An Extension Trial of Deforolimus (AP23573; MK-8669), an mTOR Inhibitor, for Patients With Advanced Cancer
Phase: PHASE2
Conditions: Advanced Cancers
Sponsor: Merck Sharp & Dohme LLC

Official Protocol Title: 
NCT number: 
NCT00836927 
Document Date: 
01-October-2008
An Extension Trial of Deforolimus (AP23573; MK-8669), an mTOR 
Inhibitor, for Patients with Advanced Cancer

ARIAD Pharmaceuticals, Inc. 
Deforolimus (AP23573; MK-8669) 
AP23573-08-901 
 
01 October 2008 
Confidential and Proprietary 
Page 1 of 64 
An Extension Trial of Deforolimus (AP23573; MK-8669), an mTOR Inhibitor, for Patients 
with Advanced Cancer 
 
ARIAD protocol number:  
AP23573-08-901 
IND Reference Numbers:  
72,003 (oral) 
65,630 (Intravenous)  
 
Date of Protocol:   
 
 
Original: 1 October 2008 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sponsor: 
ARIAD Pharmaceuticals, Inc. 
 
26 Landsdowne Street 
 
Cambridge, MA 02139-4234 
 
Telephone:
 
 
Medical Monitor: 
 
ARIAD Pharmaceuticals, Inc. 
26 Landsdowne Street 
Cambridge, MA 02139-4234 
USA 
Telephone (During business hours – US Eastern Time):  
 
 
 
Telefax: 
 
Mobile: 
 
E-mail:
 
 
 
DISCLOSURE STATEMENT 
 
This document is the exclusive property of ARIAD Pharmaceuticals, Inc. (“ARIAD”).  This document and the information 
contained herein is confidential and proprietary to ARIAD and is intended solely for the guidance of this clinical investigation.  
This information is provided to you solely for the purpose of evaluation and/or conducting a clinical trial for ARIAD.  You may 
disclose the contents of this document only to study personnel under your supervision or to your Institutional Review Board(s) 
who need to know the contents solely for purposes of this clinical trial.  No part of this document may be used for any other 
purpose, including any other clinical trial.  This document may not be disclosed to any other person or entity or reproduced, 
referenced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, 
recording, or otherwise, without the prior written authorization of ARIAD.  The foregoing shall not apply to disclosure required by 
applicable laws or governmental regulations; however, you will give notice to ARIAD of any such disclosure as soon as 
practicable. 
 
Any information that may be added to this document is confidential and proprietary to ARIAD and subject to the same 
confidentiality obligations and use restrictions descr bed above. 
PPD
PPD
PPD
PPD
PPD
PPD
 
 
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Deforolimus (AP23573; MK-8669) 
AP23573-08-901 
 
01 October 2008 
Confidential and Proprietary 
Page 2 of 64 
1. CONTACTS 
1.1 Serious Adverse Events (SAEs) 
 
Any death or serious adverse event (SAE) experienced by the patient from the time that the 
patient signs the informed consent form to 30 days after receiving study drugs or through the 
date of the post-treatment discontinuation visit (i.e., approximately 30 ± 7 days following 
the last dose of study drug; unless the patient begins alternate anti-cancer treatment in this 
time window), or any death or SAE believed to be study drug-related that occurs at anytime 
thereafter, must be promptly reported (within 24 hours of learning of the event) by telephone 
or telefax to the Sponsor or the Sponsor’s designee.  
1.2 
Contact for Emergencies and Study-related Issues 
 
A list of the Sponsor's study personnel and their contact information will be provided in the 
Investigator’s Notebook.  Additional contacts are: 
 
 
 
 
ARIAD Pharmaceuticals, Inc. 
26 Landsdowne Street 
 
Cambridge, MA 02139-4234 
USA 
 
Telephone (During business hours – US Eastern Time):  
 
 
Telephone (After Hour Emergencies) -Mobile: 
 
E-mail 
 
 
 
 
 
ARIAD Pharmaceuticals, Inc. 
26 Landsdowne Street 
 
Cambridge, MA 02139-4234 
USA 
 
Telephone (During business hours – US Eastern Time):  
 
 
Telephone (After Hour Emergencies) -Mobile: 
 
E-mail 
 
  
 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
 
 
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ARIAD Pharmaceuticals, Inc. 
Deforolimus (AP23573; MK-8669) 
AP23573-08-901 
 
01 October 2008 
Confidential and Proprietary 
Page 3 of 64 
2. APPROVAL 
 
The protocol must be read before signing. 
2.1 Investigator Signature 
 
I have read the protocol and agree that it contains all necessary details for carrying out the 
trial as described.  I will conduct this protocol as outlined therein, including all statements 
regarding confidentiality.  I will make a reasonable effort to complete the trial within the 
time designated.  I will provide copies of the protocol and access to all information 
furnished by the Sponsor to study personnel under my supervision.  I will discuss this 
material with them to ensure they are fully informed about the drug and the trial.  I 
understand that the study may be terminated or enrollment suspended at any time by the 
Sponsor, with or without cause, or by me if it becomes necessary to protect the best interests 
of the study patients. 
 
I agree to conduct this trial in full accordance with all applicable regulations. 
 
 
Investigator’s Signature 
 
 
 
 
 
 
Date (dd-mmm-yyyy)  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Investigator’s Name (print) 
 
 
 
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Deforolimus (AP23573; MK-8669) 
AP23573-08-901 
 
01 October 2008 
Confidential and Proprietary 
Page 4 of 64 
2.2 Sponsor Representative Signature 
 
ARIAD Pharmaceuticals, Inc. has approved of this protocol and assures that this trial will be 
conducted according to all stipulations of the protocol, including all statements regarding 
confidentiality.   
 
 
      
Sponsor Representative's Signature  
 
 
 
    Date (dd-mmm-yyyy)  
 
 
 
 
Sponsor Representative’s Name (print) 
 
   
 
 
 
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ARIAD Pharmaceuticals, Inc. 
Deforolimus (AP23573; MK-8669) 
AP23573-08-901 
 
01 October 2008 
Confidential and Proprietary 
Page 5 of 64 
3. INSTITUTIONAL REVIEW BOARD / ETHICS COMMITTEE 
 
The Institutional Review Board or Ethics Committee and its affiliation and address for each 
site implementing this protocol shall be identified below or on the FDA Form 1572. 
 
 
IRB/EC: 
 
 
 
Affiliation: 
 
 
 
Address: 
 
 
 
 
 
 
 
 
 
 
 
 
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ARIAD Pharmaceuticals, Inc. 
Deforolimus (AP23573; MK-8669) 
AP23573-08-901 
 
01 October 2008 
Confidential and Proprietary 
Page 6 of 64 
4. DISCLOSURE STATEMENT  
 
Restricted Distribution of Documents 
 
This document contains information that is confidential and proprietary to the Sponsor.  This 
information is being provided to you solely for the purpose of evaluation and/or conducting 
a clinical trial for the Sponsor.  For this purpose, you may disclose the contents of this 
document only to study personnel under your supervision, IRBs/ECs, or duly authorized 
representatives of regulatory agencies under the condition that they maintain confidentiality.  
The contents of this document may not be used in any other clinical trial, disclosed to any 
other person or entity, and/or published without the prior written permission of the Sponsor.  
The foregoing shall not apply to disclosure required by any regulation; however, you will 
give prompt notice to the Sponsor of any such disclosure. 
 
Any information that may be added to this document also is confidential and proprietary to 
the Sponsor and must be kept in confidence in the same manner as the contents of this 
document. 
 
The ARIAD protocol number for this trial is AP23573-08-901. 
 
 
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ARIAD Pharmaceuticals, Inc. 
Deforolimus (AP23573; MK-8669) 
AP23573-08-901 
 
01 October 2008 
Confidential and Proprietary 
Page 7 of 64 
TABLE OF CONTENTS 
 
1. 
CONTACTS..........................................................................................................................................2 
1.1 
SERIOUS ADVERSE EVENTS (SAES)..........................................................................................2 
1.2 
CONTACT FOR EMERGENCIES AND STUDY-RELATED ISSUES.....................................................2 
2. 
APPROVAL..........................................................................................................................................3 
2.1 
INVESTIGATOR SIGNATURE.......................................................................................................3 
2.2 
SPONSOR REPRESENTATIVE SIGNATURE ...................................................................................4 
3. 
INSTITUTIONAL REVIEW BOARD / ETHICS COMMITTEE...................................................5 
4. 
DISCLOSURE STATEMENT ............................................................................................................6 
5. 
LIST OF ABBREVIATIONS ............................................................................................................11 
6. 
DEFINITION OF TERMS ................................................................................................................13 
7. 
SYNOPSIS...........................................................................................................................................15 
8. 
STUDY FLOWCHARTS (SCHEDULE OF EVENTS) ..................................................................19 
9. 
INTRODUCTION ..............................................................................................................................20 
9.1 
MAMMALIAN TARGET OF RAPAMYCIN (MTOR) ......................................................................20 
9.2 
DEFOROLIMUS.........................................................................................................................20 
9.2.1 SINGLE-AGENT, INTRAVENOUS DEFOROLIMUS..............................................................20 
9.2.2 SINGLE-AGENT, ORAL DEFOROLIMUS............................................................................21 
9.2.3 COMBINATION TRIALS...................................................................................................21 
9.2.4 PHARMACOKINETIC STUDIES WITH DEFOROLIMUS........................................................22 
9.2.5 PHARMACODYNAMIC STUDIES WITH DEFOROLIMUS .....................................................23 
9.2.6 CURRENT SAFETY INFORMATION ON DEFOROLIMUS .....................................................23 
9.2.7 CURRENT EFFICACY INFORMATION ON DEFOROLIMUS..................................................24 
9.3 
LONG-TERM BENEFIT FROM DEFOROLIMUS TREATMENT........................................................24 
10. 
STUDY OBJECTIVES ......................................................................................................................26 
11. 
TRIAL DESIGN .................................................................................................................................26 
11.1 
DESCRIPTION OF TRIAL DESIGN ..............................................................................................26 
11.2 
SELECTION OF TRIAL ENDPOINTS............................................................................................26 
11.3 
PATIENT POPULATION.............................................................................................................27 
11.4 
DEFOROLIMUS DOSES AND SCHEDULES..................................................................................27 
11.5 
DURATION OF TRIAL ...............................................................................................................27 
12. 
STUDY POPULATION .....................................................................................................................28 
12.1 
INCLUSION CRITERIA ..............................................................................................................28 
12.2 
EXCLUSION CRITERIA .............................................................................................................29 
12.3 
NUMBER OF PATIENTS.............................................................................................................29 
 
 
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AP23573-08-901 
 
01 October 2008 
Confidential and Proprietary 
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12.4 
SCREENING FAILURES .............................................................................................................29 
12.5 
REPLACEMENTS ......................................................................................................................29 
13. 
STUDY PROCEDURES ....................................................................................................................29 
13.1 
PATIENT ENROLLMENT ...........................................................................................................29 
13.2 
STUDY DRUG ADMINISTRATION..............................................................................................29 
13.2.1 MANAGEMENT OF MISSED DOSES OF STUDY DRUG .................................................30 
13.3 
TREATMENT DISCONTINUATION VISIT....................................................................................30 
13.4 
FOLLOW-UP FOR SURVIVAL ....................................................................................................31 
13.5 
REMOVAL OF PATIENTS FROM STUDY DRUG ADMINISTRATION OR ASSESSMENT...................31 
13.6 
CRITERIA FOR DISCONTINUATION...........................................................................................31 
14. 
STUDY DRUG....................................................................................................................................32 
14.1 
STUDY DRUG ADMINISTRATION..............................................................................................32 
14.1.1 SINGLE-AGENT INTRAVENOUS DEFOROLIMUS ..........................................................32 
14.1.2 SINGLE-AGENT ORAL DEFOROLIMUS........................................................................33 
14.1.3 DEFOROLIMUS IN COMBINATION ..............................................................................33 
14.2 
MANAGEMENT OF ADVERSE DRUG REACTIONS - DEFOROLIMUS............................................33 
14.2.1 GENERAL ADVERSE DRUG REACTIONS AND DOSE MODIFICATIONS FOR ORAL 
DEFOROLIMUS.........................................................................................................................33 
14.2.2 MOUTH SORES FOR ORAL DEFOROLIMUS .................................................................36 
14.2.3 MANAGEMENT OF HYPERSENSITIVITY AND OTHER REACTIONS DURING IV 
ADMINISTRATION OF DEFOROLIMUS.......................................................................................37 
14.2.3.1 
Pre-Medications/Therapy for Infusion Site or Hypersensitivity Reactions
 37 
14.2.3.2 
Study Drug Infusion Modifications........................................................38 
14.2.4 GENERAL ADVERSE DRUG REACTIONS AND DOSE MODIFICATIONS FOR IV 
DEFOROLIMUS.........................................................................................................................39 
DOSE DELAYS AND REDUCTIONS............................................................................................39 
14.2.4.1 
Dose Delay and/or Reduction for Grade 1 or 2 Adverse Drug Reactions
 39 
14.2.4.2 
Dose Reduction With /Without Dose Delay for Grade 3 or 4 Adverse 
Drug Reactions.........................................................................................................39 
14.2.5 DOSE RE-ESCALATION..............................................................................................40 
14.2.6 DOSE MODIFICATIONS FOR ORAL OR IV  DEFOROLIMUS IN CASE OF PNEUMONITIS 
AND/OR HYPERTRIGLYCERIDEMIA/HYPERCHOLESTEROLEMIA................................................40 
14.2.6.1 
Pneumonitis............................................................................................40 
14.2.6.2 
Hypertriglyceridemia/Hypercholesterolemia..........................................41 
14.3 
DOSE MODIFICATION FOR UNRELATED ADVERSE EVENTS .....................................................41 
14.4 
OTHER DOSE MODIFICATIONS.................................................................................................41 
14.5 
FORMULATION, PACKAGING, AND LABELING – DEFOROLIMUS...............................................42 
14.6 
STORAGE AND STABILITY – DEFOROLIMUS.............................................................................43 
14.7 
DRUG ACCOUNTABILITY – DEFOROLIMUS ..............................................................................43 
14.7.1 DISPENSING OF STUDY DRUG AND DOSING COMPLIANCE ........................................43 
14.7.2 DISPOSITION OF USED SUPPLIES ...............................................................................43 
14.7.3 INVENTORY OF UNUSED SUPPLIES ............................................................................44 
15. 
CONCOMITANT TREATMENTS ..................................................................................................44 
15.1 
PERMITTED TREATMENT.........................................................................................................44 
 
 
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AP23573-08-901 
 
01 October 2008 
Confidential and Proprietary 
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15.2 
PROHIBITED TREATMENT........................................................................................................44 
15.3 
POTENTIAL DRUG INTERACTIONS ...........................................................................................45 
16. 
MEASURES TO MINIMIZE/AVOID BIAS ...................................................................................45 
17. 
INTERIM SAFETY AND EFFICACY ANALYSIS .......................................................................45 
18. 
SAFETY ..............................................................................................................................................45 
18.1 
SAFETY ASSESSMENT..............................................................................................................45 
18.2 
SAFETY ASSESSMENT METHODS.............................................................................................46 
19. 
STATISTICAL ANALYSIS ..............................................................................................................46 
19.1 
STUDY OVERVIEW ..................................................................................................................46 
19.2 
ENDPOINTS..............................................................................................................................47 
20. 
CONTRAINDICATIONS, PRECAUTIONS, AND WARNINGS .................................................47 
20.1 
PRECAUTIONS REGARDING PROCREATION..............................................................................47 
20.2 
ADDITIONAL PRECAUTIONS ....................................................................................................48 
21. 
ADVERSE EVENTS ..........................................................................................................................48 
21.1 
ADVERSE EVENT DEFINITION..................................................................................................48 
21.2 
EVALUATING ADVERSE EVENTS .............................................................................................49 
21.2.1 DETERMINATION OF SERIOUSNESS............................................................................49 
21.2.2 DETERMINATION OF SEVERITY .................................................................................50 
21.2.3 DEFINITIONS FOR CATEGORIES OF RELATEDNESS.....................................................51 
21.3 
DOCUMENTING ADVERSE EVENTS ..........................................................................................52 
21.4 
REPORTING SAES AND PATIENT DEATHS ...............................................................................52 
21.4.1 TIME-FRAME FOR REPORTING...................................................................................52 
21.4.2 INFORMATION TO BE PROVIDED BY THE INVESTIGATOR............................................52 
21.4.3 FOLLOW-UP INFORMATION ON AN SAE ....................................................................53 
21.5 
REVIEW OF AN SAE BY THE SPONSOR AND DETERMINATION OF FURTHER ACTION ...............53 
21.5.1 
 SUSPECTED UNEXPECTED SERIOUS ADVERSE DRUG REACTIONS (SUSAR)............53 
21.6 
REQUIRED FOLLOW-UP FOR SAES ..........................................................................................54 
22. 
DATA QUALITY ASSURANCE......................................................................................................54 
23. 
INVESTIGATOR’S REGULATORY OBLIGATIONS.................................................................54 
23.1 
INSTITUTIONAL REVIEW BOARD (IRB) / ETHICS COMMITTEE (EC) APPROVAL ......................54 
23.2 
PRESTUDY DOCUMENTATION..................................................................................................55 
23.3 
INFORMED CONSENT...............................................................................................................55 
23.4 
DECLARATION OF HELSINKI....................................................................................................56 
23.5 
CASE REPORT FORMS..............................................................................................................56 
23.6 
ADVERSE EVENT REPORTING..................................................................................................56 
23.7 
REVIEW OF SOURCE RECORDS ................................................................................................56 
23.8 
MONITORING OF THE STUDY...................................................................................................57 
23.9 
PROTOCOL AMENDMENTS.......................................................................................................57 
23.10 
CHANGE IN INVESTIGATOR......................................................................................................58 
23.11 
TERMINATION OF STUDY.........................................................................................................58 
23.11.1 TERMINATION BY THE SPONSOR ...............................................................................58 
 
 
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Deforolimus (AP23573; MK-8669) 
AP23573-08-901 
 
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23.11.2 TERMINATION OF INVESTIGATOR..............................................................................58 
23.12 
FINAL STUDY REPORT.............................................................................................................58 
23.13 
CONFIDENTIALITY...................................................................................................................59 
23.14 
RECORDS RETENTION .............................................................................................................59 
24. 
REFERENCES ...................................................................................................................................60 
25. 
ATTACHMENTS...............................................................................................................................62 
ATTACHMENT A: ECOG PERFORMANCE STATUS EVALUATION ...........................................................63 
ATTACHMENT B:  INHIBITORS AND INDUCERS OF CYP3A ....................................................................64 
 
LIST OF TABLES 
TABLE 9-1  PATIENTS CURRENTLY RECEIVING LONG-TERM DEFOROLIMUS ON PARENT 
CLINICAL TRIALS ………………………………………………………………………………………….24 
TABLE 14.2-1: MANAGEMENT OF ORAL DEFOROLIMUS DOSE MODIFICATIONS FOR ALL 
ADVERSE DRUG REACTIONS, EXCEPT MOUTH SORES AND PNEUMONITIS.............................35 
TABLE 14.2-2: DOSE MODIFICATIONS OF ORAL DEFOROLIMUS FOR MOUTH SORESA.........37 
 
 
 
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Deforolimus (AP23573; MK-8669) 
AP23573-08-901 
 
01 October 2008 
Confidential and Proprietary 
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5. LIST OF ABBREVIATIONS 
 
Abbreviation  
 
 
Term 
4E-BP1.............................eukaryotic mutation factor 4E binding protein 1 
ADR.................................adverse drug reaction  
AE....................................adverse event 
ALT..................................alanine aminotransferase 
ARIAD.............................ARIAD Pharmaceuticals, Inc. 
AST..................................aspartate aminotransferase 
AUC.................................area under the concentration curve 
ß-HCG..............................beta human chorionic gonadotropin 
BUN.................................blood urea nitrogen 
Cmax..................................maximum concentration 
CBC .................................complete blood count 
CI .....................................confidence interval 
CL/F.................................apparent total blood clearance 
CR....................................complete response 
CRF..................................case report form 
CTC..................................circulating tumor cells 
CTCAE ............................Common Terminology Criteria for Adverse Events (version 3) 
CYP3A.............................cytochrome P450, family 3, subfamily A 
DLT..................................dose-limiting toxicity 
EC ....................................Ethics Committee 
ECOG ..............................Eastern Cooperative Oncology Group 
EMEA..............................European Agency for the Evaluation of Medicinal Products 
FDA .................................Food and Drug Administration (United States) 
FKBP ...............................FK506-binding protein (12 kDa) 
GCP..................................Good Clinical Practice 
HC....................................Health Canada 
IGF-1R.............................insulin-like growth factor receptor-1 
IMP ..................................investigational medicinal product  
IRB...................................Institutional Review Board  
IV.....................................intravenous 
K ......................................potassium 
kg .....................................kilogram 
MedDRA..........................Medical Dictionary for Regulatory Activities 
min ...................................minute(s) 
mL....................................milliliter 
mg ....................................milligram 
mRNA..............................messenger ribonucleic acid  
 
 
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Deforolimus (AP23573; MK-8669) 
AP23573-08-901 
 
01 October 2008 
Confidential and Proprietary 
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MTD ................................maximum tolerated dose 
mTOR ..............................mammalian target of rapamycin 
Na.....................................sodium 
NCI ..................................National Cancer Institute (of the United States) 
OTC .................................over the counter 
OS ....................................overall survival 
PBMCs.............................peripheral blood mononuclear cells 
PD ....................................progressive disease (in context of tumor response assessment) 
PFS...................................progression-free survival 
PI3K……………………..phosphoinositide 3 kinase 
PR ....................................partial response 
PTEN ...............................phosphatase and tensin homologue deleted on chromosome 10 
QD....................................every day 
QDx4................................once daily for 4 consecutive days 
QDx5................................once daily for 5 consecutive days 
QDx5/week......................once daily for 5 consecutive days every week 
QDx21..............................once daily for 21 consecutive days 
QDx28..............................once daily for 28 consecutive days 
QW...................................once weekly 
RECIST............................Response Evaluation Criteria in Solid Tumors 
S6K ..................................S6 ribosomal protein kinase 
SAE..................................serious adverse event 
SD ....................................stable disease 
SSAR ...............................suspected serious adverse reaction 
SUSAR ............................suspected unexpected serious adverse reaction 
t1/2.....................................terminal half life 
t1/2β ...................................terminal elimination half life 
tlag.....................................mean absorption lag time 
Vss ....................................volume of distribution 
 
 
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Deforolimus (AP23573; MK-8669) 
AP23573-08-901 
 
01 October 2008 
Confidential and Proprietary 
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6. DEFINITION OF TERMS 
 
Term  
 
    
 
 
Definition 
Adverse Drug Reaction 
Any adverse event that is deemed to be at least possibly 
related to the study drug. 
 
Clinical Benefit Response 
A clinical benefit response includes patients who achieve a 
complete response (CR), a partial response (PR), or stable 
disease (SD) for ≥ 16 weeks.  
 
End-of-Trial 
The end-of-trial (completion) date is up to 6 months after the 
last patient has discontinued from the study (including follow-
up). 
 
Enrolled Patient 
 
An enrolled patient is a patient who has signed the informed 
consent form, completed all screening evaluations and has 
been deemed eligible for the trial by the investigator. 
 
Ethics Committee 
The term “ethics committee” refers to all appropriate properly 
constituted committees or boards recognized by the 
appropriate regulatory agencies for approving clinical studies.  
These include independent ethics committees and institutional 
review  boards. 
 
Follow-Up Period 
The follow-up period begins at the one-month post-treatment 
discontinuation visit and continues until the patient dies or is 
lost to follow-up.  
 
Institutional Review Board 
Throughout this document the term institutional review board 
(IRB) refers to all appropriate properly constituted committees 
or boards recognized by the appropriate regulatory agencies 
for approving clinical studies.  These include independent 
ethics committees and institutional review boards. 
 
Parent Trial 
Any other trial investigating single-agent or combination 
deforolimus. 
 
Patient 
The term patient refers to a patient in a clinical research trial. 
 
Regulation 
The term “regulation” refers to all appropriate regulations, 
laws, and guidelines.  This trial will be conducted according to 
all appropriate regulations. 
The 
regulations 
may be 
international, national, or local and may include but not be 
limited to the Code of Federal Regulations (United States), the 
 
 
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Deforolimus (AP23573; MK-8669) 
AP23573-08-901 
 
01 October 2008 
Confidential and Proprietary 
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Good Clinical Practice: Consolidated Guideline (Canada), the 
International Conference on Harmonization Guideline for 
Good Clinical Practice, the Therapeutic Goods Administration 
Annotated 
International 
Conference 
on 
Harmonization 
Guidelines (Australia), and the World Medical Association 
Declaration of Helsinki: Ethical Principles for Medical 
Research Involving Human Patients. 
 
Regulatory Agency 
The term “regulatory agency” refers to all appropriate health 
and regulatory authorities. These may be international, 
national, or local and may include but not be limited to the 
Health Canada (HC), the European Agency for the Evaluation 
of Medicinal Products (EMEA), and the United States Food 
and Drug Administration (FDA). 
 
Screening Period 
 
The screening period begins when the patient signs the 
Informed Consent Form and continues until first dose of study 
drug is administered as part of this trial. 
 
Sponsor 
The term Sponsor refers to ARIAD Pharmaceuticals, Inc. 
 
Study Drug 
The agent(s) used in the Sponsor’s clinical research and 
development trial. 
 
Study Start Date 
Date of signature of first informed consent form for this trial. 
 
Treatment Period 
The time period that extends from administration of the first 
dose of study drug and continues through to the end of the one 
month post-treatment discontinuation visit, or to the start of 
another anti-cancer therapy if it occurs before the one-month 
post-treatment visit. 
 
 
 
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Deforolimus (AP23573; MK-8669) 
AP23573-08-901 
 
01 October 2008 
Confidential and Proprietary 
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7. SYNOPSIS 
 
Study Title 
An Extension Trial of Deforolimus (AP23573; MK-8669), an mTOR Inhibitor, for 
Patients with Advanced Cancer 
Clinical Phase 
Extension Trial 
Study Rationale 
Mammalian target of rapamycin (mTOR) 
The mammalian target of rapamycin (mTOR) is a serine-threonine kinase that 
functions as a central regulator of multiple signaling pathways that control cell 
growth, division, metabolism, and angiogenesis.  mTOR is activated in response 
to environmental and nutritional conditions and plays a critical role in the 
transduction of proliferative signals mediated through the PI3K/Akt pathway by 
activating two key downstream proteins: the p70 S6 kinase (S6K) and the 
eukaryotic initiation factor 4E binding protein 1 (4E-BP1).  Deregulation of the 
PI3K/Akt pathway has been linked to oncogenesis in many human cancers.   
 
Deforolimus 
Deforolimus (AP23573; MK-8669) is a non-prodrug analog of rapamycin that has 
been shown to inhibit mTOR activity, as evidenced by reduced phosphorylation of 
4E-BP1 and S6.  Deforolimus also inhibits the proliferation of multiple tumor cell 
lines in vitro and in vivo, including tumors of breast, colon, lung, prostate, 
pancreas and glial cells.   
Deforolimus has been investigated in 16 clinical trials involving approximately 
700 patients with advanced cancer. These trials have demonstrated that 
deforolimus has a favorable safety profile and has anti-tumor activity in a broad 
range of cancers.  Single-agent oral deforolimus is being studied in a randomized, 
placebo-controlled, pivotal Phase 3 trial in patients with metastatic soft-tissue or 
bone sarcomas. Other indications under investigations include endometrial, breast, 
non-small-cell lung cancer, and prostate cancer. Combinations of deforolimus 
with other agents are being investigated. 
Clinical trials are often designed for a finite period of time, based on the average 
outcome of the investigated populations. However, some patients, even in 
populations of patients with advanced cancer, experience a long-term benefit from 
the investigational treatment well beyond the finite period of the trial. Because 
clinical protocols are not designed for long-term collection of safety and efficacy 
data, this information is often lost. 
For those patients who have a long-term benefit from deforolimus treatment, the 
standard protocol procedure with frequent assessments of safety and efficacy may 
constitute an undue burden for patients with limited additional scientific 
information. An abbreviated, less-frequent follow-up would be appropriate to 
collect sufficient information while ensuring patient safety. 
 
Summary 
The specific purpose of the present trial is to collect long-term safety and efficacy 
data from patients for whom a clinical benefit has been established in a prior 
clinical trial with deforolimus and/or in those who remain in long-term follow-up. 
These other trials are collectively designated as “parent trials”. 
 
 
Study Objective(s) 
Primary Objective: 
• 
To describe the long-term safety of deforolimus in patients for whom a 
clinical benefit has been established in a prior parent trial with the 
deforolimus and/or in those who remain in long-term follow-up.  
 
 
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AP23573-08-901 
 
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Secondary Objectives 
• 
To describe the long term efficacy of deforolimus in patients for whom a 
clinical benefit has been established in a prior parent trial with deforolimus 
and/or in those who remain in long-term follow-up. 
• 
To evaluate progressive-free survival and overall survival.  
 
Trial Design 
Open-label, non-randomized, multicenter trial for the evaluation of the long-term 
efficacy and safety of deforolimus in patients for whom a clinical benefit has been 
established in a prior parent trial with the drug or for those who are continuing on 
for long-term follow-up. The patients will continue the treatment planned in the 
parent protocol, with a simplified follow-up.  Treatment will continue as long as 
the investigator believes the patient is deriving benefit. After the treatment period 
ends, patients will continue to be followed until death, they withdraw consent, or 
they are removed from study. 
 
Study Endpoints 
Primary Endpoint: 
• 
Safety and tolerability of long-term deforolimus 
  
Secondary Endpoints: 
• 
Progression-free survival, defined as the time from the date of enrollment in 
the prior parent trial to the date of documented progressive disease (as 
defined by the parent protocol or the investigator), recurrence or death 
(whichever occurs first). 
• 
Overall survival 
• 
Duration of objective response 
 
Diagnosis and Main 
Criteria for Inclusion 
• 
Any patient enrolled in this extension trial must have been enrolled on a 
Deforolimus parent trial 
• 
Any patient enrolled in this extension trial must have derived a clinical 
benefit from the parent trial, as assessed by the parent trial investigator, or be 
in long-term follow-up. 
• 
ECOG performance status: ≤ 2 (see Attachment B) if the patient is scheduled 
to received treatment with deforolimus and/or comparators; no requirement if 
the patient is included for follow-up purpose only. 
• 
Patient is not on any other cancer-directed therapy (with the exception of 
agents included in the parent protocol regimen)  
 
Approximate Number of  
Patients 
Approximately 50 patients  
 
Approximate Duration 
of Patient Participation 
The actual duration of each patient's participation will vary because patients may 
continue to receive study drug as long as they continue to derive benefit from the 
treatment. Once study drug is discontinued, follow up will continue until death, 
withdrawal of consent, or removal from study for other reasons.. 
Approximate Number of  
Study Centers 
Not applicable 
 
Approximate Duration 
of Study 
Not applicable 
 
 
Study Drug 
Oral or IV deforolimus. 
If the parent protocol involves a combination of deforolimus with one or several 
additional drugs, the additional drug(s) may be continued as described in the 
parent protocol. 
 
 
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Patients will remain on the same study medication (including other agents) and 
dose schedule in this extension trial as in the parent trial in which they had been 
enrolled.  
Reference Therapy 
None 
Dosage and 
Administration 
Deforolimus (and other study drugs) should be provided and administered as 
described in the parent trials but investigators will need to take into account 
individual dose reductions and schedule modifications that have been made over 
the course of that prior trial. 
 
In cases of where the Parent Trial is not clear for long-term oral or IV dosing.  
The following dosing and administration schedules can be used as guidelines for 
patients > 13 years of age: 
• 
For single-agent oral deforolimus trials, the standard administration is 
40 mg once daily for 5 consecutive days per week (QDx5/week). The 
oral formulation consists of 10mg enteric-coated tablets.  
• 
For single-agent IV deforolimus trials, the standard administration is an 
IV infusion over 30 minutes on days 1-5 of each 14-day treatment course. 
• 
Each treatment cycle will be 4 weeks (28 days) in duration 
 
Dose modifications will be permitted for management of adverse events as 
stipulated in the subject’s Parent Trial.  Additional Dosage and schedule 
modifications, beyond what is stipulated in the parent trial, may be considered by 
investigators after approval from the Sponsor. 
 
Concomitant Treatment 
Palliation and supportive care are permitted during the course of the study for 
underlying conditions.  The following concurrent medications are prohibited: 
• 
Any other anticancer treatment (unless such therapy was part of the parent 
protocol), including chemotherapy, immunotherapy, biological response 
modifiers (excluding hematopoietic growth factors), radiation therapy, and 
systemic hormonal therapy administered as anti-cancer treatment 
• 
Use of any other investigational drug or device 
• 
Medications that strongly induce or inhibit CYP3A, such as ketoconazole and 
erythromycin, are prohibited unless required for urgent medical care.  
• 
Herbal preparations or related over-the-counter preparations containing herbal 
ingredients (e.g., St. John’s Wort, Blue Cohash, Estroven) 
 
Concomitant treatments with medications that are metabolized by CYP3A are 
allowed (e.g., atorvastatin or simvastatin) 
 
Efficacy Evaluation 
Efficacy endpoint variables include: duration of objective response; progression-
free survival; and overall survival. 
 
Safety Evaluation 
Safety assessments will include routine physical examinations, laboratory 
evaluations, and interim history.  Adverse events will be graded according to U.S. 
NCI Common Terminology Criteria for Adverse Events (CTCAE), version 3. 
 
Pharmacokinetics 
None for this trial 
Pharmacodynamics 
None for this trial 
Biomarkers/ 
Pharmacogenomics 
None for this trial 
Quality of Life 
No specific assessments for this trial 
 
 
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Statistical Analysis 
 
Summary statistics and analyses for safety will be provided along with 
information concerning patient demographics. 
 
The adverse event incidence rates and the frequency of study drug related adverse 
events, categorized by severity grades will be described.  Listings of applicable 
laboratory test results collected during the study will be generated. 
 
Safety and efficacy analyses will be conducted every 6 months during the life time 
of the trial. 
 
Endpoints that will be analyzed include: progression-free survival and overall 
survival.  Progression-free survival and overall survival will be estimated using 
the Kaplan-Meier procedure 
 
Rationale for Number of 
Patients  
Not Applicable for this trial  
 
 
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8. STUDY FLOWCHARTS (SCHEDULE OF EVENTS) 
Procedure 
Screening a 
/  Baseline 
Frequency of assessment 
Post-treatment 
Discontinuation Visitl 
Post-treatment 
Follow-up 
Informed Consent b 
X 
 
 
 
Reference of parent trial 
(including trial and patient 
identification)  
X 
 
 
 
Performance Status (ECOG; 
Attachment B) 
X 
every month 
X 
 
Disease Assessment 
X 
every 3 months 
X 
 
Directed physical examination d 
 
every month 
X 
 
Hematology e 
X 
every month 
X 
 
Chemistry f 
X 
every month 
X 
 
Serum cholesterol and 
Triglycerides  
X 
every month 
 
 
Additional safety assessment for 
concomitant anticancer drug g 
X  g 
X  g 
X  g 
 
Serum β-HCG  
X h 
every 6 months 
 
 
Study drug administrationi 
 
every month 
X 
 
Adverse Events j, k 
 
To be recorded throughout 
study  
 
 
Concomitant Medication k 
X 
To be recorded throughout 
study  
 
 
Survival follow-upm 
 
 
 
every 3 months 
 
Table 8-1: Key 
a 
Screening procedures are to be performed within 14 days prior to first dose of study drug on this extension trial, unless otherwise 
specified. 
b 
Written consent must be obtained prior to performing any protocol-related procedure.  Results of a test performed as part of routine 
clinical management or were required as part of the parent protocols is acceptable. 
d 
Directed physical examination includes interim history, weight and a detailed physical examination as clinically indicated. 
e 
Hematology assessments include complete blood count (CBC) with differential and platelet counts. 
f 
Chemistry assessments include Sodium (Na), Potassium (K), Chloride (Cl), bicarbonate, blood urea nitrogen (BUN), creatinine, 
glucose, cholesterol, total bilirubin (direct and indirect), AST, ALT, alkaline phosphatase, calcium (Ca), phosphorous (PO4), albumin, 
and total protein, in addition to the other laboratory tests listed in the table above.  
g 
Patients receiving deforolimus in combination with other anticancer drugs should continue any additional safety assessments as 
required for these other drugs per the parent protocol or standards of care (e.g., cardiac monitoring for patients treated with 
deforolimus + doxorubicin) 
h 
Serum pregnancy test for women of child-bearing potential is to be performed within 7 days prior to first dose of study drug received 
as part of this extension trail. 
i 
For oral administration, patients and/or a caregiver will be trained for home administration of the study medication.  Training must 
include the use of the Patient Diary (provided separately), study drug storage, management of missed doses, and emergency contact 
information.  In addition, patients should be instructed to administer all doses at approximately the same time daily (± 2 hours) and 
not less than 2 hours following or preceding meals.  Oral deforolimus  may be self-administered by the patient throughout this trial.  
IV deforolimus will be administered in the clinic.  
j 
All SAE and study drug-related adverse events must be followed to resolution or until another anti-cancer treatment is instituted.  
k 
Adverse events and concomitant medications are to be collected through the Post-treatment Discontinuation visit. 
l 
30 days (± 7 days) after last dose of deforolimus. 
m. 
Patients followed for survival should be contacted by telephone every 3 months from the date of treatment discontinuation visit or 
from the last time they were contacted until death or they end participation in the study. 
 
 
 
 
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AP23573-08-901 
 
01 October 2008 
Confidential and Proprietary 
Page 20 of 64 
9. INTRODUCTION 
9.1 
Mammalian target of rapamycin (mTOR) 
 
The mammalian target of rapamycin (mTOR) is a serine-threonine kinase that functions as a 
central regulator of multiple signaling pathways that control cell growth, division, 
metabolism, and angiogenesis (Bjornsti and Houghton, 2004; Faivre et al., 2006; Brown et 
al., 1994; Schmelzle and Hall, 2000).  mTOR is activated in response to environmental and 
nutritional conditions and plays a critical role in the transduction of proliferative signals 
mediated through the PI3K/Akt pathway by activating two key downstream proteins, the 
p70 S6 kinase (S6K) and the eukaryotic initiation factor 4E binding protein 1 (4E-BP1) 
(Janus et al., 2005).  Both of these downstream proteins are involved in ribosomal 
biosynthesis and translation of specific mRNAs required for cell-cycle regulation (Brown et 
al., 1994; Schmelzle and Hall, 2000; Mamene et al., 2006).  Dysregulation of the PI3K/Akt 
pathway has been linked to oncogenesis in many human cancers.  Mechanisms underlying 
aberrant PI3K/Akt pathway activation include mutation and silencing of the PTEN tumor 
suppressor gene, activating mutations in the PI3K catalytic subunit, and Akt amplification 
(Chan, 2004; Hennessy et al., 2005).   
9.2 
Deforolimus 
 
Deforolimus (also known as AP23573; MK-8669) is a nonprodrug analog of rapamycin that 
has been shown to inhibit mTOR activity, as evidenced by reduced phosphorylation of 4E-
BP1 and S6 (Rivera et al., 2005; Rivera et al., 2004).  Deforolimus also inhibits the 
proliferation of multiple tumor cell lines in vitro and in vivo, including tumors of breast, 
colon, lung, prostate, pancreas, and glial cells.   
 
Deforolimus is currently in clinical development as a potential treatment for patients with 
advanced malignancies in 16 clinical trials (8 Phase 1 and 7 Phase 2 trials and 1 ongoing 
Phase 3 trial) by both the intravenous and oral routes of administration either as a single-
agent or in combination therapy.  Of these, 10 trials were with intravenous administration 
and 6 trials were with oral administration.   
9.2.1 Single-agent, Intravenous Deforolimus 
 
Two schedules for intravenous administration of deforolimus have been investigated: once 
weekly (Protocol AP23573-02-101, hereafter Trial  101), and once daily for 5 days every 2 
weeks (QDx5, IV) (Protocol AP23573-02-102, hereafter Trial 102).   
 
The safety profile of escalating dose levels of QDx5, IV deforolimus was established in 
Trial 102, which was a Phase 1, accelerated-titration, dose-escalation trial in adult patients 
(≥ 18 years of age) with refractory or advanced solid tumors. A total of 32 patients were 
treated at doses ranging from 3 to 28 mg daily.  The maximum tolerated dose level was 
 
 
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01 October 2008 
Confidential and Proprietary 
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determined to be 18.75 mg QDx5, IV. Frequent (≥ 20%) adverse reactions were mucosal 
inflammation, stomatitis, fatigue, rash, anemia, leukopenia, neutropenia, thrombocytopenia, 
diarrhea, constipation, vomiting, nausea, hyperglycemia, hypercholesterolemia, and 
hypertriglyceridemia. 
Based on these Phase 1 results, the dosage of 12.5 mg QDx5, IV was recommended for 
further investigations of intravenous deforolimus. 
Additionally, a Multi-center Phase 1 study of intravenous Deforolimus is currently ongoing 
in pediatric patients with advanced solid tumors. IV Deforolimus is being given (QDx5) x 2 
weeks followed by a two week rest. One cycle is defined as 4 weeks. The starting dose level 
was 8 mg/m2 (10 mg maximum) and the MTD has yet to be determined. 
9.2.2 Single-agent, Oral Deforolimus 
The recommended dose schedule of oral deforolimus chosen is 40 mg daily for 5 
consecutive days each week (QDx5/week).  This dose schedule is being utilized in an 
ongoing randomized, placebo-controlled, blinded pivotal Phase 3 trial in sarcoma patients.  
This dose and schedule appear to provide a balance of the potential benefit of deforolimus 
treatment with the risk of adverse effects that are generally mild or moderate and 
manageable.  This dose of oral deforolimus is supported by the preliminary data from the 
Phase 1 trial of single-agent oral deforolimus in patients with refractory or advanced 
malignancies in which 147 patients were enrolled and treated (Protocol AP23573-05-106; 
Trial 106).  Trial 106 was designed to assess the safety, tolerability, and MTD of several 
dosing schedules of oral deforolimus, and found that a short holiday from dosing each week 
enhances tolerability and allows for substantially higher sustained cumulative doses.  The 
main dose-limiting toxicity (DLT) for all schedules of oral deforolimus was mouth sores.  
The MTD for the QDx5/week schedule was 40 mg daily.  This study further demonstrated 
that oral deforolimus has anti-tumor activity in patients with advanced cancers, has 
inhibitory activity on molecular targets,  as assessed by pharmacodynamic assays, and has 
acceptable absolute bioavailability.  The oral dose schedule selected from Trial 106 for use 
in future studies was 40 mg QDx5/week. This dosage schedule would provide an expected 
cumulative dose of 800 mg over 4 weeks, which is greater than the cumulative doses 
expected from continuous oral dosing schedules that have lower maximum tolerated doses. 
9.2.3 Combination Trials 
 
Four deforolimus combination trials with paclitaxel, capecitabine, doxorubicin, and 
trastuzumab have recently completed or are still ongoing.  Maximum tolerated dose levels 
include:   
(i) 
37.5 mg deforolimus (IV) + 60 mg/m2 paclitaxel or 12.5 mg deforolimus (IV) + 
80 mg/m2 paclitaxel when both agents are administered once weekly for 3 weeks of a 
4 week cycle;   
 
 
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(ii) 
75 mg deforolimus (IV)  + 1650 mg/m2 capecitabine, with deforolimus  administered 
once weekly for 3 weeks of a 4 week cycle, and capecitabine administered orally in 
2 divided daily doses for 14 consecutive days beginning on Day 1 of the cycle; and 
(iii) 
40 mg deforolimus administered orally on a QDx4 schedule in combination with 
75 mg/m2 doxorubicin (IV, every-3-weeks). 
(iv) 
40 mg deforolimus administered orally on a QDx5 schedule in combination with 
4 mg/kg trastuzumab (IV, Loading dose week 1), followed by 2 mg/kg (IV, weekly). 
 
Other combination trials are ongoing or will be initiated soon, in particular deforolimus + 
bevacizumab, deforolimus + MK-0646 (an inhibitor of IGF-1R), deforolimus + erlotinib, 
and others. These trials are Phase 1 and Phase 2 studies aimed at defining the early safety 
and efficacy of these combinations. It is anticipated that recommended doses for further 
investigations in specific indications will be identified in the future; it is possible that some 
patients who derive a benefit from the treatment will be candidate for an extension protocol, 
assessing the long-term safety and efficacy of deforolimus in these combinations. 
 
9.2.4 Pharmacokinetic Studies with Deforolimus 
 
 
Pharmacokinetic (PK) data following IV administration have revealed rapid tissue 
distribution and a slower elimination phase.  Inter-individual variation in model-predicted 
PK parameters was modest within each dose cohort. Following weekly IV administration, 
the median terminal elimination half-life (t1/2) was 48 hours, and the mean for each cohort 
ranged from 45 to 57 hours.  Following QDx5 IV administration, the median t1/2 was 61 
hours, and the mean for each cohort ranged from 56 to 74 hours.  The AUC and Cmax 
increased less than proportionately with dose, particularly at dose levels above 50 mg QW 
and 15 mg QDx5, IV.  This might be attributable to an increase in clearance with dose, and 
is consistent with saturation of distribution sites, such as red blood cells.  The volume of 
distribution (Vss) also increased with dose, which could be attributed to saturation of red 
blood cells which might allow for deeper penetration of deforolimus to other tissues.        
 
The pharmacokinetics of deforolimus after oral administration was best characterized by a 
2-compartment, oral absorption model consisting of central blood and peripheral tissue 
compartments with an additional absorption compartment representing the gastrointestinal 
tract. The compartments accounted for rapid exponential decline in blood concentrations 
followed by a slower exponential phase with linear elimination out of the body.  
 
The mean (median) terminal elimination half-life (t1/2β) of deforolimus across all doses 
following oral administration was 63.2 (42.6) hours. The terminal half life for different dose 
schedules, ranged from 31 to 110 hours. With terminal half-lives in this range, steady state 
would not be expected to be achieved until after 9 to 18 days of dosing. Mean absorption lag 
time (tlag) ranged from 1.2 to 3 hours across all dosing regimens. Based on IV data from the 
 
 
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01 October 2008 
Confidential and Proprietary 
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prior studies (Protocol AP23573-02-101 and AP23573-02-102) and oral data from this study 
(Protocol AP23573-05-106), the absolute bioavailability was estimated to be 18% to 21%. 
 
The AUC and apparent total blood clearance (CL/F) were nonlinearly related to dose. Doses 
greater than 40 to 50 mg (up to 100 mg) across all schedules had similar mean parameter 
estimates, which suggests that there would be little benefit from administration of higher 
doses. Mean terminal half-life in the blood following oral administration of deforolimus at 
doses of 10 to 100 mg ranged from 41 to 90 hours, which was similar to that following IV 
administration.  
 
9.2.5 Pharmacodynamic Studies with Deforolimus 
 
Pharmacodynamic (PD) studies using peripheral blood mononuclear cells (PBMCs) as 
surrogate tissue have demonstrated in vivo mTOR inhibition following all IV and oral dose 
levels tested.  
 
In Phase 1 clinical trials, mouth sores1 have been the dose-limiting toxicity with most dose 
schedules tested, and the maximum tolerated doses (MTDs) for the IV dosing were 75 mg 
for the QW schedule and 18.75 mg for the QDx5 schedule. The MTDs for oral dosing were 
50 mg for the QDx4 schedule, 40 mg for the QDx5 schedule, 15 mg for the QDx21 
schedule, and 10 mg for the QDx28 schedule.  Unlike chemotherapy-induced mucositis, 
mouth sores caused by deforolimus are similar to aphthous ulcers and can, depending on the 
specific location, cause significant discomfort.  
9.2.6 Current Safety Information on Deforolimus 
 
Deforolimus adverse drug reactions that have been commonly reported within any given 
trial include asthenia, fatigue, anorexia, mouth sores, rash, anemia, diarrhea, 
leukopenia/neutropenia, nausea, hypercholesterolemia, hypertriglyceridemia, vomiting, 
thrombocytopenia, and dysgeusia. Less frequent, treatment-related AEs include headache, 
fever, weight loss, paresthesia, alopecia, hyperglycemia, constipation, increased liver 
enzyme levels, hyponatremia, hypokalemia, hypophosphatemia, and nail disorders 
(discoloration and brittleness).  These side effects were mostly mild or moderate in severity 
and were reversible.  Other less frequent treatment-related AEs, including hypersensitivity 
reactions, have also been reported and are tabulated in the Clinical Investigator’s Brochure.  
Notable, treatment-related serious adverse events resulting in hospitalizations include mouth 
sores, renal failure, tumor hemorrhage, and pneumonitis. 
 
 
                                                 
1 Usually reported as mucositis.  Other MedDRA preferred terms included under ‘mouth sores’ are aphthous stomatitis, gingival pain, 
gingival ulceration, glossitis, mouth ulceration, oral discomfort, oral pain, stomatitis and mucosal inflammation. 
 
 
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AP23573-08-901 
 
01 October 2008 
Confidential and Proprietary 
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Please refer to the current edition of the deforolimus Clinical Investigator's Brochure for a 
complete description of all available safety information reported during the deforolimus 
clinical and non-clinical studies. 
 
9.2.7 Current Efficacy Information on Deforolimus 
 
Indications of antitumor activity in a broad range of tumor types have been reported in 
Phase 1 clinical trials, including partial and/or minor responses in patients with transitional 
cell carcinoma of the bladder, mesothelioma, malignant mixed mullerian carcinosarcoma, 
renal cell carcinoma, anaplastic large cell lymphoma, large cell carcinoma, non-small cell 
lung cancer, gastrointestinal stromal tumor, thyroid carcinoma, Ewing’s sarcoma, and 
liposarcoma.  In addition, prolonged periods of stable disease lasting ≥4 months have also 
been observed.  These results support the continued study and development of deforolimus 
for the treatment of advanced malignancies.  Towards this end, efficacy assessments and 
analyses are ongoing in Phase 2 trials of single-agent deforolimus in patients with 
hematological malignancies, prostate cancer, endometrial cancer, and soft-tissue and bone 
sarcomas. 
 
9.3 
Long-term Benefit from Deforolimus Treatment 
 
As of 26 August 2008,  9 patients were continuing to receive deforolimus long-term (more 
than 24 months) on one of several parent trials (Table 9-1). All of these patients were either 
from the Phase 1 or 2 program. No patients were from the Phase 3 trial because of the recent 
activation of this trial in September 2007. 
 
Table 9-2  Patients Currently Receiving Long-Term Deforolimus on Parent Clinical Trials 
Protocol Number 
Protocol Title / Short Description  
 
No. Patients 
Enrolled a 
No. Patients on 
deforolimus 
 > 24 months 
Intravenous Administration 
AP23573-02-101 
Phase I dose escalation trial to determine the safety, tolerability, and 
maximum tolerated dose of weekly administration of AP23573 (QW) 
in patients with refractory or advanced malignancies  
46 
0 
AP23573-02-102 
Phase I dose escalation trial to determine the safety, tolerability, and 
MTD of dailyx5 administration of AP23573 (QDx5, IV)  in patients 
with refractory or advanced malignancies 
32 
 
1 
AP23573-04-103 
Phase I sequential ascending dose trial of AP23573 (QDx5, IV) in 
patients with progressive or recurrent glioma 
10 
 
0 
AP23573-04-104 
Phase Ib pharmacokinetic and pharmacodynamic study to define the 
optimal dose for combining AP23573 (QW) with paclitaxel 
29 
 
0 
AP23573-04-105 
Phase Ib pharmacokinetic and pharmacodynamic study to define the 
optimal dose for combining AP23573 (QW) with capecitabine 
32 
0 
AP23573-04-201 
Phase II trial of AP23573 (QDx5, IV) in patients with relapsed or 
refractory hematologic malignancies 
57 
0 
 
 
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AP23573-04-202 
Phase II trial of AP23573 (QDx5, IV) in patients with advanced 
sarcoma 
212 
0 
AP23573-04-203 
Phase II trial of AP23573 (QDx5, IV) in female adult patients with 
recurrent or metastatic endometrial cancer 
45 
0 
AP23573-04-204 
Phase II study of the efficacy and safety of AP23573 (QW) in patients 
with taxane-resistant androgen-independent prostate cancer 
38 
0 
AP23573-07-110 
Phase I study of IV Deforolimus administered QDX5 every other 
week in pediatric patients with advanced solid tumors 
1 
0 
Oral Administration 
AP23573-05-106 
Phase I/IIa dose escalation trial to determine the safety, tolerability and 
maximum tolerated dose of AP23573 when administered orally in 
patients with refractory or advanced malignancies (QDx4, QDx5, 
QDx6, QDx21, QDx28, BIDx4) 
147 
7 
AP23573-05-107 
Phase Ib dose escalation trial to determine the safety, tolerability, and 
maximum tolerated dose of oral AP2373 (QDx4, QDx14) in 
combination with doxorubicin (every 3 weeks) 
37 
1 
AP23573-07-205 
Randomized Phase II trial of oral Deforolimus (QDx5/Week) 
compared to IV progestin (QWeek) in women with advanced 
endometrial carcinoma following one line of chemotherapy 
0 
0 
AP23573-08-206i 
Phase II study of oral Deforolimus (QDx5/Week)  in patients with 
metastatic and/or locally advanced recurrent endometrial cancer 
0 
0 
AP23573-08-207 
Phase II trial of oral Deforolimus (QDx5/Week) in combination with 
Trastuzumab for patients with HER-positive Trastuzumab-refractory 
metastatic breast cancer 
2 
0 
AP23573-07-302 
A Pivotal Trial to Determine the Efficacy and Safety of AP23573 
when Administered as Maintenance Therapy to Patients with 
Metastatic Soft-Tissue or Bone Sarcomas  
83 
0 
a:  Number of patients receiving at least 1 dose of study treatment and with data in the study database as of August 2008.  
 
 
Patients continuing on deforolimus parent protocols long-term are presumably deriving a 
clinical benefit from treatment. Patients benefiting from long-term deforolimus treatment 
have an undue burden of needing to comply with all of the follow-up procedures as 
described in the initial protocol if they want to continue on deforolimus treatment. Whereas 
the extensive or aggressive follow-up procedures are fully justified in the early phases of 
these trials that are designed to detect any efficacy and safety signals in short-term 
exposures, the procedures in the long-term follow up may not be needed in the later phases 
of clinical research and may have to be adapted for the long-term exposures.   
• 
In long-term follow-up, the efficacy parameters are not expected to change substantially 
initially; however, long-term assessments should focus on the duration of response, 
progression-free survival, overall survival, and other long-term efficacy parameters 
• 
In long-term follow-up, the probability of newly emergent acute or sub-acute adverse 
events is low. The focus should shift towards the detection of less frequent, chronic adverse 
events 
 
A reduced, less intense follow-up would appear sufficient to detect, collect and analyze the 
long term efficacy and safety of deforolimus. 
 
 
 
 
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01 October 2008 
Confidential and Proprietary 
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Summary 
 
Many patients derive clinical benefit from treatment with deforolimus. An intense long-term 
follow-up of these patients is not required to detect the long-term efficacy and safety of 
deforolimus. An intense long term follow-up procedure as would be required if the patient 
were to remain on the parent trial would clearly represent an undue burden for these 
patients. The specific purpose of the present trial is to collect long-term safety and efficacy 
data from patients for whom a clinical benefit has been established in a prior clinical trial 
(“parent trial”) with deforolimus, through simplified follow-up procedures. 
 
 
 
10. STUDY OBJECTIVES 
 
Primary objective 
• To describe the long-term safety of deforolimus in patients for whom a clinical benefit 
has been established in a prior (“parent”) clinical trial with deforolimus, as assessed by 
the parent trial investigator, and/or in those who continue in long-term follow-up. 
 
Secondary objectives 
• To describe the long-term efficacy of deforolimus in patients for whom a clinical benefit 
has been established in a prior (“parent”) clinical trial with deforolimus, as assessed by 
the parent trial investigator, and/or in those who continue in long-term follow-up. 
• To evaluate progressive-free survival and overall survival. 
 
11. TRIAL DESIGN 
 
11.1 Description of Trial Design 
 
This is an open-label, non-randomized, single-arm, extension trial designed for the long-
term evaluation of the efficacy and safety of deforolimus, in patients who have derived a 
clinical benefit from treatment with deforolimus, given either as single agent or in 
combination, in a prior parent protocol and for patients who continue in long-term follow-
up. The patients will continue the treatment planned in the parent protocol, with a reduced 
and simplified follow-up. Treatment will continue as long as the investigator believes the 
patient is deriving benefit. After the treatment period ends, patients will continued to be 
followed until death, they withdraw consent, or they are removed from study for other 
reasons. 
11.2 Selection of Trial Endpoints 
 
Primary Endpoint 
• Safety and tolerability of long-term deforolimus 
 
 
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Secondary Endpoints 
• Progression-free survival, defined as the time from the date of enrollment in the prior 
parent trial to the date of documented progressive disease, recurrence or death 
(whichever occurs first) 
• Overall survival 
• Duration of objective response  
11.3 Patient Population 
 
This trial will evaluate the efficacy and safety of deforolimus in patients with advanced 
cancers who have derived a clinical benefit from therapy with deforolimus in a prior parent 
trial. The clinical benefit will have been assessed by the investigator in the prior parent trial.  
This trial will also evaluate progressive-free survival and overall survival among patients 
who have finished treatment with deforolimus. 
 
11.4 Deforolimus Doses and Schedules 
 
Patients will remain on the same dose and schedule of deforolimus (including other 
concomitant study medications) in this extension trial as in the parent trial at s/he is coming 
from. 
 
In cases of where the parent trial is not clear for long-term oral or IV dosing, dosing and 
administration schedule guidelines will be based on current oral and IV dosage and 
administration schedules. 
 
Dose modifications will be permitted for management of adverse events as stipulated in the 
subject’s parent trial and reiterated in this protocol.  Additional dosage and schedule 
modifications, beyond what is stipulated in the parent trial, may be considered by 
investigators after approval from the Sponsor. 
 
 
 
11.5 Duration of Trial  
 
Due to the nature of this extension trial, the trial duration and the estimated duration of each 
patient's participation in the trial cannot be specified. In the treatment portion of the trial, 
patients may stay on treatment as long as the risk benefit ratio is deemed to be positive by 
the investigator. 
 
The overall risk benefit ratio for the entire patient population enrolled in this study will be 
assessed at least every 6 months.  This assessment will serve as a basis to continue this 
extension study without modification or to amend, suspend or discontinue the study 
protocol. 
 
 
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For those patients who are in the follow-up portion of the trial, they will remain on trial until 
they are no longer eligible to continue, consent is withdrawn, death, or the sponsor decides 
to end the trial. 
12. STUDY POPULATION 
Patients will be eligible for this extension study if they have participated in a prior 
deforolimus trial and are continuing to receive deforolimus under the parent protocol or if 
they are being followed for overall survival (OS) under the parent protocol.  
 
All patients must take part in the informed consent process for this protocol.  During the 
consent process, the person obtaining consent must inform the patient of all elements of 
informed consent.    Adequate time must be allowed for questions and for the patient to 
make a voluntary decision.  No protocol specific procedures are to be performed until the 
patient has signed and dated an IRB/EC approved informed consent form.  Each patient's 
participation in the trial begins with the signing and dating of the informed consent form.  
Patients must meet the inclusion and exclusion criteria to be enrolled in the trial. 
 
12.1 Inclusion Criteria 
 
Patients must meet each of the following criteria to be eligible for participation in this trial: 
 
1. 
To be considered for enrollment in this extension trial, patients must have 
participated on a deforolimus parent trial. 
2. 
Patients enrolled in this extension trial must have derived a clinical benefit from the 
parent trial, as assessed by the parent trial investigator, or continue to be in long-term 
follow-up for a deforolimus parent trial. 
3. 
Patient is not on any other anti-cancer treatment(s) unless that therapy was allowed 
in the parent protocol. This includes chemotherapy, immunotherapy, biological 
response modifiers (excluding hematopoietic growth factors), or systemic hormonal 
therapy  (see section 15.2 for more detailed list of exceptions) 
4. 
ECOG performance status: ≤ 2 (see Attachment B) if the patient is scheduled to 
receive treatment with deforolimus; no requirement if the patient is included for 
follow-up purpose only. 
5. 
Patients who are of childbearing potential and will be receiving study drug must have 
a negative serum pregnancy test within 7 days prior to screening evaluation and must 
use an approved contraceptive method as appropriate from time of study screening 
until 30 days after the last dose of study drug. Non-hormonal methods must be used 
in this trial.  Approved contraceptive methods include, for example, intra-uterine 
device, diaphragm with spermicide, cervical cap with spermicide or female condom 
with spermicide. (Spermicides alone are not an acceptable method of contraception.) 
6. 
Signed informed consent document stating that the patient understands the 
investigational nature of the proposed treatment. 
 
 
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12.2 Exclusion Criteria 
 
• Has not participated on a parent trial.  
• Women who are to receive study drug who are pregnant or lactating. 
• Any condition in the Investigator’s judgment that renders the patient unable to fully 
understand and provide informed consent and/or comply with the protocol  
12.3 Number of Patients 
 
Approximately 50 patients will be enrolled  
12.4 Screening Failures 
 
Not applicable.  
12.5 Replacements 
 
Not applicable. 
13. STUDY PROCEDURES 
 
Procedures to be performed during the study period for those patients who are on 
deforolimus are listed in Section 8: Schedule of Events.  
 
13.1 Patient Enrollment  
 
 
Patients in long term treatment and/or follow-up on a parent protocol, will be enrolled in the 
extension study using a procedure established by the Sponsor. Ideally, the off-treatment 
evaluations for the parent protocol will be used as the screening and baseline evaluations for 
this extension study. 
 
13.2 Study Drug Administration  
 
In this extension trial, patients will remain on the same study medication(s) (including other 
agents) with the same dose and schedule of deforolimus as the patient was on during the 
parent trial taking into account individual dose reductions and schedule modifications that 
have been made over the course of that prior trial. 
 
 
 
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In cases of where the Parent Trial is not clear for long-term oral or IV dosing.   The 
following dosing and administration schedules can be used as guidelines for patients > 13 
years old: 
• For single-agent oral deforolimus trials, the standard administration is 40 mg once 
daily for 5 consecutive days per week (QDx5/week). The oral formulation consists of 
10mg enteric-coated tablets.  
• For single-agent IV deforolimus trials, the standard administration is an IV infusion 
over 30 minutes on days 1-5 of each 14-day treatment course. 
• Each treatment cycle will be 4 weeks (28 days) in duration 
 
Dose modifications will be permitted for management of adverse events as stipulated in the 
subject’s Parent Trial and Section 14.2 in this protocol.  Additional Dosage and schedule 
modifications, beyond what is stipulated in the parent trial, may be considered by 
investigators after approval from the Sponsor. 
 
 
13.2.1 Management of Missed Doses of Study Drug 
 
Oral Study Drug: Patients who forget to take their scheduled dose of oral deforolimus will 
be instructed not to make up the missed dose. Missed doses will be recorded in an 
appropriate source record (e.g., clinic chart) and on the Patient Diary Card, if applicable. 
 
IV Study Drug: Under certain circumstances, it may be necessary to adjust the dosing 
schedule for any given patient.  Every attempt should be made to adjust the dosing schedule 
such that the patient receives all doses.  If a dose is missed, the dose may be administered by 
extending the cycle by one day, if possible.  For example, if a dose scheduled on a Monday 
was missed, the patient should be dosed for a 5-day course from Tuesday through Saturday.  
The following course of dosing should begin as scheduled on a Monday.   
 
13.3 Treatment Discontinuation Visit  
 
A Post-Treatment Discontinuation Visit will be conducted approximately one month (30 
days ± 7 days) after the last dose of study drug for safety evaluations.  Patients with 
ongoing, study drug-related adverse events at this follow-up visit should be followed until 
the AE has resolved, stabilized or returned to baseline status or another anti-cancer therapy 
is instituted. 
 
 
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13.4 Follow-up for Survival 
 
Patients being followed for survival should be contacted by telephone every three months 
from the date of Treatment Discontinuation Visit or from the last time the patient was 
contacted in the parent trial until death, loss to follow-up, or unless otherwise informed by 
the Sponsor to discontinue further follow up visits. 
13.5 Removal of Patients from Study Drug Administration or Assessment  
 
In the event that a patient is withdrawn from the study, every effort will be made by the 
Investigator to document and report the reasons for withdrawal as thoroughly as possible.  
The reason(s) for termination must be clearly reported on the appropriate page of the 
patient’s CRF.  A CRF must be completed for any patient who has been enrolled. 
 
If a patient on active treatment is prematurely discontinued from the trial for any reason, 
every effort must be made to perform all clinical and laboratory procedures as scheduled for 
the post-treatment discontinuation visit.  In the event that the patient fails to return for the 
necessary visit(s), an effort must be made to contact the patient to determine the reason and 
this information should be documented in the appropriate source record for the patient. 
13.6 Criteria for Discontinuation 
 
Patients will be discontinued from further study drug administration in the event of any of 
the following:  
• Intolerable adverse drug reaction, either to deforolimus single agent or to a 
deforolimus combination  
• Documented disease progression  
• Significant deviation from the protocol or eligibility criteria.  Such patients will be 
considered to have protocol violations and will be removed from study. 
• Noncompliance with study or follow-up procedures 
• Patient decision (election to discontinue study treatment versus further study 
participation) 
- Patients choosing to discontinue study treatment (without full withdrawal of 
consent to study participation) should be encouraged to continue participation in 
follow-up procedures; continued survival follow-up should be strongly 
encouraged. 
• Termination of the study by the Sponsor 
• Any other reason which, in the opinion of the Investigator, would justify removing 
the patient from the study. 
 
 
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14. STUDY DRUG 
14.1 Study Drug Administration 
 
Study drug will be administered only to eligible enrolled patients at a center listed on the 
FDA Form 1572.  Once study treatment has been initiated, study drug administration may 
continue until such time that the discontinuation criteria have been met (see Section 13.6: 
Criteria for Discontinuation).   
14.1.1 Single-agent Intravenous Deforolimus  
Deforolimus will be administered at the investigational site. Prior to the infusion of study 
drug, the study staff should ensure that the intravenous access established for the patient is 
adequate for infusion of study drug over the specified period. Study drug solution will be 
delivered via a central venous catheter or port (if available) or a peripheral vein.   The access 
device should be flushed with normal saline or water for injection prior to and following 
study drug administration.  The study drug should not be co-administered with other drugs 
in the same infusion line.  
Patients will receive deforolimus at the dosage and schedule defined in the parent trial. If the 
deforolimus dosage had been adjusted in the parent trial, the patient will start the extension 
trial at the adjusted dosage. Study drug solution will be administered, at a constant rate, over 
a 30 ± 5 minute period using an automatic dispensing pump (or timed infusion pump). 
 
In cases of where the Parent Trial is not clear for long-term IV dosing.   The following 
dosing and administration schedules can be used as guidelines for patients > 13 years of age: 
• For single-agent IV deforolimus trials, the standard administration is an IV infusion 
over 30 minutes on days 1-5 of each 14-day treatment course. 
• Each treatment cycle will be 4 weeks (28 days) in duration 
 
Dose modifications will be permitted for management of adverse events as stipulated in the 
subject’s Parent Trial.  Additional dosage and schedule modifications for deforolimus, 
beyond what may be stipulated in the parent trial, are described in Section 14.2. Any further 
dose reductions or delays may be considered by investigators after approval from the 
Sponsor. 
Qualified medical personnel will carefully monitor intravenous infusions of study drug.  
Such personnel must be available throughout the course of study drug administration to 
evaluate and treat any adverse event(s), as well as to evaluate whether continued 
participation of the patient in the study is warranted or advisable.  If clinical 
symptomatology suggests a rate of infusion-related toxicity or hypersensitivity reaction, the 
infusion will be interrupted and appropriate medical therapy instituted and/or modification 
to study drug infusion will be made (see Section 14.2.3.1).  
 
 
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14.1.2 Single-agent Oral Deforolimus 
 
Oral deforolimus may be self-administered by the patient.  Patients will continue on the dose 
and schedule defined in the parent trial.   
 
If the deforolimus dosage had been adjusted in the parent trial, the patient will start the 
extension trial at the adjusted dosage. 
 
In cases of where the Parent Trial is not clear for long-term oral dosing.   The following 
dosing and administration schedules can be used as guidelines for patients > 13 years of age: 
• For single-agent oral deforolimus trials, the standard administration is 40 mg once 
daily for 5 consecutive days per week (QDx5/week). The oral formulation consists of 
10mg enteric-coated tablets.  
• Each treatment cycle will be 4 weeks (28 days) in duration 
 
Dose modifications will be permitted for management of adverse events as stipulated in the 
subject’s Parent Trial.  Additional dosage and schedule modifications for deforolimus, 
beyond what may be stipulated in the parent trial, are described in Section 14.2. Any further 
dose reductions or delays may be considered by investigators after approval from the 
Sponsor. 
 
14.1.3 Deforolimus in Combination  
 
Deforolimus and combination drugs will be administered at the dosages defined in the 
parent trial. If the dosage of deforolimus and/or combination drugs had been adjusted in the 
parent trial, the patient will start the extension trial at the adjusted dosages. 
Further dose reductions or delays of treatment due to drug-related adverse events for 
deforolimus are described in Section 14.2. 
  
14.2 Management of Adverse Drug Reactions - Deforolimus 
14.2.1 General Adverse Drug Reactions and Dose Modifications for Oral Deforolimus 
 
Comprehensive assessments of any study drug-related adverse events (adverse drug 
reactions) including any serious adverse events experienced by the patient will be performed 
throughout the course of the study.  Anticipated adverse drug reactions that may be 
experienced are described below, and in the Clinical Investigator's Brochure.  Appropriate 
management of the patient for any adverse event experienced while participating in this trial 
will be determined by the severity of the event and the clinical judgment of the investigator 
and medical monitor. 
 
 
 
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The dosage modification rules for the majority of adverse drug reactions for oral 
deforolimus are detailed in Table 14.2-1.  This table outlines the recommended dose 
modification steps of deforolimus in the event a patient has ≥  Grade 2 adverse event (other 
than pneumonitis or mouth sores) believed to be related to deforolimus. Occurrence refers to 
a specific, repeating adverse event. That is, “second” means the second episode of the event 
following resolution of the first episode to ≤ Grade 1.  For purposes of the example, it is 
assumed that patients are taking the drug on a Monday-to-Friday schedule. 
 
See Table 14.2-2 for additional guidance on management of mouth sores. 
 
 
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Table 14.2-1: Management of Oral Deforolimus Dose Modifications for All Adverse 
Drug Reactions, Except Mouth Sores and Pneumonitis 
Occurrence* Action 
until 
Friday 
Sat/Sun 
Action during 
next week 
Sat/Sun 
Action during 
second week or 
more 
First 
Decrease 
dose to   
10 mg  
(1 tablet)  
No drug 
If AE ≤  Grade 1 
(resolved) on 
Monday may 
increase dose to 
40 mg; otherwise 
continue at 10 
mg through 
Friday 
No drug 
If AE resolved on 
Monday, may 
increase dose to 
40 mg; otherwise 
stop drug until 
resolution and 
resume at 40 mg  
Second 
Decrease 
dose to   
10 mg  
(1 tablet) 
No drug     If AE resolved 
on Monday may 
increase dose to 
30 mg for 
remainder of 
study; otherwise 
continue at  
10 mg through 
Friday 
No drug 
If AE resolved on 
Monday may 
increase dose to  
30 mg for 
remainder of study; 
otherwise stop drug 
until resolution and 
resume at 30 mg 
Third 
Decrease 
dose to   
10 mg  
(1 tablet) 
No drug 
If AE resolved 
on Monday may 
increase dose to 
20 mg for 
remainder of 
study; otherwise 
continue at  
10 mg through 
Friday 
No drug 
If AE resolved on 
Monday may 
increase dose to  
20 mg for 
remainder of study; 
otherwise stop drug 
until resolution and 
resume at 20 mg 
Fourth 
Decrease 
dose to   
10 mg  
(1 tablet) 
No drug 
Continue drug at 
10 mg through 
Friday  
No drug 
If AE resolved on 
Monday may 
continue on drug at 
10 mg; otherwise 
stop drug until 
resolution and 
resume at 10 mg or 
consider withdrawal 
of patient 
* should include adverse events that occurred in the parent protocol in addition to the extension protocol. 
 
 
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14.2.2 Mouth Sores for Oral Deforolimus 
 
Mouth sores were commonly reported among patients who received deforolimus. Terms for 
mouth sores or "mucositis" included aphthous stomatitis, gingival pain, gingival ulceration, 
glossitis, mucositis, mouth ulceration, oral discomfort, oral pain, stomatitis, and mucosal 
inflammation.  The sores associated with deforolimus are distinct punctuate ulcers that most 
closely resemble aphthous ulcers.  They are usually painful and can be up to 1 cm in widest 
diameter.  The onset of mouth sores following the first dose of deforolimus may occur as 
early as during the first week of treatment and usually resolves during regularly scheduled 
treatment holidays or following dose reductions and/or delays.   
 
Treatment of mouth sores should include dose modifications as described in Table 14.2-2, as 
well as palliative pain management with the type and strength of the analgesia escalating in 
parallel with the severity of the mouth sore pain. Topical analgesics may be employed if felt 
to be beneficial.  The following treatment plan is suggested: 
• Bicarbonate rinses 4 times a day every day if there are any oral mucosal symptoms or 
signs. (There do not have to be actual ulcers to institute this prophylactic measure.) 
• At the appearance of mouth sores, use topical analgesics such as Orajel® Medicated 
Mouth Sore Swabs, or equivalent, as needed to achieve pain relief and allow normal 
eating. 
• 
Use other agents such as Gelclair® or anesthetic mouth washes only if dose reduction and 
application of topical analgesics do not result in pain control. 
 
 
 
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Table 14.2-2: Dose Modifications of Oral Deforolimus for Mouth Soresa 
NCI CTCAE Grade b 
Dose Delay and or Reduction Required 
GRADE 1 
Continue treatment without dose interruption or reduction.  Begin symptomatic 
treatment and prophylaxis. 
GRADE 2 or higher 
First episode c 
¾ Reduce dose to 10 mg per day for remainder of week.   
• 
Resume 40 mg per day after the two-day break if improvement to 
Grade 1 or less 
• 
If Grade 2 or higher, dose 10 mg per day for additional week 
Second episode c 
¾ Reduce dose to 10 mg per day for remainder of week.   
• 
Resume 30 mg per day after the two-day break if improvement to 
Grade 1 or less 
• 
If Grade 2 or higher, dose 10 mg per day for additional week  
Third episode c 
¾ Reduce dose to 10 mg per day for remainder of week.   
• 
Resume 20 mg per day after the two-day break if improvement to 
Grade 1 or less 
• 
If Grade 2 or higher, dose 10 mg per day for additional week  
Fourth episode or greater c 
¾ Stop treatment until improved to < Grade 1 
¾ Improvement occurs in ≤  2 weeks  
• 
Resume at 10 mg per day  
¾ Improvement occurs in > 2 weeks  
• 
Contact Medical Monitor and consider permanently discontinuing 
study treatment 
 
a:  Mouth sores refers to the following terms: aphthous stomatitis, gingival pain, gingival ulceration, 
glossitis, mouth ulceration, oral discomfort, oral pain, stomatitis, and mucosal inflammation. 
b: NCI CTCAE Grade (version 3) based on functional/symptomatic criteria described for mucositis 
/stomatitis 
c:  This should include adverse events that occurred in the parent protocol in addition to the extension 
protocol. 
 
14.2.3 Management of Hypersensitivity and Other Reactions During IV 
Administration of Deforolimus  
14.2.3.1 Pre-Medications/Therapy for Infusion Site or Hypersensitivity Reactions 
 
As of March 25, 2008, there have been no reports of infusion site reactions related to 
deforolimus in any of the past or ongoing clinical trials. 
1. If clinical symptomatology suggests a hypersensitivity reaction, the infusion will be 
interrupted and appropriate medical therapy instituted.  
2. Patients with demonstrated Grade 1 or 2 hypersensitivity reactions will be 
premedicated in advance of future study drug administration.  The following 
 
 
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premedications, including H2-receptor antagonists and/or corticosteroid therapy, may 
be administered:  
• Recommended dose of diphenhydramine, 25-50 mg, IV, 30 minutes prior to 
study drug infusion 
• Recommended doses of H2-receptor antagonists, 30 minutes prior to infusion, are 
as follows: IV; ranitidine, 50 mg, IV; or famotidine, 20 mg, IV 
• Recommended corticosteroid regimen of dexamethasone, 8 mg, po, bid x 3 days 
(starting one day prior to AP23573 dosing)  
3. Patients who experience a Grade 3 or 4 hypersensitivity reaction will be discontinued 
from further study drug administration.  
 
Any medications administered for either prophylaxis or therapy of symptoms considered to 
be associated with study drug administration should be documented on the appropriate page 
of the patient’s CRF.   
14.2.3.2 Study Drug Infusion Modifications 
 
If clinical symptomatology suggests a rate of infusion-related adverse event, or if clinically 
significant changes in vital signs occur, the infusion will be interrupted for approximately 
30 minutes in order to allow for amelioration or resolution of the potential rate-related 
toxicity.  The infusion may be resumed at a slower rate such that the infusion will be 
complete within a longer time period (approximately 2 hours).  Such modifications must be 
carefully documented on the patient’s CRF.  
 
In the event of an unacceptable > Grade 3 adverse drug reaction, or significant clinical 
symptomatology that is not controlled by optimal supportive care, the Investigator will 
discontinue the study drug infusion prior to delivery of the full dose.   
 
 
 
 
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14.2.4 General Adverse Drug Reactions and Dose Modifications for IV Deforolimus  
Dose Delays and Reductions 
 
Dose delays and/or reductions will be implemented for patients who experience adverse 
drug reactions as indicated in following sections 
 
Starting Dose Level 
First Reduction* 
Second Reduction* 
Dose Level 1 (12.5 mg) 
10 mg 
7.5 mg 
 
 
* should include adverse events that occurred in the parent protocol in addition to the extension protocol. 
 
Once reduced, patients will continue study drug administration at the reduced dose level 
throughout the remainder of the active study period. If an adverse drug reaction is not 
adequately controlled following two dose reductions, further dose reductions should be 
discussed with the Sponsor or the patient should be discontinued from the study. If the 
patient is on a different starting IV dose level other than 12.5mg, dose reductions should be 
discussed with the Sponsor. 
14.2.4.1 Dose Delay and/or Reduction for Grade 1 or 2 Adverse Drug Reactions 
 
In the event of a Grade 1 or 2 adverse drug reaction that is not controlled by optimal 
supportive care, or is intolerable due to symptomatology or interference with normal daily 
activities, the patient may be managed by extending the interval between two scheduled 
doses for up to two weeks to allow for amelioration or resolution of the event.  In these 
cases, subsequent study drug administration must be at the reduced dose level according to 
the above schedule.  If a delay is required following two dose reductions, the patient should 
be discontinued from further study drug administration.  
14.2.4.2 Dose Reduction With /Without Dose Delay for Grade 3 or 4 Adverse Drug 
Reactions 
 
In the event of a Grade 3 or 4 adverse drug reaction, the patient may be managed by either 
dose reduction according to the above schedule, or a decision may be made to discontinue 
the patient from further study drug administration.  Study drug administration (at the 
reduced dose level) may be delayed for up to two weeks to allow for amelioration or 
resolution of the event.  If a delay is required following two dose reductions, further dose 
reductions should be discussed with the Sponsor, or the patient should be discontinued from 
further study drug administration. 
 
Patients with stable disease or response may continue on study without a dose reduction and 
in the presence of a Grade 3 or 4 adverse drug reaction at the discretion of the Principal 
Investigator and following discussion with the Sponsor. 
 
 
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14.2.5 Dose Re-escalation 
 
Once a patient has undergone a dose reduction, re-escalation will not be allowed. 
 
14.2.6 Dose Modifications for Oral or IV  Deforolimus in case of Pneumonitis and/or 
Hypertriglyceridemia/Hypercholesterolemia 
14.2.6.1 Pneumonitis  
 
Interstitial pneumonitis or bronchiolitis obliterans and/or organizing pneumonia have been 
observed in patients receiving rapamycin and rapamycin analogs, including deforolimus 
(Hidalgo, 2004; Champion et al., 2006; Duran et al., 2006; Nashan et al., 2004).  
Pneumonitis may be asymptomatic or may be associated with symptoms such as dyspnea, 
cough, hemoptysis and fever. Pulmonary opacities noted on thoracic radiographs need to be 
distinguished from progressive metastatic disease. 
 
Across all clinical trials, pneumonitis has been reported for approximately 2% to 4% of the 
more than 650 patients who had been treated with deforolimus as of March 2008.  Several of 
these patients experienced additional prolonged stable disease after resumption of treatment 
following dose interruption or steroid treatment.  Patients receiving the IV formulation of 
deforolimus have resumed treatment for as long as 18 months. Among the 147 patients 
enrolled and treated in the Phase 1 oral deforolimus trial (Trial 106), pneumonitis was 
reported for 10 patients (6.8%). 
 
Patients participating in this trial may have a diagnosis of pneumonitis under two 
circumstances: 1) as the result of the investigation of respiratory symptoms or 2) detection 
by scheduled tumor assessment scans for this trial.  While reviewing patient scans for tumor 
progression, the clinician and radiologist should consider pneumonitis as a cause for a 
pulmonary lesion.  What follows are guidelines for the treatment of patients diagnosed with 
pneumonitis deemed related to deforolimus.  
 
The treatment of symptomatic patients differs from asymptomatic patients. Patients with 
symptomatic pneumonitis should immediately stop receiving study drug and have an 
evaluation to rule out other causes, such as infection.   If the diagnosis is study drug-
associated (deforolimus) pneumonitis, the following recommended treatment plan should be 
applied. 
 
Recommended treatment for patients with symptomatic pneumonitis: 
• If ≤ Grade 2: Dose interruption and steroid intervention  with option to return to 
treatment if improvement to Grade 1 or resolution within 4 weeks 
- Patients should begin a regimen of steroids (prednisone 60-80 mg QD 1-2 weeks) 
tapering over 1-4 weeks. Study drug may be resumed after clinical improvement 
is observed 
 
 
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• If ≥  Grade 3: Immediate discontinuation  
 
After improvement of the pneumonitis to ≤  Grade 1, the following rules should apply for 
those on oral deforolimus (for IV recommendations call the sponsor): 
• First episode of pneumonitis (including any parent trial episodes) 
- 
Improvement occurs in ≤  2 weeks – Resume full dose 
- 
Improvement occurs in > 2 weeks – Resume at 10 mg lower than starting dose 
• Second episode of pneumonitis (including any parent trial episodes) 
- 
Permanently discontinue study treatment if upon study drug rechallenge patient 
develops pneumonitis ≥  Grade 2 
 
Recommended treatment for patients with asymptomatic pneumonitis: 
Patients who are asymptomatic but have findings of pneumonitis should stop study drug for 
one week and during that week receive steroids (60 mg prednisone). If there is no 
improvement in the signs of pneumonitis, additional diagnostic procedures should be 
considered, such as bronchoscopy, to confirm the diagnosis. If there is improvement in the 
pneumonitis, the patient may resume treatment with study drug while undergoing a 1-2 
week taper of the steroids. The patient should be followed every 2-4 months by chest x-ray 
to monitor for recurrence of the pneumonitis. 
14.2.6.2 Hypertriglyceridemia/Hypercholesterolemia 
 
Hyperlipidemia is a common adverse reaction associated with rapamycin analogs.  
Clinically significant elevations above baseline levels of cholesterol and/or triglyceride 
levels should be immediately managed with respect to the patient’s overall condition; both 
statins and fibrate agents have been used in patients receiving AP23573.  In principle, no 
dose interruptions or reductions should occur.  However, for patients with persistent 
hypercholesterolemia despite therapy with statins or fibrates, dose reduction or interruption 
may be considered. 
 
 
14.3 Dose Modification for Unrelated Adverse Events 
 
Dosage interruptions are permitted in the case of medical/surgical events (e.g., elective 
surgery, unrelated medical events) not related to study drug administration. The reason for 
the interruption must be documented in the patient’s chart. 
 
14.4 Other dose Modifications 
 
Investigators may consider dose modifications other than those described in sections 14.1 to 
14.3: for example, long-term therapy could be administered at a reduced frequency while 
maintaining the overall benefit for the patient (e.g., administering IV deforolimus for 
 
 
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5 consecutive days every 3 weeks instead of every 2 weeks). These dose modifications must 
be discussed with and approved by the Sponsor. 
14.5 Formulation, Packaging, and Labeling – Deforolimus 
 
Oral deforolimus 
Deforolimus tablets are manufactured as enteric-coated tablets for delayed release.  One 
tablet strength (i.e., 10 mg) will be used for this study.  Each tablet contains 10 mg of 
deforolimus active pharmaceutical ingredient and typical pharmaceutical excipients.  The 
study drug is packaged in a child-resistant aluminum blister pack and will be removed from 
the blister packs by the patient at the time of administration. 
 
Intravenous deforolimus 
Deforolimus vials contain deforolimus drug product (62.5 mg/mL in 2 mL 100% ethanol). 
In addition, a second vial, that contains deforolimus diluent (5.2 % propylene glycol, 5.2 % 
polysorbate 80 [Tween 80], in Water for Injection; 9.6 mL) will be provided. Vial Labels 
will bear the appropriate label text as required by governing regulatory agencies. 
 
The study drug is light sensitive and must be protected from direct and indirect light 
during preparation and administration.  
 
Study drug is to be prepared as described in the Directions For Use insert provided with 
each drug shipment.  Briefly, 0.4 mL of deforolimus drug product Vial 1 is to be transferred 
into the Diluent Vial, yielding a stock solution containing the following: 2.5 mg/mL study 
drug stock solution (25 mg in 10.0 mL total volume) in 4% ethanol, 5% propylene glycol, 
5% polysorbate 80 (Tween), in water for injection. 
 
The stock solution should be used within 2 hours following preparation, stored at room 
temperature, and protected from light.   
 
The study drug dosing solution is then prepared by transferring the appropriate volume of 
stock solution into a glass bottle or non-PVC bag containing approximately 250 mL of 
Normal Saline.   
 
Gently invert the infusion bottle or bag several times to ensure that the dosing solution is 
well mixed. 
 
The dosing solution should be stored at room temperature, protected from light, and 
administered within six hours following preparation (study drug contains no 
preservative or bacteriostatic agents). Only non-PVC infusion sets must be used.  In-
line filters must not be used. 
 
 
 
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14.6 Storage and Stability – Deforolimus 
 
Oral deforolimus 
The recommended storage condition for deforolimus tablets is refrigerated at 2ºC to 8°C 
(36°F to 46°F). Formal ICH stability studies are ongoing to determine the shelf life of the 
product. Currently, the stability period for deforolimus tablets is at least 18 months under 
refrigeration. 
 
Intravenous deforolimus 
The recommended storage condition for deforolimus drug product (vial 1) is ≤ -20ºC. The 
recommended storage condition for deforolimus diluent (vial 2) is 2ºC to 8ºC. Formal ICH 
stability studies are ongoing to determine the shelf-life of the product. Currently, the retest 
period for deforolimus drug product is 26 months and deforolimus diluent is at least 36 
months. 
 
14.7 Drug Accountability – Deforolimus 
14.7.1 Dispensing of Study Drug and Dosing Compliance 
 
The study pharmacist at the site will be responsible for handling study drug and completion 
of associated paperwork.   
 
Supplies are shipped to the investigational site at appropriate intervals, depending on patient 
accrual.  The site must use an appropriate dispensing log/accountability form provided by 
the Sponsor or an acceptable substitute approved by the Sponsor. Each time a kit is 
dispensed for a patient the following information must be recorded: patient initials, patient 
study number, the kit number dispensed with their corresponding lot number, and the initials 
of the person dispensing the dose. These logs are to be maintained by the study pharmacist 
in the pharmacy throughout the duration of the study and will be periodically verified by a 
representative of the Sponsor. 
14.7.2 Disposition of Used Supplies 
 
Use of deforolimus tablets or IV product outside the scope of this trial is NOT authorized by 
the Sponsor.  The Principal Investigator or his/her designee will be responsible for the 
appropriate handling and disposition of any remaining unused study drug and containers. 
 
 
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14.7.3 Inventory of Unused Supplies 
 
During the trial and at termination, patients must return all unused oral drug supplies to the 
investigational site and this must be recorded. These returned supplies must not be 
redispensed. 
 
Periodically throughout and at the conclusion of the trial, a representative of the Sponsor 
will conduct an inventory of unused study drug. At the completion of the trial, a final drug 
accountability review will be conducted.  Any discrepancies must be investigated and all 
unused study drug MUST be returned to the Sponsor, or designee, with the appropriate 
forms unless otherwise authorized in writing by the Sponsor.  
15. CONCOMITANT TREATMENTS 
All concomitant medications administered during the active study period are to be 
reported on the appropriate case report forms for each patient.   
15.1 Permitted Treatment 
 
Palliative and supportive care will be provided during this trial, as clinically indicated, and 
in accordance with the standard practices of the institution.  Clinical judgment should be 
utilized in the treatment of any adverse event experienced by the patient. 
 
Information on all concomitant medications, blood products administered, as well as 
interventions occurring during the study period must be recorded on the patient’s case report 
form. 
 
15.2 Prohibited Treatment 
Surgery or radiotherapy for tumor control is not permitted while patients are on treatment. 
 
The following drugs and other treatments are not permitted:  
• Anti-cancer treatments including chemotherapy, immunotherapy, biological response 
modifiers (excluding hematopoietic growth factors), and systemic hormonal therapy 
Exceptions: 
− When the agent was allowed during the parent protocol 
− hormonal therapy (e.g., Megace) for appetite stimulation 
− nasal, ophthalmic, and topical glucocorticoid preparations 
− a stable dose of corticosteroids for at least two weeks 
− low dose maintenance steroid therapy for other conditions 
− physiologic hormone replacement therapy (e.g., thyroid supplementation for 
thyroid deficiency or oral replacement glucocorticoid therapy for adrenal 
insufficiency) 
 
 
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• Herbal preparations or related OTC preparations containing herbal ingredients that are 
known to affect CYP3A isoenzymes (e.g., St. John’s Wort)  
• Elective use of recombinant hematopoietic growth during study treatment 
15.3 Potential Drug Interactions 
 
Caution should be used when administering concomitant medications that induce, inhibit, or 
are metabolized by cytochrome P450 (CYP3A).  Deforolimus is extensively metabolized by 
CYP3A.  As a result, the potential for drug-drug interactions should be considered.  
Concomitant administration of products that interfere with P450 enzyme systems (see 
Attachment C) will be clearly documented in the CRF.  The use of such agents should be 
avoided whenever possible. 
 
Caution should also be used when administering concomitant medications, such as warfarin, 
propranolol, phenytoin, and diazepam, which are extensively bound to plasma protein.  In 
vitro, deforolimus was found to be 96.8% bound to plasma proteins.  In vivo, it is likely that 
most deforolimus will be bound to FKBP in red blood cells because of the high affinity of 
deforolimus for FKBP.  Thus, it is anticipated that a very small amount of deforolimus will 
be in plasma at any given time.  Nevertheless, drugs that are extensively bound to plasma 
proteins may displace deforolimus from binding sites in plasma.  Concomitant 
administration of products that are bound to plasma proteins must be clearly documented in 
the CRF. 
16. MEASURES TO MINIMIZE/AVOID BIAS 
 
As this is an open label study, bias minimization is not applicable. 
17. INTERIM SAFETY AND EFFICACY ANALYSIS 
 
Safety and efficacy analyses will be conducted and the overall risk benefit ratio of long-term 
deforolimus treatment will be assessed every 6 months during the trial.  The available data 
will be reviewed by a team comprised of the Sponsor’s representatives, including at least the 
Sponsor’s medical monitor, 20% of principal investigators of the sites with enrolled patients, 
and any other individuals deemed appropriate by the Sponsor.   
 
18. SAFETY 
18.1 Safety Assessment 
 
Safety will be assessed by physical examination, interim history, and laboratory 
assessments.  Severity of adverse events will be graded according to the NCI Common 
 
 
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Terminology Criteria for Adverse Events (CTCAE), Version 3.0 (provided with the study 
administration documents). 
18.2 Safety Assessment Methods 
 
Patients who did not receive any protocol treatment during the extension this trial will not be 
included in the safety analysis.  All patients who received any study treatment on this 
extension protocol will be included in the safety analysis according to their actual treatment.  
Patients will be monitored for the occurrence of adverse events (AEs) from the time of 
signing informed consent through the post-treatment discontinuation visit. 
 
Safety evaluations will be based on the incidence, intensity, and type of adverse events, and 
clinically significant changes in the patient’s physical examination findings, vital signs and 
clinical laboratory results.  Safety variables will be tabulated and presented for all patients 
who receive any amount of study medication. 
 
The incidence of adverse events will be evaluated.  Patients are to be followed for adverse 
events through the post-treatment discontinuation visit.  All study drug-related adverse 
events and all serious adverse events will be followed until resolution or until administration 
of another anti-cancer therapy.  All safety assessments will be recorded on the CRF. 
 
Serum pregnancy tests (ß-HCG) in women of child-bearing potential will be performed 
according to the Schedule of Events (see Section 8: Schedule of Events). 
 
19. STATISTICAL ANALYSIS 
 
19.1 
Study Overview 
Patients will be eligible for the extension study if they have participated in a prior 
deforolimus trial and are continuing to receive deforolimus under the parent protocol or if 
they are being followed for overall survival (OS) under the parent protocol. 
Patients may continue to receive deforolimus and/or be followed for overall survival (OS) 
during the extension study. 
 
 
 
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19.2 
Endpoints 
 
Primary Endpoint 
• Safety and tolerability of long-term deforolimus 
 
Secondary Endpoints 
• 
Progressive Disease (PD) will be assessed by the investigator as determined by the 
parent protocol. For consistency, the RECIST guidelines are used in most cases, when 
applicable.  
• 
Overall survival, defined as the time from the date of first dose of study drug in the 
parent trial to the date of death, 
 
Progression-free survival (PFS), overall survival (OS), and duration of response will be 
evaluated using the Kaplan-Meier method and graphed as in the parent protocols.   
Progression free survival, overall survival, and duration of response at fixed time points 
(e.g., 6 months, 12 months, and 2 years), will be estimated using the Kaplan-Meier method. 
Confidence intervals for PFS, OS, and duration of response will be computed and graphed. 
 
20. CONTRAINDICATIONS, PRECAUTIONS, AND WARNINGS 
20.1 
Precautions Regarding Procreation 
 
Deforolimus does not induce microbial or mammalian cell gene mutations in vitro, and does 
not produce chromosomal aberrations in vitro or in vivo.  Reproductive effects have not been 
studied in women. Reproductive effects of deforolimus were seen in repeat-dose studies in 
rats. In repeat-dose toxicity studies with IV deforolimus, deforolimus was associated with 
testicular degeneration with decreased epididymal spermatogenesis.  In preliminary results 
from the dose-ranging portion of a fetal development study in female rats, the incidence of 
early fetal resorption was 100% for all doses of deforolimus tested (i.e., 10, 25, 50, and 100 
mg/kg/day). Early embryonic or fetal mortality is a class effect that has been reported with 
other mTOR inhibitors. 
 
 
Women of childbearing potential will be informed as to the potential risk of procreation 
while participating in this trial and will be advised that they must use approved 
contraceptive method as appropriate from time of study screening until 30 days after the last 
dose of study drug.  Non-hormonal methods must be used in this trial.  Approved 
contraceptive methods include, for example, intra-uterine device, diaphragm with 
spermicide, cervical cap with spermicide or female condom with spermicide. (Spermicides 
alone are not an acceptable method of contraception.).  A pregnancy test will be performed 
on each pre-menopausal female of childbearing potential immediately prior to entry into the 
study (at the time of Baseline for this study), every 6 months while on study, and at the post-
treatment discontinuation visit. 
 
 
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If a patient is confirmed to be pregnant during the trial, study drug administration must be 
discontinued immediately.  Any pregnancy occurring during this study is to be reported as 
an SAE.  The Investigator must immediately notify the medical monitor about the pregnancy 
and record it as a Serious Adverse Event on the SAE Form as well as on the adverse event 
page of the CRF (or other CRF specifically provided for this purpose).  In addition, the 
Investigator must report follow-up information to the Sponsor regarding the course of the 
pregnancy, including perinatal and neonatal outcome, regardless of whether the patient has 
discontinued participation in the study, unless the patient has received other anti-cancer 
therapy. 
 
Once the newborn is determined to be healthy, additional follow-up will no longer be 
required. 
20.2 
Additional Precautions 
 
Caution should be used when administering concomitant medications that induce, inhibit, or 
are metabolized by cytochrome P450 or that are extensively protein bound (see Section 
15.4: Potential Drug Interactions). 
  
Caution should also be used when administering concomitant medications, such as warfarin, 
propranolol, phenytoin, and diazepam, which are extensively bound to plasma protein.  In 
vitro, deforolimus was found to be 96.8% bound to plasma proteins.  In vivo, it is likely that 
most deforolimus will be bound to FKBP in red blood cells because of the high affinity of 
deforolimus for FKBP.  Thus, it is anticipated that a very small amount of deforolimus will 
be in plasma at any given time.  Nevertheless, drugs that are extensively bound to plasma 
proteins may displace deforolimus from binding sites in plasma.   
 
Please refer to the current edition of the deforolimus Clinical Investigator's Brochure for a 
complete description of all available safety information reported during the deforolimus 
clinical and non-clinical studies.  
21. ADVERSE EVENTS 
21.1 
Adverse Event Definition 
 
An adverse event (AE) is defined as any unintended or undesirable, noxious, or pathological 
change, compared to pre-existing conditions, experienced by a patient during a clinical study 
or the follow-up period, regardless of relationship to study drug.  Adverse events include: 
• Suspected adverse drug reactions 
• Reactions from drug overdose, abuse, withdrawal, sensitivity, or toxicity 
• Significant changes or abnormalities, when compared to baseline, in structure (sign), 
function (symptom), clinical laboratory results, or physiological testing.  This 
 
 
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includes any worsening of a pre-existing condition temporally associated with the 
use of study drug 
• Other medical events, regardless of their relationship to the study drug, such as 
injury, surgery, accidents, extensions of symptomatology, or apparently unrelated 
illnesses 
21.2 
Evaluating Adverse Events 
 
21.2.1 Determination of Seriousness 
 
The Investigator will determine the seriousness of an adverse event based on the following 
definitions: 
 1. Serious Adverse Events (SAEs) 
An SAE is any adverse event occurring at any dose that: 
o Results in death  
o Is life-threatening or places the patient, in the view of the investigator, at 
immediate risk of death as the event occurred (note: this does not include an 
adverse event that had it occurred in a more severe form, might have caused 
death). 
o Results in in-patient hospitalization or prolongation of existing 
hospitalization  
o Is a persistent or significant disability/incapacity  
o Is a congenital anomaly/birth defect (in offspring of a patient who is taking or 
has taken study medication) 
o Is a new cancer (does not include metastasis or progression of primary cancer 
unless the metastasis or progression meets one of the 5 serious criteria stated 
above) 
o Is an overdose (accidental or intentional) 
o Other important medical events that may not result in death, not be life 
threatening, or not require or prolong hospitalization may be considered a 
serious adverse event when, based upon appropriate medical judgment, the 
event may jeopardize the patient and may require medical or surgical 
intervention to prevent one of the outcomes listed above 
 
 
Hospitalization refers to admission of a patient into a hospital for any length of time.  
A prescheduled or elective procedure or routinely scheduled treatment will not be considered an 
SAE, even if the patient is hospitalized, provided the study site stipulates: 
 
• 
The prescheduled elective procedure or routinely scheduled treatment was scheduled (or was 
on a waiting list to be scheduled) prior to obtaining the patient’s consent to participate in the 
study. 
• 
The condition requiring the prescheduled elective procedure or routinely scheduled 
treatment was present before and did not worsen or progress between the patient’s consent 
 
 
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The term “life-threatening” describes any adverse event or experience, suspected to be drug 
related that places the patient or subject in the view of the investigator, at immediate risk of 
death at the time of the event.  This does not include events that may have caused death had 
they been more severe. 
 
Persistent or significant disability refers to a significant disruption of a person’s ability to 
conduct life functions. 
 
A congenital anomaly/birth defect refers to a fixed, permanent impairment established at or 
before birth. 
 
 
 
For the purposes of this protocol, a deforolimus overdose is defined as: 
 
 (a) Oral formulation: 
• A single dose in excess of 100 mg 
• A cumulative 28-day dose of greater than 800 mg for daily or 
intermittent dosing schedules 
 
 
(b) Intravenous formulation: 
• A single dose in excess of 100 mg 
• A cumulative 28-day dose of greater than 200 mg for daily or 
intermittent dosing schedules.  
 
2. Non-serious Adverse Events  
All other adverse events, not fulfilling the previous definitions, are classified as non-
serious adverse events. 
 
21.2.2 Determination of Severity 
 
The severity of AEs will be assessed according to the Common Terminology Criteria for 
Adverse Events (CTCAE), Version 3.0.  If the AE is not defined in the CTCAE, the 
Investigator will determine the severity of an adverse event based on the following 
definitions: 
• Mild (Grade 1): The AE is noticeable to the patient but does not interfere with 
routine activity.  The AE does not require discontinuing administration or reducing 
the dose of the study drug. 
• Moderate (Grade 2): The AE interferes with routine activity but responds to 
symptomatic therapy or rest.  The AE may require reducing the dose but not 
discontinuing administration of the study drug.  
 
 
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• Severe (Grade 3): The AE significantly limits the patient’s ability to perform routine 
activities despite symptomatic therapy.  In addition, the AE leads to discontinuing 
administration or reducing the dose of the study drug.  
• Life-Threatening (Grade 4): The AE requires discontinuing administration of the 
study drug.  The patient is at immediate risk of death.  
 
21.2.3 Definitions for Categories of Relatedness 
 
The Investigator will determine the relatedness of an adverse event with the study drug 
based on the following definitions: 
 
A. Definitely related to test drug (drug related):  
• There is evidence of exposure to the test drug. 
• The temporal sequence of the AE onset relative to administration of the test 
drug is reasonable. 
• The AE is more likely explained by the test drug than by another cause. 
• Dechallenge is positive. 
• Rechallenge (if feasible) is positive. 
• 
The AE shows a pattern consistent with previous knowledge of the test drug or test 
drug class  
B.  Probably related to test drug (drug related):  
• There is evidence of exposure to the test drug. 
• The temporal sequence of the AE onset relative to administration of the test 
drug is reasonable. 
• The AE is more likely explained by the test drug than by another cause. 
• Dechallenge (if performed) is positive. 
C.  Possibly related to test drug (drug related): 
• There is evidence of exposure to the test drug. 
• The temporal sequence of the AE onset relative to administration of the test 
drug is reasonable. 
• The AE could have been due to another equally likely cause. 
• Dechallenge (if performed) is positive. 
D.  Probably not related to test drug (not drug related):  
• There is evidence of exposure to the test drug. 
• There is another more likely cause of the AE. 
• Dechallenge (if performed) is negative or ambiguous. 
 
 
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• Rechallenge (if performed) is negative or ambiguous 
E. Definitely not related to test drug (not drug related): 
• The patient did not receive the test drug. 
OR 
• Temporal sequence of the AE onset relative to administration of the test drug 
is not reasonable. 
OR 
• There is another obvious cause of the AE. 
Note: Not all criteria in each category of relatedness need to be present. 
 
21.3 
Documenting Adverse Events  
 
All adverse events (including SAEs) are to be accurately recorded on the Adverse Event 
page of the patient’s case report form from the time the patient signs the informed consent 
until the post-treatment discontinuation visit.  Each event will be graded for severity, 
intensity, and relatedness (see Section 21.2: Evaluating Adverse Events). The date of onset 
as well as the duration of the event will be recorded.  In addition, the method used to treat 
the adverse event and the outcome of the adverse event will also be noted.   
21.4 
Reporting SAEs and Patient Deaths 
 
21.4.1 Time-frame for Reporting 
 
Any death or serious adverse event experienced by the patient from the time the patient 
signs informed consent to 30 days after receiving study drugs or through the date of the 
post-treatment discontinuation visit (i.e., approximately 30 ± 7 days following the last dose 
of study drugs), or any death or SAE believed to be study drug-related that occurs at anytime 
thereafter, must be  reported within 24 hours of learning of the event by telephone or telefax 
to the Sponsor or the Sponsor’s designee.   
 
21.4.2 Information to be provided by the Investigator 
 
Within 24 hours of learning about the SAE or patient death, the Investigator must notify the 
Sponsor or designee and transmit information to the Sponsor or designee.  The Sponsor or 
designee will require of the following information: 
1. Patient identification code, sex, age or date of birth 
2. Investigator/reporter information – name, site number, contact information 
 
 
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3.  Description of suspect medication (study drug(s) - including dose and frequency of study 
drug administered, data of administration if available 
4. Description of event  
5. Date of death (if applicable) 
 
In addition to the above information, the Sponsor will require the Investigator’s assessment 
of the following: 
1. Severity of the adverse event 
2. Relationship of the adverse event to the study drug 
3. Outcome of the adverse event 
 
21.4.3 Follow-up Information on an SAE 
 
Appropriate diagnostic tests should be performed and therapeutic measures, if indicated, 
should be instituted.  Appropriate consultation and follow-up evaluations should be carried 
out until the event has resolved or is otherwise explained by the Principal Investigator. 
 
Follow-up data concerning the SAE (e.g., diagnostic test reports, physician's summaries, 
etc.) must also be submitted to the Sponsor within 24 hours of the study site becoming aware 
of new information.  Should the FDA or National Regulatory Authorities require that the 
Sponsor submit additional data on the event, the Investigator will be asked to provide those 
data to the Sponsor in a timely fashion. 
 
21.5 
Review of an SAE by the Sponsor and Determination of Further Action  
 
Based in part on the Investigator’s assessment of the adverse event, the Sponsor will 
determine regulatory reportability of the SAE.    
 
21.5.1 Suspected Unexpected Serious Adverse Drug Reactions (SUSAR) 
 
SUSARs are SAEs that are unexpected and judged by the Investigator or the Sponsor to be 
related to study drug.  In accordance with applicable regulations, SUSARs will be submitted 
by the Sponsor (or designee) to appropriate regulatory authorities, ethics committees and 
Investigators.   
 
If the discovery of a new adverse event related to study drug raises concern over the safety 
of its continued administration to patients, the Sponsor may take further action which may 
include the following: 
• Alteration of the existing research program by modification of the protocol 
 
 
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• Discontinuation or suspension of the trial 
• Alteration of the informed consent process by modification of the existing consent 
 
form and informing current study participants of new findings 
21.6 
Required Follow-up for SAEs 
 
There should be routine follow-up for 30 days after study drug discontinuation in all patients 
in order to monitor for the occurrence of serious adverse events.  In addition, limited follow-
up at three and six months after the end of the last dosing cycle will be conducted to 
evaluate for cessation of any adverse drug reaction that may have arisen during the trial, 
unless the patient has received another anti-cancer agent.  The Medical Monitor may specify 
a longer period of time, if required to ensure the safety of the patient. 
 
22. DATA QUALITY ASSURANCE 
The Sponsor will perform quality control and assurance checks on all clinical studies that it 
sponsors.  Before enrolling any patients into this trial, Sponsor personnel and the 
Investigator will review the protocol, the Clinical Investigator's Brochure, the CRFs and 
instructions for their completion, the procedure for obtaining informed consent, and the 
procedure for reporting AEs.  A qualified representative of the Sponsor will monitor the 
conduct of the trial by visiting the site and by contacting the site by telephone.  During the 
visits, information recorded on the CRFs will be verified against source documents.  If paper 
CRFs are used, those data are entered into the database using a double data entry procedure 
(or other quality assurance procedure).  The Sponsor’s medical monitor will review the data 
for safety information.  The Sponsor’s clinical data associates will review the data for 
legibility, completeness, and logical consistency.  Additionally, the Sponsor clinical data 
associates will use automated validation programs to help identify missing data, selected 
protocol violations, out-of-range data, and other data inconsistencies.  Requests for data 
clarification or correction will be forwarded to the investigational site for resolution.  A 
sample set of records from the final database will be fully audited against the corresponding 
CRFs. 
23. INVESTIGATOR’S REGULATORY OBLIGATIONS 
23.1 
Institutional Review Board (IRB) / Ethics Committee (EC) Approval 
This extension protocol and the informed consent document, as well as the parent 
protocol(s) and informed consent document(s) justifying enrollment into this extension 
protocol must have the initial and at least annual (when required) approval of an IRB/EC.  
The signed IRB/EC approval letter must identify the documents approved (i.e., list the 
Investigator’s name, the protocol number and title, the date of the protocol and informed 
consent document, and the date of approval of the protocol and the informed consent 
 
 
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document).  The Sponsor will not ship clinical supplies until a signed approval letter from 
the IRB/EC has been received and a contractual agreement has been signed by the Sponsor 
and the clinical site. 
23.2 
Prestudy Documentation 
The Investigator must provide the Sponsor with the following documents BEFORE 
enrolling any patients: 
• Completed and signed FDA Form 1572 
• All applicable country specific regulatory forms 
• Current curricula vitae for the Investigator and all subinvestigators 
• Copy of the IRB/EC approval letter for the protocol and informed consent.   
• Copy of the IRB/EC-approved informed consent document to be used 
• When applicable, a list of the IRB/EC members or a statement of compliance with 
regulations 
• Copy of the protocol signature page signed by the Investigator 
• Fully executed clinical trial agreement 
• Certification or accreditation with the name of the laboratory at which protocol 
required tests are performed.  To be provided for all laboratories listed on the 1572. 
• List of normal reference ranges for all laboratories performing tests required by the 
protocol.  The name of the laboratory and effective dates should be specified.  To be 
provided for all laboratories listed on the 1572. 
23.3 
Informed Consent 
Regulatory agencies have issued regulations to provide protection for human patients in 
clinical investigations and to describe the general requirements for informed consent. 
A copy of your proposed informed consent document should be submitted to the Sponsor for 
review and comment before submission to your IRB/EC.  The trial should not begin until the 
document has been reviewed by the Sponsor and must not begin until the document has been 
approved by the IRB/EC.  In some instances the trial must not begin until the document has 
been approved by a regulatory agency. 
 
 
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The informed consent document shall contain all of the elements of informed consent 
specified in the regulations.  Some regulations may require the disclosure of additional 
information to the patient and/or inclusion of additional information in an informed consent 
document.   
23.4 
Declaration of Helsinki 
This trial will be conducted in accordance with the ethical principles that have their origin in 
the Declaration of Helsinki and that are consistent with GCP and the applicable regulatory 
requirements. 
23.5 
Case Report Forms 
1. All data will be reported on CRFs provided by the Sponsor 
2. If paper CRFs are used, the originals must be returned to the Sponsor; the 
Investigator must retain a copy for his/her files.  If an Electronic Data Capture 
system is used, an electronic copy of the CRFs will be provided to the Investigator 
for retention in the study files 
3. CRFs and other pertinent records are to be submitted to the Sponsor during and/or at 
completion or termination of the trial 
4. The Investigator also must submit all incomplete CRFs that document patient 
experience with the study drug, including retrievable data on patients who withdraw 
before completion of the trial 
All study information should be recorded in an appropriate source document (e.g., clinic 
chart). 
23.6 
Adverse Event Reporting 
The Investigator agrees to report all AEs to the Sponsor as described in the Adverse Event 
section (see Section 21.4: Reporting SAEs and Patient Deaths).  Furthermore, the 
Investigator is responsible for ensuring that any coinvestigator or subinvestigator promptly 
brings AEs to the attention of the Investigator.  If applicable, the Investigator also is 
responsible for informing the participating IRB/EC of any SAEs. 
23.7 
Review of Source Records 
The Investigator agrees that qualified representatives of the Sponsor and regulatory agencies 
will have the right, both during and after this trial, to conduct inspections and to audit and 
review medical records pertinent to the clinical study as permitted by the regulations.  
Patients will not be identified by name, and confidentiality of information in medical records 
 
 
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will be preserved.  The confidentiality of the patient will be maintained unless disclosure is 
required by regulations.  Accordingly, the following statement (or similar statement) that 
permits the release of the patient’s medical records will be included in the informed consent 
document: 
Representatives of regulatory agencies, IRB/EC, the Sponsor, and your personal physician 
may review your medical records and all information related to this trial as permitted by 
law.  The Sponsor will not know your identity.  Your identity will remain confidential unless 
disclosure is required by law. 
23.8 
Monitoring of the Study 
This trial is monitored by a representative of the Sponsor.  Site visits are made before the 
trial begins, at regular intervals during the study, and at the study closeout.  Communication 
by telephone, mail and e-mail may be used as needed to supplement site visits.  The 
Investigator and study personnel will cooperate with the Sponsor, provide all appropriate 
documentation, and be available to discuss the trial.  The purpose of the site visits is to 
verify: 
1. Adherence to the protocol (The Investigator should document and explain any 
deviation from the approved protocol) 
2. The completeness and accuracy of the CRFs and the dispensing and inventory record 
(Adequate time and space for these visits should be allocated by the Investigator) 
3. Compliance with regulations.  The verification will require comparison of the source 
documents to the CRFs 
23.9 
Protocol Amendments 
Any significant change in the study protocol will require an amendment.  The Investigator 
and the appropriate Sponsor medical monitor indicate their approval by signing the approval 
page of the amendment.  Once a protocol amendment has received approval from the 
Sponsor, the Investigator submits it to the IRB/EC for written approval.  The approval letter, 
signed by the IRB/EC chair, must refer specifically to the investigator, the Sponsor protocol 
number, the protocol title, the protocol amendment number, and the date of the protocol 
amendment.  The Sponsor submits a copy of the protocol amendment to the appropriate 
regulatory agency/agencies.  A protocol amendment may be implemented after it has been 
approved by the IRB/EC. 
A protocol change intended to eliminate an apparent immediate hazard to patients may be 
implemented immediately, but the change must then be documented in an amendment and 
reported to the IRB/EC within 5 working days. 
 
 
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23.10 Change in Investigator 
If any investigator retires, relocates, or otherwise withdraws from conducting a trial, the 
responsibility for maintaining records may be transferred to another person (Sponsor, 
IRB/EC, other investigators) who will accept the responsibility.  The Sponsor must be 
notified of and agree to the change.  An updated FDA Form 1572 will be filed with the 
Sponsor and the FDA for any changes in the study personnel reported in the current FDA 
Form 1572. 
23.11 Termination of Study 
23.11.1 
Termination by the Sponsor 
The Sponsor may terminate the trial at anytime for any of the following reasons: 
1. Failure to enroll patients 
2. Protocol violations 
3. Inaccurate or incomplete data 
4. Unsafe or unethical practices 
5. Questionable safety of the study drug 
6. Suspected lack of efficacy of the study drug 
7. Administrative decision 
23.11.2 
Termination of Investigator 
If the Investigator terminates participation in the trial prematurely, the Investigator does the 
following: 
1. Return all study drugs, CRFs, and related study materials to the Sponsor 
2. Provide a written statement describing why the trial was terminated prematurely 
23.12 Final Study Report 
The Investigator must complete a report notifying the IRB/EC of the conclusion of the 
clinical trial.  This report should be made within 3 months of completion or termination of 
the trial. 
The final report sent to the IRB/EC is also sent to the Sponsor and, along with the completed 
CRFs, constitutes the final summary to the Sponsor, thereby fulfilling the Investigator’s 
regulatory responsibility. 
 
 
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23.13 Confidentiality 
All unpublished information that the Sponsor gives to the Investigator shall be kept 
confidential and shall not be published or disclosed to a third party without the prior written 
consent of the Sponsor. 
When the Sponsor generates reports for presentations to regulatory agencies, 1 or more of 
the investigators who have contributed significantly to the trial will be asked to endorse the 
final report.  The endorsement is required by some regulatory agencies. 
The investigator shall not make a patent application based on the results of this trial and 
shall not assist any third party in making such an application without the written 
authorization of the Sponsor. 
23.14 Records Retention 
All correspondence related to this clinical trial should be kept in appropriate study files.  
Record of patients, source documents, CRFs, drug inventory, and IRB/EC and Sponsor 
correspondence pertaining to the trial must be kept on file.  All original patient, laboratory, 
and drug inventory records relating to the trial are retained for not less than 5 years after 
notification by the Sponsor that all studies using the study drug have been discontinued or 
that a regulatory agency has approved an application for the marketing of the study drug.  
Thereafter, records will not be destroyed without giving the Sponsor prior written notice and 
the opportunity to further store such records, at the Sponsor’s cost and expense.  
 
 
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24. REFERENCES 
Atabai K, Ishigaki M, Geiser T, et al. Keratinocyte growth factor can enhance alveolar 
epithelial repair by nonmitogenic mechanisms. Am. J. Physiol. Lung Cell. Mol. Physiol. 
2002; 283:163–9. 
Bjornsti MA, Houghton PJ. The TOR pathway: A target for cancer therapy. Nat Rev Cancer 
2004;4:335-348. 
Brown EJ, Albers MW, Shin TB, et al. A mammalian protein targeted by G1-arresting 
rapamycin-receptor complex. Nature 1994;369:756-758. 
Champion L, Stern M, Israel-Biet D, et al.  Brief communication: sirolimus-associated 
pneumonitis: 24 cases in renal transplant recipients.  Ann Int Med 2006;144: 505-509. 
Chan S. Targeting the mammalian target of rapamycin (mTOR): a new approach to treating 
cancer. Br J Cancer 2004;91:1420-1424. 
Duran I, Siu LL, Oza AM, et al.  Characterisation of the lung toxicity of the cell cycle 
inhibitor temsirolimus.  Eur J Cancer 2006;42: 1875–18. 
Faivre S, Kroemer G, Raymond E. Current development of mTOR inhibitors as anticancer 
agents. Nat Rev Drug Discov 2006;5:671-688. 
Ferlay J, Autier P, Boniol M, et al.  Estimates of the cancer incidence and mortality in 
Europe in 2006. Ann Oncol 2007;18:581-592. 
Hennessy BT, Smith DL, Ram PT, et al. Exploiting the PI3K/AKT pathway for cancer drug 
discovery. Nat Rev Drug Discov 2005;4:988-1004. 
Hidalgo M. New target, new drug, old paradigm. J Clin Oncol, 2004;22(12):2270-222. 
http::\\www.cancer.org. Breast cancer. Accessed February 3, 2008. 
Jemal A, Siegel R, Ward E, et al. Cancer statistics 2007. CA Cancer J Clin 2007;57:43-66. 
Janus A, Robak T, Smolewski P. The mammalian target of the rapamycin (mTOR) kinase 
pathway: its role in tumourigenesis and targeted antitumour therapy. Cell Mol Biol Lett 
2005;10:479-498. 
Karakas B, Bachman KE, Park BH. Mutation of the PIK3CA oncogene in human cancers. 
Br J Cancer 2006;94:455–459. 
Mamane Y, Petroulakis E, LeBacquer O, et al. MTOR, translation initiation and cancer. 
Oncogene 2006;25:6416-6422. 
Miettinen PJ, Warburton D, Bu D et al. Impaired lung branching morphogenesis in the 
absence of functional EGF receptor. Dev Biol 1997;186:224–36. 
 
 
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Nashan B, Curtis J, Ponticelli C, et al. Everolimus and reduced-exposure cyclosporine in de 
novo renal-transplant recipients: a three-year phase II, randomized, multicenter, open-label 
study.  Transplantation 2004;74:1332-1340. 
Rivera VM, Berk L, Mita M, et al. Pharmacodynamic evaluation of the mTOR inhibitor 
AP23573 in phase 1 clinical trials. Eur J Cancer 2004;2 (Abstract 123). 
Rivera V, Kreisberg J, Mita M, et al. Pharmacodynamic study of skin biopsy specimens in 
patients (pts) with refractory or advanced malignancies following administration of 
AP23573, an mTOR inhibitor. J Clin Oncol 2005;23:200s (suppl; abstract 3033). 
Saal LH, Holm K, Maurer M, et al. PIK3CA mutations correlate with hormone receptors, 
node metastasis, and ERBB2, and are mutually exclusive with PTEN loss in human breast 
carcinoma. Cancer Res 2005;65:2554–2559. 
Schmelzle T, Hall MN. TOR, a central controller of cell growth. Cell 2000;103:253-262. 
Shaw RJ, Cantley LC. Ras, PI(3)K and mTOR signalling controls tumour cell growth. 
Nature 2006;441:424-430. 
Therasse P, Arbuck SG, Eisenhauer EA, et al. New guidelines to evaluate the response to 
treatment in solid tumors. J Nat Cancer Inst 2000;92:205-216. 
 
 
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25. ATTACHMENTS 
Attachment A: 
ECOG Performance Status Evaluation  
Attachment B: 
Inhibitors and Inducers of CYP3A 
 
 
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Attachment A: ECOG Performance Status Evaluation 
 
 
Level 
 
ECOG 
 
0 
 
 
 
Normal activity 
 
1 
 
 
 
Symptoms but ambulatory 
 
2 
 
 
 
In bed < 50% of time 
 
3 
 
 
 
In bed > 50 % of time 
 
4 
 
 
 
100 % bedridden 
 
5 
 
Death 
 
 
 
 
Oken M, Creech RH, Tormey DC, Horton J, Davis TE, McFadden E, and Carbone PP.  Toxicity and response criteria of the 
Eastern Cooperative Oncology Group.  Am J Clin Oncol (CCT) 1982, 5:649-655. 
  
 
 
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Attachment B:  Inhibitors and Inducers of CYP3A 
 
 
 
EXAMPLES OF CYTOCHROME P450 ISOENZYME INHIBITORS AND INDUCERS 
 
Inhibitors 
Inducers 
amiodarone 
indinavir 
barbiturates 
phenobarbital 
cimetidine 
itraconazole 
carbamazepine 
phenytoin 
ciprofloxacin 
ketoconazole 
efavirenz 
rifampin 
clarithromycin 
mibefradil 
glucocorticoids 
St. John’s Wort 
delaviridine 
mifepristone 
modafinil 
troglitazone 
diltiazem 
nefazodone 
nevirapine 
 
erythromycin 
nelfinavir 
 
 
fluconazole 
norfloxacin 
 
 
fluvoxamine 
ritonavir 
 
 
gestodene 
saquinavir 
 
 
grapefruit juice 
troleandomycin 
 
 
 
 
 
 
 
 
From: http://medicine.iupui.edu/flockhart/ 
 
 
 
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