Clinical trial NCT02008877
Conditions: Malignant Peripheral Nerve Sheath Tumors (MPNST) Sarcoma
Keywords: Malignant Peripheral Nerve Sheath Tumors MPNST Sarcoma Ganetespib Sirolimus mTOR inhibitor Heat shock protein Hsp90
Sponsor: Sarcoma Alliance for Research through Collaboration
Start date: 2013-12-01; Completion date: 2018-07-01
Enrollment: 20 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Phase 1: To assess the safety, tolerability, and maximum tolerated dose (MTD)/ recommended dose of ganetespib when administered in combination with sirolimus in patients with refractory or relapsed sarcomas including unresectable or metastatic sporadic or neurofibromatosis type 1 (NF1) associated MPNST. Phase I enrollment has been closed.

Phase 2: To determine the clinical benefit of ganetespib in combination with sirolimus for patients with unresectable or metastatic sporadic or NF1 associated MPNST.

Detailed description:
Previously, no targeted agents have been able to cause tumor regression in a genetically engineered MPNST mouse model or human MPNST. Recently published data from Dr. Cichowski's laboratory demonstrated using Hsp90 inhibitors to enhance endoplasmic reticulum stress coupled with the mammalian target of rapamycin (mTOR) inhibitor sirolimus led to dramatic tumor shrinkage in a transgenic MPNST mouse model, which correlated with profound damage to the endoplasmic reticulum and cell death. Ganetespib is a novel, injectable, small molecule inhibitor of Hsp90 and is currently being investigated in adults with a broad range of tumor types with a favorable safety profile and promising early results. Ganetespib has been studied in preclinical in vivo models with a variety of targeted agents with no marked apparent pharmacological interactions. Sirolimus is a commercially available orally administered mTOR inhibitor and is the active metabolite of temsirolimus, which is FDA approved agent for advanced metastatic renal cell carcinoma. Sirolimus has been studied and tolerated in combination with multiple cytotoxic and targeted agents in a variety of tumor types. Based on strong preclinical rationale, the investigators hypothesize that ganetespib in combination with sirolimus will cause tumor regression in patients with refractory MPNSTs.

The investigators propose a multi-institutional open label phase I/II trial of ganetespib in combination with sirolimus in patients with refractory sarcoma including MPNST. Hsp90 inhibitors and mTOR inhibitors have also both demonstrated benefit in a variety of preclinical bone and soft tissue sarcoma models. The investigators hypothesize that these agents that work on separate and potentially synergistic pathways will also be beneficial for other refractory bone and soft tissue sarcomas. Thus, the phase I component will be open to patients with refractory sarcomas, which will also expedite enrollment. Upon determination of the recommended dosing, a phase II study will be conducted. The phase II study population will be limited to patients with a diagnosis of MPNST.

Arms: arm 1: 28-day cycles of ganetespib + sirolimus
Interventions: intervention 1: ganetespib intervention 2: Sirolimus
Intervention descriptions: intervention 1: Phase 1 Dose 1: 150 mg/m² IV on days 1, 8, and 15 intravenously over 1 hour; Phase 1 Dose 2: 200 mg/m² IV on days 1, 8, and 15 intravenously over 1 hour; Phase 2: 200 mg/m² IV on days 1, 8, and 15 intravenously over 1 hour intervention 2: 4mg taken orally once daily on a continuous dosing schedule; Loading dose 12 mg on cycle 1 day 1 only.

Protocol documents:
Prot_SAP_000.pdf: 
Confidential  
 
 
Copyright©SARC (Sarcoma Alliance for Research through Collaboration)  
 
SARC Protocol #: 
SARC023 
 
TITLE:   
A Phase I/II Trial of ganetespib in combination with the mTOR inhibitor 
sirolimus for patients with recurrent or refractory sarcomas including 
unresectable or metastatic malignant peripheral nerve sheath tumors 
 
Sponsor: 
SARC (Sarcoma Alliance for Research through Collaboration)  
 
Funding:  
      Department of Defense 
 
Supporter:   
Synta Pharmaceuticals  
 
 
 
 
 
 
Confidentiality Statement 
The information contained in this document, especially the unpublished data, has 
been generated by [SARC, Children’s National Medical Center, and Synta 
Pharmaceuticals] and therefore provided to you in confidence as an investigator, 
potential investigator or consultant, for review by you, your staff and applicable 
Independent Ethics Committee/Institutional Review Board.  It is understood that 
this information will not be disclosed to others without written authorization from 
SARC except to the extent necessary to obtain informed consent from those persons 
to whom the drug may be administered. 
 
 
 
 
 
IND #119061 
 
Version # / Version Date 
Version 7/ Version Date 13JAN2016 
 
 
 
 
 
 
 
 
 
 
 
 


 
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Principal Investigator: 
AeRang Kim, MD, PhD 
Children’s National Medical Center 
111 Michigan Ave, NW 
Washington, DC 20010 
202-476-2800 
202-476-5685 
aekim@childrensnational.org 
 
Co-Principal Investigator: Brigitte Widemann, MD  
 
National Cancer Institute 
Pediatric Oncology Branch 
10 Center Drive, room 1-5750 
Bethesda, MD 20892-1101 
Phone: 301-496-7387 
Fax: 301-480-8871 
E-mail: widemanb@mail.nih.gov 
 
Statistician:                         Seth Steinberg, PhD  
 
Head, Biostatistics and Data Management Section 
Center for Cancer Research 
6116 Executive Blvd, Room 702 
Bethesda, MD 20892-8325 
Phone: 301-496-9502 
Fax: 301-402-1259 
E-mail: steinbes@mail.nih.gov 
 
SARC Operations Office:    24 Frank Lloyd Wright Drive 
 
Lobby A, Suite 3100; PO Box 406 
 
Ann Arbor, MI 48105 
 
Telephone: (734) 930-7600 
 
Fax: (734) 930-7557                      
 
 
Email:  sarc@sarctrials.org 
 
 
Medical Monitor/                  SARC Medical Officer 
DoD Independent  
Scott Okuno, MD 
Research Monitor: 
Mayo Clinic 
200 1st St SW 
Rochester, MN  55905 
Phone: 507-284-4849 
Email: okuno.scott@mayo.edu 
 
 
 


 
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Roles and Responsibilities of Study Personnel: 
 
AeRang Kim, MD, PhD:  Principal Investigator of the study 
 
Brigitte Widemann, MD:  Co-Principal Investigator of the study  
 
Karen Cichowski, PhD:  Scientific Investigator and preclinical collaborator 
 
Scot Okuno, MD:  SARC Medical Officer, providing SARC oversight to the conduct of this 
study and ongoing medical monitoring 
 
Denise Reinke, MS, NP, MBA:  President, SARC and CEO 
 
Vesna Milacic, PhD:  Director of Research Project Management 
 
Rachel Luchs, BS: Research Project Manager 
 
Eva Dombi, MD:  Associate Investigator; Volumetric MRI analysis of MPNSTs on protocol 
 
John Perenetesis, MD:  Associate Investigator; Clinical and preclinical collaborator 
 
Seth Steinberg, PhD:  Study Statistician 
 
Pam Wolters, PhD:  Associate Investigator, pain outcome analysis 
 
Staci Martin, PhD:  Associate Investigator; pain outcome analysis 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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GLOSSARY OF ABBREVIATIONS 
ALP 
Alkaline phosphatase 
ALT (SGPT) 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
AST (SGOT) 
Aspartate aminotransferase 
AUC 
Area under the curve 
CBR 
Clinical benefit rate 
CI 
Confidence interval 
CR 
Complete Response 
DLT 
Dose Limiting Toxicity 
DoD 
Department of Defense 
ECOG 
Eastern Cooperative Oncology Group 
EGFR 
Epidermal growth factor receptor 
EIAEDS 
CYP3A4-Enzyme inducing anti-epileptic drugs 
eIF2 
Eukaryotic translational initiation factor 2 alpha 
ER 
Endoplasmic reticulum 
FISH 
Fluorescence in situ hybridization 
G6PD 
Glucose 6-phosphate dehydrogenase 
HCC 
Hepatocellular Carcinoma 
Hsp 
Heat shock protein 
IP 
Intraperitoneal 
LLN 
Lower Limit of Normal 
LVEF 
Left Ventricular Ejection Fraction 
MPNST 
Malignant Peripheral Nerve Sheath Tumor 
MRI 
Magnetic Resonance Imaging 
 
 


 
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GLOSSARY OF ABBREVIATIONS 
 
 
MUGA 
Multiple Gated Acquisition scan 
NCIMUGA 
National Cancer Institute Multiple Gated Acquisition scan 
NCI-CTCNCI 
National Cancer Institute-Common Toxicity Criteria National Cancer 
Institute 
NCI-CTCAENCI-
CTC 
National Cancer Institute-Common Terminology Criteria for Adverse 
Events National Cancer Institute-Common Toxicity Criteria 
ORRNCI-CTCAE 
Objective Response Rate National Cancer Institute-Common Terminology 
Criteria for Adverse Events 
OSORR 
Overall Survival Objective Response Rate 
PDOS 
Progressive disease or Pharmacodynamic Overall Survival 
PFSPD 
Progression Free Survival Progressive Disease or Pharmacodynamic 
PSPFS 
Performance Status Progression Free Survival  
PRPS 
Partial Response Performance Status 
RECISTPR 
Response Evaluation Criteria in Solid Tumors Partial Response 
SDRECIST 
Stable Disease Response Evaluation Criteria in Solid Tumors 
SFSD 
Shortening Fraction Stable Disease 
TNMSF 
primary tumor/regional lymph nodes/distant metastasis Shortening Fraction 
TTPTNM 
Time to Tumor Progression primary tumor/regional lymph nodes/distant 
metastasis 
TTP 
Time to Tumor Progression 
 
 
 
 
 
 


 
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SCHEMA 
 
 
Treatment  
Days 1, 8, 15 
Ganetespib IV over 1 hour 
Days 1-28 
Sirolimus once daily 
Day 28 
End of Cycle 
 
Patients will receive 28 day cycles of Ganetespib + Sirolimus until disease progression or 
unacceptable toxicity for up to 1 year (13 cycles). 
 
Response evaluations (using WHO criteria) will be performed after every 2 treatment cycles 
(prior to each odd cycle 3, 5, 7, etc.).


 
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Synopsis 
 
Primary Objective 
 
1. Phase I:  To assess the safety, tolerability, and maximum tolerated/ recommended 
dose of ganetespib when administered in combination with sirolimus in patients 
with refractory sarcomas or unresectable or metastatic sporadic or 
neurofibromatosis type 1 (NF1) associated MPNST. 
2. Phase II:  To determine the clinical benefit of ganetespib in combination with 
sirolimus for patients with unresectable or metastatic sporadic or 
neurofibromatosis type 1 (NF1) associated MPNST. 
 
Secondary Objectives 
 
1. Phase I:  To describe the plasma pharmacokinetic profile of ganetespib and 
sirolimus when administered in combination therapy 
2. Phase I/II:  To determine changes in pharmacodynamic parameters including 
phospho-S6, phosphorylated eIF2 alpha, Akt Phosphorylation, Hsp70, and G6PD 
in tumor tissue and peripheral blood mononuclear cells at baseline and during 
treatment and correlate with changes in clinical or radiologic outcome.   
3. Phase I/II:  To assess patient-reported pain severity and the impact of pain on 
daily activities before and during treatment with ganetespib and sirolimus and to 
correlate with changes in clinical or radiologic outcome. 
4. Phase I/II:  To evaluate the utility of three-dimensional MRI (3D-MRI) analysis in 
comparison to 1-dimensional and 2-dimensional measurements as a method to 
more sensitively monitor response. 
 
 
Hypothesis and Rationale 
 
Previously, no targeted agents have been able to cause tumor regression in a genetically 
engineered MPNST mouse model or human MPNST.  Recently published data from the 
Cichowski laboratory demonstrated using Hsp90 inhibitors to enhance endoplasmic reticulum 
stress coupled with the mTOR inhibitor sirolimus led to dramatic tumor shrinkage in a transgenic 
MPNST mouse model, which correlated with profound damage to the endoplasmic reticulum 
and cell death.  Ganetespib is a novel, injectable, small molecule inhibitor of Hsp90 and is 
currently being investigated in adults with a broad range of tumor types with a favorable safety 
profile and promising early results.  Ganetespib has been studied in preclinical in vivo models 
with a variety of targeted agents with no marked apparent pharmacological interactions.  
Sirolimus is a commercially available orally administered mTOR inhibitor and is the active 
metabolite of temsirolimus, which is FDA approved agent for advanced metastatic renal cell 
carcinoma.  Sirolimus has been studied and tolerated in combination with multiple cytotoxic and 
targeted agents in a variety of tumor types.  Based on strong preclinical rationale, we hypothesize 
that ganetespib in combination with sirolimus will cause tumor regression in patients with 
refractory MPNSTs.  


 
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Trial Design 
We propose a multi-institutional open label phase I/II trial of ganetespib in combination with 
sirolimus in patients with refractory sarcoma including MPNST.  The primary objective of the 
initial component is to determine the safety, tolerability and recommended dose of this novel 
combination in a limited dose escalation phase I trial.  Hsp90 inhibitors and mTOR inhibitors 
have also both demonstrated benefit in a variety of preclinical bone and soft tissue sarcoma 
models.  We hypothesize that these agents that work on separate and potentially synergistic 
pathways will also be beneficial for other refractory bone and soft tissue sarcomas.  Thus, the 
phase I component will be open to patients with refractory sarcomas, which will also expedite 
enrollment.  Ganetespib will be given intravenously over one hour on days 1, 8, and 15 every 28 
days.  Sirolimus will be given orally daily continuously (28 days = 1 cycle).  Upon determination 
of the recommended dosing, the primary objectives of the phase II portion will be to determine 
the clinical benefit rate (CR, PR, or stable disease ≥ 4 months using WHO criteria) of ganetespib 
in combination with sirolimus for patients with refractory MPNST.  Secondary objectives 
include determination of the pharmacokinetic profile of these agents in combination and 
pharmacodynamic markers in tumor tissue and peripheral blood mononuclear cells, patient 
reported pain outcomes, and volumetric MRI analysis of tumor measurement.    
 
Maximum Total Number of Subjects 
Phase I:  3 to 6 patients per cohort with 1 dose escalations (potential for 2 de-escalations). Thus a 
minimum of 6 patients to a maximum of 18 patients are required. 
Phase II:  10 patients in first stage with an additional 10 patients in the second stage for a total of 
20 patients.  The maximum number of evaluable patients for entire study will be 38. 
 
Target Population 
Individuals ≥ 16 years of age with unresectable or metastatic histologically confirmed sporadic 
or NF1 associated high grade MPNST who have experienced progression after one or more prior 
regimens of cytotoxic chemotherapy.  Phase I component will also be open to patients with other 
refractory or relapsed sarcomas. 
 
Anticipated Length of Study (patient enrollment period, overall length including follow-up) 
Patients will be able to remain on treatment for up to 1 year (13 cycles) as long as they do not 
experience progressive disease or unacceptable toxicity.  It is expected that 15-25 patients will be 
enrolled per year, and enrollment is expected to be completed in approximately 2.5 years 
 
Study Drug (s) 
Ganetespib intravenous 
Sirolimus 2 mg oral tablets  
 
Dosing and Administration 
Ganetespib will be administered intravenously over 1 hour on days 1, 8, 15 every 28 days 
Sirolimus will be administered once daily continuously 
1 cycle = 28 days 


 
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Efficacy Evaluations 
 
Response evaluations (WHO) with appropriate imaging studies (MRI/CT) will be performed at 
baseline and prior to odd cycles (3, 5, 7, etc.). 
 
Safety Evaluations/Concerns 
 
History and physical examinations and laboratory evaluations will be routinely performed during 
treatment study. For the phase I component:  The recommended doses will be based on toxicities 
observed over the first treatment cycle.  Dose modifications and management plans are specified 
in the protocol.   
 
Correlative Studies 
 
 Pharmacokinetic samples will be collected in all phase I patients (mandatory) and in upwards 
of 10 patients in the phase II component for data and experience at the recommended dose.  
Detailed pharmacokinetic sampling will occur at steady state during cycle 1.  
 Correlative studies evaluating pharmacodynamic parameters on Hsp inhibition (Hsp70), 
mTOR inhibition (phospho-S6 and Akt Phosphorylation), UPR activation (EIF2 
phosphorylation), and oxidative stress (G6PD) will be explored in tumor tissue and 
peripheral blood mononuclear cells at baseline and during treatment. 
 The patient-reported pain evaluation will consist of two validated scales.  The Numerical 
Rating Scale-11 (NRS-11) will be used to assess pain severity, and the Pain Interference 
Scale from the Brief Pain Inventory will be used to assess the impact of pain on daily 
activities.  These tests will be given prior to treatment and then prior to cycle 3, 5, 9, and 13 
when disease evaluation is performed.   
 
Brief Statistical Design 
 
In the phase I component, a conventional 3+3 dose-escalation design is used.  The initial starting 
dose of ganetespib is 150 mg/m2, approximately 1 dose level below the recommended phase 2 
weekly dose, in combination with the recommended adult dose of sirolimus of 4 mg once daily.  
This will be followed by one dose escalation of the ganetespib to 200 mg/m2 weekly 
(recommended phase 2 dose) and sirolimus recommended adult dose. The Maximum tolerated 
dose (MTD)/Recommended dose will be defined as the dose level immediately below the level at 
which ≥ 33% of patients in a cohort experience a dose-limiting toxicity (DLT) based on 
toxicities observed in the first treatment cycle.  
 
In the phase II component, the primary endpoint will be clinical benefit rate, which will be 
defined as a CR, PR, or stable disease ≥ 4 cycles. An evaluable patient will be classified as a 
responder (success) for the primary endpoint if the patient achieves a PR, CR or stable disease at 
≥ 4 months. The target clinical benefit rate will be 25%, and a clinical benefit rate ≤ 5% will be 
considered uninteresting. Using a Simon’s optimal two-stage phase II design, the first stage will 
require 10 patients, with no further accrual if 0 of 10 respond. If > 1/10 patients respond, accrual 
will continue until a total of 20 patients have been enrolled. If > 3/20 patients respond, this 


 
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combination will be considered of sufficient activity.  Assuming the number of successes is 
binomially distributed, this design has a one sided alpha of 0.07 and a power of 88% for 
detecting a true success probability of at least 25% versus the null hypothesis success rate of 5% 
or less. 


 
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TABLE OF CONTENTS 
SCHEMA ........................................................................................................................................ 6 
1. 
OBJECTIVES ....................................................................................................................... 14 
1.1 
Primary Objective ......................................................................................................... 14 
1.2. 
Secondary Objectives.................................................................................................... 14 
2. 
BACKGROUND .................................................................................................................. 14 
2.1 
Malignant peripheral nerve sheath tumors .................................................................... 14 
2.2 
Refractory bone and soft tissue sarcomas ..................................................................... 17 
2.3 
Study Agents:  Ganetespib and Sirolimus .................................................................... 17 
2.4 
Rationale ....................................................................................................................... 23 
2.5 
Preliminary results of current study (March 2015) ....................................................... 25 
2.6 
Study Design ................................................................................................................. 26 
2.7 
Correlative Studies Background ................................................................................... 27 
3. 
PATIENT SELECTION ....................................................................................................... 29 
Eligibility Criteria ..................................................................................................................... 29 
3.1 
Inclusion Criteria .......................................................................................................... 30 
3.2 
Exclusion Criteria ......................................................................................................... 32 
3.3 
Inclusion of Women and Minorities ............................................................................. 34 
4. 
REGISTRATION PROCEDURES ...................................................................................... 34 
4.1 
General Guidelines........................................................................................................ 34 
4.2 
Registration Process ...................................................................................................... 35 
5. 
TREATMENT PLAN ........................................................................................................... 35 
5.1 
Agent Administration.................................................................................................... 35 
5.2 
Criteria for starting subsequent cycles .......................................................................... 36 
5.3 
Dose Escalation Schema [Phase I component]- Completed ........................................ 36 
5.3.1 Inter-patient Escalation ................................................................................................ 36 
5.3.2 Criteria for Dose Escalation ......................................................................................... 37 
5.3.3 Definition of Dose Limiting Toxicity (DLT) (Criteria for entire study) ...................... 37 
5.3.3.1 
Non-hematological DLT ........................................................................................... 37 
5.3.3.2 
Hematological DLT .................................................................................................. 38 
5.3.4 Intra-Patient Escalation ................................................................................................. 38 
5.3.5 Definition of Maximum Tolerated Dose (MTD) .......................................................... 38 
5.4 
Dosing for Phase II component..................................................................................... 38 
5.5 
General Concomitant Medication and Supportive Care Guidelines ............................. 39 
5.5.1 Concomitant Cancer and other Therapy ....................................................................... 39 
5.5.2 Supportive Care ............................................................................................................ 39 
5.5.3 Management for Surgery .............................................................................................. 40 
5.6 
Duration of Therapy ...................................................................................................... 40 
5.7 
Duration of Follow Up .................................................................................................. 41 
5.8 
Criteria for Removal from Study Treatment ................................................................. 41 


 
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5.9 
Off Study Criteria ......................................................................................................... 41 
6. 
DOSING MODIFICATIONS/ MANAGEMENT FOR SPECIFIC SIDE EFFECTS ......... 41 
6.1  Dose modifications for non-hematological toxicity .......................................................... 41 
6.2  Dose modifications for hematological toxicity .................................................................. 42 
6.3  Ganetespib dose level modifications ................................................................................. 42 
6.4  Sirolimus dose level modification ..................................................................................... 42 
6.5  Management of Specific Side Effects ................................................................................ 42 
6.5.1   Management of hypersensitivity reactions to ganetespib infusions ........................................ 42 
6.5.2   Management of stomatitis/oral mucositis/mouth ulcers ............................................................. 43 
6.5.3    Management of hyperlipidemia and hyperglycemia ..................................................................... 44 
6.5.4  
Management of non-infectious pneumonitis .............................................................................. 45 
7. 
ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS ................................ 46 
7.1 
Adverse Event and Laboratory Abnormalities ............................................................. 47 
7.2 
Handling of Safety Parameters ..................................................................................... 51 
8. 
PHARMACEUTICAL INFORMATION ............................................................................. 52 
8.1 
Ganetespib..................................................................................................................... 52 
8.2 
Sirolimus ....................................................................................................................... 57 
9. 
CORRELATIVE/SPECIAL STUDIES ................................................................................ 60 
9.1 
Laboratory Correlative Studies ..................................................................................... 60 
9.1.1 Mandatory ..................................................................................................................... 60 
9.1.1.1 
Pharmacokinetics ...................................................................................................... 60 
9.1.1.2 
Pain (Appendix V) .................................................................................................... 60 
9.1.1.3 
Volumetric MRI analysis .......................................................................................... 60 
9.1.2 Optional......................................................................................................................... 61 
9.1.2.1 
Pharmacokinetics ...................................................................................................... 61 
9.1.2.2 
Pharmacodynamics ................................................................................................... 61 
10. 
STUDY EVALUATIONS AND STUDY CALENDAR ................................................. 61 
10.1 
SCREENING STUDIES ................................................................................................... 61 
10.2 
ON STUDY EVALUATIONS ..................................................................................... 62 
10.3 
OFF STUDY EVALUATIONS .................................................................................... 63 
10.4   STUDY EVALUATIONS .............................................................................................. 64 
11. 
MEASUREMENT OF EFFECT....................................................................................... 66 
11.1 
Antitumor Effect – Solid Tumors ................................................................................. 66 
12. 
DATA REPORTING / REGULATORY CONSIDERATIONS ...................................... 70 
12.1 
Data Reporting .............................................................................................................. 70 
12.2 
Multi-institutional guidelines ........................................................................................ 72 
12.3 
Data and Participating Institution Monitoring .............................................................. 74 
12.4    Human Subjects Protection ............................................................................................ 74 


 
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13. 
STATISTICAL CONSIDERATIONS.............................................................................. 76 
13.1 
Study Design/Endpoints................................................................................................ 76 
13.2 
Definitions..................................................................................................................... 77 
13.3 
Sample Size/Accrual Rate ............................................................................................. 78 
13.4 
Analysis of Secondary Endpoints ................................................................................. 78 
REFERENCES ............................................................................................................................. 80 
APPENDIX I:  PERFORMANCE STATUS CRITERIA ............................................................ 85 
APPENDIX II:  DRUG INTERACTION TABLE ....................................................................... 86 
APPENDIX III:  PATIENT DIARY ............................................................................................ 87 
APPENDIX IV: DOCUMENTATION OF FINDINGS OF NF1 ................................................ 91 
APPENDIX V: PAIN QUESTIONNAIRE .................................................................................. 95 
APPENDIX VI: DRUGS WITH RISK OF TORSADES DE POINTES ..................................... 96 
 


 
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1. OBJECTIVES 
 
1.1 
Primary Objective 
 
1. Phase I:  To assess the safety, tolerability, and maximum tolerated dose (MTD)/ 
recommended dose of ganetespib when administered in combination with 
sirolimus in patients with refractory or relapsed sarcomas including unresectable 
or metastatic sporadic or neurofibromatosis type 1 (NF1) associated MPNST. 
2. Phase II:  To determine the clinical benefit of ganetespib in combination with 
sirolimus for patients with unresectable or metastatic sporadic or NF1 associated 
MPNST. 
 
1.2. 
Secondary Objectives 
 
1. Phase I:  To describe the plasma pharmacokinetic profile of ganetespib and 
sirolimus when administered in combination therapy 
2. Phase I/II:  To determine changes in pharmacodynamic parameters including 
phospho-S6, phosphorylated eIF2 alpha, Akt Phosphorylation, Hsp70, and G6PD 
in tumor tissue and peripheral blood mononuclear cells at baseline and during 
treatment and correlate with changes in clinical or radiologic outcome.   
3. Phase I/II:  To assess patient-reported pain severity and the impact of pain on 
daily activities before and during treatment with ganetespib and sirolimus and to 
correlate with changes in clinical or radiologic outcome. 
4. Phase I/II:  To evaluate the utility of three-dimensional MRI (3D-MRI) analysis in 
comparison to 1-dimensional and 2-dimensional measurements as a method to 
more sensitively monitor response. 
 
 
2. BACKGROUND 
 
2.1 
Malignant peripheral nerve sheath tumors 
Malignant peripheral nerve sheath tumors (MPNSTs) are soft tissue sarcomas arising from 
peripheral nerve or show nerve sheath differentiation and are associated with a high risk of 
local recurrence and metastasis 1.  MPNSTs account for 10% of all soft tissue sarcomas, and 
carry the highest risk for sarcoma specific death among all the soft tissue sarcoma histologies 
2.  At present, complete surgical resection is the only curative treatment for MPNST 3,4.  
MPNSTs are at high risk for local recurrence (32-65%) 5 and metastasis (40%) 6.  The most 
frequent sites of metastasis of MPNSTs are lung, liver, brain, soft tissue, bone, lymph nodes, 
and retroperitoneum 7.  The outcome for unresectable, recurrent, or metastatic MPNST is 
dismal.   
 
Neurofibromatosis Type 1 and MPNST 
Approximately half of all MPNSTs arise from individuals with NF1 8.  NF1 is a common 
autosomal dominant tumor predisposition syndrome.  The gene responsible for NF1 encodes 
for a protein called neurofibromin, which includes a GTPase activating protein that regulates 
hydrolysis of Ras-GTP to Ras-GDP 9,10.  Patients with NF1 have decreased levels of 


 
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neurofibromin, which can lead to dysregulated Ras and tumorigenesis 11.  MPNSTs are the 
most common NF1-associated malignancy.  The lifetime risk of MPNST in NF1 is 8-13% 
compared to 0.001% in the general population 7,8.  The majority of NF1-associated MPNSTs 
arise within pre-existing plexiform neurofibromas 12.  This may lead to difficulty and delay in 
diagnosing MPNSTs in patients with NF1 because the clinical indicators of malignancy such 
as mass, pain, and edema may also be features of active, benign plexiform neurofibromas.  
NF1 associated MPNSTs are frequently more located in the trunk 13,14 as opposed to 
extremity location seen more commonly in sporadic MPNSTs, tend to be large (>5cm) 15, 
and may have a greater propensity to metastasize 7.  These may be potential reasons why 
NF1-assoicated MPNSTs appear to have a worse outcome than sporadic MPNSTs.  Gene 
expression profiling of NF1 associated (n=25) and sporadic (n=17) MPNSTs did not identify 
a molecular signature that could reliably distinguish between both groups 16,17.   
 
Treatment 
The only known curative approach to MPNSTs is complete surgical resection with wide 
negative margins 3,4.  Thus, early diagnosis of MPNST is crucial, which may be difficult in 
patients with NF1 for the reasons stated above.  Radiotherapy is used in situations where the 
sarcoma is not amenable to surgical resection, but extremely high doses are needed, and the 
local control rate is only 30-60%.  Clinical trials have shown that external beam radiation or 
brachytherapy in addition to limb sparing surgery can improve local control in patients with 
soft tissue sarcomas 18,19.  Thus adjuvant radiotherapy is recommended to improve local 
control in intermediate and high grade lesions > 5 cm after a marginal excision 1,19.   The role 
of chemotherapy for MPNSTs has not been defined to date. In retrospective reviews, NF1 
associated MPNSTs have been described to have much lower response to chemotherapy than 
sporadic MPNSTs 3,15.   
 
There is a current DoD sponsored, SARC coordinated phase II clinical trial evaluating the 
response rate of high grade unresectable MPNST to standard chemotherapy agents 
(Doxorubicin, Ifosfamide, Etoposide) (SARC006). The primary trial endpoint (CR and PR 
rate) is determined after 4 cycles of chemotherapy (2 cycles of IA followed by 2 cycles of 
IE). Local control with surgery and or radiation follows cycle 4, and the administration of 2 
additional cycles IE and IA each.  Patients are stratified for the presence of a sporadic vs. 
NF1 associated MPNST, and a two-stage phase II design is used targeting a response rate  
40% (rule out < 20%). Seventeen patients are enrolled on the initial stage, and enrollment in 
a stratum is expanded if ≥ 4/17 respond after 4 cycles of chemotherapy. In the NF1 MPNST 
stratum 4 partial responses were observed in the first 17 patients enrolled, and enrollment 
was thus expanded. To date (February 2013), 33 patients with NF1 MPNST have been 
enrolled. Of these, 29 patients are currently evaluable for response. Five patients had a partial 
response as best response, 21 stable disease, and 3 progressive disease (Objective Response 
(OR) rate 17.2%. Fifteen patients with sporadic MPNST have been enrolled. Of 12 patients 
currently evaluable for response, 4 partial responses, 6 stable disease and 2 progressive 
disease have been observed (OR rate 33.3%). The study was closed before full enrollment 
due to slow accrual.  While the primary trial objective was not reached, with only 5/29 ORs 
in the NF1 stratum, the desired OR rate of 11+/37 would have unlikely been met even if 
accrual had been completed. A lower OR rate in NF1 compared to sporadic MPNSTs was 


 
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observed similar to retrospective literature reports. In addition to PRs after both IA and IE, 
disease stabilization was achieved in most patients. 
 
Based on the high incidence of MPNST in NF1, limited treatment options, and high 
mortality, there is clearly a desperate need for more effective medical treatments for 
MPNSTs.  With increasing understanding in the molecular pathogenesis of MPNSTs, clinical 
trials with targeted agents have become available.  Several histology specific trials with 
targeted agents have been performed for MPNSTs (Table 1).  A phase II trial of the EGFR 
inhibitor erlotinib was the first histology specific trial with a targeted agent to be completed 
in patients with NF1 and sporadic MPNST.  Twenty-four patients were enrolled within 22 
months in 13 institutions.  Although this trial and other completed trials demonstrate lack of 
activity and rapid disease progression with a median time to progression of < 2.0 months in 
MPNST, they did demonstrate that timely completion of specific trials in this rare 
malignancy is feasibly, and novel therapies are warranted in this aggressive disease.    
 
Table 1.  Completed and select ongoing clinical trials with targeted agents for 
refractory MPNST 
 
Selection and prioritization of agents for clinical trials is a key challenge in drug 
development for NF1 as only a few agents can be tested in the clinical setting due to patient 
numbers, time, and cost.  Transgenic mouse models of MPNST have become available, and 
preclinical trials in these models may have utility in the rational development of drugs for 
NF1 and MPNSTs.  Mammalian target of rapamycin (mTOR) has been reported to be 
hyperactivated in NF1-deficient tumors as a consequence of aberrant Ras signaling.  Using 
an Nf1/p53-mutant MPNST model, the Cichowski laboratory demonstrated that sirolimus, an 
mTOR inhibitor, suppressed tumor growth in potent, but cytostatic effect 27.  The MPNST 
transgenic mouse model tumors ultimately became resistant to treatment with sirolimus, 
which was associated with re-vascularization and upregulation of vascular endothelial growth 
factor (VEGF).  Based on this data, we collaboratively developed a phase II trial of RAD001 
and bevacizumab for refractory MPNST.  The primary trial objectives are to determine the 
clinical benefit rate (CR, PR, and SD at ≥ 4 months using WHO criteria) of this treatment. 
The consistently rapid disease progression justifies inclusion of SD ≥4 months as clinical 
Drug 
Target 
Phase 
n = 
Schedule 
Outcome 
Results 
Ref 
Erlotinib 
EGFR 
II 
24 
Oral 
continuous 
Response 
WHO20 
19/20 pts. Progressive 
disease at 2 months  
1 stable disease 
21 
Sorafenib 
C-Raf, B-Raf, 
VEGFR2, C-
Kit, PDGFR 
II 
12 
Oral 
continuous 
Response 
RECIST22 
 
No responses; median 
progression free 
survival 1.7 months 
23 
Imatinib 
C-Kit, 
PDGFR, 
VEGFR 
II 
7 
Oral 
continuous  
Response 
RECIST22 
No responses; 1 stable 
disease 
24 
Dasatinib 
C-Kit, SRC 
II 
14 
Oral 
continuous  
Response 
Choi25 
 
No response or stable 
disease 
26 
Bevacizumab/
RAD001 
Angiogenesis
/mTOR 
II 
- 
IV q14d / oral 
continuous 
Response 
WHO20  
Currently ongoing 
-- 


 
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benefit. Secondary objectives are to evaluate the spectrum of germline NF1 mutations, and to 
analyze the PD of RAD001 in peripheral blood specimens including p70 S6 kinase 1, eIF4E, 
eIF2 alpha VEGF, VEGFR, and Akt phosphorylation.  RAD001 is administered at a dose of 
10 mg orally once daily on a continuous dosing schedule (28 days = 1 cycle). Bevacizumab 
is administered IV at a dose of 10 mg/kg/dose every 14 days.  A two-stage design is used 
with a target clinical benefit rate of 25%.  This trial will be coordinated by SARC, and SARC 
and NF Consortium sites will participate. Novartis provides RAD001 and Genentech 
bevacizumab. The DoD is providing support to this trial through a Clinical Trial Award. The 
trial opened for enrollment in December 2012.   
 
Building on this study, and identifying alternative targets in combination with mTOR may be 
beneficial.  Proteotoxic or endoplasmic reticulum (ER) stress is induced when unfolded 
proteins accumulate in the ER 28.  Oncogenic RAS also causes ER stress 29, and when ER 
stress level become insurmountable, cell death ensues, suggesting agents that enhance ER 
stress may be developed as anti-cancer agents.  In an exciting new development, the 
Cichowski laboratory recently demonstrated that further enhancing ER stress using HSP90 
inhibitors coupled with sirolimus led to dramatic tumor shrinkage in the transgenic mouse 
model, which correlated with profound damage to the ER and cell death 30.  Previously, no 
targeted agents have been able to cause tumor regression in a genetically engineered models 
or human MPNST trials (Table 1).   
 
2.2 
Refractory bone and soft tissue sarcomas 
The prognosis in advanced and metastatic sarcomas remains poor.  Continued progress while 
minimizing acute and late effects of current therapy is dependent on the development of 
novel therapeutic approaches for malignant sarcomas.  Hsp90 inhibitors have demonstrated 
benefit in a variety preclinical of bone and soft tissue sarcomas, including synovial 
sarcoma31,32 Ewing Sarcoma 33, osteosarcoma 34,35, and rhabdomyosarcoma 36,37.  Disruptions 
of the PI3K-Akt-mTOR signaling pathway are associated with different sarcoma types38.  
Rapamycin and other mTOR inhibitors have demonstrated inhibition of growth in a variety 
of in vitro and in vivo sarcoma preclinical models 39-43.  Early clinical studies of single agent 
mTOR inhibition have demonstrated potential benefit in a subset of sarcoma patients who 
have failed standard therapy (variety of soft tissue sarcoma, GIST, Ewing Sarcoma, and 
Osteosarcoma), however the activity of this drug has been primarily cytostatic 38, and 
activation of feedback mechanisms have been of concern 44.  Thus rationale combination of 
agents with mTOR inhibitors may result in improved responses in these difficult to treat 
patients. mTOR signaling has also been implicated in ER stress pathway 45.  We hypothesize 
that ganetespib and rapamycin, two agents that work on separate and synergistic pathways, 
will not only be beneficial to MPNSTs, but other refractory bone and soft tissue sarcomas.  
Thus, we will also include other sarcoma types to the phase I component of this trial. 
 
2.3 
Study Agents:  Ganetespib and Sirolimus 
Ganetespib 
Ganetespib (formerly called STA-9090) is a novel, injectable resorcinolic triazolone small 
molecule inhibitor of Hsp90 46.  Hsp90 is a molecular chaperone that regulates 
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critical roles in cell growth, differentiation, and survival 47,48.  Ganetespib inhibits Hsp90 
chaperone activity by binding to its N-terminal adenosine triphosphate (ATP) pocket.  Hsp90 
inhibition causes its client proteins to adopt aberrant conformations, which are then targeted 
for ubiquination and degradation by the proteosome 49.  Hsp90 client proteins include wild 
type and mutated forms of many important signaling proteins associated with cancer, such as 
BCR-ABL, BRAF, CDK4, KIT, c-MET, c-SRC, EGFR, LCK, HER2 and VEGFR.  
Ganetespib is currently being investigated in adults with a broad range of tumor types.  It is 
being explored in both once weekly and twice weekly schedule, and has been generally well 
tolerated.  Most frequent adverse events were gastrointestinal or constitutional in nature, and 
were generally mild to moderate in severity.  Preliminary signals of anti-tumor activity have 
been observed on the ongoing clinical trials in a broad range of tumor types.   
 
Preclinical studies 
Anti-tumor in vitro and in vivo studies: 
Detailed descriptions are provided in the investigator’s brochure and results are highlighted 
here 50. Ganetespib is a potent inhibitor of cell death in a broad range of hematologic and 
solid tumor cell lines including those expressing mutant Hsp90 client proteins with IC50 in 
the low nM concentrations.  Ganetespib was also able to induce the degradation of various 
client proteins, including those that are mutated, amplified, or rearranged.  In a KRAS mutant 
NSCLC cell line, ganetespib effectively destabilizes the KRAS effector CRAF and blocks 
both MAPK and AKT signaling.  Ganetespib has demonstrated in vivo efficacy in > 13 
human tumor xenograft models including a broad spectrum of tumor histologies, and 
response appeared to be dose responsive in some cell lines.   
 
Animal Toxicology: 
A comprehensive, non-clinical program has been conducted to characterize the toxicological 
and toxokinetic profile of ganetespib.  Detailed descriptions of all these studies are provided 
in the investigator’s brochure and highlighted here. Rats survived a single 30 mg/kg dose of 
ganetespib, but doses of 85 or 250 mg/kg elicited morbidity and mortality. For rats given 100 
mg/kg (reduced to 85 mg/kg beginning with the third dose) and assigned to a 14-day 
recovery evaluation, most changes returned to normal or improved.  Rats given 10, 30, 75, or 
100 mg/kg once weekly for 4 weeks had no abnormal clinical findings.  The maximum 
tolerated single-administration dose in cynomolgus monkeys was 11 mg/kg. When 
administered on 2 consecutive days, up to 3 mg/kg/day was well tolerated.  In 3-month 
studies with ganetespib administered on Days 1 and 15 of four 21-day cycles, rats tolerated 
20 mg/kg/dose of ganetespib, the NOAEL.  Transient decreases in weight gain occurred at 50 
and 100 mg/kg/dose, and early deaths occurred at 100 mg/kg/dose.  In another 3-month 
study, cynomolgus monkeys on that regimen tolerated doses up to 7 mg/kg/dose, the 
NOAEL.  Transient diarrhea occurred at 2, 4, and 7 mg/kg/dose, with reversible microscopic 
pathologic changes occurring at 7 mg/kg/dose.  Ganetespib was considered to be well 
tolerated by cynomolgus monkeys when administered by 1-hour infusion twice weekly for 4 
weeks via an implanted silicone venous catheter.  When pregnant female rats were given 
ganetespib daily by infusion during organogenesis, maternal toxicity (clinical signs, 
decreased weight gain and food consumption) and developmental toxicity (post-implantation 
loss) occurred at doses of 3 mg/kg/day and higher.  Ganetespib was rapidly eliminated from 


 
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retinal tissue and did not cause photoreceptor cell apoptosis.  Unlike 17-DMAG and 
AUY922, ganetespib was not associated with ocular toxicity in the rat model. 
 
Preclinical pharmacology 
Studies evaluating the distribution, biotransformation, and elimination, ganetespib exposure 
increased dose proportionally.  Ganetespib is highly protein bound (98.6-98.7% in human 
plasma) and highly distributed throughout tissue with the exception of the central nervous 
system.  Mean terminal half-life (t1/2) for ganetespib after multiple doses were approximately 
6 and 11 hours in rates and monkeys respectively.  Ganetespib was extensively metabolized 
in the liver to mainly glucoronide conjugates.  Ganetespib is excreted through the feces, the 
major route of excretion.  Ganetespib does not appear to accumulate after multiple dosing.  
Fecal elimination via bile is the major route of excretion. Ganetespib is an inhibitor of 
CYPC19 and CYP3A4 (midazolam specific) in human liver microsomal systems but does 
not markedly inhibit transporters including P-gp.  Ganetespib does not appear to be an 
inducer of CYP or UGT enzymes.  In mice, ganetespib did not show marked 
pharmacokinetic interactions when co-administered with paclitaxel, docetaxel, erlotinib, 
fulvestrant, BEZ235, AZD6244, bortezomib, and irinotecan.    
 
Clinical experience 
Clinical studies 
As of September 2014, approximately 1362 subjects have received ganetespib.  Overall, 
ganetespib has been well tolerated with most reported adverse events (AEs) being mild to 
moderate in severity.  The most frequently reported AEs in the largest pooled data set (single 
agent studies, n=402) are related to gastrointestinal (GI) toxicity, including diarrhea (79%), 
nausea (44%), decreased appetite (31%), vomiting (27%), constipation (22%), and abdominal 
pain (20%). Non-GI related toxicity includes fatigue (53%), headache (20%), and anemia 
(21%). In the Phase 2b study in patients treated with ganetespib in combination with 
docetaxel, preliminary findings show similar safety profile with 53% reduction in the 
incidence of diarrhea due to implementation of anti-diarrheal prophylactic medicine.    
 
Ocular toxicity, manifested as visual disturbances, has been reported for several Hsp90 
inhibitors.  Of the 601 patients treated with ganetespib (single and combination studies), 6 
(1%) of patients experienced event of blurred vision and 4 (< 1%) experienced visual 
impairment that was assessed as related.  The studies using single agent ganetespib (n=378), 
4 patients (1%) experienced treatment related blurred vision and 3 patients (< 1%) 
experienced treatment related visual impairment.  In studies using single agent ganetespib, 
visual disturbances regardless of relationship to treatment included blurred vision (5%), 
visual impairment (2%), vitreous floaters, cataract, conjunctival hemorrhage, conjunctivitis,  
dry eye, eyelid edema, periorbital edema, reduced visual acuity, chromatopsia, conjunctival 
hyperemia, eye swelling, eyelid ptosis, glaucoma, night blindness, ocular hyperemia, 
photopsia, and scotoma (all < 1%).   
 
The mechanism of visual disturbances is linked to induction of apoptosis in cells in the outer 
nuclear layer of the retina, which occurs following treatment with 17-DMAG or AUY922 51.  
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models, consistent with the very low number of reported visual disturbance cases in the 
clinic.   
 
Hepatocellular injuries are usually detected by enzyme elevations in serum aminotransferases 
(ATs), total bilirubin, and alkaline phosphatase.  In the combination treatment arm of Study 
9090-08, AEs of elevated aspartate aminotransferase (AST) and alanine aminotransferase 
(ALT) were reported in 3% and 2%, of patients, respectively.  An AE of elevated alkaline 
phosphatase was reported in 3% of patients and an AE of elevated bilirubin was reported in < 
1% of patients.  Grade 3 elevations of AST and ALT were reported in < 1% and 2% of 
patients, respectively.  In the pooled data from 322 patients who received single-agent 
ganetespib, AEs of elevated AST and ALT were reported in 14% of patients.  An AE of 
elevated alkaline phosphatase was reported in 16% of these patients and an AE of elevated 
bilirubin was reported in 6%.  Grade ≥ 3 elevations of AST and alkaline phosphatase were 
reported in 4% of patients and Grade ≥ 3 elevations of ALT and bilirubin in 3% of patients.  
None of the patients reported concomitant elevations of ATs ≥ 3X the upper limit of normal 
(ULN) and bilirubin ≥ 2X ULN. 
 
Liver toxicity in the 1st-generation geldanamycin-derivative Hsp90 inhibitors is an off-target 
effect.  According to a study by Cysyk et al, the presence of benzoquinone moiety in the 
molecule is the suspected cause of liver toxicity [Cysyk et al, Chem Res Toxicol, 2006].  
Ganetespib does not contain the benzoquinone moiety and, therefore, liver toxicity is not 
expected.  This correlates with the safety information collected to date. 
 
Cardiac Findings:  A thorough QT study examining ECG intervals and morphology was 
conducted in accordance with ICH E14.  The study was conducted as a randomized partially 
double blind, placebo and positive controlled, 3-arm, crossover study to assess the effect of 
ganetespib on ECG parameters in healthy volunteers.  Volunteers were administered a single 
dose of 200 mg/m2 ganetespib.  Analyses of ECG data revealed a placebo-corrected modest 
change in QTcF from baseline of 21.5 msec at 24 hours post-dose.  No increase of QTcF was 
observed at the time of ganetespib Cmax (at end of infusion).  QTcF was back to baseline 7 
days after the ganetespib dose.  To date in the clinical development program, there have been 
362 patients treated with ganetespib as a single agent and 218 treated with ganetespib with 
docetaxel (total 580 patients).  Seven patients (1.2%) had prolonged QT interval reported as 
AE and none had torsades de pointes or other ventricular arrhythimias on any ECG 
recording.  Eight potential deaths resulting from cardiovascular SAEs have been reported and 
were described by investigators as cardiac arrest (n=3), sudden cardiac death (n=2), 
cardiopulmonary failure (n=1), and cardiovascular insufficiency (n=1).  The incidence of 
deaths on ganetespib due to cardiovascular SAEs does not seem excessive for this advanced 
cancer population.  While the effect of ganetespib on QT interval is being completely 
characterized, we have added recommended provisions to eligibility criteria for the 
cardiovascular system and included interval ECG monitoring for all patients on study.  
 
In phase I solid tumor trials, the doses have ranged from 7 to 259 mg/m2 once weekly and 2 
to 200 mg/m2 twice weekly.  The MTD for once weekly dosing in solid tumors was 
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single agent dose is 200 mg/m2 once weekly x 3, one week off.  For the twice weekly dosing, 
the recommended dose is 150 mg/m2 (Monday/Thursday) x 3, one week off.  In 
hematological malignancies, the single agent once weekly is 200 mg/m2 and 90 mg/m2 twice 
weekly with no week off for either schedule. 
 
Ongoing phase 2 studies are evaluating the activity of ganetespib in a variety of solid tumors 
including HCC, colorectal cancer, lung cancer, melanoma, prostate, pancreatic, and breast.   
 
A phase I study of ganetespib in combination with docetaxel has completed enrollment.   The 
GI AEs continued to be observed with ganetespib and hematologic AEs are primarily seen 
with docetaxel.  Following the evaluation of DLTs and overall tolerability, the recommended 
combination dose is 150 mg/m2 of ganetespib on days 1 and 15 in combination with 75 
mg/m2 of docetaxel on day 1 in a 21 day cycle.  The current phase 2 randomized phase 2B/3 
looking at this combination in comparison to docetaxel alone in NSCLC is ongoing.  Interim 
results show promising signals of activity in pre-specified populations.  This combination 
appears to be well-tolerated in this patient population. 
 
Pharmacokinetics and Correlative Biology Studies 
The pharmacokinetics of ganetespib administered at various doses on a weekly or twice 
weekly schedule are under investigation.  Ganetespib pharmacokinetics appears to be linear 
and dose proportional.  The mean terminal half-lives have ranged from approximately 5 to 15 
hours. Ganetespib plasma concentrations following the first and subsequent doses are 
comparable following either once or twice-weekly dosing, indicating the lack of drug 
accumulation.  Ganetespib plasma concentrations are also comparable in the solid and 
hematologic tumor patients.  Cmax and AUC increase in approximate proportion to dose 
irrespective of dosing day with virtually identical dose-exposure ratios for doses given on 
different days, indicating linear PK (r2 = 0.7080 and 0. 7596 for Cmax and AUC versus dose, 
respectively).  Ganetespib Cmax correlates well with AUC (r2 = 0.9338).  CL and Vd are 
approximately constant across doses.  
 
Hsp70 was quantified from RNA that was purified from blood cell pellets derived from 
subjects in a phase I trial (protocol 9090-02) at multiple time points on the first day of 
treatment hours.  Peak maximum induction occurred at 2 hours post start of infusion.  
Additional genes were also investigated to supplement RNA analysis in order to monitor 
downstream targets of Hsp90 client proteins.  The Janus kinase (JAK) signal transducer and 
activator of transcription (STAT) signaling pathway is disrupted by drug treatment, and 
results in downstream regulation of the genes controlled by the transcription factor STAT3. 
 
Sirolimus 
Sirolimus (rapamycin) is a mammalian target of rapamycin (mTOR) kinase inhibitor that has 
been FDA approved for immunosuppression following kidney transplantation 52.  Sirolimus 
inhibited tumor growth in preclinical models by inducing cell cycle arrest and apoptosis, 
leading to recognition of the mTOR pathway as a target for cancer therapy 53,54.  Rapamycin 
analogs, such as temsirolimus 55, an intravenous soluble ester (pro drug) of sirolimus and 
everolimus 56, and oral mTOR inhibitor, have been FDA approved for the treatment of 


 
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advanced renal cell carcinoma.  At this time, it is unclear whether one compound will have 
advantage over the others in a particular tumor type.   
 
Preclinical studies 
Preclinical studies have demonstrated efficacy of sirolimus analogs and parent compound in 
multiple tumor types.  In the NCI 60 tumor cell line panel, mTOR inhibitors demonstrated 
growth inhibitory activity against a broad spectrum of tumors including leukemia, brain, 
renal, breast and melanoma 57,58 with an average IC50 of 8.2 nM.  Subsequent xenograft 
studies have confirmed the cytostatic properties of the mTOR inhibitors.  
 
Clinical studies in malignancy 
A pharmacodynamic continuous reassessment method-based phase I study of rapamycin in 
adult patients with solid tumors was performed 59.  The pharmacodynamic endpoint used was 
skin phospho-P70 change after 28 days and effect was defined as at least 80% inhibition 
from baseline.  Twenty-one patients enrolled at doses between 2 and 9 mg.  Toxicities seen in 
at least 20% were hyperglycemia, hyperlipidemia, elevated transaminases, anemia, 
leucopenia, neutropenia, and mucositis.  Hyperlipidemias responded well to statin treatments.  
The MTD was determined to be 6 mg daily on an uninterrupted schedule in solid cancer 
patients.  Pharmacokinetics was similar to that seen in previous trials with rapid absorption 
and slow elimination.  Steady state was reached by day 8.  There was an increase in day 28 
half-life compared to day 1 (13 vs. 24 hours respectively).  Five patients enrolled with 
previous progression on other therapy remained on drug for greater than 12 months.  
 
Another phase I study of rapamycin was evaluated in advanced malignancies using a once 
weekly dose 60.  The MTD was determined to be 90 mg orally once weekly.  The most 
common toxicities included nausea, diarrhea, asthenia, hyperglycemia, anemia, and 
lymphopenia.  Preliminary evidence suggest that prolong suppression of phospho-S6K in 
peripheral T cells is possible at well-tolerated doses.   
 
Sirolimus induced radiographic and clinical responses in three patients with malignant 
perivascular epithelioid cell tumors (PEComa), a rare tumor with no known previous 
treatments.  Tuberous sclerosis (TSC) related tumors are characterized by constitutively 
activated mTOR signaling due to mutations in TSC1 and TSC2.  Patients were treated to 
initially meet a target dose of 3-9 ng/mL and then 9-15 ng/mL after 16 weeks.  Single agent 
sirolimus induced regression of tumors related to tuberous sclerosis with an overall response 
rate of 44% (16/36 had a partial response).   
 
Sirolimus is being studied in combination with other agents for malignancy.  A phase I study 
of sirolimus and bevacizumab in patients with advanced malignancies demonstrated that this 
combination was tolerable even when the drugs are combined at full doses 61.  Fatigue was 
the most common grade 3 toxicity.  The recommended dose of sirolimus is 90 mg weekly (in 
two divided doses on consecutive days) or 4 mg daily in combination with bevacizumab 15 
mg/kg IV q3weeks. Sirolimus has also been studied in combination with cytotoxic 
chemotherapy in refractory acute myelogenous leukemia 62 and chemoradiation in NSCLC 63 
in phase I trials.  In both studies, combination therapy was well tolerated.  Sirolimus has been 


 
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studied in combination with erlotinib in adults with recurrent glioblastoma (n=32).  The 
doses of erlotinib and sirolimus were 150 mg and 5 mg for patients not on concurrent 
CYP3A-inducing anti-epileptics (EIAEDS), and 450 mg and 10 mg for patients on EIAEDS.  
The most common adverse effects (grade ≥ 2) were rash (59%), mucositis (34%), and 
diarrhea (31%).  Grade 3 or higher events were rare. 
 
2.4 
Rationale 
mTOR and NF1 
Signaling intermediates downstream of Ras are hyperactivated as a result of NF1 gene 
inactivation and these specific proteins are critical for transmitting the Ras growth signal and 
for the development of neoplasia in patients with NF1 11.  One of these downstream proteins 
is the mTOR molecule.  Studies have demonstrated that the NF1 tumor suppressor regulates 
mTOR pathway activation.  mTOR was found to be activated in both NF1 deficient primary 
human and mouse cells as well as in human and genetically-engineered Nf1 mouse tumor 
models. This aberrant activation was dependent on Ras and PI3 kinase/AKT signaling 64,65. 
In this regard, Nf1 loss in mouse embryonic fibroblasts 65 and primary mouse astrocytes 64 
was shown to result in Ras- and PI3K-dependent mTOR pathway activation, which could be 
inhibited with sirolimus.  Moreover, Nf1-/- astrocytes are highly sensitive to sirolimus 
treatments that have no effect on normal astrocyte growth 64.  The increased proliferation 
associated with loss of neurofibromin expression in human MPNST cell lines was 
dramatically reduced by treatment with sirolimus 65.  Sirolimus treatment of optic gliomas 
developing in a genetically-engineered Nf1 mouse model resulted in attenuated mTOR 
signaling in vivo 58as well as tumor growth in vivo 66.  While tumors rapidly ceased to 
proliferate, there was no evidence of apoptosis or senescence, and sirolimus had no early 
effect on microvasculature in either preclinical model.  
 
mTOR and MPNST 
A transgenic mouse model 67 carrying compound mutations in the Nf1 and p53 tumor 
suppressors on the same chromosome develop aggressive MPNSTs that are histologically 
indistinguishable from human MPNSTs. Tumors grow with consistent and rapid kinetics, and 
on average mice only survive 10.7 days after the tumor is detected.  This model was used to 
test the role of mTOR in tumorigenesis in vivo and assess the therapeutic utility of rapamycin 
27.  Animals with palpable tumors (approximately 300 mm3) were injected I.P. with 5 mg/kg 
rapamycin per day.  Control mice died on average in 12.2 days, and tumors grew 9.7-fold.  In 
contrast, rapamycin potently suppressed MPNST growth, and allowed the animals to survive.  
Inhibition of S6 phosphorylation was observed in tumor and non-tumor tissue, demonstrating 
that rapamycin was effectively suppressing the mTOR pathway in vivo.  Moreover 
rapamycin mediated its anti-tumor effects within 24 hours by potently suppressing 
proliferation, as assessed by BrDU incorporation in control and rapamycin treated tumors.  
Consistent with in vitro observations, apoptotic and senescent cells were not detected.  As 
such, tumor growth was dependent on continued exposure to rapamycin, as tumors re-
exhibited S6 phosphorylation and resumed growing at a rate comparable to control treated 
tumors following rapamycin removal.  Although the response to rapamycin was potent, 
effects were cytostatic.  Therefore, Dr. Cichowski and her lab have been using this model to 
develop more effective mTOR-inhibitor based combination therapies 30.  To identify 


 
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additional therapeutic targets, her group considered drugs that might exploit cellular 
vulnerabilities of cancer cells.   
 
Hsp90 and mTOR combination 
Tumor cells often exhibit specific stress-related phenotypes caused by insults such as 
excessive DNA damage as well as replicative, metabolic, and proteotoxic stress 68.  Agents 
that further enhance or sensitize cancer cells to these stresses could thus be developed as 
potential anti-cancer therapies 69,70.  Proteotoxic or endoplasmic reticulum (ER) stress is 
induced when unfolded proteins accumulate in the ER 28.  Cancer cells frequently exhibit 
high levels of ER stress caused by a multitude of factors 69,70.  Oncogenic RAS also causes 
ER stress 29.  Aneuploidy in particular has been shown to induce proteotoxic stress in cells 71.  
ER stress activates a signal transduction pathway called the unfolded protein response (UPR) 
28.  The UPR is an initially protective mechanism to reduce protein accumulation, however, 
when ER stress levels become insurmountable, cell death ensues 28.  Hsp90 maintains protein 
homeostasis by folding newly synthesized and misfolded proteins, assembling and 
dissembling protein complexes and resolving protein aggregates 47.  Hsp90 also directly 
stabilizes two key stress sensing components of UPR:  IRE1 and pPERK/PERK 72.  
Therefore Hsp90 inhibitors would expect to promote ER stress in cancer cells directly by 
impairing global protein folding in already compromised tumor cells and inactivating 
subsequent adaptive responses of UPR.  Under these observations, the Cichowski group 
hypothesized the therapeutic benefits of Hsp90 inhibitors alone and in combination with 
mTOR inhibition for Ras and/or mTOR driven tumors 30.  The following summarizes the 
exciting new discovery recently published 30.  
 
MPNSTs are highly aneuploid and are driven by constitutive activation of Ras.  They were 
demonstrated to have much higher levels of ER stress when compared to normal peripheral 
nerve as confirmed by three markers of UPR activation (BiP upregulation, eukaryotic 
translational initiation factor 2 (eIF2) phosphorylation, and accumulation of the spliced 
active form of XBP-1 (sXBP-1).  In addition, agents that induced ER stress triggered cell 
death at concentrations that did not affect the viability of normal cells.   
 
The Hsp90 inhibitor used in this pre-clinical model was IPI-504.  However, two additional 
structural distinct Hsp90 inhibitors BEP800, AUY-922, and 17-AAG killed MPNSTs, 
induced ER stress, and impacted UPR with the same kinetics IPI-504, confirming that these 
agents all function by suppressing Hsp90 30.  In addition, subsequent studies using ganetespib 
demonstrated similar results (Personal Communication, Karen Cichowski).  IPI-504 was 
administered at a dose of 100 mg/kg once weekly, and rapamycin was administered at 5 
mg/kg daily.  Alone, IPI-504 was unable to promote tumor regression, but when combined 
with rapamycin, tumors shrank on average 49%.  Tumor regression was visually apparent 
and histologic analysis revealed massive cell death and accumulating debris.  Maximal tumor 
regression occurred with 3-5 days and no acute or long-term toxicity was observed.   
 
IPI-504 rapidly induced ER stress and UPR activation and rapamycin sensitized MPNSTs to 
IPI-504.  Rapamycin and IPI-504 trigger catastrophic destruction of the ER and mitochondria 
in MPNSTs as evidenced by ER swelling, destruction, and mitochondrial damage that was 


 
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seen in all tumors treated with both agents, but was not detected in tumors from animals 
exposed to single agents.  This process is fueled by oxidative stress, which is caused by IPI-
504 dependent production of reactive oxygen species, and rapamycin dependent suppression 
of glutathione, an important endogenous anti-oxidant.  Similar tumor regression from this 
combination extended to a KRAS mutant mouse model of NSCLC.     
 
To date, no previous targeted agents have been shown capable of causing tumor regression in 
the highly aggressive genetically engineered MPNST model or in human tumors (See Table 
1).  Pre-clinical data presented demonstrate strong scientific rationale to study this 
combination in a clinical trial.  Ganetespib is a potent, next generation Hsp90 inhibitor that 
has shown superior activity to first generation agents in preclinical studies.  It has a favorable 
safety profile and promising anti-tumor activity over a broad range of tumor types in early 
clinical trials.  Sirolimus is commercially available, oral, and relatively inexpensive.  It has a 
long safety record, demonstrated efficacy in preclinical cancer models, and was used in the 
transgenic MPNST mouse model.  We propose a multi-institutional open label phase I/II trial 
of ganetespib in combination with sirolimus in patients with refractory MPNST.  There is 
data to support this combination will benefit other sarcomas in addition to MPNST.  Thus, 
we will include other sarcoma types to be eligible for the phase I component of this trial, 
which will also benefit in expediting enrollment.  Pre-clinical work with this combination of 
agents in other sarcomas is currently underway, which will aid in the further development of 
this combination for other sarcomas. The results of this trial will provide valuable toxicity, 
tolerability, and pharmacokinetic information for a drug combination with potential 
uses other Ras driven tumors.  By taking agents selected through this model to a clinical 
trial, we will be able to explore the utility of the mouse model for predicting response in NF1 
clinical trials.  Importantly, if the combination proves as effective as hypothesized in 
MPNSTs, it could provide a therapeutic strategy for this highly refractory and aggressive 
malignancy.   
 
2.5 
Preliminary results of current study (March 2015) 
A total of 10 patients (9 evaluable) have enrolled on the phase I portion of this study.  Three 
patients were enrolled on dose level 1. No DLTs were observed on the first dose level.  On 
dose level 2, one out of 3 patients experienced a DLT of grade 4 thrombocytopenia and thus 
the cohort was expanded to an additional 3 patients (1 patient came off of protocol therapy 
due to physician decision prior to completing cycle one without experiencing a DLT and was 
thus replaced). The most common adverse effects were grade 1 or 2 diarrhea, grade 1 
thrombocytopenia, and grade 1 increase in liver transaminases. No other DLTs were 
experienced, and dose level 2 was determined to be the recommended phase II dose to move 
forward.  
 
Three out of 9 patients experienced a grade 1 or 2 infusion reaction. After being treated with 
steroids and diphenhydramine and in some cases slowing the infusion time to 2 hours, all 
patients recovered and were able to receive subsequent ganetespib with pre-medication 
without additional infusion reactions. Infusion reactions in general may occur in up to 10% 
of patients without pre-medication, and lower with pre-medication, which is generally being 
recommended across studies with ganetespib. Our study saw a slightly higher occurrence in 


 
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the small number of patients treated with this combination.  Thus, we will require pre-
medication prior to administration of ganetespib with steroids and anti-histamines for the 
phase II portion of the study.   
 
2.6 
Study Design 
We propose an open label phase I/II trial of ganetespib in combination with sirolimus in 
patients with refractory sarcomas and MPNSTs.  The primary objective of the initial phase I 
component is to evaluate the safety and tolerability of this combination, and to determine the 
maximum tolerated dose (MTD)/recommend dose for this combination.  The phase I 
component will be open to all patients with refractory sarcomas.  Secondary objectives of 
this portion will be to describe the plasma pharmacokinetic profile of ganetespib and 
sirolimus when administered in this combination therapy.  The starting dose and escalation 
schema are as described below.   
Dose 
Level 
Ganetespib 
(mg/m2) 
IV days 1, 8, 15 
every 28 days 
Sirolimus (mg) 
Loading dose 
C1 D1 only 
Maintenance 
PO once daily 
continuous 
-2 
100 
6 
2 
-1 
150 
6 
2 
1* 
150 
12 
4 
2 
200 
12 
4 
* Starting dose 
Each cycle is considered 28 days 
 
The recommended phase II dose of weekly single agent ganetespib is 200 mg/m2/dose IV 
over one hour x 3 weeks; 1 week off.  The starting dose of Ganetespib selected is a 25% dose 
decrease and used previously in the docetaxel combination trials 49.  The starting dose for 
sirolimus was selected using similar doses derived from earlier phase I single and 
combination studies 59,61,62 with sirolimus trough levels ranging from 5-10 ng/mL.  There will 
be no plans to exceed the recommended doses of either agent (Dose level 2).  Three to six 
patients will be entered per dose level using standard 3+3 design.  Patients will be closely 
evaluated for the development of toxicity.  Toxicities observed during the first cycle will be 
used to define the MTD/Recommended dose.   
 
The recommended phase II dose of this combination is dose level 2 with ganetespib 200 
mg/m2/dose IV given over one hour x 3 weeks (days 1, 8, 15), 1 week off combined with 
sirolimus 4 mg by mouth once daily continuously (loading dose of 12 mg given on day 1 of 
cycle 1 only). One cycle equals 28 days. The phase I portion is complete and the phase II 
component will open. The primary objective of the phase II portion will be to determine the 
clinical benefit rate (CR, PR, or stable disease ≥ 4 months using WHO criteria) of ganetespib 
in combination with sirolimus for patients with refractory sporadic or NF1 associated 
MPNST.  Additional sarcoma strata may be considered directed by preclinical findings and 
rationale.  We propose an open label Simon’s optimal two-stage design with a target benefit 
rate of 25%.  
 


 
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Ten patients will be enrolled on the first stage, with no further accrual if no response (CR, 
PR, or stable disease ≥ 4 months) is observed.  If at least one response is observe, accrual 
will continue until a total of 20 patients have been enrolled.  If ≥ 3 of 20 evaluable patients 
responds, this regimen will be considered active and could provide a therapeutic upfront 
strategy for this malignancy.  Sites of measureable disease will be evaluated within 4 weeks 
prior to starting therapy and then every 2 cycles.  Patients will be able to remain on treatment 
as long as they do not experience progressive disease or unacceptable toxicity up to 13 cycles 
(1 year).  If after 13 cycles, patients who in the opinion of the treating investigator are 
deriving benefit may be eligible for additional cycles, but will be determined at the discretion 
of the study PI, sponsor, and medical officer. Response will be determined by WHO criteria.  
MPNSTs are typically complex, non-spherical tumors and 2-D may thus reflect changes in 
tumor size better than 1-D (RECIST).  In addition, previous and ongoing trials of refractory 
phase II MPNST trials (erlotinib and bevacizumab/everolimus) have used WHO criteria and 
will allow for direct comparisons. However, patients who experience disease progression 
based on WHO criteria, but who are receiving benefit from ganetespib and sirolimus as 
evidenced by decrease in the MPNST growth rate or clinical improvement may continue 
treatment with ganetespib and sirolimus provided they have: 
 
stable disease based on RECIST 1.1 criteria 
 
not met other off treatment / study criteria (Sections 5.8 and 5.9) 
 
Treatment may continue until criteria for disease progression by RECIST 1.1 are met. 
 
Secondary objectives will be to determine changes in pharmacodynamic parameters 
including phospho-S6, AKT phosphorylation, pEIF2, Hsp70, and G6PD in tumor tissues 
from diagnosis/recurrence, and on treatment if feasible.  These markers will also be evaluated 
in peripheral blood mononuclear cells at baseline and during treatment.  Changes in patient 
reported pain and impact of pain on daily activities will also be assessed before and during 
treatment.  
 
2.7 
Correlative Studies Background 
1) Pharmacokinetics 
We will describe the plasma pharmacokinetic profile of ganetespib and sirolimus when 
administered in combination therapy. Pre-therapy levels will be drawn at baseline.  
Pharmacokinetic analysis will occur on cycle 1, day 15 as to capture steady state sirolimus 
levels.  Ganetespib has previously demonstrated no accumulation.   On day 15:  Ganetespib 
will be collected at  0h, 0.5h, 50min* (to be drawn 10 minutes prior to the end of infusion), 
2h, 4h, 6h, 8h, and 24 hours.  Sirolimus will be collected at hours 0, 1, 2, 4, and 24 hours.  
All patients enrolled in the phase I portion will be required to participate in pharmacokinetic 
testing.  In the phase II component, up to 10 patients will have optional pharmacokinetic 
analysis performed for broader experience at the MTD/recommended dose.   
 
Drug PK 
Pre-therapy 
levels 
Day 15:  Time  
Ganetespib 
X 
0h 
0.5h 
50min* 
2h 
4h 
6h 
8h 
24h 
Sirolimus 
X 
0h 
 
1h 
2h 
4h 
 
 
24h 


 
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There are no additional required sirolimus trough levels.  However, sirolimus trough levels 
can be drawn if concerns for toxicity or any other clinical indication, and recommendations 
to be discussed with principal investigator. 
 
*If infusion duration is prolonged, draw sample 10 minutes prior to the end of infusion.   
 
2) Pharmacodynamics 
Correlative studies evaluating pharmacodynamic parameters on Hsp inhibition, mTOR 
inhibition, UPR activation, and oxidative stress will be explored in tumor tissue and 
peripheral blood mononuclear cells.  Hsp70 levels increase when Hsp90 is effectively 
inhibited and has been used as a pharmacodynamic response to Hsp90 inhibitors 73.  
Phospho-S6 is the marker of choice in mTOR PD studies 59,74 and recent data indicate that 
baseline expression could have predictive value 75.  The limited clinical efficacy of mTOR 
inhibitors have been proposed to result from AKT activation that can occur via the negative 
feedback pathways 76.  Sirolimus did not induce AKT activation in MPNSTs in vivo 27, and 
combined rapamycin/IPI-504 did not suppress AKT phosphorylation or expression levels in 
the mouse model, indicating that this combination is not more effective because it inhibits 
AKT 30.  EIF2 phosphorylation is a marker of UPR activation 28 and was observed in the 
preclinical model as a marker of ER stress 30.  Hsp90 inhibition appears to stimulate ROS 
production, and sirolimus appears to enhance these effects by suppressing endogenous anti-
oxidants 30.  Glucose 6-phosphate dehydrogenase (G6PD) has a well-established role in 
protecting cells from oxidative stress via its effects on glutathione production, one of the 
most important endogenous cellular antioxidants 77-79.  G6PD expression can be suppressed 
by mTOR inhibitors in vitro through inhibitory effects on the transcription factor SREBP1 80.  
Dr. Cichowski’s lab demonstrated that sirolimus potently suppressed G6PD mRNA levels in 
MPNST tumor tissue 30.  Sirolimus and Hsp90 inhibition combined dramatically suppressed 
G6PD mRNA and protein expression MPNSTs in vivo.   
 
We will explore changes in pharmacodynamic parameters:  Hsp70, Phospho-S6, AKT 
phosphorylation, EIF2, and G6PD in peripheral blood mononuclear cells performed on day 
1 prior to ganetespib and sirolimus administration, and on day 15, 6 hours post drug 
administration.  We will also obtain archival tissue at diagnosis and/or recurrence to evaluate 
these tests if available.  For consenting patients with tumors accessible safely by 
percutaneous biopsy, on the phase II component only, we will obtain tumor biopsy at 
baseline and then on day 8 or 15 of cycle 1 at some time point within 12 hours after infusion 
of ganetespib.   
 
3) Patient reported pain and impact of pain of daily activities 
Pain associated with a mass was found to be greatest risk factor associated with the 
development of MPNSTs in NF1 12.  Pain may also serve a surrogate marker for tumor 
response and clinical benefit.  We propose assessing patient reported pain severity and the 
impact of pain on daily activities prior to treatment and during treatment prior to cycles 3, 5, 
9 and 13.  We will explore the relationship in the change in pain with radiologic response.  
The patient-reported pain evaluation will consist of two validated scales. The Numerical 


 
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Rating Scale-11 (NRS-11) will be used to assess pain severity, and the Pain Interference 
Scale from the Brief Pain Inventory will be used to assess the impact of pain on daily 
activities.  These scales have been placed on a single page to simplify administration 
(Appendix V).  Total administration time is less than 3 minutes.   
 
i) The Numerical Rating Scale-11 (NRS-11) is a self-report segmented 11-point 
numeric scale that assesses pain severity 81.  It consists of a horizontal line with 0 
representing “no pain” at the right end of the line and 10 representing “worst pain you 
can imagine” at the left end.  Patients are asked to circle the one number from 0 to 10 
that best describes how much their “most important tumor pain” hurt during the past 
week.  It takes less than 1 minute to complete.   
 
ii) The Brief Pain Inventory is a 7-item self-report questionnaire that measures the extent 
to which pain interferes with daily functioning 82.  Patients are asked to indicate how 
much pain interfered with various activities (general activity, mood, walking, normal 
work, relations with other people, sleep, and enjoyment of life) in the past week, with 
scores ranging from 0 (does not interfere) to 10 (completely interferes).  A total score 
is obtained by taking the mean of the scores for all 7 items; thus, the total pain 
interference score can range from 0 to 7. This scale takes less than 2 minutes to 
complete.   
 
4) Volumetric Tumor measurements 
Using volumetric 3-dimensional MRI analysis of MPNSTs, we may be able to more 
sensitively monitor response to ganetespib and sirolimus compared to conventional two-
dimensional MRI and one-dimensional MRI data analysis.  Volumetric MRI analysis has 
become the standard method to evaluate the growth rate of plexiform neurofibromas on 
clinical trials 83,84.  This method may have utility for MPNSTs, which are typically large and 
have a complex shape.   
 
Volumetric MRI analysis will be performed centrally at the NIH as a secondary objective and 
compared to standard response evaluation with 1D-and 2D- measurements.  MRI studies 
performed for response evaluation will be used for volumetric analysis, and no MRI 
sequence other than STIR MRI (Short T1 inversion recovery), which is commonly used in 
the evaluation of sarcomas and does not require contrast administration, will be required. 
 
3. PATIENT SELECTION 
 
Eligibility Criteria 
Patients must have baseline evaluations performed prior to the first dose of study drug 
and must meet all inclusion / exclusion criteria.  Results of all baseline evaluations, 
which assure that all inclusion and exclusion criteria have been satisfied must be 
reviewed by the Principal Investigator or his/her designee prior to enrollment of the 
patient.  In addition, the patient must be thoroughly informed about all aspects of the 
study, including the study visit schedule and required evaluations and all regulatory 
requirements for informed consent. The written informed consent must be obtained 
from the patient prior to enrollment. The following criteria apply to all patients 


 
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enrolled onto the study unless otherwise specified.  
 
3.1 
Inclusion Criteria 
 
3.1.1 Age  16 years 
 
3.1.2 Phase I:  Patients with unresectable, recurrent, or metastatic histologically 
confirmed soft tissue or bone sarcoma of one of the following subtypes: 
 Leiomyosarcoma* 
 Liposarcoma* 
 MFH/pleomorphic undifferentiated sarcoma* 
 Rhabdomyosarcoma* 
 Malignant peripheral nerve sheath tumor (MPNST)* 
 Osteosarcoma* 
 Ewings* 
 Alveolar soft part sarcoma 
 Malignant giant cell tumor of bone 
 Desmoplastic small round blue cell tumor 
 Synovial Sarcoma 
 Undifferentiated sarcoma 
*Patients with leiomyosarcoma, liposarcoma, osteosarcoma, Ewings, MPNST, 
rhabdomyosarcoma or MFH must have documentation that they have received, 
not been eligible for, or refused at least one prior chemotherapy regimen prior to 
enrollment. 
 
Phase II:  Patients with unresectable or metastatic histologically confirmed 
sporadic or NF1 associated high grade MPNST who have experienced 
progression after one or more prior regimens of cytotoxic chemotherapy.  Patients 
who have refused cytotoxic chemotherapy or for whom treatment on this protocol 
prior to receiving cytotoxic chemotherapy is felt to be in the best interest for the 
patient by the local investigator will also be eligible.   
 
3.1.3 For patients with NF1, diagnostic criteria leading to the diagnosis of NF1 and 
other NF1 findings must be documented on the eligibility checklist and on the 
form provided in Appendix IV.  
Diagnostic criteria for NF1 are (NIH Consensus Conference 1987): 
Presence of 2 or more of the following criteria: 
1. Six or more café-au-lait spots (≥ 0.5 cm in prepubertal subjects or ≥ 
1.5 cm in postpubertal subjects) 
2. ≥ 2 neurofibromas or 1 plexiform neurofibroma 
3. Freckling in the axilla or groin 
4. Optic glioma 
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6. A distinctive bony lesion (dysplasia of the sphenoid bone or 
dysplasia or thinning of long bone cortex) 
7. A first degree relative with NF1 
 
3.1.4 ECOG Performance Status of ≤ 2. 
 
3.1.5 Must be able to swallow whole pills. 
 
3.1.6 Patients must have measurable disease, defined as at least one tumor that is 
measurable (defined as those that can be accurately measured in at least two 
dimensions (longest diameter > 20 mm with conventional techniques or > 10 mm 
using spiral CT scan) in two dimensions on CT or MRI scan.  Baseline radiologic 
scans must be performed within 4 weeks of starting treatment. 
 
3.1.7 Adequate organ function within 2 weeks of Day 1 of study defined as:  
 
3.1.7.1 Adequate hematologic function as shown by:  ANC ≥ 1.0 x 109/L, Platelets ≥ 
75,000 x 109/L, Hgb > 9 g/dL (transfusion of packed red blood cells allowed). 
 
3.1.7.2 Adequate liver function as shown by: serum bilirubin ≤ 1.5 x ULN, ALT and 
AST ≤ 3.0 x ULN (≤ 5x ULN in patients with liver metastases). 
 
3.1.7.3 Fasting serum cholesterol ≤ 300 mg/dL OR ≤ 7.75 mmol/L AND fasting 
triglycerides ≤ 300 mg/dL OR < 3.42 mmol/L. NOTE: In the case one or both 
of these thresholds are exceeded, the patient can only be included after 
initiation of appropriate lipid lowering medication. 
 
3.1.7.4 Serum creatinine ≤ ULN or creatinine clearance > 60 ml/min/1.73 m2 
 
3.1.7.5 Adequate Cardiac Function defined as: 
 
 No history of congenital prolonged QTc syndrome, NYHA Class III or IV 
congestive heart failure (CHF) 
 No clinically significant cardiac arrhythmias, stroke or myocardial 
infarction within 6 months prior to enrollment 
 Second or third degree atrioventricular block unless treated with a 
permanent pacemaker 
 Complete left bundle branch block 
 QTcF ≤ 480 ms. Note:  Patients with Grade 1 prolonged QTcF (450-480 
msec) at the time of study enrollment should have correctable causes of 
prolonged QTc addressed if possible (i.e. electrolytes, medications). 
 Use of medications that have been linked to the occurrence of torsades de 
pointes (see Appendix VI) within the last 7 days. 
 
3.1.8 Prior therapy:  Patients must have fully recovered from the acute toxic effects of 


 
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all prior anti-cancer therapy.  Recovery is defined as a toxicity < grade 2 (CTCAE 
v 4.0), unless otherwise specified in the inclusion/exclusion criteria.   
a.   Myelosuppressive chemotherapy:  Patients must have not received 
myelosuppressive chemotherapy within 3 weeks of enrollment onto this 
study. 
b. Biologic agent:  At least 7 days after the last dose of biologic agent.  For 
agents that have known adverse events occurring beyond 7 days after 
administration, this period must be extended beyond the time which 
adverse events are known to occur.   
c.  Immunotherapy:  At least 42 days after the completion of any type of 
immunotherapy, e.g. tumor vaccines. 
d. Monoclonal antibodies:  Patients may not have received monoclonal 
antibodies within 3 weeks of enrollment onto this study. 
e.  Radiation:  At least 14 days after local palliative XRT (small port); or at 
least 4 weeks otherwise.  
f.   Stem Cell Transplant:  No evidence of graft versus host disease, and ≥ 2 
months must have elapsed since transplant. 
g. Hematopoietic growth factors:  At least 7 days must have elapsed since 
completion of therapy with a growth factor.  At least 14 days must have 
elapsed after receiving pegfilgrastim. 
  
3.1.9 Fertile men and women of childbearing potential must agree to use an effective 
method of birth control from Day 1 of study and for 120 days after last study drug 
administration in both sexes.  Effective methods of birth control includes: 
surgically sterile, barrier device (condom, diaphragm), contraceptive coil, 
abstinence, or oral contraception. 
 
3.1.10 Written, voluntary informed consent. 
 
3.1.11 Durable power of attorney (DPA):  All patients ≥ 18 years of age will be offered 
the opportunity to assign DPA so that another person can make decisions about 
their medical care if they become incapacitated or cognitively impaired. 
 
 
3.2 
Exclusion Criteria 
 
3.2.1  Patients currently receiving other anti-cancer agents are not eligible.  
 
3.2.2 Patients receiving chronic, systemic treatment with corticosteroids or another 
immunosuppressive agent (for example, cyclosporine). Topical or inhaled 
corticosteroids are allowed. 
 
3.2.3 Patients should not receive immunization with attenuated live vaccines within one 
week of study entry or during study period. 
 


 
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3.2.4 Uncontrolled brain or leptomeningeal metastases, including patients who continue 
to require glucocorticoids for brain or leptomeningeal metastases.  
 
3.2.5 Other malignancies within the past 3 years except for adequately treated 
carcinoma of the cervix or basal or squamous cell carcinomas of the skin. Stable 
NF1 related tumors, such as optic pathway tumors, which do not require treatment 
at time of study enrollment, will not be considered an exclusion criterion. 
 
3.2.6 Patients who have any known severe and/or uncontrolled medical conditions or 
other conditions that could affect their participation in the study such as: 
 
 Severely impaired lung function defined as spirometry and DLCO that is 50% of 
the normal predicted value corrected for hemoglobin and alveolar volume and/or 
O2 saturation that is 88% or less at rest on room air.  For patients who do not have 
respiratory symptoms (e.g. dyspnea at rest, known requirement for supplemental 
oxygen), pulmonary function tests are not required. 
 
 Significant vascular disease (e.g. aortic aneurysm, symptomatic peripheral 
vascular disease) within 6 months prior to enrollment 
 
 Uncontrolled diabetes as defined by fasting serum glucose >1.5 x ULN 
 
 A known history of HIV seropositivity, as immune deficiency increases the risk 
for opportunistic infection. 
 
 Impairment of gastrointestinal function or gastrointestinal disease that may 
significantly alter the absorption of sirolimus (e.g., ulcerative disease, 
uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome or small bowel 
resection). 
 
 Patients with an active, bleeding diathesis or significant coagulopathy (in absence 
of therapeutic anticoagulation). 
 
3.2.7 Female patients who are pregnant or breast feeding, or adults of reproductive 
potential who are not using effective birth control methods. (Women of 
childbearing potential must have a negative urine or serum pregnancy test within 
7 days prior to administration of study drugs) 
 
3.2.8 Patients with a known hypersensitivity to rapamycins (sirolimus, temsirolimus, 
everolimus) or to its excipients. Excipients: Tablets: butylhyroxytoluene/butylated 
hydroxytoluene (BHT), magnesium stearate, lactose monohydrate, 
hypromellose/hydroxypropyl methylcellulose, crospovidone, lactose anhydrous. 
The excipients comply with the requirements of the applicable compendial 
monographs (Ph. Eur., USP/NF). 
 


 
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3.2.9 Patients unwilling or unable to comply with the protocol. 
 
3.2.10 CYP3A4/CYP2C19 substrates:  See the list on Appendix II:  Patients should not 
have received these medications within 1 week of entry and is not allowed while 
on study.   
 
3.2.11 Seville orange, star fruit, grapefruit and their juices, and St. John’s Wort use are 
not allowed while on study. 
 
3.2.12 Enzyme inducing anticonvulsants: Patients may not be taking enzyme –inducing 
anticonvulsants, and may not have received these medications within 1 week of 
entry, as these patients may experience different drug disposition.  These 
medications include: 
 Carbamazepine (Tegretol) 
 Felbamate (Felbtol) 
 Phenobarbitol 
 Phenytoin (Dilantin) 
 Primidone (Mysoline) 
 Oxcarbazepine (Trileptal) 
 
3.3 
Inclusion of Women and Minorities 
 
Subjects of both genders and from all racial and ethnic groups are eligible for this trial if they 
meet the criteria. To date, there is no information that suggests differences in absorption, 
metabolism, or disposition or disease response among racial or ethnic groups or between the 
genders, indicating that results of the trial will be applicable to all groups. Efforts will be 
made to extend the accrual to a representative population, but in a phase I/II trial which will 
accrue a limited number of patients, a balance must be struck between patient safety 
considerations and limitations on the number of individuals exposed to potentially toxic or 
ineffective treatments on the one hand and the need to explore gender, racial, and ethnic 
aspects of clinical research on the other. If differences in outcome that correlate to gender, 
racial, or ethnic identity are noted, accrual may be expanded or additional studies may be 
performed to investigate those differences more fully 
 
4. REGISTRATION PROCEDURES 
4.1 
General Guidelines 
After obtaining Informed Consent, eligible patients will be enrolled on this trial. Subjects 
will be registered by local sites through an electronic database, and will be issued a 
subject unique identifying numbers for eligible participants. An investigator is required to 
prepare and maintain adequate and accurate case histories designed to record all 
observations and other data pertinent to the investigation on each subject treated with the 
investigational product in the study or registered to the study. SARC may request faxed 
copies of selected source documents with PHI redacted for verification of records, 
accuracy of electronic submissions and review of data. 


 
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While all study evaluations must be performed by the Investigator as described in Section 
10, Study Evaluations and Study Calendar, only data related to the primary and 
secondary endpoints, as well as safety data, will be captured in the eCRFs. 
 
4.2 
Registration Process 
This study uses a web based data entry system for data submission. All subject 
registrations and Case Report Forms (CRFs) will be submitted electronically via the 
study web site. All subjects must be registered on the study website prior to start of 
treatment.  Data Managers and other authorized users will be provided with a unique user 
identification number and password to access the site.  All study case report forms may 
be accessed online through the study website.  In case there are problems accessing the 
website, please contact the SARC office directly at: Phone: 734-930-7600, Fax: 734-930-
7557. 
 
 
5. TREATMENT PLAN 
5.1 
Agent Administration 
 
Treatment Schedule Table 
Days 1, 8, 15 
Ganetespib IV over 1 hour 
Days 1-28 
Sirolimus once daily 
Day 28 
End of Cycle 
 
Ganetespib will be provided by Synta pharmaceuticals.  Ganetespib will be diluted to 
appropriate dose in D5W prior to administration.  Ganetespib will be given at hour 0 on days 
1, 8, and 15 intravenously over 1 hour.  For patients who have infusion reactions or it is felt 
in the best interest of the patient to have the infusion given for longer duration, ganetespib 
may be administered over up to 2 hours and will not be considered a protocol deviation. The 
infusion duration should be noted on the medical administration record, case report form and 
pharmacokinetic worksheet, if applicable. *All efforts should be made to adhere to this 
schedule.  However, to provide some flexibility to changes in patients’ schedules and 
holidays for long-term treatment, +/- 1 day in changes will not be considered a protocol 
deviation and will not require reporting to the NCI, IRB, or FDA.   
 
Required Pre-medications: 
 
1) Loperamide 2 mg should be given 1 to 2 hours prior to ganetespib administration and then 
every 4 hours for 12 hours post infusion to all patients as prophylactic diarrhea management.   
 
2) Dexamethasone 10 mg IV and diphenhydramine HCl 25 mg to 50 mg IV or PO (or 
therapeutic equivalents) should be given prior to administration of each ganetespib infusion.  
The premedication may be modified per institutional guidelines or as clinically indicated.  
 


 
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Based on timing of laboratory correlates (pharmacokinetics and pharmacodynamics), we 
would recommend that treatment day 1 to start on a Monday, Tuesday, or Wednesday if at all 
feasible.   
 
Sirolimus will be purchased commercially (2 mg tablets) and administered once daily.  On 
cycle 1, on day 1 a loading dose of sirolimus will be given orally x 1. Subsequent doses of 
sirolimus will be given once daily continuously with no breaks in between cycles.  On days 
when sirolimus and ganetespib are given together, they should begin at hour 0 together.  
Sirolimus should be taken at approximately the same time every day, preferably in the 
morning, consistently with or without food.  If a patient misses a dose, the dose may be taken 
within 6 hours of missed dose.  Otherwise, patient must wait until the next day’s dose.  If a 
patient vomits after a dose of sirolimus it will not be repeated.  All doses prescribed and 
dispensed to the patient and all dose changes during the study will be recorded in the patient 
diary (Appendix III).    
 
A cycle of therapy is considered to be 28 days. 
 
Ganetespib drug doses should be adjusted based on BSA determined prior to the beginning of 
each cycle. 
 
5.2 
Criteria for starting subsequent cycles 
A cycle may be repeated every 28 days if the patient has at least stable disease, has not 
experienced dose-limiting toxicity, and has recovered from the prior cycle as evidenced by 
return to baseline eligibility.  Patients who experience progression based on WHO criteria as 
outlined in section 11.1.4, but in the opinion of the treating investigator are deriving benefit 
from treatment and do not meet off treatment or off study criteria (Sections 5.8 and 5.9), may 
continue on therapy as long as they have not met progression by RECIST 1.1 criteria 
(11.1.7). The study PI must be notified and SARC RECIST 1.1 form in Operations Manual 
must be sent to SARC demonstrating at least stable disease.   
 
A cycle can be extended by an additional 14 days (to day 42) to allow for recovery without 
modifying the dose of the drug on subsequent cycles if toxicity did not meet dose limiting 
criteria.  Patient must not met one of the off protocol therapy or off study criteria defined in 
section 5.8 and 5.9.  A cycle may be administered up to 13 times. Patients who in the opinion 
of the treating investigator are deriving benefit may be eligible for additional cycles, but will 
be determined at the discretion of the study PI, sponsor, and medical officer.  
 
5.3 
Dose Escalation Schema [Phase I component]- Completed 
 
5.3.1 Inter-patient Escalation  
 
Dose 
Level 
Ganetespib 
(mg/m2) 
IV days 1, 8, 15 
every 28 days 
Sirolimus (mg) 
Loading dose 
C1 D1 only 
Maintenance 
PO once daily 
continuous 


 
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-2 
100 
6 
2 
-1 
150 
6 
2 
1* 
150 
12 
4 
2 
200 
12 
4 
* Starting dose 
Each cycle is considered 28 days 
 
5.3.2 Criteria for Dose Escalation  
 Cohorts of 3 to 6 patients will be treated with drug combination at each dose 
level.  When a minimum of three patients who are evaluable for toxicity have 
completed one cycle of therapy at a dose level without evidence of dose-limiting 
toxicity (DLT) (section 5.3.3), subsequent patients may be enrolled at the next 
higher dose level.   
 If DLT is observed in 1 patient from the initial cohort of 3 patients at a given dose 
level, an additional 3 patients will be entered at that dose level.  If none of these 
additional patients experiences a DLT (1/6 with DLT), the dose will be escalated.  
If ≥ 1 of the additional patients experience a DLT (≥ 2/6 with DLT), the MTD has 
been exceeded, and the next lower dose level will be considered the MTD.  
 If the MTD has been exceeded at the starting dose level, then the subsequent 
cohort of patients will be de-escalated per schema above. 
 
5.3.3 Definition of Dose Limiting Toxicity (DLT) (Criteria for entire study)  
Toxicity will be graded using the NCI Common Terminology Criteria for Adverse 
Events (CTCAE) version 4.0.  A copy of the CTCAE version 4.0 can be 
downloaded from the CTEP website (http://ctep.cancer.gov).  Any suspected or 
confirmed dose-limiting toxicity should be reported within 24 hours to the overall 
study Principal Investigator.   
 
DLT will be defined as any of the following events that are possibly, probably, or 
definitely attributable to ganetespib or sirolimus.  The DLT observation period for 
the purposes of dose escalation will be the first cycle of therapy.  Dose limiting 
hematological and non-hematological toxicities are defined below: 
 
5.3.3.1 Non-hematological DLT 
 Any Grade ≥ 4 non-hematological toxicity 
 Any Grade 3 non-hematological toxicity with the specific exclusion of 
 Grade 3 nausea and vomiting of < 3 day duration. 
 Grade 3 Diarrhea ≤ 3 days duration 
 Grade 3 ALT/AST that returns to meet initial eligibility criteria within 
7 days of study drug interruption and that do not recur upon study re-
challenge. 
 Grade 3 fever or infection < 5 days duration. 
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supplementation. 
 Allergic reactions that necessitate discontinuation of study drug will not be 
considered dose-limiting. 
 Grade 2 non-hematological toxicity that persists for ≥ 7 days and is considered 
sufficiently medically significant or intolerable by patients that it requires 
treatment interruption. 
 Any adverse event requiring interruption of study drug for ≥ 7 days or which 
recurs upon drug challenge. 
 
 
5.3.3.2 Hematological DLT 
 Grade 4 Thrombocytopenia 
 Grade 4 Neutropenia 
 Grade 4 Anemia 
 
5.3.4 Intra-Patient Escalation 
Intra-patient dose escalation is not allowed. 
 
 
5.3.5 Definition of Maximum Tolerated Dose (MTD) 
The MTD is defined as the dose level immediately below the dose at which ≥ 
33% of patients in a cohort experience a DLT.   
 In order to escalate a dose level, < 33% of patients in a cohort should 
have a DLT. 
 At least 3 patients in a cohort must be evaluable for the definition of 
the MTD in order to escalate.   
 If 1 out of 3 patients in a cohort experience a DLT, then at least 6 
patients must be enrolled and evaluable for the definition of MTD 
prior to dose escalation.   
To determine extended tolerability, toxicities observed during the first treatment 
cycle will be used to define the MTD.  A patient will be considered evaluable for 
definition of the MTD if at least 85% of the prescribed sirolimus dose has been 
administered to the patient during the first treatment cycle (unless held for 
toxicity) based on diary review and pill count of returned drug, and patient must 
have received all 3 doses of ganetespib in the cycle.  If a discrepancy occurs, pill 
count will be used for adherence measurement.  If a patient has less than 85% 
adherence for reasons other than toxicity, the patient will be replaced in the 
cohort.  In addition, anyone who receives one or more doses and experiences a 
DLT will be considered evaluable for definition of MTD. 
 
5.4 
Dosing for Phase II component 
Patients will be treated at the recommend dose from the Phase I component of this trial, 
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(days 1, 8, 15), 1 week off combined with sirolimus 4 mg by mouth once daily 
continuously (loading dose of 12 mg given on day 1 of cycle 1 only). One cycle equals 28 
days. 
 
5.5 
General Concomitant Medication and Supportive Care Guidelines 
Patients must be instructed not to take any additional medications (including over-the-
counter products) during the trial without prior consultation with the investigator. All 
medications taken at the time of screening should be recorded. If concomitant therapy 
must be added or changed, the reason and name of the drug/therapy should be recorded. 
In general, the use of any concomitant medication/therapies deemed necessary for the 
care of the patient are allowed, including drugs given prophylactically (e.g. antiemetics), 
with the following exceptions: 
 No other investigational therapy should be given to patients 
 No chronic treatment with systemic steroids or another immunosuppressive 
agent (for example, cyclosporine) with the exception of patients with 
endocrine deficiencies who are allowed to received physiologic or stress doses 
of steroids if necessary.  
 The CYP3A4/ CYP2C19 substrates listed on Appendix II and enzyme 
inducing anticonvulsants listed in section 3.2.10 and 3.2.11, and 3.2.12 are 
prohibited on this trial. Exercise caution when using sirolimus with other 
drugs or agents that are modulators of CYP3A4.   
 Use of medications that have been linked to the occurrence of torsades de 
pointes (See Appendix VI) are prohibited. 
 Patients should not receive immunization with attenuated live vaccines during 
the study period. Close contact with those who have received attenuated live 
vaccines should be avoided. Examples of live vaccines include intranasal 
influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella 
and TY21a typhoid vaccines. 
 
5.5.1 Concomitant Cancer and other Therapy 
 Concurrent cancer therapy, including chemotherapy, radiation therapy, 
immunotherapy, or biologic therapy may NOT be administered.  
 
5.5.2 Supportive Care 
 Appropriate antibiotics, blood products, antiemetics (EXCEPT systemic steroids and 
aprepitant), fluids, electrolytes and general supportive care are to be used as 
necessary.  Platelets should be transfused for thrombocytopenia following 
institutional guidelines.  All blood products will be administered following 
institutional guidelines to prevent graft-versus-host disease.  Corticosteroids are 
permissible as premedication for blood product transfusions, or as treatment for 
an acute allergic reaction. 
 Diarrhea management (refer to Operations Manual):   


 
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o All patients will receive prophylactic loperamide 2 mg prior to and every 4 
hours during the first 12 hours post infusion of ganetespib.   
o For patients with Grade 1 or 2 Diarrhea:  Loperamide as an initial 4 mg 
dose followed by 2 mg doses every 4 hours (Do not exceed 16 mg in 24 
hours).  Patient should continue until free of diarrhea for 12 hours.   
o For Grade 3 or 4 Diarrhea:  Consider hospitalization with IVF if clinically 
indicated and antibiotics as appropriate.  
 Patients must take some form of PCP prophylaxis while on sirolimus.  For 
example: trimethoprim/sulfamethoxazole as per institutional guidelines, or 
suitable alternative (Of note, injectable pentamidine is on the list of medication at 
risk for Torsades de Pointes [Appendix VI].  This does not apply to inhaled 
pentamidine. Inhaled pentamidine is a suitable alternative for PCP prophylaxis). 
 Good oral hygiene and mouth care are encouraged, as mucositis is one of the 
toxicities of sirolimus. 
 Growth Factors that support platelet or white cell number or function can only be 
administered for culture proven bacteremia, clinical sepsis, or invasive fungal 
infection with neutropenia. ASCO guidelines and regulatory authority labeling for 
providing growth factor support are recommended.  
 Vaccinations: Patients receiving immunosuppressants, including sirolimus, should 
not be administered live vaccines. In addition, the response to vaccines (non-live) 
administered while the patient is immunosuppressed can be variable, and 
clinicians should check titers following for response if a non-live vaccine must be 
administered during this time. 
 
5.5.3 Management for Surgery 
Patients undergoing minor surgery should hold study drugs for 2 weeks prior to 
procedure, if feasible, and for 2 weeks after.  Patients will be considered evaluable 
for toxicity and/or response as long as they meet criteria as defined in Section 
11.1.1. 
 
5.6 
Duration of Therapy 
Treatment may continue for up to 1 year (13 cycles) in the absence of disease progression or 
unacceptable adverse events. See section 5.2 for criteria to start subsequent cycles. Patients 
who experience progression based on WHO criteria as outlined in section 11.1.4, but in the 
opinion of the treating investigator are deriving benefit from treatment and do not meet off 
treatment or off study criteria (Sections 5.8 and 5.9), may continue on therapy up to 1 year as 
long as they have not met progression by RECIST 1.1 criteria (11.1.7).  After 13 cycles, 
patients who in the opinion of the treating investigator are deriving benefit may be eligible 
for additional cycles, but will be determined at the discretion of the study PI, sponsor, and 
medical officer. 
 


 
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5.7 
Duration of Follow Up 
Patients will be followed until 30 days after the last dose of ganetespib and sirolimus or 
longer if the patient is removed from treatment with ganetespib and sirolimus for 
unacceptable adverse events.  Adverse events will be followed until resolution or 
stabilization of the adverse event as detailed in Section 7.1.2.  
 
5.8 
Criteria for Removal from Study Treatment  
1. Disease progression by WHO criteria.  For patients who by their treating 
physician feel as though they are deriving benefit from study, may stay on study 
as long as they do not meet progression defined by RECIST 1.1 (Section 11.1.7). 
2. Intercurrent illness that prevents further administration of treatment 
3. Unacceptable adverse event(s), including significant irreversible grade 4 toxicity 
attributed to sirolimus or ganetespib 
4. Patients with Grade 4 QTcF prolongation and torsades de pointes or polymorphic 
ventricular tachycardia or signs and symptoms of serious arrhythmia OR repeated 
grade 3 or higher QTcF prolongation must discontinue treatment with ganetespib 
5. Greater than 3 weeks have elapsed since the last dose of sirolimus or greater than 
8 weeks since the last dose of ganetespib 
6. Patient decides to withdraw from the study 
7. General or specific changes in the patient’s condition render the patient 
unacceptable for further treatment in the judgment of the investigator 
 
5.9 
Off Study Criteria 
1. Thirty days after the last dose of investigational agent 
2. Death 
3. Lost to follow-up 
4. Withdrawal of consent for any further data submission 
5. Entry onto another therapeutic study 
 
 
6. DOSING MODIFICATIONS/ MANAGEMENT FOR SPECIFIC SIDE EFFECTS 
Dosing changes for ganetespib related toxicities are described in Section 6.3 and for 
sirolimus in Section 6.4.  If toxicity cannot be clearly attributed to either agent alone, the 
toxicity will be attributed to both agents, and modifications will be made to both agents.  
Should a patient require permanent discontinuation of either ganetespib or sirolimus, the 
patient can continue on study receiving the agent, which is tolerated for as long as no other 
off treatment criteria are met.  The study PIs should be contacted to discuss questions 
regarding toxicity attribution and to discuss patients who may meet criteria to continue 
treatment with either agent alone. 
 
6.1  Dose modifications for non-hematological toxicity 
1. If a patient experiences a non-hematological dose limiting toxicity as defined in 
Section 5.3.3.1, the attributable treatment will be withheld.  If the toxicity resolves to 


 
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meet on study parameters within 14 days of drug discontinuation, the patient may 
resume treatment at a reduced dose.  Doses reduced for toxicity will not be re-
escalated, even if there is minimal to no toxicity with the reduced dose. 
2. If toxicity does not resolve to meet on study entry parameters within 14 days of drug 
discontinuation, the patient must discontinue the protocol therapy. 
3. If dose-limiting toxicity recurs in a patient who has resumed treatment at a reduced 
dose, the patient must discontinue the protocol therapy. 
4. Patients with reported Grade 3 severity at any of the specified ECG time points 
(QTcF > 500 ms), ganetespib should be withheld.  Ganetespib may be restarted at 
dose reduction (Section 6.3) when QTcF is ≤ Grade 1.  While the QTcF prolongation 
is Grade 3 or higher, patients should have additional ECG monitoring until QTcF 
prolongation returns to ≤ Grade 1. Patients with grade 3 QTcF prolongation who 
restart at reduced dose, should have 24 hour +/- 2 hours EKG performed after reduced 
dose. If no evidence of QTcF prolongation, then patient will only require pre-dose 
EKG every other cycle as previously performed. 
 
6.2  Dose modifications for hematological toxicity 
1. If a patient experiences hematological dose-limiting toxicity as defined in Section 
5.3.3.2, the attributable treatment will be withheld. Counts should be checked twice 
weekly during this time. When toxicity resolves to meet study parameters within 14 
days of drug discontinuation, the patient may resume treatment at the reduced dose.  
Doses reduced for toxicity will not be re-escalated, even if there is minimal to no 
toxicity with the reduced dose. 
2. If toxicity does not resolve to meet on study entry parameters within 14 days of drug 
discontinuation, the patient must discontinue protocol therapy. 
3. If dose-limiting toxicity recurs in a patient who has resumed treatment at a reduced 
dose, the patient must discontinue the protocol therapy. 
 
6.3  Ganetespib dose level modifications 
A single dose reduction of 30% is allowed for toxicities outlined Section 5.3.3. 
 
6.4  Sirolimus dose level modification 
 
A single dose reduction of 50% is allowed for toxicities outlined in Section 5.3.3. 
 
6.5  Management of Specific Side Effects 
6.5.1   Management of hypersensitivity reactions to ganetespib infusions 
 
Ganetespib contains a surfactant (polysorbate 80) that has been associated with 
hypersensitivity reactions in other medications administered by infusion. 
Symptoms have included pruritis, flushing, shortness of breath, chest tightness, 
dizziness, headache, increased systolic BP and HR. Therefore, we are requiring 
premedication with steroid and anti-histamine prior to each ganetespib infusion 
(see Section 5.1).  Despite premedication, if an infusion hypersensitivity reaction 


 
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to ganetespib is suspected, the following management is provided as guidance.  
Treatment should be based on clinical presentation. Institution specific procedures 
and regimens may be appropriate in lieu of these guidelines. 
 
Mild or moderate symptoms: 
 Stop ganetespib infusion 
 Administer IV dexamethasone and diphenhydramine HCl or therapeutic 
equivalent 
 After recovery from symptoms, resume ganetespib infusion at reduced rate 
 In subsequent cycle, consider optimizing premedication regimen (e.g., begin 
steroids the day before infusion or increase dose of steroids) 
 
Severe Symptoms (such as hypotension requiring pressor therapy or IV fluids, 
angioedema, respiratory distress requiring bronchodilator therapy, or generalized 
uticaria): 
 Stop ganetespib infusion  
 Administer IV dexamethasone, diphenhydramine HCl or therapeutic 
equivalent 
 Add adrenaline (1:1000) or bronchodilators as indicated 
 
In subsequent cycles, optimize the premedication regimen (e.g., begin steroids the 
day before infusion or increase the dose of steroids) and reduce the flow rate of 
the ganetespib infusion. 
 
The following is an example of infusion premedication regimen: 
 Dexamethasone 12 mg orally and diphenhydramine HCl 25-50 mg orally 
approximately 12 to 24 hours prior to next dose of study 
 Repeat dexamethasone 12 mg orally and diphenhydramine HCl 25-50 mg 
orally approximately 4-6 hours prior to the re-challenge. 
 
If severe symptoms recur with optimal premedication, treatment with ganetespib 
must be discontinued. 
6.5.2   Management of stomatitis/oral mucositis/mouth ulcers 
Stomatitis/oral mucositis/mouth ulcers due to sirolimus should be treated using 
local supportive care. Please note that investigators in earlier trials have described 
the oral toxicities associated with sirolimus as mouth ulcers, rather than mucositis 
or stomatitis. If your examination reveals mouth ulcers rather than a more general 
inflammation of the mouth, please classify the adverse event as such. Please 
follow the paradigm below for treatment of stomatitis/oral mucositis/mouth 
ulcers: 
1. For mild toxicity (Grade 1), use conservative measures such as non-alcoholic 
mouth wash or salt water (0.9%) mouth wash several times a day until 
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2. For more severe toxicity (Grade 2 in which case patients have pain but are 
able to maintain adequate oral alimentation, or Grade 3 in which case patients 
cannot maintain adequate oral alimentation), the suggested treatments are 
topical analgesic mouth treatments (i.e., local anesthetics such as benzocaine, 
butyl aminobenzoate, tetracaine hydrochloride, menthol, or phenol) with or 
without topical corticosteroids, such as triamcinolone oral paste 0.1% 
(Kenalog in Orabase®). For intolerable grade ≥ 2 stomatitis/oral 
mucositis/mouth ulcers, sirolimus will be held, and restarted with a dose 
reduction by 1 dose level after recovery from toxicity to grade 1 or less. 
3. Agents containing hydrogen peroxide, iodine, and thyme derivatives may tend 
to worsen mouth ulcers.  It is preferable to avoid these agents. 
4. Antifungal agents must be avoided unless a fungal infection is diagnosed. In 
particular, systemic imidazole antifungal agents (ketoconazole, fluconazole, 
itraconazole, etc.) should be avoided in all patients due to their strong 
inhibition of sirolimus metabolism, thereby leading to higher sirolimus 
exposures. Therefore, topical antifungal agents are preferred if an infection is 
diagnosed. Similarly, antiviral agents such as acyclovir should be avoided 
unless a viral infection is diagnosed. 
  
Note: Stomatitis/oral mucositis should be appropriately graded using the 
functional grading given on the NCI-CTC for adverse events, version 4. 
 
6.5.3    Management of hyperlipidemia and hyperglycemia 
 
Treatment of hyperlipidemia should take into account the pre-treatment status and 
dietary habits. Blood tests to monitor hyperlipidemia must be taken in the fasting 
state. Grade 2 or greater hypercholesterolemia (> 300 mg/dL or 7.75 mmol/L) or 
Grade 2 or greater hypertriglyceridemia (> 300 mg/dL or > 3.42 mmol/L) should 
be treated with a 3-hydroxy-3-methyl-glutaryl (HMG)-CoA reductase inhibitor 
(e.g., atorvastatin, pravastatin) or appropriate lipid-lowering medication, in 
addition to diet. Patients should be monitored clinically and through serum 
biochemistry for the development of rhabdomyolysis and other adverse events as 
required in the product label/data sheets for HMG-CoA reductase inhibitors. 
Note: Concomitant therapy with fibrates and an HMG-CoA reductase inhibitor is 
associated with an increased risk of a rare but serious skeletal muscle toxicity 
manifested by rhabdomyolysis, markedly elevated creatinine kinase (CPK) levels 
and myoglobinuria, acute renal failure and sometimes death. The risk versus 
benefit of using this therapy should be determined for individual patients based on 
their risk of cardiovascular complications of hyperlipidemia.  Grade 4 
hypercholesterolemia (> 500 mg/dL or > 12.92 mmol/L) hold sirolimus until 
cholesterol is < Grade 4.  If triglycerides > 500-1,000, and HDL is low, consider 
fibrate or niacin. For triglycerides > 1000 mg/dL or >11.4mmol/L, hold sirolimus 
while instituting fibrate or niacin therapy until triglycerides are < Grade 4. 
 
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therapy. In many cases the affected patients had an abnormal fasting glucose at 
baseline. Based on this finding, it is suggested that optimal glucose control should 
be achieved before starting a patient on sirolimus and should be monitored during 
sirolimus therapy. 
 
6.5.4  Management of non-infectious pneumonitis 
Non-infectious pneumonitis is a class effect of rapamycin derivatives. Cases of 
non-infectious pneumonitis (including interstitial lung disease) have also been 
described in patients taking sirolimus. Some of these have been severe and on rare 
occasions, a fatal outcome was observed.  
A diagnosis of non-infectious pneumonitis should be considered in patients 
presenting with non-specific respiratory signs and symptoms such as hypoxia, 
pleural effusion, cough or dyspnea, and in whom infectious, neoplastic and other 
non-medicinal causes have been excluded by means of appropriate investigations. 
Patients should be advised to report promptly any new or worsening respiratory 
symptoms.  
Patients who develop radiological changes suggestive of non-infectious 
pneumonitis and have few or no symptoms may continue sirolimus therapy 
without dose alteration.  Dose modifications and retreatment are described in 
Table 3 below. 
 


 
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Table 3: Management of non-infectious pneumonitis 
Worst Grade 
Pneumonitis 
Required Investigations 
Management of 
Pneumonitis  
Sirolimus Dose 
Adjustment 
Grade 1 
CT scans with lung windows 
and pulmonary function testing 
including: spirometry, DLCO, 
and room air O2 saturation at 
rest. Repeat chest x-ray/CT 
scan every 2 cycles until return 
to baseline. 
No specific therapy is 
required 
Administer 100% of 
sirolimus dose. 
Grade 2 
CT scan with lung windows 
and pulmonary function testing 
including: spirometry, DLCO, 
and room air O2 saturation at 
rest. Repeat each subsequent 
cycle until return to baseline. 
Consider bronchoscopy *  
Symptomatic only. 
Prescribe corticosteroids 
if cough is troublesome. 
Reduce sirolimus dose to 
50% lower dose than 
previously administered 
until recovery to ≤ Grade 
1. Sirolimus may also be 
interrupted if symptoms 
are troublesome. Patients 
will be withdrawn from 
protocol treatment if they 
fail to recover to ≤ Grade 
1 within 3 weeks. 
Grade 3 
CT scan with lung windows 
and pulmonary function testing 
including: spirometry, DLCO, 
and room air O2 saturation at 
rest; Repeat each subsequent 
cycle until return to baseline. 
Bronchoscopy is recommended 
* 
Prescribe corticosteroids 
if infective origin is ruled 
out. Taper as medically 
indicated. 
Hold treatment until 
recovery to ≤ Grade 1. 
May restart protocol 
treatment within 2 weeks 
at a reduced dose if 
evidence of clinical 
benefit. 
Patients will be withdrawn 
from the study if they fail 
to recover to ≤ Grade 1 
within 2 weeks.  
Grade 4 
CT scan with lung windows 
and required pulmonary 
function testing includes: 
spirometry, DLCO, and room 
air O2 saturation at rest. Repeat 
each subsequent cycle until 
return to baseline. 
Bronchoscopy is recommended 
*. 
Prescribe corticosteroids 
if infective origin is ruled 
out. Taper as medically 
indicated. 
Discontinue treatment. 
*A bronchoscopy with biopsy and/or bronchoalveolar lavage should be 
considered (grade 2) or is recommended (grade 3 or 4). For any grade infection 
should be ruled out prior to prescribing corticosteroids. 
 
7. ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The 
following list of AEs (Section 7.1) and the characteristics of an observed AE (Section 
7.2) will determine whether the event requires expedited reporting in addition to routine 
reporting.   


 
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7.1 
Adverse Event and Laboratory Abnormalities 
 
7.1.1 Clinical AEs   
7.1.1.1 Definition of Adverse Events 
Per the International Conference of Harmonisation (ICH), an AE is any 
untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product and which does not 
necessarily have a causal relationship with the treatment.  An AE can 
therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medicinal (investigational) product, 
whether or not considered related to the medicinal (investigational) 
product.  Pre-existing conditions which worsen during a study are to be 
reported as AEs. 
 
7.1.1.2 CTCAE term (AE description) 
The descriptions found in the revised NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for 
AE reporting.  All appropriate treatment areas should have access to a 
copy of the CTCAE version 4.0.  A copy of the CTCAE version 4.0 can 
be downloaded from the CTEP web site (http://ctep.cancer.gov). 
 
7.1.1.3  Intensity  
Intensity of all adverse events will be graded according to the NCI 
Common Terminology Criteria for Adverse Events v 4.0 (CTCAE) on a 
five-point scale (grades 1 to 5) and reported in detail on the CRF.  
Adverse events not listed on the CTCAE should be graded as follows:   
 


 
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CTC 
Grade: 
Equivalent 
To: 
Definition 
Grade 1 
Mild 
Discomfort noticed but no disruption of normal daily 
activity  
Grade 2 
Moderate 
Discomfort sufficient to reduce or affect daily activity; 
no treatment or medical intervention is indicated 
although this could improve the overall well-being or 
symptoms of the patient. 
Grade 3 
Severe 
Inability to work or perform normal daily activity; 
treatment or medical intervention is indicated in order 
to improve the overall well-being or symptoms; 
delaying the onset of treatment is not putting the 
survival of the patient at direct risk. 
Grade 4 
Life 
threatening/ 
disabling 
An immediate threat to life or leading to a permanent 
mental or physical conditions that prevents work or 
performing normal daily activities; treatment or 
medical intervention is required in order to maintain 
survival. 
Grade 5 
Death  
AE resulting in death  
 
7.1.1.4 Drug-Adverse Event relationship 
The causality relationship of study drug to the adverse event will be 
assessed by the investigator as either: 
Yes or No 
If there is a reasonable suspected causal relationship to the study 
medication, i.e. there are facts (evidence) or arguments to suggest a 
causal relationship, drug-event relationship should be assessed as Yes. 
The following criteria should be considered in order to assess the 
relationship as Yes: 
– Reasonable temporal association with drug administration 
– Known response pattern to suspected drug 
– Disappears or decreases on cessation or reduction in dose 
– Reappears on rechallenge. 
 
The following criteria should be considered in order to assess the 
relationship as No: 


 
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– It does not follow a reasonable temporal sequence from 
administration of the drug 
– It may readily have been produced by the subject’s clinical state, 
environmental or toxic factors, or other modes of therapy 
administered to the subject 
– It does not follow a known pattern of response to the suspected drug 
– It does not reappear or worsen when the drug is readministered. 
7.1.1.5 Definition of Serious Adverse Events 
A serious adverse event (SAE) is any experience that suggests a 
significant hazard, contraindication, side effect or precaution.  It is any 
Adverse Event that at any dose fulfils at least one of the following 
criteria: 
– is fatal; (results in death; NOTE: death is an outcome, not an event); 
– is life-Threatening (NOTE: the term "Life-Threatening" refers to an 
event in which the patient was at immediate risk of death at the time 
of the event; it does not refer to an event which could hypothetically 
have caused a death had it been more severe); 
– requires in-patient hospitalization or prolongation of existing 
hospitalization; 
– results in persistent or significant disability/incapacity; 
– is a congenital anomaly/birth defect; 
– is medically significant or requires intervention to prevent one or 
other of the outcomes listed above. 
 
7.1.1.6  Progression of Underlying Malignancy  
Progression of underlying malignancy is not reported as an adverse 
event if it is clearly consistent with the suspected progression of the 
underlying cancer as defined by WHO criteria, or other criteria as 
determined by protocol. Hospitalization due solely to the progression of 
underlying malignancy should NOT be reported as a serious adverse 
event.  Clinical symptoms of progression may be reported as adverse 
events if the symptom cannot be determined as exclusively due to the 
progression of the underlying malignancy, or does not fit the expected 
pattern of progression for the disease under study. 
Symptomatic deterioration may occur in some patients.  In this 
situation, progression is evident in the patient’s clinical symptoms, but 
is not supported by the tumor measurements.  Or, the disease 
progression is so evident that the investigator may elect not to perform 
further disease assessments.  In such cases, the determination of clinical 


 
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progression is based on symptomatic deterioration.  These 
determinations should be a rare exception as every effort should be 
made to document the objective progression of underlying malignancy. 
If there is any uncertainty about an adverse event being due only to the 
disease under study, it should be reported as an AE or SAE. 
 
7.1.2 Treatment and Follow-up AEs   
After the discontinuation of therapy, continue to follow up AEs as follows: 
Related AEs:  Follow until one of the following occurs: 
- 
Resolved or improved to baseline 
- 
Relationship is reassessed as unrelated 
- 
Death 
- 
Start of new anti-cancer regimen 
- 
Investigator confirms that no further improvement can be expected 
- 
Clinical or safety data will no longer be collected, or final database closure 
 
Unrelated severe or life threatening AEs:  Follow until one of the following 
occurs: 
- 
Resolved or improved to baseline 
- 
Severity improved to grade 2 
- 
Death 
- 
Start of new anti-cancer regimen 
- 
Investigator confirms that no further improvement can be expected 
- 
Clinical or safety data will no longer be collected, or final database closure 
 
Grade 2 AEs judged to be clinically significant:  Follow as clinically 
indicated. 
The final outcome of each adverse event must be recorded on the eCRF  
 
7.1.3 Laboratory Test Abnormalities   
Any laboratory result abnormality fulfilling the criteria for a serious adverse 
event should be reported as such. 
Any treatment-emergent abnormal laboratory result, which is clinically 
significant, i.e., meeting one or more of the following conditions, should be 
recorded on the adverse event page in the CRF: 


 
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- 
Accompanied by clinical symptoms 
- 
Leading to a change in study medication (e.g. dose modification, 
interruption or permanent discontinuation) 
- 
Requiring a change in concomitant therapy (e.g. addition of, interruption 
of, discontinuation of, or any other change in a concomitant medication, 
therapy or treatment) 
 
7.1.4 Follow-up of Abnormal Laboratory Test   
In the event of medically significant unexplained abnormal laboratory test 
values, the test should be repeated and followed until it has returned to the 
normal range, baseline value and/or an adequate explanation of the 
abnormality is found. If a clear explanation is established it should be 
recorded in the eCRF. 
7.2 
Handling of Safety Parameters 
7.2.1  Reporting of Adverse Events  
All adverse events ≥ Grade 3 occurring during the study and up to 30 days 
after the last dose of study medication must be reported.  Reporting the 
specific time of onset of a given AE is only necessary when it occurs in 
relation to study drug administration.     
7.2.2  Reporting of Serious Adverse Events (immediately reportable) 
Any clinical adverse event or abnormal laboratory test value that is serious 
and which occurs during the course of the study (as defined in section 7.1.1.5 
above) must be reported to SARC within 24 hours of the site PI becoming 
aware of the event (expedited reporting). If only limited information is 
initially available, follow-up reports are required. The original SAE Form 
must be kept on file at the study site. SARC will report all serious adverse 
events to the Principal Investigator, Medical Monitor, Dr. Scott Okuno and to 
Synta within 1 working day. 
SAEs must be reported on the MedWatch 3500A form included in the 
Operations Manual with the completed Fax/Email Coversheet and 
faxed/emailed to SARC (see Operations Manual). 
Related Serious Adverse Events MUST be collected and reported regardless 
of the time elapsed from the last study drug administration, even if the study 
has been closed.  
Unrelated Serious Adverse Events must be collected and reported during the 
study and for up to 30 days after the last dose of study medication. 
 


 
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7.2.3   Reporting of all Unanticipated Problems Involving Risk to Subjects or 
Others (UPIRTSOs) to the HRPO 
The HRPO Reporting requirements ask only for UPIRTSOs to be 
reported:  “All unanticipated problems involving risk to subjects or others 
must be promptly reported by telephone (301-619-2165), by email 
(usarmy.detrick.medcom-usamrmc.other.hrpo@mail.mil), or by facsimile 
(301-619-7803) to the HRPO.  A complete written report will follow the 
initial notification.  In addition to the methods above, the complete report can 
be sent to the US Army Medical Research and Materiel Command, 
ATTN:  MCMR-RP, 810 Schreider Street, Fort Detrick, Maryland  21702-
5000.” 
7.2.4   Pregnancy  
Females must be instructed to stop taking the study medication and 
immediately inform the investigator if pregnancy occurs during the study. 
Pregnancies occurring up to 120 days after the completion of the study 
medication must also be reported to the investigator.  The investigator must 
report all pregnancies within 24 hours to the sponsor. 
The investigator should counsel the patient; discuss the risks of continuing 
with the pregnancy and the possible effects on the fetus.  Monitoring of the 
patient should continue until conclusion of the pregnancy.  Depending on 
maternal/fetal outcomes, follow-up beyond pregnancy may be required. 
Pregnancy occurring in the partner of a male patient participating in the study 
should also be reported to the investigator and the sponsor. The partner should 
be counseled and followed as described above. 
 
  
8. PHARMACEUTICAL INFORMATION   
8.1 
Ganetespib 
Ganetespib, chemical name: 5-[2,4-dihydroxy-5-(1-methylethyl)phenyl]- 
2,4-dihydro-4-(1-methyl-1H-indol-5-yl)-3H-1,2,4-triazole-3-one, is a novel triazolone 
heterocyclic compound. Its molecular formula is C20H20N4O3. Ganetespib is a white to off-
white powder with a molecular weight of 364.40 g/mol. 
 
 
 
 
 
 
 
 
 


 
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8.1.1   Preparation and Administration 
The current ganetespib investigational product is a concentrate for solution for 
infusion provided in a single-use vial containing 300 mg /vial of ganetespib, as 
described in the Pharmacy Manual. The concentration of ganetespib is 
25 mg/mL in a polyethylene glycol 300 (PEG 300), polysorbate 80 (Tween-80) 
and dehydrated alcohol non-aqueous solvent system.  The drug product is a 
clear, colorless-to-pale-yellow solution, essentially free of visible particles. 
Note: Ensure correct administration instructions are followed prior to use 
of either product (see Pharmacy Manual). 
 
Ganetespib Drug Product, 25 mg/mL, 300 mg/vial (identified with a dark 
blue color cap and applicable product label):  Each vial contains 12 mL of 
deliverable volume (12.84 mL total including an overage per USP 
requirements) equivalent to 300 mg of ganetespib at a concentration of 25 
mg/mL in a PEG 300, polysorbate 80, and dehydrated alcohol non-aqueous 
solvent system.  The drug product, as noted, is a clear, colorless-to-pale-yellow 
solution. 
 
The amount of ganetespib administered will depend upon the patient’s body 
surface area.  The drug product is diluted before infusion. 
 
Ganetespib must be diluted prior to administration.  The appropriate drug 
administration instructions per the preparation guidelines must be 
carefully followed prior to use.  Refer to the Pharmacy Manual for detailed 
ganetespib preparation guidelines. 
 
Based on preclinical data, use of vascular access devices (VADs) (such as ports 
and peripherally-inserted central catheters [PICCS]) containing silicone 
catheters for ganetespib administration is permitted.  Use of VADs made of 
any other material is not permitted.  Following ganetespib administration 
through a VAD, care should be taken to flush the line after each dose of study 
drug. 
 
8.1.2   Formulation, Packaging and Labeling  
 
 
Container/Closure 
The ganetespib drug product is provided in a 30 mL type I amber glass vial 
fitted with a 20 millimeter stopper and sealed with an aluminum crimp and 
flip-off cap. 
Starting with the 300 mg drug product, the storage condition will be changed to 
20-25°C (68°F to 77°F) with excursions allowed between 15°C and 30°C 
(59°F and 86°F). 


 
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8.1.3  Agent Ordering 
For this trial, Ganetespib will be provided by Synta Pharmaceuticals.     
Details will be provided in the Operations Manual.  
 
8.1.4  Agent Accountability 
Accountability and patient compliance will be assessed by maintaining 
adequate drug dispensing and return records.  Compliance with individual 
patient dosing is assured as the drug is administered intravenously and 
recorded at the clinical site.  
Accurate records must be kept for each study drug provided by the sponsor. 
The drug dispensing log must be kept current and contain the following 
information: 
- 
documentation of drug shipments received from the sponsor (date 
received and quantity) 
- 
disposition of unused study drug not dispensed to patient 
- 
the identification of the patient to whom the study medication was 
dispensed 
- 
the date(s) and quantity of the study medication dispensed to the 
patient 
This inventory must be available for inspection by the Monitor. All supplies, 
including partially used or empty containers and copies of the dispensing & 
inventory logs, must be returned to the SARC Monitor at the end of the study, 
unless alternate destruction has been authorized by SARC, or required by 
local or institutional regulations (Section 8.7). 
8.1.5  Destruction of ganetespib 
Local or institutional regulations may require immediate destruction of used 
investigational product for safety reasons e.g., cytotoxicity.  In these cases, it 
may be acceptable for investigational site staff to destroy dispensed 
investigational product before a monitoring inspection provided that source 
document verification is performed on the remaining inventory and reconciled 
against the documentation of quantity shipped, dispensed, returned and 
destroyed.  
Written documentation of destruction must contain the following: 
- 
Identity (batch numbers or patient numbers) of investigational 
product(s) destroyed 
- 
Quantity of investigational product(s) destroyed 
- 
Date of destruction (date discarded in designated hazardous container 
for destruction) 


 
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- 
Method of destruction (the site must provide the sponsor with 
documentation of their institutional policy and procedures for handling 
and disposing of hazardous drugs) 
- 
Name and signature of responsible person (or company) who 
destroyed investigational products(s) 
8.1.6  Ganetespib toxicities (please refer to most recent IB) 
 
 
Single-Agent Studies 
The following adverse reactions were observed in patients with cancer (either 
solid tumor or hematologic malignancies) receiving single-agent ganetespib at 
varying dose levels and schedules.  Frequency (%) provided is based on the 
largest aggregate data set (n=402). 
Very Common Adverse Reactions (≥ 10%) 
The most common adverse reactions in 402 single-agent patients include 
diarrhea (80%), fatigue (53%), nausea (44%), decreased appetite (31%), 
vomiting (27%). 
 
Table 1.  Very Common (≥ 10%) Adverse Reactions, Single Agent Studies 
(n=402) 
 
Preferred Term 
AEs (≥ 10%) 
(N=402) 
n (%) 
Diarrhea 
320( 79.6)) 
Fatigue 
214 ( 53.2) 
Nausea 
177 ( 44.0) 
Decreased appetite 
126 ( 31.3) 
Vomiting 
109 ( 27.1) 
Anemia 
85( 21.1) 
Constipation  
88 ( 21.1) 
Insomnia 
85 (8.0) 
Abdominal pain 
81 ( 20.1) 
Headache 
81 ( 20.1) 
Dyspnea 
70( 17.4) 
Back pain 
63( 15.7) 
Blood alkaline phosphatase 
increased 
65( 16.2) 
Aspartate aminotransferase 
increased 
65(16.2) 
Dehydration  
59( 14.7) 
Weight decreased 
62( 15.4) 
Hypokalaemia 
55( 13.7) 


 
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Alanine aminotransferase increased 
62 ( 15.4) 
Cough 
52 ( 12.9) 
Hyponatremia 
54 ( 13.4) 
Dizziness 
53 ( 13.2) 
Edema peripheral 
53 ( 13.2) 
 
Common (≥ 1% and < 10%) Adverse Reactions 
Adverse reactions that were common, Grade ≥ 3, and related are increased lipase (3%), 
hypophosphatemia (2%), and lymphopenia (1%).  One of the 10 patients with increased 
lipase had an event that was assessed as serious.  None of the other common, Grade ≥ 3, 
and related AEs was assessed as serious 
 
Table 2.  Common (≥ 1% and < 10%); Grade ≥ 3 and Related and Serious Adverse 
Reactions in Single Agent studies (n=402) 
 
Preferred Term[1] 
Grade ≥ 3 and Related AE 
SAE 
Lipase increased 
10 (  2.5) 
1 (< 1) 
Hypophosphataemia 
8 (  2.0) 
0 
Lymphopenia 
5 (  1.2) 
0 
Asthenia 
5 (1.2) 
1 (<1) 
[1] A patient counts once for a preferred term with any incidence of the event. 
Note:  This table includes only adverse reactions that are not listed in Table 1. 
 
Adverse events that were uncommon (< 1%), related and serious are presented in Table 3. 
 
Table 3.  Uncommon (< 1%) Related, and Serious Adverse Reactions  
in Single-Agent Studies (N=402) 
 
Amylase increase 
ECG QT prolonged 
 Infection 
Atrial fibrillation 
Failure to thrive 
 Infusion related reaction 
Cardiac arrest 
Febrile neutropenia 
 Pneumonia 
Colonic fistula 
Gastrointestinal Perforation  Rales 
Confusional state 
Hyperbilirubinaemia  
 Renal failure 
Pain in extremity 
Hypoxia  
 Syncope 
Blood lactate 
dehydrogenase increase 
Hyperuricemia  
Thrombocytopenia  
Note:  Related AEs are those with a Relationship of Possible, Probable, Definite, Unknown, or  
Missing 
This table includes only adverse reactions that are not listed in Table 1 or Table 2. 
 
Note: Recent review of database for ganetespib (September 2015, n=1509) has identified 
Gastrointestinal perforation (GIP) as potential rare risk (0.33%) 


 
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8.2 
Sirolimus 
Sirolimus is a macrocyclic lactone produced by Streptomyces hygroscopicus. The 
chemical name of sirolimus (also known as rapamycin) is (3S,6R ,7E,9R ,10R,12R 
,14S,15E ,17E,19E ,21S,23S ,26R,27R ,34aS)-
9,10,12,13,14,21,22,23,24,25,26,27,32,33,34, 34a-hexadecahydro-9,27-dihydroxy-3-
[(1R)-2-[(1S,3R,4R)-4-hydroxy-3-methoxycyclohexyl]-1-methylethyl]-10,21-
dimethoxy-6,8,12,14,20,26-hexamethyl-23,27-epoxy-3H-pyrido[2,1-c][1,4] 
oxaazacyclohentriacontine-1,5,11,28,29 (4H,6H ,31H)-pentone. Its molecular formula 
is C51H79NO13 and its molecular weight is 914.2 
 
8.2.1 Preparation and Administration 
For this trial 2 mg tablets will be used. 
Food effects: In 22 healthy volunteers receiving Rapamune Oral Solution, a high-fat 
meal (861.8 kcal, 54.9% kcal from fat) altered the bioavailability characteristics of 
sirolimus. Compared with fasting, a 34% decrease in the peak blood sirolimus 
concentration (Cmax), a 3.5-fold increase in the time-to-peak concentration (tmax), 
and a 35% increase in total exposure (AUC) was observed. After administration of 
Rapamune Tablets and a high-fat meal in 24 healthy volunteers, Cmax, tmax, and 
AUC showed increases of 65%, 32%, and 23%, respectively. To minimize variability, 
tablets should be taken consistently with or without food. 
 
8.2.2 Formulation, Packaging and Labelling  
Tablets should be stored at 20° to 25°C (USP Controlled Room Temperature) (68° to 
77°F). Use cartons to protect blister cards and strips from light. Dispense in a tight, 
light-resistant container as defined in the USP.  
 
8.2.3 Agent Ordering 
Sirolimus is commercially available.  For this study, sirolimus will be supplied 
through the study.  For agent ordering, see operations manual. 
 
8.2.4 Agent Accountability 
See Section 8.1.4 
 
8.2.5 Sirolimus toxicities 
Phase III studies of sirolimus in cyclosporine-based regimens revealed mild dose related 
thrombocytopenia and increases in serum triglycerides and cholesterol (in 40% to 50% of 
patients), which have responded well to HMG-CoA reductase inhibitors as well as 
fibricacid derivatives. Additionally, the unexpected finding of nephrotoxicity has been 
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apotentiation 
of 
cyclosporine’s 
nephrotoxicity. 
Other 
common 
side 
effects 
includeleukopenia (20%), hypertension (45%), anemia (30%), headaches (29%), tremors 
(26%), nausea and vomiting (30%), diarrhea (34%), constipation (32%), urinary tract 
infections (25%), decreased phosphate (19%), decreased potassium (26%), peripheral 
edema (25%),rash and acne. The 5 mg dose did produce more marrow suppression and 
hyperlipidemia. 
 
Side effects were related to drug concentration and were improved with maintenance of 
the sirolimus level between 10 to 20 ng/mL. Sirolimus’s effect on the developing fetus is 
not known and is not recommended for administration to nursing mothers. Patients 
receiving immunosupressants, including sirolimus, should not be administered live 
vaccines. In addition, the response to vaccines (non-live) administered while the patient 
isimmunosuppressed can be variable and some clinicians should check titers following 
for response, if a killed vaccine must be administered while taking sirolimus. Recently, 
case reports have described a drug-induced pneumonitis in some patients receiving 
sirolimus, which was reversible upon discontinuation of the drug.  mTOR inhibitors, such 
as sirolimus, have been shown in vitro to inhibit production of certain growth factors that 
may affect angiogenesis, fibroblast proliferation, and vascular permeability. There have 
been reports of impaired or delayed wound healing in patients receiving sirolimus 
including lymphocele and wound dehiscence. Patients with a body mass index (BMI) 
greater than 30 kg/m2 may be at increased risk of abnormal wound healing based on data 
from the medical literature. There have also been reports of fluid accumulation, including 
peripheral edema, lymphedema, pleural effusion and pericardial effusions (including 
hemodynamically significant effusions and tamponade requiring intervention in children 
and adults), in patients receiving sirolimus. There is also new evidence of incisional 
hernia noted in patients who undergo transplant surgery. Hepatotoxicity has been 
reported, including fatal hepatic necrosis with elevated sirolimus trough concentrations. 
There have been reports of neutropenia, proteinuria, nephritic syndrome, pancytopenia, 
joint disorders, and lymphedema. Azoospermia has been reported with the use of 
sirolimus and has been reversible upon discontinuation of sirolimus in most cases. 
Hypersensitivity reactions, including anaphylactic/anaphylactoid reactions, angioedema, 
exfoliative dermatitis, and hypersensitivity vasculitis, have been associated with the 
administration of sirolimus. In addition, a 5-fold increase in the reports of tuberculosis 
among sirolimus (11/551) and comparator (1/273) treatment group was observed with 2:1 
randomization scheme. 
Table 1.  Most Common (≥ 30%) Adverse Reactions Observed 
Side Effect Term* 
Percentage out of 100 
Patients 
Peripheral edema 
58 
Hypertriglyceridemia 
57 
Hypertension 
49 
Hypercholesterolemia 
46 


 
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Creatinine increased 
40 
Constipation 
38 
Abdominal pain 
36 
Diarrhea 
35 
Fever 
34 
Headache 
34 
Anemia 
33 
Pain 
33 
Urinary tract infection 
33 
Arthralgia 
31 
Nausea 
31 
Thrombocytopenia 
30 
*From rxlist.com 
 
Table 2.  Less Likely (≥ 3%, but < 20%) Adverse Reactions Observed 
Side Effect Term* 
Azoospermia 
Capillary leak syndrome 
Epistaxis 
Febrile neutropenia 
Fluid accumulations 
Hyponatremia/hypokalemia 
Hypophosphatemia 
Hypotension 
Immune suppression and resulting risk for opportunistic infections 
Leukopenia 
Pneumonitis 
Stomatitis 
Thrombotic thrombocytopenic 
Vomiting 
Wound dehiscence 
*From rxlist.com 
 


 
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9. CORRELATIVE/SPECIAL STUDIES 
9.1 
Laboratory Correlative Studies 
Some of the following correlative studies are mandatory for trial participation, and 
some are optional and will only be performed in patients providing informed consent.   
 
After analyses, any remaining correlative samples may be retained in a SARC 
designated specimen bank with the consent of the patient. No personal health 
information will be linked to the sample. The specimen will be marked with the 
patient study identification number only. 
 
9.1.1 Mandatory 
9.1.1.1  Pharmacokinetics 
Pharmacokinetic samples will be collected in all phase I patients.  A pre-treatment 
sample will be obtained on day 1 prior to either medication.  Pharmacokinetic 
samples for ganetespib will be performed by Synta pharmaceuticals.  At baseline, 
pre-treatment levels will be drawn.  On cycle 1, day 15, ganetespib 
pharmacokinetic samples will be collected at  0h, 0.5h, 50min.* (to be drawn 10 
minutes prior to the end of infusion), 2h, 4h, 6h, 8h, and 24 hours post infusion.  
Pharmacokinetic analysis of samples for sirolimus will be performed by 
Cincinnati Medical Center in the laboratory of Kenneth Setchell.  At baseline, 
pre-treatment levels will be drawn.  On cycle 1, day 15, sirolimus 
pharmacokinetic samples will be collected at hour 0, 1, 2, 4, and 24 hours post 
dose.  Collection instructions, PK sheets, handling, and shipment are provided in 
the operations manual. 
*If infusion duration is prolonged, draw sample 10 minutes prior to the end of 
infusion.   
9.1.1.2 Pain (Appendix V) 
The patient-reported pain evaluation will consist of two validated scales.  The 
Numerical Rating Scale-11 (NRS-11) will be used to assess pain severity, and the 
Pain Interference Scale from the Brief Pain Inventory will be used to assess the 
impact of pain on daily activities.  These scales have been placed on a single page 
to simplify administration.  Total administration time is less than 3 minutes.  
These tests will be given prior to treatment and then prior cycle 3, 5, 9 and 13.  
Details regarding collection and assessment will be provided in the operations 
manual. 
 
9.1.1.3 Volumetric MRI analysis 
To evaluate the utility of 3-dimensional MRI analysis for MPNST, MRIs obtained 
for disease evaluation at baseline and as part of response evaluation will be 
analyzed using 3D MRI in addition to 1D and 2D analysis.  This will be done 
centrally at NIH.  Details regarding handling and shipping of MRI studies are 
provided in the Operations Manual. 


 
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9.1.2 Optional 
 
9.1.2.1 Pharmacokinetics 
Pharmacokinetic samples will be collected in up to 10 patients in the phase II 
component for data and experience at the recommended dose.  Collection time 
will be as described above in Section 9.1.1.1. 
 
9.1.2.2 Pharmacodynamics 
 
Correlative studies evaluating pharmacodynamic parameters on Hsp inhibition 
(Hsp70), mTOR inhibition (phospho-S6 and Akt Phosphorylation), UPR 
activation (EIF2 phosphorylation), and oxidative stress (G6PD) will be explored 
in tumor tissue and peripheral blood mononuclear cells.  15 mL of blood will be 
collected prior to treatment with either agent and then on day 15 approximately 6 
hours post ganetespib administration.  
 
Diagnostic and/or relapsed archival MPNST tissue will be collected if available 
and feasible.  
 
For patients on the phase II component only who consent to optional tumor 
biopsies and whose biopsies are easily accessible with percutaneous biopsy, 
tumor biopsy will be collected pre-treatment and then during cycle 1 on either day 
8 or 15, within 12 hours after ganetespib administration to look at similar 
markers. 
 
Detailed timing, instructions, handling, and shipment are provided in the 
operations manual. 
 
 
10. 
STUDY EVALUATIONS AND STUDY CALENDAR 
10.1 
SCREENING STUDIES 
 
The following procedures will be performed during the screening period within 2 weeks 
prior to treatment unless otherwise specified: 
 
 
Informed consent (within 1 month) 
 
History/demographics 
 
Physical exam 
 
Vital signs: 
 
Height (first visit), pulse, blood pressure, respiration rate, oxygen saturation by 
pulse oximeter, temperature, weight, and BSA.  
 
Performance Status (see Appendix I) 
 
Documentation of clinical findings of NF1 (Appendix IV) 
 
Hematology: CBC and differential, PT, PTT, INR.  


 
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 
Serum Chemistry:  
 
Must include sodium, potassium, chloride, bicarbonate, calcium, phosphorous, 
magnesium, FASTING glucose, creatinine, blood urea nitrogen, albumin, total 
protein, SGOT (AST), SGPT (ALT), total bilirubin, alkaline phosphatase, uric 
acid, and FASTING serum lipid profile (triglycerides, total cholesterol, HDL and 
LDL). 
 
*FASTING=12 hours prior to glucose testing and lipid testing 
 
Serum or urine pregnancy to all females of childbearing potential within 7 days 
prior to starting treatment. 
 
   EKG and QTc (QTc will be calculated as QTcF using the Fridericia’s formula) 
 
   Disease evaluation using appropriate test (CT and/or MRI) must be performed 
within 4 weeks prior to treatment 
 
Patients should start study treatment within 2 weeks of enrollment/registration in 
the study database. 
10.2 
ON STUDY EVALUATIONS 
 
The following procedures will be performed during the treatment period (Test 
required prior to subsequent cycles should be performed within a time frame of 4 
days prior to cycle):  
 
 
History and physical: Weekly during cycle 1 and then prior to each cycle 
 
      Vital Signs:  Weekly during cycle 1 and then prior to each cycle:  Pulse, blood 
pressure, respiration rate, oxygen saturation by pulse oximeter, temperature, 
weight, and BSA.  
 
Performance Status:  Prior to each cycle 
 
Hematology: CBC weekly during cycle 1 and then every two weeks.  If 
hematological DLT follow Section 6.2.  
 
Serum Chemistry:  weekly during cycle 1 and then every two weeks.  Must 
include sodium, potassium, chloride, bicarbonate, calcium, phosphorous, 
magnesium, glucose, creatinine, blood urea nitrogen, albumin, total protein, 
SGOT (AST), SGPT (ALT), total bilirubin, alkaline phosphatase weekly during 
cycle 1, and then prior to every cycle. 
 
FASTING glucose and serum lipid profile (triglycerides, total cholesterol, HDL 
and LDL) prior to each cycle  
 
EKG and QTcF:  During Cycle 1:  24 hours (+/- 2 hours) post infusion on Day 1 
and then prior to every other cycle.  If Grade ≥ 3, follow guidelines in Section 6.1. 
 
Disease evaluation using appropriate test (CT and/or MRI): Prior to cycles 3, 5, 7, 
9, etc. Tumor imaging should NOT be delayed, if possible, if a subject 
temporarily or permanently suspends study drug treatment for toxicity or non-
compliance with administration of drug. In patients who experience a PR or CR 
confirmation of the response after 4 weeks should be performed, if feasible. 


 
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 
Administration of study drug:  
 A sirolimus diary will be kept by the patient and/or proxy to document each 
dose of drug taken.  Toxicities experienced will be documented on the diary.  
The diary will be reviewed weekly during cycle 1and then prior to each cycle.  
Pill count will occur after each cycle.    
 
Correlative studies (See Operations Manual for exact timing, collection, handling, 
shipping) 
 
Pharmacokinetics: Performed prior to treatment, and on Day 15, Cycle 1. 
 
Pharmacodynamics:  Performed prior to treatment, and on Day 15, Cycle 1 (If 
patients consent to tumor biopsy, then can occur on day 8 or 15). 
 
Patient reported Pain and Impact Measurements:  Performed prior to treatment 
and prior to cycles 3, 5, 9, and 13. 
 
MRI studies for volumetric analysis: 
MRI studies performed for restaging purposes at the time points of response 
evaluations will be analyzed using volumetric MRI analysis centrally in addition 
to standard 2-dimensional response evaluations (see Operations Manual). 
 
10.3 
OFF STUDY EVALUATIONS 
 
The following studies should be performed, if feasible, at the time a patient is removed 
from the study: 
 
 
History and Physical exam 
 
Vital signs: 
 
Pulse, blood pressure, respiration rate, oxygen saturation by pulse oximeter, 
temperature and weight.  
 
Performance Status (see Appendix I) 
 
Hematology:  
 
Hemoglobin, hematocrit, platelets, total white blood cell count (WBC) and 
differential, PT, PTT.   
 
Serum Chemistry:  
 
Must include sodium, potassium, chloride, bicarbonate, calcium, phosphorous, 
FASTING glucose, creatinine, blood urea nitrogen, albumin, total protein, SGOT 
(AST), SGPT (ALT), total bilirubin, alkaline phosphatase, uric acid, and 
FASTING serum lipid profile (triglycerides, total cholesterol, HDL and LDL). 
*FASTING = 12 hours prior to glucose and lipid panel 
 
Disease evaluation using appropriate test (CT and/or MRI). 


 
 
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10.4   STUDY EVALUATIONS  
 
Studies to be obtained 
Pre-Study 
During 
Cycle 1 
Prior to 
subsequent 
Cycles* 
During 
Subsequent Cycles 
End of 
Therapy 
Informed Consent 
X 
 
 
 
 
History and Physical with 
vitals a 
X 
Weekly 
X 
 
X 
Performance Status b 
X 
 
X 
 
X 
Documentation of NF1 
findingsc 
X 
 
 
 
 
CBC with differential 
X 
Weeklyd 
X 
Every Two Weeksd 
X 
PT, PTT, INR 
X 
 
 
 
X 
Serum Chemistrye 
X 
Weekly 
X 
Every Two Weeks 
X 
Fasting glucose and serum 
lipid profilef 
X 
 
X 
 
X 
Pregnancy Testg 
X 
 
Prior to odd Cycles 
(3, 5, 7, etc) 
 
 
EKG and QTcFh 
X 
Day 2 i 
Prior to odd Cycles 
(3, 5, 7, etc) 
 
X 
Tumor Evaluationj 
X 
 
Prior to odd cycles 
(3, 5, 7, etc) 
 
X 
Pharmacokineticsk 
X 
X 
 
 
 
Pharmacodynamic Studiesl 
X 
X 
 
 
 
Patient reported painm 
X 
 
Prior to cycles 3, 5, 
9, 13 
 
 
MRI for 3-D analysisn 
X 
 
Prior to odd cycles 
(3, 5, 7, etc) 
 
X 
Patient Diaryo 
 
Weekly 
X 
Prior to each cycle 
X 
 


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a Vitals signs: Height (first visit only), pulse, blood pressure, respiratory rate, oxygen saturation by pulse oximeter, temperature, 
weight, and BSA calculation 
b See Appendix I for performance status criteria 
c See Appendix IV for documentation of findings for patients with NF1 
d If a patient experiences a Grade 4 hematologic DLT, then CBCs should be checked twice weekly until recovery to Grade 3. 
e Sodium, potassium, chloride, bicarbonate, calcium, phosphorus, magnesium, creatinine, glucose, blood urea nitrogen, albumin, 
total protein, SGOT (AST), SGPT (ALT), total bilirubin, alkaline phosphatase, uric acid 
f Fasting= 12 hours prior to testing.  Glucose and serum lipid panel (trigylcerides, total cholesterol, HDL, and LDL) 
g Standard pregnancy test given to all females of childbearing age ≤ 7 days prior to starting medication, and prior to each 
radiological evaluation 
h QTc calculated using Fridericia’s formula 
iTo be done 24 +/- 2 hours hours post infusion of day 1 ganetespib 
jPerformed ≤ 4 weeks prior to trial entry.  Disease evaluation using appropriate tests (CT/MRI) for volumetric analysis must be 
performed within 4 weeks of trial entry and prior to cycles 3, 5, 7, etc.   
k See Section 2.6 and Operations manual for timing/instructions of PK collection 
l See Section 2.6 and Operations manual for timing/instructions of PD collection 
m See Section 2.6 and Operations for timing /instructions of Pain reported pain and impact on daily activities 
n Only for MPNST patients 
o See Appendix III.  
* Can be performed within 4 days of prior to cycle 
 
 
 
 
 
 
 
 


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11. MEASUREMENT OF EFFECT 
 
11.1 
Antitumor Effect – Solid Tumors 
 
11.1.1 Definitions  
 
Evaluable for toxicity for Phase I component:  A patient will be considered evaluable for 
definition of the MTD if at least 70% of the prescribed sirolimus dose has been 
administered to the patient during the first treatment cycle based on diary review and pill 
count of returned drug [if a discrepancy occurs, pill count will be used for adherence 
measurement] and all 3 doses of ganetespib in the first cycle.  If a patient has less than 
70% adherence, the patient will be replaced in the cohort.  In addition, anyone who 
receives one or more doses and experiences a DLT will be considered evaluable for 
definition of MTD. 
 
In the phase II component:  Patients who have received at least one dose of study drug 
will be considered evaluable for toxicity from the time of their first dose of ganetespib 
and sirolimus until the last evaluation on trial. 
 
Evaluable for objective response:  
 
Measurable disease:  Measurable lesions are defined as those that can be accurately 
measured in at least two dimensions (longest diameter > 20mm with conventional 
techniques or >10 mm using spiral CT scan). All tumor measurements must be recorded 
in millimeters (or decimal fractions of centimeters). 
 
Non-measurable disease:  All other lesions (or sites of disease), including small lesions 
(longest diameter < 20mm with conventional techniques or <10 mm using spiral CT 
scan), are considered non-measurable disease.  Bone lesions, leptomeningeal disease, 
ascites, pleural/pericardial effusions, lymphangitis cutis/pulmonis, inflammatory breast 
disease, abdominal masses (not followed by CT or MRI), and cystic lesions are all non-
measurable. 
 
Any patient who is enrolled and receives at least one dose of sirolimus and ganetespib 
will be considered evaluable for response provided: (1) the patient demonstrates 
progressive disease or death while on protocol therapy; (2) the patient is observed on 
protocol therapy for at least one cycle and the tumor is not removed surgically prior to the 
time complete response or partial response is confirmed; or (3) the patient demonstrates a 
complete or partial response or stable disease as confirmed according to protocol criteria.  
Patients who electively terminate therapy before receiving all ganetespib doses and ≥ 
80% of the required sirolimus doses during the first treatment cycle and do not expire 
within 28 days from start of treatment will be replaced.  


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11.1.2 - Disease Parameters 
 
Measurable, bidimensional:    Malignant disease measurable in two dimensions by ruler 
with surface area determined by multiplying the longest diameter by the greatest 
perpendicular diameter.   
 
Index Lesions:    Index lesions should be selected on the basis of their measurability in 
two dimensions and their suitability for accurate repeated measurements (by imaging 
techniques CT or MRI).  A sum of the product(s) of the longest diameter (LD) and 
greatest perpendicular diameter of all index lesions will be calculated and reported as the 
baseline sum.   The baseline sum will be used as a reference by which to characterize the 
objective tumor response. 
 
Non-index Lesions: 
All other lesions (or sites of disease) including any measurable 
lesions over and above the index lesions should be identified as non-index lesions and 
should also be recorded at baseline.  Measurement of these lesions is not required, but the 
presence or absence of each should be noted throughout follow-up. 
 
11.1.3 Methods for Evaluation of Measurable Disease 
 
All measurements should be taken and recorded in metric notation using a ruler or 
calipers.  All baseline evaluations should be performed as closely as possible to the 
beginning of treatment and never more than 4 weeks before the beginning of the 
treatment. 
 
The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up. Imaging-based 
evaluation is preferred to evaluation by clinical examination when both methods have 
been used to assess the antitumor effect of a treatment. 
 
Conventional CT and MRI:  These techniques should be performed with cuts of 10 mm 
or less in slice thickness contiguously.  Spiral CT should be performed using a 5 mm 
contiguous reconstruction algorithm.  This applies to tumors of the chest, abdomen, and 
pelvis.  Head and neck tumors and those of extremities may require specific protocols. 
 
11.1.4 WHO response criteria  
 
WHO will be used for this trial for several reasons: 
 
1) MPNSTs are typically complex non spherical tumors, and 2-dimensional 
measurements may thus better reflect changes in tumor size than 1-dimensional 
measurements (RECIST). 
 
2) The phase 2 trial of erlotinib and everolimus/bevacizumab, which will be used as a 
historical control for determination of time to progression, used WHO criteria. In order to 


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allow for the closest comparison, this trial will therefore use WHO response criteria. 
 
 
11.1.4.1 
Evaluation of Index Lesions 
 
Complete Response (CR): Disappearance of all known disease, determined by two 
consecutive observations not less than 4 weeks apart. 
 
Partial Response (PR):  A > 50% decrease in the total tumor load of the lesions that have 
been measured to determine the effect of therapy not less than four weeks apart. The 
observations must be consecutive. 
 
Bidimensionally measurable: single lesion, > 50% decrease in tumor area 
(multiplication of longest diameter by the greatest perpendicular diameter); multiple 
lesions, a 50% decrease in the sum of the products of the perpendicular diameters of 
the multiple lesions. 
 
In addition there can be no appearance of new lesions or progression of any lesion. 
 
Stable Disease (SD):  A 50% decrease in total tumor area cannot be established nor has a 
25% increase in the size of one or more measurable lesions been demonstrated. 
 
Progressive Disease (PD):  A > 25% increase in the area of one or more measurable 
lesions or the appearance of new lesions.   
 
11.1.4.2 
Evaluation of Non-Index Lesions 
Complete Response (CR): Complete disappearance of all known disease for at least four 
weeks. 
Partial Response (PR):  Estimated decrease in tumor area of > 50% for at least four 
weeks. 
Stable Disease (SD): No significant change for at least four weeks.  This includes stable 
disease, estimated decrease of < 50%, and lesions with estimated increase of < 25%. 
Progressive Disease (PD): Appearance of any new lesions not previously identified or an 
estimated increase of > 25% in existent lesions. 
 
Although a clear progression of “non-index” lesions only is exceptional, the opinion of 
the treating physician should prevail in such circumstances, and the progression status 
should be confirmed at a later time by the Principal Investigator. 
 


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Evaluation of Best Overall Response 
 
Index 
Lesions 
Non-Index 
Lesions 
New 
Lesions 
Overall 
Response 
Best Response for this 
Category also requires: 
CR 
CR 
No 
CR 
> 4 weeks confirmation 
CR 
PR/SD 
No 
PR 
PR 
CR/PR/SD 
No 
PR 
SD 
CR/PR/SD 
No 
SD 
Documented at least once 
>4 wks from baseline 
PD 
Any 
Yes or 
No 
PD 
no prior SD, PR or CR 
Any 
PD* 
Yes or 
No 
PD 
Any 
Any 
Yes 
PD 
*   In exceptional circumstances, unequivocal progression in non-index 
lesions may be accepted as disease progression. 
 
11.1.5 Duration of Response 
 
Duration of overall response:  The duration of overall response is measured from the 
time measurement criteria are met for CR or PR (whichever is first recorded) until the 
first date that recurrent or progressive disease is objectively documented (taking as 
reference for progressive disease the smallest measurements recorded since the 
treatment started, best response scan). 
The duration of overall CR is measured from the time measurement criteria are first 
met for CR until the first date that recurrent disease is objectively documented. 
 
Duration of stable disease:  Stable disease is measured from the start of the treatment 
until the criteria for progression are met, taking as reference the smallest 
measurements recorded since the treatment started.  
 
11.1.6  
Progression-Free Survival 
 
PFS is defined as the duration of time from start of treatment to time of objective 
progression or death. 
 
11.1.7  
RECIST 1.1 Criteria 85 
 
For patients who experience progression by WHO criteria as outlined above, but in 
the opinion of the treating investigator are deriving benefit from therapy and have not 
otherwise met off treatment or off study criteria, may continue on treatment as long as 
patient has not met progression by RECIST1.1 criteria outlined below. 
 
Key points to RECIST version 1.1 are that 5 target lesions are identified and that 
changes in the largest diameter (unidimensional measurement) of the tumor lesions 


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are used in the RECIST v1.1 criteria.  The sum of the longest diameter (LD) for all 
target lesions will be calculated and reported as the disease measurement. 
 
Progression by RECIST 1.1 is at least 20% increase in the disease measurement, 
taking as reference the smallest disease measurement recorded since the start of 
treatment or the appearance of one or more new lesions or evidence of laboratory or 
clinical progression. 
 
12. DATA REPORTING / REGULATORY CONSIDERATIONS 
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 
7.0 (Adverse Events: List and Reporting Requirements). 
 
12.1 
Data Reporting  
 
12.1.1  Method 
 
A final study report describing the outcome of the trial will be created at the end of the 
study.  
 
12.1.2  Data Safety Monitoring and Medical Monitor 
 
SARC is responsible for the Data Safety Monitoring for this trial. SARC Clinical Trials 
Review Committee convenes monthly and will provide safety oversight for this trial.  The 
purpose of the Clinical Trials Review Committee is to review the status of the on-going 
SARC studies, which includes, but is not limited to: 
 
 Review of all safety data (Serious Adverse Events reported)  
 Review of protocol deviations/violations 
 Review of study progress/accrual 
 Discussion of statistical aspects of all protocols 
 
The committee is chaired by the SARC Medical Officer, Dr. Scott Okuno, who is 
responsible for leading the meeting and providing medical oversight.  Attendance 
includes all Principal Investigators on active SARC studies, SARC Research Project 
Managers, SARC President, and a biostatistician. 
 
Safety oversight for this trial is also supported by the SARC Clinical Research 
Committee which is made up of senior sarcoma investigators and the SARC President 
and Chief Operating Officer.  This committee is provided with the clinical trial review 
committee minutes monthly for their review, and also convenes quarterly.  The medical 
officer updates the committee on the ongoing clinical trial status as well as any areas of 
concern particularly related to safety.  This committee provides an additional level of 
medical oversight for this trial. 
 


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Dr. Okuno will also be the Medical Monitor for this study. 
 
The Medical Monitor is required to review all unanticipated problems involving risk to 
subjects or others, serious adverse events and all subject deaths associated with the 
protocol and provide an unbiased written report of the event.  At a minimum, the medical 
monitor must comment on the outcomes of the event or problem, and in the case of a 
serious adverse event or death, comment on the relationship to participation in the study.  
The medical monitor must also indicate whether he/she concurs with the details of the 
report provided by the principal investigator.  Reports for events determined by either the 
investigator or medical monitor to be possibly or definitely related to participation and 
reports of events resulting in death must be promptly forwarded to Synta 
Pharmaceuticals. SARC will be responsible for forwarding reports to the SARC medical 
officer. 
 
In addition to the Medical Monitor role, Scott Okuno, MD will function as the 
Department of Defense required “Independent Research Monitor”.  The Independent 
Research Monitor will be responsible evaluating any risks or concerns of the research in 
addition to overseeing the safety of the research and reporting observations/findings to 
the IRB of Record or a designated official.  The Independent Research Monitor will 
review all unanticipated problems involving risk to volunteers or others associated with 
the protocol and provide an unbiased written report of the event to the IRB of Record.  
The Independent Research Monitor may discuss the research protocol with the 
investigators, interview human subjects, and consult with others outside of the study 
about the research.  The Independent Research Monitor shall have authority to stop the 
research protocol in progress, remove individual human subjects from the study, and take 
whatever steps are necessary to protect the safety and well-being of human subjects until 
the IRB can assess the monitor’s report.  The Independent Research Monitor is 
responsible for promptly reporting their observations and findings to the IRB. 
 
 
Independent Research monitor functions may include: 
 
 
Observing recruitment and enrollment procedures and the consent process for 
individuals, groups or units,  
 
Overseeing study interventions and interactions,  
 
Reviewing monitoring plans and UPIRTSO reports;  
 
Overseeing data matching, data collection, and analysis 
 
At a minimum, the Independent Research Monitor: 
 
 
May discuss the research protocol with the investigators, interview human subjects, 
and consult with others outside of the study about the research;  
 
Shall have authority to stop a research protocol in progress, remove individual 
human subjects from a research protocol, and take whatever steps are necessary to 
protect the safety and well-being of human subjects until the IRB can assess the 
monitor’s report; 


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 
Shall have the responsibility to promptly report their observations and findings to 
the IRB or other designated official and the HRPO. 
 
 
 
 
Participating study sites will be informed of findings on a regular basis and be provided 
with ample information to report to their local IRB in accordance with local site policies.  
 
The knowledge of any pending compliance inspection/visit by the FDA, OHRP, or other 
government agency concerning clinical investigation or research, the issuance of 
Inspection Reports, FDA Form 483, warning letters or actions taken by any Regulatory 
Agencies including legal or medical actions and any instances of serious or continuing 
noncompliance with the regulations or requirements will be reported immediately to 
USAMRMC ORP HRPO.  
 
12.1.3  Patient Accrual and Participating Centers 
 
The study would be conducted through the SARC consortium in collaboration of the NF 
Consortium with the phase I component conducted at 5 centers with phase I expertise and 
the phase II at 10 consortium centers.  We anticipate that accrual will take approximately 
2.5 years.   
 
This trial is posted at ClinicalTrials.gov website.  
 
12.2 
Multi-institutional guidelines 
 
The trial coordinating center (Operations Center) will be SARC. Patients will be 
registered electronically via the study website, and adverse events (as defined in Section 
7.0) will be reported to the operations center.  
 
IRB Approvals: 
SARC will be the Operations Center.  The protocol must be approved at the treating 
institution prior to enrolling patients.  Documentation of individual institutional IRB 
approval, for the current protocol must be provided to the SARC Operations Office prior 
to enrolling patients on the trial. They may be provided via e-mail, fax, or US Mail.  In 
addition, documentation of approval of all protocol amendments and of yearly continuing 
review must be provided to the SARC Operations Office Research Project Manager to 
allow patient entry. The mailing address is: 
 
SARC 
24 Frank Lloyd Wright Drive, PO Box 406 
Ann Arbor, MI  48105 
Phone: 734-930-7600 
Fax: 734-930-7557 
Email: SARC023@sarctrials.org 
 
As this trial receives funding by the Department of Defense, approval of the protocol 
must be obtained from the USAMRMC ORP HRPO in addition to the institutional IRB 


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prior to implementation.  Documentation of individual institutional IRB approval, for the 
current protocol must be provided to SARC at the Operations Center prior to enrolling 
patients on the trial. In addition, documentation of approval of all protocol amendments 
and of yearly continuing review must be provided to the Operations Center to allow 
patient entry.  They may be submitted via e-mail, fax, or US Mail.  SARC will submit 
these documents to the USAMRMC Office of Research Protections (ORP), Human 
Research Protections Office (HRPO).   
 
The mailing address is: 
SARC 
24 Frank Lloyd Wright Drive, PO Box 406 
Ann Arbor, MI  48105 
Phone: 734-930-7600 
Fax: 734-930-7557 
Email:  SARC023@sarctrials.org 
 
Major modifications to the research protocol and any modifications that could potentially 
increase risk to subjects must be submitted to the USAMRMC ORP HRPO for approval 
prior to implementation.  All other amendments will be submitted with the continuing 
review report to the USAMRMC ORP HRPO for acceptance.  A copy of the approved 
continuing review report and the local IRB approval notification will be submitted to the 
USAMRMC ORP HRPO as soon as these documents become available.  A copy of the 
approved final study report and local IRB approval notification will be submitted to the 
USAMRMC ORP HRPO as soon as these documents become available. 
 
Amendments and Consents: 
SARC will be the Operations Center. IRB approval of the current protocol, protocol 
amendments, and yearly continuing review must be provided to the SARC Operations 
Office. In addition, a copy of the currently approved informed consent of each 
participating site will be kept on file at SARC. SARC will submit these documents to the 
USAMRMC ORP HRPO. 
 
Patient Registration: 
Patient Registration will be centrally managed by the Operations Center electronically via 
the study website (see Section 4.2).  
 
Data Collection and Toxicity Reporting:  
Registration reports will be generated by the Operations Center to monitor patient 
accruals and completeness of registration data. Routine data quality reports will be 
generated to assess missing data and inconsistencies by the study coordinator. Any 
potential problems will be brought to the attention of the Principal Investigator for 
discussion and action. 
Access to the password protected study database will be limited to individuals involved 
in the clinical trial: SARC, Study PI, participating site PIs, and research nurses and data 
managers responsible for this trial.  


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Shipment and receipt of specimens and imaging studies sent for correlative studies will 
be entered on the study website and can thus be tracked.  
 
MRI studies will be sent on CD or optical disk with patient identifiers to the NCI POB. 
CDs and optical disks will be locked in a filing cabinet with access only to authorized 
personnel. Imaging studies will be analyzed on 2 Sun Workstations, which are password 
protected, and limit access to authorized personnel.  
 
A monthly phone conference will be held on an as needed basis between the Principal 
Investigator, the Operations Center, associate investigators, and participating sites to 
address QA issues, accrual, observed toxicities, and compliance with submission of 
required studies.  
 
Adverse Events reporting will be performed as outlined in Section 7.0. 
 
12.3 
Data and Participating Institution Monitoring 
Approximately 10% of the patients will be monitored on site, every 3 years. Selected 
patient charts as well as the participating institution’s Standard Operating Procedures 
may be monitored at the time of the visit.  Data from participating institutions should be 
available when the protocol is monitored.  The institutional principal investigator is 
responsible for having all records and data for all patients enrolled at his/her institution 
available at that institution for monitoring. Data entered at the website will be reviewed 
by the PI and study coordinator for any inconsistency.  Queries as appropriate will be 
submitted to sites to clarify data. Submission of biologic specimens and imaging studies 
will be tracked on the study database.  
12.4    Human Subjects Protection 
 
12.4.1 Rationale for Subject Selection 
 
Subjects of both genders and from all racial and ethnic groups are eligible for this trial if 
they meet the eligibility criteria outlined in Section 3.1. No groups are being excluded 
from participation in the trial.  Approximately 50% of MPNSTs develop in individuals 
with NF1, and we expect that approximately 50% of individuals enrolled will have NF1 
associated MPNST, and 50% will have a sporadic MPNST. 
 
12.4.2 Participation of Children  
 
The treatment approach to MPNST is similar for children and adults. However, 
ganetespib alone nor in combination has been studied in children.  Given the limited 
treatment options for refractory MPNST we plan to enroll patients ≥ 16 years old.    
 
12.4.3 Evaluation of the Benefits and Risks/Discomforts 
 


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The primary risk to patients participating in this research study is from toxicity of the 
combination of ganetespib and sirolimus. The primary objective of this phase I/II trial is 
to determine the safety and tolerability and recommended doses of this combination and 
to then assess the clinical response rate in patients with refractory MPNST. Patients will 
thus be treated with therapeutic intent and response to the therapy will be closely 
monitored.  Treatment options for these patients are very limited, as most patients will 
have received prior cytotoxic chemotherapy, which is considered first line treatment by 
many oncologists for unresectable high-grade MPNSTs.  The potential benefits from this 
therapy are disease stabilization, tumor shrinkage, and a reduction in symptoms caused 
by the cancer.  Therefore, this protocol involves greater than minimal risk to the patients 
entered, but presents the potential for direct benefit to individual subjects. 
 
The medical, hospital, and research records associated with this study are considered 
confidential. Members of the treating team and designated research study assistants will 
have access to the records as required to administer treatment and comply with the 
protocol. Neither the name nor other identifying information for an individual will be 
used in the report or publication concerning this study. Patient records may be inspected 
by auditing agencies including the NCI the FDA to satisfy regulatory requirements, and 
Synta Pharmaceuticals. 
 
12.4.4 Risks/Benefits Analysis 
 
The protocol provides for detailed and careful monitoring of all patients to assess for 
toxicity and response to treatment. Patients will be treated with therapeutic intent and 
response to the therapy will be closely monitored. The potential benefit from this therapy 
is disease stabilization, tumor shrinkage, and decrease tumor related symptoms. 
Therefore, this protocol involves greater than minimal risk to subjects, but presents the 
potential for direct benefit to individual subjects. For patients who cannot provide 
informed consent by themselves, but have a durable power of attorney (DPA) this legal 
representative will be able to provide informed consent for this study.    
 
12.4.5 Consent and Assent Process and Documentation 
 
The investigational nature and research objectives of this trial, the procedures and 
treatments involved and their attendant risks and discomforts and benefits, and potential 
alternative therapies will be carefully explained to the patient. The PI or an associate 
investigator on the trial will obtain consent from the patient or legal representative.  The 
PI or associate investigator will meet with the patient to discuss the protocol treatment 
and alternative options in detail. It will be stated clearly that participation in the research 
study is voluntary and that participants can withdraw from the study without losing 
benefits they would otherwise be entitled to. The patient and family members will be 
encouraged to ask questions, and additional meetings to discuss the treatment options will 
be arranged as necessary.  
 
12.4.6 Handling of Research Samples 


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This study is coordinated by SARC.  Laboratory correlative studies are not mandatory 
and will be conducted as outlined in section 9.  A detailed operations manual will be 
provide to each participating site, which will outline sample labeling, collection and 
processing.  Once analyzed for studies outlined in this protocol any remaining samples 
will be stored at the site performing the analyses or at the SARC designated specimen 
bank until the study is complete, and the manuscript describing the study has been 
accepted for publication. The study will remain open and status reported to the IRB until 
all samples have been analyzed, reported, banked or destroyed. Unintentional loss or 
destruction of any samples will be reported to the IRB as part of annual continuing 
reviews.  Any use of these samples for purposes not described in Section 9 will require 
prospective IRB review and approval. Tumor specimens will be sent to a SARC 
identified expert and will be delineated in the Operations Manual.  Should tumor sample 
be left after completion of research studies described in the protocol, prospective 
approval from the appropriate IRB will be obtained prior to performing additional 
studies.  
 
12.4.7 Handling of Patient Data 
 
All patient data will be captured and maintained in a study specific database with 
password protected access. Data is entered using an assigned study subject identification 
number.  
 
The data provided to those reviewing the results, for example the study statistician will 
include the subject identification numbers, but will not include patient identifiable data. 
 
The research samples obtained on this study will only be sent using the study subject 
identification number, which can only be linked to the patient at a given institution by the 
treating physician. 
 
All documentation that contains personal health information that may include patient 
identifiable information will be maintained at the site to preserve patient confidentiality.  
 
 
13. STATISTICAL CONSIDERATIONS  
 
13.1 
Study Design/Endpoints 
 
Phase I 
In the phase I component, a conventional dose-escalation design is used.  The initial 
starting dose of ganetespib is approximately 1 dose level below the recommended 
phase 2 weekly dose in combination with the recommended adult dose of sirolimus of 
4 mg once daily.  This will be followed by one dose escalation to the ganetespib 
weekly recommended phase 2 dose and sirolimus recommended adult dose.  The total 
number of dose levels will likely only be 2, with the possibility of 2 dose de-
escalations.  Cohorts of 3 to 6 patients will be treated per dose level.  At the MTD, the 


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cohort may be expanded to up to an additional 6 patients for further pharmacokinetic 
and tolerability experience. The MTD/Recommended dose will be defined as the dose 
level immediately below the level at which ≥33% of patients in a cohort experience a 
DLT based on toxicities observed in the first treatment cycle.  In the phase 1 portion, 
this study is largely exploratory, precluding formal statistical comparisons of 
treatment groups.  Toxicity and tolerability will be measured using CTCAE-4 and 
summarized by dose level.  Grade ≥3 toxicities attributable to agents will be 
presented in frequency tables for each dose level.   
 
Phase II 
In the phase II component, the primary endpoint will be clinical benefit rate, which 
will be defined as a CR, PR, or stable disease ≥4 months.  A completed trial of 
erlotinib in patients with refractory MPNST demonstrated a median time to 
progression of 48 days and progressive disease in the first response evaluation after 
completion of 2 treatment cycles in 19/20 patients 21.  Thus stable disease ≥ 4 months 
can be considered potentially beneficial and worthy of further investigation.  An 
evaluable patient will be classified a responder (success) for the primary endpoint if 
the patient achieves a PR, CR or stable disease at ≥ 4 months as defined by WHO 
criteria. The target clinical benefit rate will be 25%, and a clinical benefit rate ≤ 5% 
will be considered uninteresting. Using Simon’s optimal two-stage phase II design, 
the first stage will require 10 patients, with no further accrual if 0 of 10 respond. If 
>1/10 patients respond, accrual will continue until a total of 20 patients have been 
enrolled. If >3/20 patients respond, this combination will be considered of sufficient 
activity. Assuming the number of successes is binomially distributed, this design has 
a one sided alpha of 0.07 and a power of 88% for detecting a true success probability 
of at least 25% versus the null hypothesis success rate of 5% or less. 
 
13.2 
Definitions 
 
Evaluable for Adverse Effects 
Any patient who experiences DLT at any time during protocol therapy is considered 
evaluable for adverse effects.  Patient without DLT who receive at least 85% of the 
prescribed sirolimus dose per protocols guidelines and had the appropriate toxicity 
monitoring performed are also considered evaluable for adverse effects.  Patients who 
are not evaluable for adverse effects at a given dose level will be replaced. 
 
Evaluable for Response 
Any eligible patient who is enrolled and receives at least one dose of drug will be 
considered evaluable for response provided: 1) the patient demonstrates progressive 
disease or death while on protocol therapy or 2) the patient is observed on protocol 
therapy for at least one cycle and the tumor is not removed surgically prior to the time 
complete response or partial response or stable disease is confirmed, or 3) patient 
demonstrates a complete or partial response or stable disease per protocol criteria.  
The evaluation period for determination of best response will be 6 treatment cycles.  
All other patients will be considered non-responders 
 


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13.3 
Sample Size/Accrual Rate 
 
Phase I:  3 to 6 patients per cohort with 1 dose escalations (potential for 2 de-
escalation).  Thus a minimum of 6 patients to a maximum of 18 patients will be 
enrolled. 
 
Phase II:  10 patients in first stage with an additional 10 patients in the second stage 
for a total of 20 patients.  The maximum number of patients for entire study will be 
38.  It is expected that 15-25 patients be enrolled per year, and enrollment is expected 
to be completed in approximately 2.5 years. 
 
13.4 
Analysis of Secondary Endpoints 
 
Summary statistics will be used to describe the study population and baseline 
characteristics. 
Pharmacokinetic analysis will be conducted using non-compartmental methods and 
estimated pharmacokinetic parameters including AUC, clearance, half-life and 
volume of distribution presented for each dose level using summary statistics (mean, 
standard deviation, median and range). 
 
Analysis of secondary endpoints will be predominantly descriptive using primarily 
non-parametric analyses and will be interpreted as being exploratory and hypothesis 
generating.  Results will be summarized with graphical analysis and correlations will 
be made if feasible.   
 
Pharmacodynamic parameters including phospho-S6, phospho-S6, phosphorylated 
eIF2 alpha, Akt Phosphorylation, Hsp70, and G6PD will be evaluated in surrogate 
tissue (peripheral blood mononuclear cells) and tumor tissue (when feasible) at 
baseline and during treatment.  Changes in these parameters will be correlated to 
radiographic response using logistic regression analysis.   
 
Patient reported pain severity and impact of pain on activities of daily living will be 
summarized using descriptive statistics.  Analysis of change in pain severity and pain 
interference over time may involve individual t-tests between 2 time points (or non-
parametric Wilcoxon-Mann-Whitney tests) and repeated measures Analysis of 
Variance when appropriate.  Correlations and chi-square analyses to compare pain 
severity and impact with objective tumor response and adverse events will be made if 
feasible. 
 
Volumetric MRI: An automated method of volumetric analysis of plexiform 
neurofibromas in NF1 was recently developed, and is in use in clinical trials. This 
method is reproducible and allows detection of smaller changes in tumor size than 
conventional response criteria. Similar to plexiform neurofibromas, MPNSTs have a 


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complex shape (non spherical), and RECIST (1-dimensional)22 or WHO (2-
dimensional) criteria may have limited applicability. Volumetric MRI tumor analysis 
will be applied to MPNSTs as a tool for response assessment. Response evaluation 
using volumetric measurements will be compared to standard 2-dimensional response 
measurements (WHO criteria), and to 1-dimensional measurements (RECIST 
criteria). Spearman rank correlation will be used to describe the association. 
 
 
 


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APPENDIX I:  PERFORMANCE STATUS CRITERIA 
 
 
ECOG Performance Status Scale 
Grade 
Descriptions 
0 
Normal activity.  Fully active, able to carry on all pre-disease 
performance without restriction. 
1 
Symptoms, but ambulatory.  Restricted in physically strenuous activity, 
but ambulatory and able to carry out work of a light or sedentary nature 
(e.g., light housework, office work) 
2 
In bed < 50% of the time.  Ambulatory and capable of all self-care, but 
unable to carry out any work activities.  Up and about more than 50% of 
waking hours. 
3 
In bed > 50% of the time.  Capable of only limited self-care, confined in 
bed or chair more than 50% of waking hours. 
4 
100% bedridden.  Completely disabled.  Cannot carry on any self-care.  
Totally confined to bed or chair 
5 
Dead 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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APPENDIX II:  Drug Interaction Table 
 
 
Substrates of CYP3A4 or CYP2C19 
Ganetespib is an inhibitor of CYP2C19 and CYP3A4. Concomitant medications that are substrates 
of CYP3A4 or CYP2C19 on this list are to be avoided.  Refer to most recent ganetespib IB. 
 
Examples of Medications that are Substrates of CYP3A4 or CYP2C19 
Drug Class 
Drug 
CYP3A4 substrate examples 
Antibiotics (Macrolide) 
clarithromycin 
 
erythromycin 
Antifungals 
ketoconazole 
 
itraconazole 
Antiretrovirals 
amprenavir 
 
indinavir 
 
lopinavir 
 
nevirapine 
 
ritonavir 
 
saquinavir 
 
nelfinavir 
Benzodiazepines  
midazolam 
 
alprazolam 
 
triazolam  
Calcium channel blockers 
diltiazem 
 
felodipine 
 
nifedipine 
 
verapamil 
GI Agents 
aprepitant 
 
CYP2C19 substrate examples 
Anticonvulsants 
phenytoin 
Antifungals 
voriconazole 
Antiretrovirals 
nelfinavir 


 
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APPENDIX III:  PATIENT DIARY 
OTHER MEDICATIONS TAKEN 
If you take a daily medication (prescribed or otherwise), please use one line per 
drug and indicate the start and stop dates under the “Date(s) Taken” section (i.e., 
6/2/09-6/5/09). 
 
Drug Name 
Dose 
Dates 
Taken 
Reason Taken 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Participant Initials _____________ Date __________ 
 
FOR OFFICE USE 
Staff Initials:  
Date Dispensed:     
Date Returned:  
 
# pills/tabs dispensed:  
# pills/tabs returned:  
# pills/tabs that should have been taken:  
 
Discrepancy Notes: 
 
 
 
 
 
 
 
 
 
 
 
Participant Identifier: ________________________________________ 
Cycle # _______________ Cycle Start Date: _____________________ 
Your MD______________________________  Phone______________  
Your RN_______________________________ Phone______________ 
Study treatment instructions 
Study treatment will be given in 28 day cycles. 
Sirolimus 
 Your dose of sirolimus  is _____________ 
 You will take sirolimus once per day every day of each 28 day cycle (except for very 
first dose in first cycle). 
 Take each dose at the same time each day, preferably in the morning consistently 
with or without food. 
 If you forget to take your dose at the scheduled time, you may still take it up to 6 
hours after the normal scheduled time.  If more than 6 hours have elapsed, you 
should skip the dose for that day.  Mark the missed dose in this diary. Take the next 
day’s dose as scheduled. 
 If you vomit your dose of sirolimus, do not take that dose again. Mark the vomited 
dose in this diary. Take the next day’s dose as scheduled. 
 It is important that your dietary habits remain as consistent as possible throughout 
the study around the time you take sirolimus. You should avoid grapefruit, Seville 
oranges, or star fruit and the juices of these fruits and St. John’s Wort while you are 
taking sirolimus, as these items may change how your body handles sirolimus. 
 It is important that you maintain good oral hygiene (mouth care) while you are 
taking sirolimus to help prevent inflammation of the mouth tissues.   
 Bring any unused sirolimus, all containers (empty and full), and this diary to each 
clinic visit. The study staff will make sure you have an adequate supply of 
sirolimus to take home at the end of each clinic visit. 
SARC023 Participant Study Drug Diary 
“Site Name” 


 
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SYMPTOMS/SIDE EFFECTS 
 
Please record any side effects experienced during this cycle. Include the date the particular symptom started and when it ended. Please evaluate the 
severity of the symptom according to the following scale: 
 
Mild: Awareness of sign or symptom; easily tolerated and did not affect ability to perform normal daily activities. Symptom did not require 
medication or therapeutic intervention. 
 
Moderate: Significant discomfort which interfered with ability to perform normal daily activities. Symptom was easily resolved with at home 
medication or simple therapeutic intervention. 
 
Severe: Marked discomfort with an inability to carry out normal daily activities. Symptom required new medication and/or therapeutic intervention 
in order to resolve. 
 
Please Note: The severity should reflect the most severe level experienced during the time period. 
Symptom 
Start Date 
End Date 
Severity 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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Sirolimus Diary 
 
Sirolimus: For each dose, take __________.  Please indicate the date, time, amount taken and any comments. 
Date & 
Time 
Amount 
Taken 
Comments 
Ex: 
6/1/15 
6:30 am 
2 tablets Vomited dose 
 
Day 1 
 
 
 
2 
 
 
 
3 
 
 
 
4 
 
 
 
5 
 
 
 
6 
 
 
 
7 
 
 
 
8 
 
 
 
9 
 
 
 
10 
 
 
 
11 
 
 
 
12 
 
 
 
13 
 
 
 
14 
 
 
 


 
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Sirolimus Diary Continued… 
 
Date & 
Time 
Amount 
Taken 
Comments 
Ex: 
6/1/15 
6:30 am 
2 tablets Vomited dose 
 
15 
 
 
 
16 
 
 
 
17 
 
 
 
18 
 
 
 
19 
 
 
 
20 
 
 
 
21 
 
 
 
22 
 
 
 
23 
 
 
 
24 
 
 
 
25 
 
 
 
26 
 
 
 
27 
 
 
 
28 
 
 
 
 


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APPENDIX IV: Documentation of findings of NF1 
 
Demographic information: 
DOB:  
Sex:  
Mother’s race:  
Father’s race:  
NF1 Inherited: Yes:            No: 
NF1 sporadic: Yes:           No: 
 
 
1 
Exam Date 
_ __ _ / _ _ / _ _ 
  year  month  day 
 
2 
Height/length 
_ _ _ . _ cm 
 
or    _ ft  _ _ . _ in 
 
Unknown 
 
3 
Head circumference 
_ _ . _ cm 
 
_ _ . _ in 
 
Unknown 
4 
 
Number of café au lait  
(In pre-pubertal individuals, include CAL 
between 0.5 and 1.5cm)  
None 
1 
2 
3 
4 
5 
6 or more 
Present, number unknown 
Unknown 
5 
 
Intertriginous Freckling 
Absent 
Present 
Unknown 
 
6 
 
Subcutaneous neurofibromas 
None 
1 
2  
3 - 9 
10-50 
>50 
Unknown 


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7 
 
Cutaneous neurofibromas 
(Includes pendulous) 
None 
1 
2  
3 - 9 
10-50 
>50 
Unknown 
8 
 
Plexiform neurofibroma  - Location 
(Check as many as apply) 
None 
Orbit 
Face 
Head/neck 
Trunk - dorsal 
Trunk - ventral 
Arm 
Leg 
Unknown 
9 
 
 
 
 
 
10 
 
Paraspinal neurofibromas 
        
 
 
 
 
Xanthogranulomas 
Absent by scan 
Absent clinically 
*Present 
Unknown 
 
 
Absent 
Present 
Unknown 
11 
 
Lisch nodules 
Absent 
Present on slit lamp exam 
Possible 
Unknown 
12 
 
 
 
 
 
Proptosis 
Absent 
Unilateral 
Bilateral 
Present, laterality unknown 
Unknown 
13 
 
Optic glioma 
Absent by scan 
Absent clinically 
Present - asymptomatic 
Present - symptomatic 
Unknown 
14 
 
 
 
 
 
 
 
Seizures - type 
 
 
None 
Febrile only 
Hypsarrhythmia 
Generalized 
Partial 
Multiple types 
Present - type unknown 
*Other 


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15 
 
 
 
 
 
 
Hydrocephalus 
Absent clinically 
Absent by scan 
Aqueductal stenosis 
Other non-communicating 
Communicating 
Present - type unknown 
Unknown 
16 
 
 
 
Intellectual Development 
 
 
 
Normal 
Mildly Delayed 
Significant delay 
Unknown 
17 
Learning Problems 
None 
Specific learning problems present 
Unknown 
18 
Hypertension 
Absent 
Present 
Unknown 
19 
Congenital heart disease 
 
 
Absent clinically 
Absent by special testing 
Aortic stenosis 
ASD 
Patent ductus arteriosus 
Pulmonic stenosis 
Tetralogy of Fallot 
VSD 
Other type of CHD 
Multiple types of CHD 
Possible CHD 
Unknown 
20 
 
 
 
 
 
 
 
21 
 
Vascular anomalies 
 
 
 
 
 
 
 
Age puberty began 
absent clinically 
*renal artery stenosis 
*arterial stenosis (non-renal) 
*moya moya 
*other 
unknown 
 
 
<10 years 
10-15 years 
>15 years 
Not applicable 
Unknown 
22 
 
Dysmorphic features 
 
 
 
 
No 
Yes 
Possible 
Unknown 
 
23 
 
Congenitally bowed tibia or pseudarthrosis 
Absent clinically 
Absent radiographically 
Present 
Unknown 


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24 
 
Dysplastic vertebrae 
Absent clinically 
Absent radiographically 
Present 
Unknown 
25 
 
Scoliosis 
Absent clinically 
Absent radiographically 
Present 
Unknown 
26 
 
Dysplastic sphenoid wing 
Absent clinically 
Absent radiographically 
Present, bilateral 
Present, unilateral 
Present, laterality unknown 
Unknown 
 
27 
Neoplasm - type 
(Please check as many as apply) 
 
 
None 
Carcinoma 
Ependymoma 
Glioma 
Leukemia 
Lymphoma  
Malignant peripheral nerve sheath tumour 
Meningioangiomatosis 
Meningioma 
Pheochromocytoma 
Sarcoma 
Schwannoma 
Malignancy present, type unknown 
Other 
 
 
 
 
 
 
 
 
 
 
 
 
 


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APPENDIX V: Pain Questionnaire 
Protocol: SARC023  
Patient Study ID: _______________ 
Check One: 
 Baseline  Prior to cycle 3  Prior to cycle 5  Prior to cycle 9  Prior to cycle 13 
 
Numeric Rating Scale (NRS-11) – Pain Intensity 
Below are lines with numbers from 0 to 10 where 0 means no pain and 10 means the worst pain 
you can imagine. 
 
1. For this question, please circle the one number that best describes your most important 
tumor pain at its worst during the past week.  Please rate your pain for the same tumor 
throughout the study (specify the location of the tumor: _________________________).      
 
 
 
  
 0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
No  
 
 
 
 
 
 
 
 
       Worst pain  
           Pain 
 
 
                          
 
 
 
   you can imagine 
 
 
2. For this question, please circle the one number that best describes your overall tumor 
pain at its worst during the past week.        
 
 
 
  
 0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
            No  
 
 
                               
 
 
 
       Worst pain  
           Pain 
                                   
 
 
 
 
   you can imagine 
 
Brief Pain Inventory (BPI) – Pain Interference 
For the following questions, a “0” means that pain did not interfere with (get in the way of) the 
activity and a “10” means that pain complete interfered. 
 
3. Circle the one number that describes how much, during the past week, tumor pain has 
interfered with your ________.         
 
     
 
 
 
 
      Does not   
 
 
    Completely 
 
 
 
 
 
 
      interfere 
 
 
 
       interferes 
1. General activity………………………….... 0    1    2    3    4    5    6    7    8    9    10 
2. Mood………………………………………. 0    1    2    3    4    5    6    7    8    9    10 
3. Walking ability…………………………..... 0    1    2    3    4    5    6    7    8    9    10 
4. School, work, or chores……………..…….. 0    1    2    3    4    5    6    7    8    9    10 
5. Relations with other people……………….. 0    1    2    3    4    5    6    7    8    9    10 
6. Sleep……………………………………..... 0    1    2    3    4    5    6    7    8    9    10 
7. Enjoyment of life………………………….. 0    1    2    3    4    5    6    7    8    9    10 
 


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APPENDIX VI: Drugs with Risk of Torsades De Pointes 
 
For the most current list of medications, please refer to the following website powered by 
azert.org: http://crediblemeds.org 
 
Generic Name 
Brand Names 
Drug Class 
Therapeutic Use 
Amiodarone 
Cordarone®, Pacerone®, 
Nexterone® 
Anti-arrhythmic 
Abnormal heart rhythm 
Anagrelide 
Agrylin®, Xagrid® 
Phosphodiesterase 3 inhibitor 
Thrombocythemia 
Arsenic trioxide 
Trisenox® 
Anti-cancer 
Leukemia 
Azithromycin 
Zithromax®, Zmax® 
Antibiotic 
Bacterial infection 
Chloroquine 
Aralen® 
Anti-malarial 
Malaria infection 
Chlorpromazine 
Thorazine®, Largactil®, 
Megaphen® 
Anti-psychotic / Anti-emetic 
Schizophrenia/ nausea 
Citalopram 
Celexa®, Cipramil® 
Anti-depressant, SSRI 
Depression 
Clarithromycin 
Biaxin®, Prevpac® 
Antibiotic 
Bacterial infection 
Cocaine 
Cocaine 
Local anesthetic 
Topical anesthetic 
Disopyramide 
Norpace® 
Anti-arrhythmic 
Abnormal heart rhythm 
Dofetilide 
Tikosyn® 
Anti-arrhythmic 
Abnormal heart rhythm 
Dronedarone 
Multaq® 
Anti-arrhythmic 
Atrial Fibrillation 
Droperidol 
Inapsine®, Droleptan®, 
Dridol®, Xomolix® 
Anti-psychotic / Anti-emetic 
Anesthesia 
adjunct, nausea 
Erythromycin 
E.E.S.®, Robimycin®, 
EMycin®, Erymax®, Ery-
Tab®, Eryc Ranbaxy®, 
Erypar®, Eryped®, 
Erythrocin Stearate 
Filmtab®, Erythrocot®, E-
Base®, Erythroped®, 
Ilosone®,  MY-E®, 
Pediamycin®, Zineryt®, 
Abboticin®, Abboticin-
ES®, Erycin®, PCE 
Dispertab®, Stiemycine®, 
Acnasol®, Tiloryth® 
Antibiotic 
Bacterial infection; 
increase GI motility 
Escitalopram 
Cipralex®, Lexapro®, 
Nexito®, Anxiset-E® 
(India), Exodus® (Brazil), 
Esto® (Israel), 
Seroplex®, Elicea®, 
Lexamil®, Lexam®, 
Entact® (Greece), Losita® 
(Bangladesh), Reposil® 
(Chile), Animaxen® 
(Colombia), Esitalo® 
(Australia), Lexamil® 
(South Africa) 
Anti-depressant, SSRI 
Major depression/ 
Anxiety disorders 
Flecainide 
Tambocor®, Almarytm®, 
Apocard®, Ecrinal®, 
Flécaine® 
Anti-arrhythmic 
Abnormal heart rhythm 


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Halofantrine 
Halfan® 
Anti-malarial 
Malaria infection 
Haloperidol 
Haldol® (US & UK), 
Aloperidin®, 
Bioperidolo®, Brotopon®, 
Dozic®, Duraperidol® 
(Germany), Einalon S®, 
Eukystol®, Halosten®, 
Keselan®, Linton®, 
Peluces®, Serenace®, 
Serenase®, Sigaperidol® 
Anti-psychotic 
Schizophrenia, agitation 
Ibutilide 
Corvert® 
Anti-arrhythmic 
Abnormal heart rhythm 
Methadone 
Dolophine®, Symoron®, 
Amidone®, Methadose®, 
Physeptone®, Heptadon® 
Opiate 
Pain control, narcotic 
dependence 
Moxifloxacin 
Avelox®, Avalox®, 
Avelon® 
Antibiotic 
Bacterial infection 
Ondansetron 
Zofran®, Anset®, 
Ondemet®, Zuplenz®, 
Emetron®, Ondavell®, 
Emeset®, Ondisolv®, 
Setronax® 
Anti-emetic 
Nausea, vomiting 
Pentamidine* 
NebuPent®, Pentam® 
Antibiotic 
Pneumocystis 
pneumonia 
Pimozide 
Orap® 
Anti-psychotic 
Tourette's tics 
Procainamide (Oral 
off US mkt) 
Pronestyl®, Procan® 
Anti-arrhythmic 
Abnormal heart rhythm 
Quinidine 
Quinaglute®, Duraquin®, 
Quinact®, Quinidex®, 
Cin-Quin®, Quinora® 
Anti-arrhythmic 
Abnormal heart rhythm 
Sevoflurane 
Ulane®, Sojourn® 
Anesthetic, general 
Anesthesia 
Sotalol 
Betapace®, Sotalex®, 
Sotacor® 
Anti-arrhythmic 
Abnormal heart rhythm 
Thioridazine 
Mellaril®, Novoridazine®, 
Thioril® 
Anti-psychotic 
Schizophrenia 
Vandetanib 
Caprelsa® 
Anti-cancer 
Thyroid cancer 
* Injectable form (Inhaled formulation is allowed)