols.  This document will be provided separately to 
each Participating Institution. 
 
Participating Institutions are to send their version of the informed consent document and 
HIPAA authorization, if a separate document, to the Coordinating Center for review and 
approval prior to submission to their local IRB. The approved consent form must also be 
submitted to the Coordinating Center after approval by the local IRB for all consent 
versions. 
 
The Principal Investigator (PI) at each Participating Institution will identify the physician 
members of the study team who will be obtaining consent and signing the consent form 
for therapeutic protocols. Participating institutions must follow the DF/HCC requirement 
that only attending physicians obtain informed consent and re-consent to interventional 
trials (i.e. drug and/or device trials).   
 
3.4 IRB Documentation 
 
The following must be on file with the Coordinating Center: 
• Initial approval letter of the Participating Institution's IRB.  
• Copy of the Informed Consent Form(s) approved by the Participating Institution’s 
IRB.  
• Participating Institution’s IRB approval for all amendments. 
• Annual approval letters by the Participating Institution's IRB. 
 


Everolimus in TSC1 and TSC2 mutated tumors 
13-March-2017  
 
66
 
3.5 
IRB Re-Approval 
 
Verification of IRB re-approval from the Participating Institutions is required in order to 
continue research activities.  There is no grace period for continuing approvals. 
 
The Coordinating Center will not register participants if a re-approval letter is not received 
from the Participating Institution on or before the anniversary of the previous approval 
date.   
 
 
3.6 
Participant Confidentiality and Authorization Statement 
 
In 1996, congress passed the first federal law covering the privacy of health information 
known as the Health Insurance Portability and Accountability Act (HIPPA). Any 
information, related to the physical or mental health of an individual is called Protected 
Health Information (PHI). HIPAA outlines how and under what circumstances PHI can be 
used or disclosed.  
 
In order for covered entities to use or disclose protected health information during the 
course of a study, the study participant must sign an authorization statement.  This 
authorization statement may or may not be separate from the informed consent document.  
The Coordinating Center, with the approval from the DFCI IRB, will provide a consent 
template, with information regarding authorization for the disclosure of protected health 
information.  
 
The DF/HCC Sponsor will use all efforts to limit its use of protected health information in 
its trials. However, because of the nature of these trials, certain protected health 
information must be collected. DF/HCC has chosen to use authorizations, signed by the 
participant in the trial, rather than limited data sets with data use agreements. 
 
3.6.1  DF/HCC Multi-Center Protocol Confidentiality 
 
All documents, investigative reports, or information relating to the participant are strictly 
confidential. Whenever reasonably feasible, any participant specific reports (i.e. Pathology 
Reports, MRI Reports, Operative Reports, etc.) submitted to the Coordinating Center 
should be de-identified. It is recommended that the assigned DF/HCC ODQ case number 
(as described below) be used for all participant specific documents. Participant initials 
may be included or retained for cross verification of identification.  
 
 
3.7 
DF/HCC Multi-Center Protocol Registration Policy 
 
3.7.1  Participant Registration and Randomization  


Everolimus in TSC1 and TSC2 mutated tumors 
13-March-2017  
 
67
Eligible participants will be registered onto the trial with the DF/HCC Office of Data 
Quality (ODQ) central registration system.  Registration must occur prior to the 
initiation of therapy.  Registration should occur during ODQ’s normal business hours, 
Monday through Friday from 8:00AM to 5:00PM Eastern Time.  Same day treatment 
registrations and off-hour registrations for a participant at a non-DF/HCC site will only 
be accepted with prior notice and discussion with the Coordinating Center. 
 
3.7.2 Participant Registration at a non-DF/HCC Site 
 
Eligible participants will be entered on study centrally at the Coordinating Center by the 
Study Coordinator.  All sites should call the Study Coordinator to verify dose level 
availabilities.  The required forms mentioned below will be provided to sites by the 
Coordinating Center during site activation.  Issues that would cause treatment delays 
should be discussed with the Overall Principal Investigator (PI).  If a participant does not 
receive protocol therapy following registration, the participant’s registration on the study 
must be cancelled.  The Study Coordinator should be notified of cancellations as soon as 
possible.   
 
To register a participant at any non-DF/HCC site, the subsequent procedures must be 
followed.  Contact information for the Coordinating Center is located in section 2.2.1: 
 
1.  The Participating Site should contact the Coordinating Center to: 
a. Notify regarding a potential participant 
b. Confirm the methods of sending documents and communication for the 
registration 
c. Communicate desired timeline for the registration and start date 
 
2.  The Participating Site should send the following documents to the Coordinating 
Center: 
a. Completed DF/HCC Eligibility Source Worksheet (ESW), which will be 
provided to site 
b. Copy of all protocol required screening test results, as requested on the ESW 
c. Copy of the pathology and surgical reports, as requested on the ESW 
d. List of all concomitant medications with review by a clinician 
e. Copy of the signed informed consent document 
f. Copy of the signed HIPAA authorization form (if separate from the informed 
consent document) 
 
3.  After having received all documentation, the Coordinating Center will review the 
documents to verify eligibility.  
  
4.  The Coordinating Center will register the participant with ODQ and subsequently 
inform the participating site of the successful registration via fax or email which 
will include: 
a. Participant Identification Number 
b. Applicable dose treatment level 


Everolimus in TSC1 and TSC2 mutated tumors 
13-March-2017  
 
68
5. Treatment may not begin without confirmation from the Coordinating Center 
that the participant has been registered.    
6. After the participant is registered, additional documentation is to be sent to the 
Coordinating Center if it was not provided in the initial submission.  The specifics 
and timeline of this will be specified by the Coordinating Center within the 
instructions of the Eligibility Source Worksheet.   
NOTE:  Registration and randomization with ODQ can only be conducted during 
the business hours of 8:00AM and 5:00PM Eastern Standard Time Monday 
through Friday.  Same day treatment registrations will only be accepted with 
prior notice and discussion with the DF/HCC Lead Institution.   
 
3.7.3 Participant Registration at a DF/HCC Site 
 
Please refer to section 4.2 of the protocol 
 
 
3.7.4  Initiation of Therapy 
 
Participants must be registered with the DF/HCC ODQ before receiving treatment.  
Treatment may not be initiated until the Participating Institution receives confirmation of 
the participant’s registration from the Coordinating Center. The DF/HCC Sponsor and 
DFCI IRB must be notified of any violations to this policy. 
 
3.7.5  Eligibility Exceptions 
 
The DF/HCC ODQ will make no exceptions to the eligibility requirements for a protocol 
without DFCI IRB approval. The DF/HCC ODQ requires each institution to fully comply 
with this requirement. 
 
 
 
3.8 DF/HCC Protocol Case Number 
 
At the time of registration, ODQ requires the following identifiers for all subjects: 
initials, date of birth, gender, race and ethnicity. Once eligibility has been established and 
the participant successfully registered, the participant is assigned a unique protocol case 
number.  Participating Institutions should submit all de-identified subsequent 
communication and documents to the Coordinating Center, using this case number to 
identify the subject.   
 


Everolimus in TSC1 and TSC2 mutated tumors 
13-March-2017  
 
69
3.9 Protocol Deviations, Exceptions and Violations 
 
Federal Regulations require an IRB to review proposed changes in a research activity to 
ensure that researchers do not initiate changes in approved research without IRB review 
and approval, except when necessary to eliminate apparent immediate hazards to the 
participant. DF/HCC requires all departures from the defined procedures set forth in the 
IRB approved protocol to be reported to the DF/HCC Sponsor, who in turn is responsible 
for reporting to the DFCI IRB. 
  
For reporting purposes, DF/HCC uses the terms “violation”, “deviation” and “exception” 
to describe departures from a protocol. All Participating Institutions must adhere to these 
requirements for reporting to the DF/HCC Sponsor and will follow their institutional 
policy for reporting to their local IRB. 
 
3.9.1  Definitions 
 
Protocol Deviation: Any departure from the defined procedures set forth in the IRB-
approved protocol which is prospectively approved prior to its implementation. 
 
Protocol Exception:  Any protocol deviation that relates to the eligibility criteria, e.g. 
enrollment of a participant who does not meet all inclusion/exclusion criteria. 
  
 
Protocol Violation: Any protocol deviation that was not prospectively approved by the 
IRB prior to its initiation or implementation.   
 
3.9.2  Reporting Procedures 
 
DF/HCC Sponsor: is responsible for ensuring that clear documentation is available in the 
medical record and/or regulatory documents to describe all protocol exceptions, 
deviations and violations. The DF/HCC Sponsor will also be responsible for ensuring that 
all protocol violations/deviations are promptly reported per DFCI IRB guidelines.  
 
Participating Institutions: Protocol deviations require prospective approval from the 
DFCI IRB. The Participating Institution must submit the deviation request to the 
Coordinating Center who will then submit the deviation request to the DFCI IRB. Upon 
DFCI IRB approval the deviation is submitted to the Participating Institution IRB, per 
institutional policy. A copy of the Participating Institution’s IRB report and determination 
will be forwarded to the Coordinating Center within 10 business days after the original 
submission.  
 
All protocol violations must be sent to the Coordinating Center in a timely manner.  
 
Coordinating Center:  Upon receipt of the violation/deviation report from the 
Participating Institution, the Coordinating Center will submit the report to the DF/HCC 


Everolimus in TSC1 and TSC2 mutated tumors 
13-March-2017  
 
70
Sponsor for review. Subsequently, the Participating Institution’s IRB violation/deviation 
report will be submitted to the DFCI IRB for review per DFCI IRB reporting guidelines.  
 
3.10 Safety Assessments and Toxicity Monitoring 
 
The study teams at all participating institutions are responsible for protecting the safety, 
rights and well-being of study participants. Recording and reporting of adverse events 
that occur during the course of a study help ensure the continuing safety of study 
participants.  
 
All participants receiving investigational agents and/or other protocol mandated treatment 
will be evaluated for safety. The safety parameters include all laboratory tests and 
hematological abnormalities, physical examination findings, and spontaneous reports of 
adverse events reported by participants.  All toxicities encountered during the study will 
be evaluated according to the NCI criteria specified in the protocol. Life-threatening 
toxicities must be reported immediately to the DF/HCC Sponsor via the Coordinating 
Center.  
 
Additional safety assessments and toxicity monitoring will be outlined in the protocol. 
 
3.10.1 Guidelines for Reporting Serious Adverse Events  
 
Guidelines for reporting Adverse Events (AEs) and Serious Adverse Events (SAEs) are 
detailed in protocol section 11.  
 
 
 
 
 
Participating Institutions must report the SAEs to the DF/HCC Sponsor and the 
Coordinating Center following the DFCI IRB Adverse Event Reporting Policy.  
 
The Coordinating Center will maintain documentation of all Participating Institution 
Adverse Event reports and be responsible for communicating to all participating 
investigators, any observations reportable under the DFCI IRB Reporting Requirements.  
Participating Institutions will review and submit to their IRB according to their 
institutional policies and procedures 
 
3.10.2 Guidelines for Processing IND Safety Reports  
 
The DF/HCC Sponsor will review all IND Safety Reports and ensure that all IND Safety 
Reports are distributed to the Participating Institutions. Participating Institutions will 
review and submit to their IRB according to their institutional policies and procedures. 
  
  
3.11 Data Management 
 


Everolimus in TSC1 and TSC2 mutated tumors 
13-March-2017  
 
71
The DF/HCC ODQ develops case report forms (CRF/eCRFs), for use with the protocol.  
These forms are designed to collect data for each study. The DF/HCC ODQ provides a 
web based training for eCRF users. 
   
3.11.1 Data Forms Review 
 
Data submissions are monitored for timeliness and completeness of submission. 
Participating Institutions are notified of their data submission delinquencies in 
accordance with the following: 
 
Incomplete or Questionable Data 
If study forms are received with missing or questionable data, the submitting institution 
will receive a written or electronic query from the DF/HCC ODQ Data Analyst, 
Coordinating Center or designee.  Responses to all queries should be completed and 
submitted within 14 calendar days.  Responses may be returned on the written query or 
on an amended paper case report form, or in the case of electronic queries, within the 
electronic data capture (eDC) system. In the case of a written query for data submitted on 
a paper case report form, the query must be attached to the specific data being re-
submitted in response.   
 
Missing Forms 
If study forms are not submitted on schedule, the Participating Institution will receive a 
Missing Form Report from the Coordinating Center noting the missing forms.  These 
reports are compiled by the DF/HCC ODQ and distributed on a monthly basis.  
 
 
4. REQUISITIONING INVESTIGATIONAL DRUG 
  
The ordering of investigational agent is specified in the protocol section 7.   
Participating Institutions should order their own agent regardless of the supplier. (i.e., a 
pharmaceutical company).   
 
For investigational agents (Everolimus), participating institutions should ensure that the 
pharmacy will be able to receive and store the agent according to state and federal 
requirements. The local IRB should be kept informed of who will supply the agent (i.e., a 
pharmaceutical company) so that any regulatory responsibilities can be met in a timely 
fashion.  
 
5. MONITORING: QUALITY CONTROL 
 
The quality control process for a clinical trial requires verification of protocol compliance 
and data accuracy. The Coordinating Center, with the aid of the ODQ provides quality 
control oversight for the protocol. 
 
5.1 Ongoing Monitoring of Protocol Compliance 
 


Everolimus in TSC1 and TSC2 mutated tumors 
13-March-2017  
 
72
The Participating Institutions may be required to submit participant source documents to 
the Coordinating Center for monitoring. Participating Institution may also be subject to 
on-site monitoring conducted by the Coordinating Center.  
 
The Coordinating Center will implement ongoing monitoring activities to ensure that 
Participating Institutions are complying with regulatory and protocol requirements, data 
quality, and participant safety. Monitoring will occur before the clinical phase of the 
protocol begins, continue during protocol performance and through study completion. 
Additional monitoring practices may include but are not limited to; source verification, 
review and analysis of the following: eligibility requirements of all participants, informed 
consent procedures, adverse events and all associated documentation, study drug 
administration/treatment, regulatory files, protocol departures, pharmacy records, 
response assessments, and data management.  
 
Additionally, sites will be required to participate in Coordinating Center initiated 
teleconferences. 
These will be planned for bi-weekly during Stage 1 of the protocol and monthly during 
Stage 2, although they may be more/less frequent at the discretion of the Protocol Chair. 
During the teleconferences, sites will be expected to convey the following information: 
• Updates on participants taking agent: holds, dose reductions, significant 
events, how the participant is doing, whether or not underwent re-consenting 
• Protocol status – which version is being used, and the status of any 
amendments 
• Any reportable adverse events or deviations/violations that have yet to be 
submitted 
• Review of prospective patients 
 
If sites are not able to have a representative participant present at the teleconferences, 
they should email this information to the Coordinating Center.   
 
Virtual Monitoring will be the primary mode of monitoring, although on-site monitoring 
may occur if felt to be necessary by the Coordinating Center and Protocol Chair. Upon 
request, sites will be required to forward de-identified copies of participants’ medical 
record and source documents to the Coordinating Center to aid in source data 
verification. 
 
Virtual monitoring of participant eligibility, human subject’s protection via the initial 
informed consent document and process, and screening evaluation completion will occur, 
if feasible, within 2 weeks of the first participant registration. 
 
Interim monitoring visits will occur on the following schedule: 
Once a site has registered a participant, up until all participants have discontinued taking 
study agent (may be in follow-up), interim monitoring visits will occur approximately 
every 6 months, with the primary mode being virtual visits. This frequency may be 
adjusted depending on accrual, site compliance and Protocol Chair discretion. The first 


Everolimus in TSC1 and TSC2 mutated tumors 
13-March-2017  
 
73
interim monitoring visit will occur approximately two months after the registration of the 
site’s first participant. 
 
Once a site is closed to accrual and all participants have discontinued study agent, interim 
monitoring visits will occur approximately annually until study completion. 
 
Monitoring visits will focus on reviewing some or all of the following: 
• Adverse events and altered results 
• Response assessment including measurements and clinical assessments 
• Study drug administration and accountability 
• Concomitant medications 
• Consent and re-consenting 
• Presence of key documents: original consent, eligibility and screening source 
information, registration confirmation, off treatment and off study forms, 
collection and transfer of samples 
• Reason off treatment and reason off study 
• Timeliness of data completion 
• Completion of study procedures per protocol 
• Agreement between recorded results and source documentation 
• Analysis of data for any events that meet criteria for reportable adverse events, 
dose holds, dose reductions, or discontinuation of treatment  
• Regulatory binder: accessibility, organization, random sampling for relevant 
documents and agreement with the trial master file 
• Collection of research samples per protocol and appropriately entered onto CRFs, 
as this will be the primary mode of tracking samples across sites 
 
The Coordinating Center will be available to all sites’ study team members for resolving 
questions and concerns and facilitating compliance. 
 
All data submitted to the DF/HCC ODQ will be monitored for timeliness of submission, 
completeness, and adherence to protocol requirements. The Coordinating Center and if 
applicable, ODQ Data Analysts assigned to the protocol, will perform the ongoing 
protocol data compliance monitoring. 
 
5.2 Monitoring Reports 
 
The DF/HCC Sponsor will review all monitoring reports for on-site and remote 
monitoring of Participating Institutions to ensure protocol compliance. The DF/HCC 
Sponsor may increase the monitoring activities at Participating Institutions that are 
unable to comply with the protocol, DF/HCC Sponsor requirements or federal and local 
regulations. Participating Institutions may also be subject to an audit as determined by the 
DF/HCC Sponsor. 
 
5.3 Accrual Monitoring 
 


Everolimus in TSC1 and TSC2 mutated tumors 
13-March-2017  
 
74
Prior to extending a protocol to an external site, the DF/HCC Sponsor will establish 
accrual requirements for each participating institution. Accrual will be monitored for each 
participating institution by the DF/HCC Sponsor or designee. The minimum accrual 
requirements for this study are 10 subjects per site per year. Sites that are not meeting 
their accrual expectations may be subject to termination. 
 
 
 
6. AUDITING: QUALITY ASSURANCE 
 
Auditing is a method of Quality Assurance. Its main focus is to measure whether 
standards and procedures were followed. Auditing is the systematic and independent 
examination of all trial related activities and documents.  Audits determine if evaluated 
activities were appropriately conducted and whether data was generated, recorded and 
analyzed, and accurately reported per the protocol, Standard Operating Procedures 
(SOPs), and the Code of Federal Regulations (CFR). 
 
 
6.1 Audit Plan: DF/HCC Sponsored Trials 
 
This study is IND exempt and a combination of virtual and on-site monitoring will be 
performed by an experienced DF/HCC monitor (Clinical Research Specialist). According 
to the DF/HCC MCC audit plan guidelines a formal Audit plan is not required for this 
trial. An audit may be performed by the ODQ at the request of the DF/HCC Sponsor if 
instances on non-compliance are found during routine monitoring. 
 
 
6.2 Participating Institution Performance 
 
The DF/HCC Sponsor and DFCI IRB are charged with considering the totality of an 
institution’s performance in considering institutional participation in the protocol. 
 
Corrective Actions 
 
Participating Institutions that fail to meet the performance goals of accrual, submission of 
timely and accurate data, adherence to protocol requirements, and compliance with state 
and federal regulations, may be recommended for a six-month probation period. Such 
institutions must respond with a corrective action plan and must demonstrate during the 
probation period that deficiencies have been corrected, as evidenced by the improved 
performance measures. Participating Institutions that fail to demonstrate significant 
improvement will be considered by the DF/HCC Sponsor for revocation of participation. 
A DF/HCC Sponsor and/or the DFCI IRB may terminate a site’s participation if it is 
determined that a site is not fulfilling its responsibilities as described above.