A Randomized, Double-Blinded, Placebo-Controlled, Multi-Institutional, Cross-over, Phase II.5 Study of Saracatinib (AZD0530), a Selective Src Kinase Inhibitor, In Patients With Recurrent Osteosarcoma Localized to the Lung
Phase: PHASE2
Conditions: Osteosarcoma
Sponsor: Sarcoma Alliance for Research through Collaboration

 
  
 
 
 
A Randomized, Double-Blinded, Placebo-Controlled, Multi-Institutional, Cross-
Over, 
Phase II.5 Study of Saracatinib (AZD0530), a Selective Src Kinase Inhibitor, 
In Patients with Recurrent Osteosarcoma Localized to the Lung 
 
 
Principal Investigator 
Scott Okuno 
Mayo Clinic Oncology 
 
 
 
 
Non-clinical Investigator 
Chand Khanna 
NCI 
Pediatric Oncology 
 
Paul Meltzer 
NCI 
Pediatric Oncology 
 
Mark Raffeld 
NCI 
Pathology 
 
Seth Steinberg 
NCI 
Statistics 
 
 
Coordinating Center 
SARC 
 
SARC Coordinator 
Denise Reinke 
 
AstraZeneca 
Richard Finkelman 
 
Mary Stuart 
 
 
 
Investigational Agent 
saracatinib (AZD0530) 
Distributor 
AstraZeneca 
Study Sponsor 
SARC 
IND Holder 
SARC 
IND Number 
103,268 
 
 
Version/Date 
Version 5/ 9-4-2015 
 
 
 
Scott Okuno, MD 
Mayo Clinic 
200 First Street SW 
Rochester, MN 55905 
Phone: 507-266-9161       E-mail: okuno.scott@mayo.edu  
 
 
 
 
 
 
 
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Treatment Schema 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Patients with suspected recurrence of osteosaroma in the lung are eligible for enrollment 
 
Patients will undergo biopsy or definitive resection 
Extensive bilateral nodules 
requiring staged thoracotomy 
Remaining nodules 
 
No remaining nodules 
 
Resection of one side 
Definitive Resection 
Randomization 
Randomization 
Randomization 
Begin oral therapy with 
saracatinib or placebo 
 
Begin oral therapy with 
saracatinib or placebo 
 
Begin oral therapy with 
saracatinib or placebo 
 
Resection of the other side to 
remove remaining nodules 
 
Treatment with saracatinib or placebo will continue for (thirteen -28 day cycles (364 days) 
 
Patients who have been enrolled are eligible for randomization if the following criteria are met: 
 
1. Must have histological confirmation of osteosarcoma in the resected sample 
2. Must have complete resection of all nodules 
 
Cross-over 
Patients who recur in the lung while on study will be unblinded. 
Those who were receiving placebo will be offered the option of undergoing another surgical 
resection and if fully resected, will be given the option of receiving saracatinib for thirteen 28-day 
cycles (364 days). 
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Precis 
 
Background 
• Saracatinib is a potent and selective Src kinase inhibitor. 
• In vitro studies demonstrate that 95% of patients with osteosarcoma have activation 
of Src, or one of its substrates. 
• A Phase I study of saracatinib, given daily, in adult patients with advanced solid 
malignancies, has identified 175 mg as the maximum tolerated dose. 
 
Primary Objective 
• To determine if the addition of saracatinib to pulmonary metastasectomy, versus 
placebo and pulmonary metastasectomy, results in an increase in progression free 
survival. 
 
Secondary Objectives 
• To determine if the addition of saracatinib to pulmonary metastasectomy, versus 
placebo and pulmonary metastasectomy, results in an increase in overall survival. 
• To determine if the addition of saracatinib to pulmonary metastasectomy, versus 
placebo and pulmonary metastasectomy, results in an increase in the time to 
treatment failure, defined as a composite endpoint measuring time from 
randomization to discontinuation of treatment for any reason, including disease 
progression, treatment toxicity, or death.   
• To perform microarray analysis of tumor samples to identify a gene signature that 
predicts for recurrence of osteosarcoma. 
• To evaluate tumor samples for biomarkers related to activation of Src and Src 
substrates. 
• To establish cell lines and murine xenografts from recurrent tumor samples. 
• To perform sequencing analysis of DNA and RNA in tumor samples compared to 
normal blood to detect mutations that may be causative for recurrent osteosarcoma. 
 
Eligibility 
• Patients >15 and <75 years of age, with suspected recurrence of osteosarcoma, 
localized to the lung, are eligible for enrollment 
• Patients with histological confirmation of recurrent osteosarcoma, localized to the 
lung, who have had complete surgical removal of all lung nodules, will be eligible 
for randomization. 
 
 
Design 
• Only after complete resection of all lung nodules, patients will be randomized to 
treatment with saracatinib or placebo.  Eighty-eight patients will be randomized, 44 
patients in each arm of the study.  This will be a multi-institutional study. 
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• Saracatinib, or placebo, will be administered as a once daily, oral dose of 175 mg, 
for a 28-day cycle, with no breaks between cycles.  The duration of treatment with 
saracatinib or placebo will be 13 cycles (364 days total). 
• Patients will begin cycle 1 after complete surgical resection. 
 
Cross-Over Component 
• Patients who recur in the lung while on-study and who are thought to be amenable 
to complete surgical resection will be un-blinded.  Those patients who were 
receiving placebo may then have the option of undergoing surgical resection. If 
fully resected (staged thoracotomy is acceptable), they will be given the option of 
receiving oral therapy with saracatinib. Saracatinib will be administered as a once 
daily, oral dose of 175 mg, for a 28-day cycle, with no breaks between cycles.  The 
duration of treatment with saracatinib will be thirteen 28-day cycles (364 days 
total). 
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Table of Contents 
 
Title Page   
 
   1 
Treatment Schema   
   2 
Precis   
 
 
   3 
Table of Contents   
  5 
Investigator Signature Sheet   
  8 
1 
Introduction   
   9 
 
1.1 Study Objectives   
   9 
 
 
1.1.1 Primary Objective   
   9 
 
 
1.1.2 Secondary Objectives   
   9 
 
 
 
 
1.2 Background and Rationale   
   9 
 
 
1.2.1 Recurrent Osteosarcoma   
   9 
 
 
1.2.2 Src and Cancer   
  11 
 
 
1.2.3 Src and Osteosarcoma   
  12 
 
 
1.2.4 Saracatinib   
  14 
 
 
1.2.5 Effect of Saracatinib on Osteoclast Activity   
  14 
 
 
1.2.6 Activity of Saracatinib in Pre-Clinical Studies   
  15 
 
 
1.2.7 Clinical Pharmacokinetics of Saracatinib   
  16 
 
 
1.2.8 Phase I Trials of Saracatinib   
  18 
 
 
1.2.9 Rationale for the Use of Saracatinib in Recurrent Osteosarcoma     21 
2 
Eligibility Assessment and Enrollment   
  23 
 
2.1 Eligibility Criteria   
  23 
 
 
2.1.1 Inclusion Criteria   
  23 
 
 
2.1.2 Exclusion Criteria   
  24 
 
2.2 Screening   
  24 
 
2.3 Patient Enrollment   
  26 
3 
Study Implementation   
  27 
 
3.1 Study Design   
  27 
 
3.2 Treatment Administration   
  28 
 
 
3.2.1 Administration and Commencement of Oral Therapy   
  28 
 
 
3.2.2 Distinction between Enrollment and Randomization   
  29 
 
 
3.2.3 Regimen for Patients Who Have Been Fully Resected   
  29 
 
 
3.2.4 Regimen for Patients Who Require Definitive Resection   
  29 
 
 
3.2.5 Regimen for Patients Who Require Staged Thoracotomies   
  30 
 
 
3.2.6 Cross-over Regimen for Patients Who Recur 
 
 
 
 in the Lung While On-Study   
  30 
 
3.3 Treatment Modifications   
  31 
 
 
3.3.1 Dose Modification Criteria   
  31 
 
 
3.3.2 Dose Reduction of Oral Therapy   
  32 
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3.3.3 Dose Reduction of Oral Therapy for Hypophosphatemia   
  32 
 
3.4 On Study Evaluations   
  33 
 
3.5 Concurrent Therapies   
  35 
 
 
3.5.1 Surgical Guidelines   
  35 
 
3.6 Biological Studies   
  35 
 
 
3.6.1 Microarray Analysis   
  36 
 
 
3.6.2 Biomarkers Related to Activation of Src and Src Substrates   
  37 
 
 
3.6.3 Establishment of Cell Lines and Murine Xenografts   
  37 
 
 
3.6.4    Sequencing Analysis………………………………………………    37 
 
3.7 Off Study Criteria   
  38 
 
 
3.7.1 Definition of Disease Progression   
  38 
 
 
3.7.2 Criteria for Removal from Protocol   
  39 
 
3.8 Post Study Evaluation   
  40 
4 
Supportive Care   
  40 
 
4.1 General   
  40 
 
4.2 Management of an Overdose of Saracatinib   
  40 
 
4.3 Procedures in Case of Pregnancy   
  41 
 
4.4 Respiratory Care   
  41 
 
4.5 List of Contra-Indicated Medications   
  42 
 
4.6 Use of Concomitant Medications   
  44 
 
4.7 List of Contra-Indicated Foods   
  45 
5 
Data Collection and Evaluation   
  45 
 
5.1 Data Collection   
  45 
 
5.2 Toxicity Criteria   
  46 
 
5.3 Statistical Considerations   
  46 
 
 
5.3.1 Patient Randomization   
  48 
 
5.4 Multi-Institutional Guidelines   
  48 
 
 
5.4.1 IRB Approvals   
  49 
 
 
5.4.2 Amendments and Consents   
  49 
 
 
5.4.3 Data Collection and Toxicity Reporting   
  49 
 
 
5.4.4 Data and Participating Institution Audits   
  49 
 
5.5 Data and Safety Monitoring Plan   
  50 
6 
Human Subjects Protections   
  50 
 
6.1 Rationale for Subject Selection   
  50 
 
6.2 Participation of Children   
  50 
 
6.3 Evaluation of Benefits and Risks/Discomforts   
  51 
 
6.4 Risks/Benefits Analysis   
  51 
 
6.5 Consent and Assent Processes and Documentation   
  51 
 
6.6 Handling of Research Samples   
  52 
7 
Data Reporting   
  54 
 
7.1 Patient Registration and Case Report Forms   
  54 
 
7.2 Adverse Event Recording   
  55 
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7.2.1 Definitions   
  55 
 
 
7.2.2 Recording Procedures for All Adverse Events   
  56 
 
7.3 Adverse Event Reporting   
  56 
 
 
7.3.1 Reporting Procedures for Serious Adverse Events   
  56 
 
 
7.3.2 Reporting Procedures to the NCI IRB   
  58 
 
7.4 Treatment Regimen Unblinding  
  59 
 
 
7.4.1 Criteria for Unblinding for Adverse Events   
  59 
 
 
7.4.2 Unblinding for Disease Recurrence in the Lung   
  60 
8 
Pharmaceutical Information   
  60 
 
8.1 Saracatinib   
  60 
 
 
8.1.1 Chemical Information   
  60 
 
 
8.1.2 Supplier and Trial Sponsor   
  61 
 
 
8.1.3 Preparation and Storage   
  61 
 
 
8.1.4 Administration of Saracatinib   
  61 
 
 
8.1.5 Known Toxicities of Saracatinib   
  63 
 
8.2 Placebo   
  63 
 
8.3 Drug Ordering   
  64 
 
 
8.3.1 Initial Supply   
  64 
 
 
8.3.2 Re-Supply   
  64 
 
8.4 Investigational Product Records at Investigational Site(s)   
  64 
 
8.5 Destruction of Investigational Product   
  65 
9 
References   
  66 
10 
Appendices   
  68 
 
Appendix A - Follow Up Schedule   
  68 
 
Appendix B - Patient Pill Diary   
  69 
 
Appendix C - SAE Fax Coversheet   
  70 
 
Appendix D - Drug Supply Form   
  71 
 
Appendix E – Local MD Guidelines……………………………………………. 72 
 
Appendix F – Local MD Agreement Letter……………………………………..73 
 
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INVESTIGATOR SIGNATURE SHEET 
 
I have read the attached protocol and agree that it contains all the necessary details for 
conducting SARC012: A Randomized, Double-Blinded, Placebo-Controlled, Multi-
Institutional, Phase II.5 Study of Saracatinib (AZD0530), a Selective Src Kinase 
Inhibitor, In Patients with Recurrent Osteosarcoma Localized to the Lung 
 
I will provide copies of the protocol and any pre-clinical information on the study drug, 
which were furnished to me by SARC, to all members of the study team for whom I am 
responsible and who participate in the study.  I will discuss this material with them to 
ensure that they are fully informed regarding the study drug and the conduct of the study. 
 
Once the protocol has been approved by the IRB, I will not modify this protocol without 
obtaining the prior approval of SARC and of the IRB.   
 
I understand the protocol and agree to follow the principles of Good Clinical Practice 
(current ICH guidelines), and the Declaration of Helsinki (1964) including all 
amendments up to and including the Tokyo Clarification (2004).  
 
 
 
 
  
 
 
Print Name 
 Investigator’s Signature 
 
Date 
 
  
 
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1 
Introduction 
 
 
1.1 
Study Objectives 
 
 
1.1.1 Primary Objective 
 
To determine if the addition of saracatinib to pulmonary metastasectomy, versus 
placebo and pulmonary metastasectomy, results in an increase in progression free 
survival. 
 
 
1.1.2 Secondary Objectives 
 
To determine if the addition of saracatinib to pulmonary metastasectomy, versus 
placebo and pulmonary metastasectomy, results in an increase in overall survival. 
 
To determine if the addition of saracatinib to pulmonary metastasectomy, versus 
placebo and pulmonary metastasectomy, results in an increase in the time to 
treatment failure. 
 
To perform microarray analysis of tumor samples to identify a gene signature that 
predicts for recurrence of osteosarcoma. 
 
To evaluate tumor samples for biomarkers related to activation of Src and Src 
substrates. 
 
To establish cell lines and murine xenografts from recurrent tumor samples. 
 
 
 
 
1.2 
Background and Rationale 
 
 
1.2.1 Recurrent Osteosarcoma 
 
Osteosarcoma is the most common malignant bone tumor in the United States and 
Europe.  Historically, this was once a fatal diagnosis.  However, with the increasing use 
of chemotherapy in the late 1970s, patients who underwent both surgery and 
chemotherapy had a marked improvement in survival.  Currently the overall cure rate is 
65%, representing a dramatic improvement over previous decades (1,2).  Unfortunately, 
patients who recur with disease have only a 25% five-year survival rate (3,4).  
Approximately 33% of patients who have completed therapy for osteosarcoma will recur.  
In large retrospective analyses performed by the Cooperative Osteosarcoma Study Group 
(3) and the Rizzoli Institute (4), the only patients who survived long-term were those who 
achieved complete surgical removal of recurrent tumor, illustrated in the survival curve 
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on the right (3).  Specifically, 291 patients did not 
achieve surgical remission, and none of these patients 
survived long-term.  In contrast, 512 patients 
achieved surgical remission and five-year overall 
survival rates were 38% and 30% in the two studies.  
These patients received either multi-agent, single 
agent or no chemotherapy, but they shared the 
common feature that everyone had achieved a second 
surgical remission.  It did not appear that the addition 
of adjuvant treatment increased survival (40% 
survival with chemotherapy versus 35% survival 
without chemotherapy, p=0.35) (3).  However, this 
trend may eventually prove to be statistically 
significant in larger cohorts.  Conversely, for those treated with chemotherapy or 
radiation therapy only without surgery, there were no survivors (4). 
 
One of the significant prognostic factors that predicts for long-term survival is the 
number of nodules at the time of recurrence.  In the Cooperative Osteosarcoma Study 
Group study, patients who had one nodule had a 38% 5-year overall survival rate, 
compared to 15% for patients with two or more nodules (p<0.01) (3).  Comparably, in the 
Rizzoli Institute study, patients who had one or two nodules had a 44% 5-year event free 
survival rate, compared to 22% for patients with three or more nodules (p<0.01) (4). 
 
Another factor that impacts outcome is the number of recurrences.  The only study that 
has examined these subsets of patients is the retrospective analysis performed at the 
Rizzoli Institute (4).  The following shows the number of long-term survivors as a 
percentage of those who were able to obtain surgical remission.  First relapse – 30.6% 
(53 of 173 patients).  Second relapse – 25.9% (14 of 54 patients).  Third relapse – 16.7% 
(2 of 12 patients).  Ten patients had a fourth relapse and six of these patients achieved 
surgical remission.  However, all six patients progressed to have a fifth relapse.  Not 
surprisingly, patients have decreased survival probability when they have multiple 
recurrences. 
 
The role of chemotherapy in the treatment of recurrent osteosarcoma is unclear.  To date, 
there have not been any randomized studies that have evaluated the benefit of 
chemotherapy in this setting.  However, multiple Phase II studies have failed to show 
improvement in outcome.  Several of these include the use of cyclophosphamide and 
topotecan (5), docetaxel (6), ecteinascidin 743 (7), as well as imatinib mesylate (8).  The 
latter is a potent inhibitor of the abl receptor tyrosine kinase family, including platelet-
derived growth factor receptor and KIT kinase, but is a poor inhibitor of Src.  The use of 
high-dose chemotherapy followed by stem cell rescue showed that induction of complete 
remission was feasible, but that treatment outcomes were not improved (9,10). 
 
A report from the Children’s Cancer Group showed a small increase in overall response 
following treatment with ifosphamide, carboplatin and etoposide, however, the result was 
not statistically significant (11).  A retrospective report from the Memorial Sloan-
Kettering Cancer Center suggested a benefit from the addition of high-dose ifosphamide 
following surgery, but the result did not reach statistical significance (12).  The use of 
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high-dose ifosphamide for recurrent osteosarcoma at the M.D. Anderson Cancer Center 
resulted in 30% (5/16 patients) disease-free survival (13).  However, three of these 
patients had not previously received ifosphamide.  In addition, four patients developed 
renal toxicity, two of which, progressed to acute renal failure.  To date, there has not been 
a study of sufficient size to justify the use of high-dose ifosphamide in this setting. 
 
Unfortunately, these results show that there is no effective salvage regimen for patients 
with recurrent osteosarcoma.  Therefore, the current standard of care is to resect the 
recurrent tumor if possible, followed by observation.  If any chemotherapeutic agent with 
activity against osteosarcoma (adriamycin, cisplatin, ifosphamide, methotrexate) was not 
used during treatment of the primary tumor, then that agent may be administered as 
adjuvant therapy following surgical resection.  Unfortunately, even those patients who 
achieve complete surgical remission have only a 35% long-term survival rate.  All of 
these factors point to the importance of identifying new biological agents for the 
treatment of recurrent osteosarcoma. 
 
 
1.2.2 Src and Cancer 
 
In 1911, Peyton Rous described his work on hens that had large tumors that could be 
transplanted into other chickens (14).  Surprisingly, cell-free filtrates of these tumors 
were also able to produce tumors when injected into healthy birds.  Forty years later, 
Harry Rubin showed that the tumor cells released infectious virus, subsequently called 
Rous sarcoma virus.  In addition to the three proteins that are needed for the virus to 
replicate and package its genome, Rous sarcoma virus also contained a fourth gene 
named v-src, for viral sarcoma.  It was the v-src gene that was responsible for the tumor 
potential of the virus and v-src was the first oncogene to be identified. 
 
The relevance of v-src to human cancers came with the demonstration that many 
oncogenes had normal counterparts in humans (14).  The gene c-src, the human homolog 
of v-src, is a member of the tyrosine kinase family.  Src contains four SH (Src 
Homology) domains, as illustrated in the 
diagram on the right (15).  SH1 is the catalytic 
kinase domain.  The SH2 domain binds 
peptides that contain phosphorylated tyrosine 
residues.  The SH3 domain binds proline rich 
sequences and the SH4 domain contains the 
myristoylation site that allows for membrane 
localization.  There is a tyrosine residue (Tyr 
530) at the carboxy terminal of c-src.  When 
this residue is phosphorylated, it binds the SH2 
domain of Src, resulting in a closed inactivate 
molecular conformation.  Conversely, Src 
activation occurs following removal of the 
carboxy phosphotyrosine, resulting in the loss 
of intramolecular interactions and an open conformation.  Complete activation of Src 
involves additional phosphorylation of the Tyr 419 residue. 
 
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Src is a non-receptor tyrosine kinase (14,15).  Activation of Src frees the SH2 and SH3 
domains to participate in interactions that target Src to its substrates.  Src can directly 
phosphorylate its substrates or act as a docking site for the binding of other signaling 
proteins that contain SH2 domains.  This dual mechanism involves Src, both directly and 
indirectly, in many signaling pathways.  Some of these include the PI3K/AKT/mTOR, 
Ras/Raf/MEK/MAPK and STAT3 pathways, all of which affect proliferation and 
survival of the cell.  Src also targets another set of substrates at focal adhesions including 
focal adhesion kinase (FAK) and paxillin.  The latter is a scaffolding molecule that 
regulates the organization of the actin cytoskeleton and plays an important role in cell 
motility (16).  Upon integrin signaling, recruitment of FAK to sites of cell-extracellular 
matrix contact, leads to phosphorylation of paxillin and multiple downstream signaling 
events, eventually resulting in cell migration (17). 
 
Increased Src activity was first described in sarcomas.  Examination of tumor samples 
from nine patients with sarcomas showed that 33% had enzyme activity levels that were 
4-10 fold higher than that seen in normal tissue (18).  Similar findings were also found in 
mammary carcinomas (18).  Subsequently, increased activity or expression of Src has 
been seen in many common solid tumors, including the lung and several gastrointestinal 
tumors involving the esophagus, stomach, liver, pancreas and colon (15).  In some 
cancers, Src activity correlated with poor prognosis.  Most importantly, Irby et al, showed 
that a small number of metastatic colon cancer cases had a single base pair mutation in 
Src, resulting in truncation of the protein at codon 531 (19).  Although the tyrosine 
residue at codon 530 was still phosphorylated, it was unlikely to be capable of 
functioning in a negative regulatory role due to lack of C-terminal residues.  Transfection 
of this truncated form of Src into 3Y1 rat fibroblasts, followed by injection into nude 
mice, resulted in formation of lung metastases and 100% mortality.  In contrast, cells 
transfected with wildtype c-src were not metastatic, demonstrating that the truncation 
mutant was highly activating.  These findings are concordant with the fact that v-src also 
contains various base pair substitutions, one of which results in truncation of the carboxy 
terminal prior to the phosphorylation site, leading to constitutive activation of Src (14).  
The sum of these results confirms the important role of Src activation in human tumor 
progression. 
 
 
1.2.3 Src and Osteosarcoma 
 
Recent data from microarray analysis of 61 primary and metastatic osteosarcoma patient 
samples revealed that Src is expressed in all of the samples (20).  In addition, a tissue 
array containing 23 osteosarcoma patient samples was tested for activation of Src, and its 
substrates, FAK and paxillin, by immunohistochemistry (21).  15 of 17 (88%) samples 
showed activated Src.  18 of 19 (94%) samples were positive for phosphorylated FAK.  
10 of 20 (50%) samples were positive of phosphorylated paxillin.  In total, 19 of 20 
(95%) samples had activation of at least one of the above three genes.  These findings 
demonstrate that the Src pathway is activated in 95% of patients with osteosarcoma.  This 
included two patients with recurrent osteosarcoma and both of these samples had very 
high levels of Src activation. 
 
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A large body of in vitro data also reveals the importance of Src activation in the 
progression of osteosarcoma.  CD99 is a transmembrane glycoprotein that shows very 
little expression in human osteosarcoma samples.  Forced expression of CD99 into a 
metastatic osteosarcoma cell line drastically reduced the number of lung metastases (22).  
CD99 over-expressing cells were found to have decreased phosphorylation of the Src Tyr 
419 residue (resulting in decreased Src activity).  In addition, CD99 was found to co-
localize with Src and the scaffold protein caveolin-1, possibly resulting in allosteric 
inhibition of Src activity.  Treatment of cells with PP1 and PP2 (Src kinase inhibitors) 
resulted in suppression of motility of parental cells, again suggesting the importance of 
Src activation for the migratory behavior of wild-type cells. 
 
Further underscoring the importance of the above are the more recent findings that 
caveolin-1 (Cav-1) expression reduces osteosarcoma metastases by inhibiting Src activity 
and Met signaling (23).  Specifically, the mean number of metastatic nodules was >250 in 
mice receiving Cav-1 deficient osteosarcoma cells, and 0 in mice inoculated with Cav-1 
over-expressing cells.  There were high levels of both expression and activity of Src in 
Cav-1 deficient cells, whereas Cav-1 over-expressing cells had a significant decrease in 
Src kinase activity.  Over-expression of Cav-1 also resulted in inhibition of anchorage 
independent growth, migration and invasion in vitro. 
 
Similar results were obtained in osteosarcoma cells treated with dasatinib, a small 
molecule inhibitor of Src kinase activity (24).  Inhibition of Src signaling was 
accompanied by blockade of cell migration (wound healing assay), invasion (matrigel 
invasion chamber) and apoptosis in two osteosarcoma cell lines.  In addition, inhibition 
of Src protein expression by small interfering RNA also induced apoptosis, indicating 
that these osteosarcoma cell lines were dependent on Src activity for survival (24). 
 
Src interacts with Focal Adhesion Kinase (FAK), leading to the subsequent 
phosphorylation of paxillin and p130 Crk-associated substrate.  Neither molecule has 
intrinsic enzymatic activity.  However, they have multiple domains that interact with 
cytoskeletal and signaling molecules, allowing them to function as scaffold proteins.  One 
murine osteosarcoma model suggests the importance of paxillin expression in metastatic 
disease (25).  Highly metastatic variants of the human osteosarcoma cell line HuO9 
showed high phospho-paxillin expression, while poorly metastatic variants of the cell line 
showed low phospho-paxillin expression.  Treatment of highly metastatic cells with PP2 
(Src kinase inhibitor) resulted in suppression of motility.  These results demonstrate the 
importance of activated Src kinase in the metastatic process. 
 
Src activation is also required for anoikis resistance of human osteosarcoma cells (26).  
Anoikis is a form of apoptosis that is triggered when survival signals generated from 
interactions with the extracellular membrane are severed.  Physiological anoikis is 
important in the maintenance of homeostasis and tissue architecture.  Transformed cells 
that are resistant to anoikis have increased survival times in the absence of matrix 
attachments, thus facilitating their migration and colonization at secondary sites.  Src was 
found to be upregulated in anoikis resistant SAOS human osteosarcoma cells and 
pharmacological inhibition of Src activity resulted in restoration of anoikis sensitivity.  In 
total, these results identify biochemical mechanisms that link the activation of Src kinase 
to the metastatic process. 
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1.2.4 Saracatinib 
 
Saracatinib is a highly selective, orally bio-available, dual-specific Src/Abl kinase 
inhibitor that has high potency against all Src family members tested (27).  This includes 
c-yes and c-fyn, the members that are most closely related to c-src.  IC50 c-src = 2.7 nM.  
IC50 c-yes = 4 nM.  IC50 c-fyn = 10 nM. 
 
 
1.2.5 Effects of saracatinib on Osteoclast Activity 
 
Bone remodeling is the key metabolic process that regulates bone structure, and 
osteoclasts are the predominant mediators of this function (28).  Most adult skeletal 
diseases, such as osteoporosis and cancers that metastasize to bone, are due to excessive 
osteoclastic activity and increased bone resorption.  The important role of c-src in 
osteoclasts was identified when Src knockout mice were generated (29).  These mice 
developed osteopetrosis (excessive bone density), secondary to a severe deficiency in 
osteoclast function.  Although they had increased numbers of osteoclasts, they remained 
in an inactive form due to the failure to form ruffled borders.  Src is activated in 
osteoclasts in response to integrin binding and allows signaling to proceed through 
RANK (receptor activator of nuclear factor κB).  This results in intracellular cytoskeletal 
reorganization, the formation of a ruffled border, and activation of the osteoclast. 
 
The effect of saracatinib on osteoclast activity was tested in a series of in vitro 
experiments.  Treatment with saracatinib reduced the resorption area and the number of 
resorption pits when isolated rabbit osteoclasts were applied to bone slices (30).  In 
addition, saracatinib inhibited calcium release from pre-labeled neonatal mouse calvariae 
in a dose-dependent manner (30).  Both of these results strongly suggested that 
saracatinib is a potent inhibitor of osteoclast-mediated bone resorption. 
 
In healthy adult volunteers, once daily treatment with saracatinib for 10-14 days resulted 
in a significant, dose-dependent reduction in serum beta-CTx (C-terminal telopeptide), 
serum TRAP 5b (tartrate-resistant acid phosphatase) and urinary NTx/creatinine (N-
telopeptide/creatinine) (31).  Beta-CTx and NTx are specific resorption markers for 
degradation of type I bone collagen by osteoclasts.  The TRAP 5b isoform is specific to 
osteoclasts and is required in activated osteoclasts.  The effect was evident as early as one 
day after the start of dosing and up to 24 days after the cessation of dosing.  Similar 
results, with a trend towards dose-dependence, were seen in patients with advanced 
cancer who had received saracatinib (32).  Taken together, these data demonstrate that 
saracatinib inhibits osteoclast activity in a dose-dependent manner, thereby proving 
mechanism of action. 
 
 
 
 
 
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1.2.6 Activity of Saracatinib in Pre-Clinical Studies 
 
Preliminary studies by Dr. Chand Khanna have utilized two metastatic osteosarcoma cell 
lines (20).  K7M2 is a murine cell line and MNNG/HOS is a chemically transformed 
variant of the human osteosarcoma cell line HOS.  Treatment of either of these 
osteosarcoma cell lines with saracatinib did not lead to changes in cell proliferation in 
vitro as determined by MTT assays.  This is similar to results found in breast, colon, lung 
and prostate tumor cell lines (33).  However, treatment of both murine and human 
osteosarcoma cell lines with saracatinib led to inhibition of tumor cell migration as 
determine by a wound-healing assay and migration through a porous membrane.  Again, 
this effect is in concordance with data obtained using MDA-MB231 and MCF-7 breast 
cancer cell lines (33). 
 
The photograph on the right demonstrates that treatment of osteosarcoma cell lines with 
saracatinib led to a marked decrease in phosphorylation levels of both Focal Adhesion 
Kinase (FAK) and Paxillin.  This occurred most markedly at a concentration of 10 uM, 
but even as low as 0.1 uM, in MNNG/HOS cells.  
A similar result was obtained with K7M2 cells.  
The results of immunohistochemistry (IHC) 
studies using phospho-FAK and phospho-paxillin 
are pending.  However, marked decrease in 
phospho-paxillin has been detected by IHC in 
Calu-6 human lung cancer xenografts following a 
single dose of saracatinib (33). 
 
Many pre-clinical in vivo studies point to the 
ability of saracatinib to inhibit primary tumor 
growth.  NIH3T3 fibroblasts that overexpress a 
constitutively active human c-src construct, form 
primary tumors in athymic mice following subcutaneous implantation.  Mice that were 
treated with saracatinib (6 mg/kg) by once 
daily gavage had >95% inhibition of tumor 
volume and tumor weight after 18 days of 
treatment (27).  Mice treated with saracatinib 
at a slightly higher dose of 10 mg/kg had 
almost complete inhibition of tumor growth, 
depicted in the figure on the right. 
 
Shown below are results demonstrating 
reduced 
metastases 
in 
an 
orthotopic 
pancreatic cancer model and a subcutaneous 
bladder cancer model.  In both cases, there was marked decrease in the number of 
animals that developed metastatic disease when treated with saracatinib (33). 
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In total, these findings suggest that saracatinib markedly inhibits Src substrates in vitro, 
by altering pathways unrelated to proliferation.  The anti-metastatic activity of saracatinib 
may be linked to its anti-migratory property seen in vitro.  These features make 
saracatinib a very attractive biological agent to move forward in advanced clinical trials. 
 
 
1.2.7 Clinical Pharmacokinetics of Saracatinib 
 
The initial evaluation of saracatinib was carried out in healthy male volunteers (33).  
Following single oral doses between 2.5 mg and 1000 mg, saracatinib was relatively 
slowly absorbed (median tmax of 5 hours), extensively distributed outside the blood, and 
cleared moderately slowly.  After Cmax, the disposition was biphasic with a terminal 
phase from 24 hours after dosing, having a t1/2 of approximately 40 hours.  The increase 
in exposure with the dose tended to be slightly greater than proportional.  Across the dose 
range, a doubling of the dose led to a 30% higher than proportional increase in both 
Cmax and the area under the curve (AUC). 
 
Saracatinib, given at daily doses from 60 to 250 mg/day, resulted in steady state levels 
after 10 to 12 days.  At steady state, the plasma concentrations of saracatinib in an 
individual remained within a 2-3 fold range.  The degree of accumulation (6-8 fold) was 
greater, and the time to steady state was longer, than predicted from the single dose 
pharmacokinetics (PK).  Also, at steady state, the exposure was greater than proportional 
to the dose.  A doubling of the dose resulted in a 3-fold increase in exposure to 
saracatinib.  The average urinary recovery of saracatinib at steady state ranged from 8% 
to 14% across the dose groups. 
 
The most likely reason for these pharmacokinetic changes with dose and time appeared to 
be increased bioavailability.  This may be the result of saturation of efflux transporters or 
metabolizing enzymes.  However, the possibility of a reduction in systemic clearance of 
saracatinib cannot be ruled out.  These changes in the pharmacokinetics of saracatinib 
were observed as a result of the relatively wide dose ranges employed in the studies.  
Non-proportionality is easier to observe when a wide range of doses is employed.  It is 
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unlikely that non-proportionality would be relevant for a patient taking a fixed dose of 
saracatinib. 
 
In patients with advanced cancer, the pharmacokinetic profile of saracatinib, at doses 
between 50 mg and 250 mg, was generally similar to that observed in healthy volunteers.  
However, there was a tendency for patients to have slightly higher plasma concentrations.  
Exposure to saracatinib increased in an apparently dose-proportional manner after a 
single dose.  Accumulation with once daily dosing was 4-6 fold across the dose levels.  
Steady state was achieved after 10 days, at which point the increase in exposure with the 
dose was proportional, up to the 175mg dose.  The table below summarizes the results of 
this two-part study.  
 
 
Demographics and drug exposure 
Steady State Pharmacokinetics (geometric mean) 
Dose 
(mg/day) 
N 
Time on Treatment 
(days) 
Age 
(years) 
Weight 
(kg) 
N 
Css,max  
(ng/mL) 
AUCss 
(ng.h/mL) 
CL/F 
(L/h) 
Part B 
 
 
 
 
 
 
 
 
    50 
16 
9-51 
40-72 
49-92 
11 
95 
1597 
31.3 
  125 
16 
22-210 
42-75 
34-88 
15 
247 
3691 
34 
  175 
19 
7-45 
20-71 
35-110 
16 
444 
7588 
23.2 
Part A 
 
 
 
 
 
 
 
 
  175  
5 
11-65 
49-73 
37-98 
4 
484 
7911 
22.2 
  250 
7 
6-61 
23-70 
52-88 
2 
493, 1090 
9070, 198000 
28.7, 12.6 
 
N 
 
Number of patients providing data for the particular endpoint 
Css, max 
Maximum plasma concentrations at steady state 
AUCss 
Area under the plasma concentration curve during the dosing interval at steady state 
CL/F 
Oral drug clearance 
 
To determine saracatinib levels in tumors, tissue was homogenized, subjected to solvent 
extraction and analyzed by high performance liquid chromatography with mass 
spectrometric detection.  At steady state, the concentrations of saracatinib in tumor tissue 
were approximately 70 times greater than in plasma, in human patients. 
 
Saracatinib is an inhibitor of CYP3A4 in vitro.  The relevance of this finding was 
examined in a clinical study using midazolam, a recognized substrate of CYP3A4.  
Saracatinib, at a dose of 125 mg/day, resulted in an average increase in the plasma AUC 
of midazolam of 2.7-fold.  This observation classifies saracatinib as a moderate inhibitor 
of CYP3A4 and suggests the possibility that it could affect the exposure and effects of 
co-administered drugs.  Medications that are contra-indicated (see Section 4.5) and 
recommendations regarding the use of drugs known to be sensitive to inhibition of this 
enzyme are included in this protocol (see Section 4.6).  A list of contra-indicated foods is 
also provided (see Section 4.7). 
 
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The early studies with saracatinib were conducted using a provisional tablet formulation 
(the “Phase I” formulation).  The performance of a tablet with less mannitol that is more 
resistant to physical damage (the “Phase II” tablet) was examined in a clinical study.  
Based on the pharmacokinetic profile, the new tablet is considered interchangeable with 
the saracatinib “Phase I” formulation.  Thus, the data generated with the early 
formulation is of direct relevance.  The effect of food on the bioavailability of saracatinib 
in the “Phase II” tablet was examined in the same study.  These results led to the 
recommendation that saracatinib can be taken with or without food.  The “Phase II” tablet 
will be used in this study. 
 
 
1.2.8 Phase I Trials of Saracatinib 
 
Saracatinib has been evaluated in healthy volunteers and patients with advanced cancer.  
Single oral doses of up to 1000 mg and multiple, oral daily doses of up to 500 mg have 
been administered. 
 
The results of a single-dose, ascending study of saracatinib in healthy adult volunteers 
showed that doses between 2.5 mg to 500 mg were well tolerated (33).  However, at 1000 
mg, patients experienced severe vomiting and diarrhea.  Multiple daily doses for 14 days 
were also well tolerated from 60 mg to 185 mg.  The next dose, 250 mg, was also 
tolerated.  However, adverse effects (influenza-like syndrome and diarrhea) were more 
frequent and severe at this dose level.  Dose escalation was stopped and the maximum 
tolerated dose (MTD) was defined as 250 mg.  Other side effects observed were as 
follows: acneform rash (125 mg), loose stools and mild diarrhea (185 mg), muscular 
shoulder pain (185 mg), mild flu-like symptoms (185 mg) and elevated C-reactive protein 
(CRP) (250 mg). 
 
A monotherapy study has also been performed in 81 patients with advanced solid 
malignancies refractory to or unsuitable for standard therapy, or for whom no standard 
therapy existed.  In this study, patients received saracatinib continuously, every day, 
without any breaks between cycles.  This was a two-part, Phase 1, open-label, multi-
center study.  Part A had the aim of establishing the appropriate dose of saracatinib 
monotherapy for use in future studies of patients with advanced solid malignancies.  Part 
B had the aim of evaluating the effect of saracatinib on c-Src kinase activity in human 
cancers over a range of doses.  In Part A, 30 patients received daily doses of saracatinib 
from 60 mg to 250 mg.  The duration of therapy ranged from 6 to 150 days, with a 
median of 23 days.  Dose limiting toxicity (DLT) was defined using the Common 
Terminology 
Criteria 
for 
Adverse 
Events 
(CTCAE) 
Version 
3 
(http://ctep.cancer.gov/forms/CTCAEv3.pdf).  Part A defined the MTD in the patient 
population who participated as 175 mg daily.  DLTs at 250 mg were as follows: grade 5 
septic shock with grade 3 renal failure, grade 3 fatigue and grade 3 leucopenia.  DLTs at 
200 mg were grade 3 febrile neutropenia and grade 3 dyspnea.  In Part B, 51 patients 
were randomized in a parallel-group cohort-expansion phase of three doses of saracatinib 
previously declared tolerable in Part A.  In Part B of the study, 16 patients received 50 
mg saracatinib daily, 16 patients received 125 mg saracatinib daily and 19 patients 
received 175 mg saracatinib daily.  The duration of therapy ranged from 7 to 210 days, 
with a median of 25 days. 
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The patient who developed grade 5 septic shock was a 55 year old female, who had been 
heavily pre-treated for breast adenocarcinoma, metastatic to multiple sites. This patient 
developed renal failure (oligouria, increased creatinine, maximum CTCAEv3 grade 2) on 
day 9 of treatment with saracatinib at 250 mg.  On day 12 of treatment, she developed 
pyrexia and septic shock (maximum CTCAEv3 grade 4) and saracatinib was 
discontinued.  On day 13, the renal failure worsened to grade 3.  Despite antibiotics, the 
patient deteriorated and died 4 days following treatment discontinuation (septic shock 
worsening to grade 5).  The investigator felt that the renal failure was causally related to a 
study procedure (administration of intravenous radiological contrast medium and 
dehydration) and was not causally related to treatment with saracatinib.  AstraZeneca felt 
that the relationship to treatment to saracatinib could not be excluded. 
 
There were two additional pulmonary serious adverse events (SAEs) in this trial.  One 
patient had rapidly progressive colorectal cancer with extensive metastatic burden in the 
lungs and liver.  The patient had been taking saracatinib at 200 mg.  On day 18, the 
patient presented with acute onset dyspnea, and had an arterial oxygen saturation of 70% 
on room air.  Despite the use of oxygen, morphine and corticosteroids, this patient died 
on the same day.  At autopsy, histopathology demonstrated diffuse alveolar damage, 
consistent with acute respiratory distress syndrome.  In the second case, a minimally 
symptomatic patient, with locally advanced malignant melanoma and metastases to the 
lung pleura, had diffuse pulmonary findings on a planned follow-up CT scan following 
21 days of treatment with saracatinib at 175 mg once daily.  These findings resolved 
following discontinuation of saracatinib and the start of steroid therapy. 
 
Two other pulmonary SAEs have been recorded in subsequent trials of saracatinib in 
combination with chemotherapy.  The third patient had been taking 175 mg of saracatinib 
daily and paclitaxil weekly for approximately 4 months for metastatic gastric 
adenocarcinoma.  She had a complex treatment history that included recurrent urinary 
tract infections.  She developed cough and dyspnea and a thoracic CT scan revealed 
patchy ground glass opacities in all lobes of the lung, at which time saracatinib was 
stopped.  Her symptoms progressed despite treatment with steroids and antibiotics and 
the patient died 10 days later.  The fourth patient was receiving 175 mg of saracatinib 
daily and gemcitabine on days 1, 8 and 15 for metastatic pancreatic cancer.  During cycle 
2, worsening of flu-like symptoms prompted a thoracic CT scan that revealed diffuse 
ground glass opacities consistent with interstitial lung disease.  Both the symptoms and 
the radiographic findings resolved after saracatinib was stopped.  In all four cases, the 
pulmonic events were considered to be possibly related to treatment with saracatinib, 
even though it was not possible to establish a clear etiology.  The common finding of 
diffuse interstitial lung changes in these patients has prompted early monitoring to detect 
these changes using thoracic CT scans (see Sections 2.2, 3.4 and 4.4). 
 
Other events, irrespective of reported causality, that have been seen in greater than 10% 
of the study population (healthy volunteers and patients with advanced cancer) included 
anemia, neutropenia, fatigue, pyrexia, dyspnea, anorexia, nausea, diarrhea, vomiting and 
constipation.  The most common treatment-related adverse events reported in the Phase I 
population of patients with advanced caner were: anemia, anorexia, nausea, diarrhea and 
vomiting.  Decreases in total white cell counts and platelet counts, and increases in serum 
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creatinine (within the normal range) have also been seen in some healthy volunteers and 
patients, and are described below. 
 
A dose related effect of saracatinib on neutrophil and platelet counts in healthy volunteers 
has been identified.  These effects are seen following multiple dosing (up to 14 days has 
been evaluated in healthy volunteer studies) but were not apparent following single dose 
administrations of up to 1000 mg.  In all cases within healthy volunteers, neutrophil and 
platelets counts returned to near baseline values within a period of time that drug levels 
may be considered pharmacologically relevant (within 3 days, t1/2 of saracatinib is 40 
hours) or during therapy.  Moderate declines in neutrophil counts were also observed in 
patients with advanced cancer, with a nadir at 10 to 25 days of continuous saracatinib 
treatment.  However, the majority of these declines were not clinically significant, with 
counts recovering without the need for dose interruption or the addition of supportive 
care. 
 
Declines in hemoglobin levels were observed in patients with advanced cancer.  The 
majority of these declines were of little clinical significance with counts recovering 
without the need for dose interruption or dose reduction.  These declines occurred in 
patients with multiple confounding factors (treatment with multiple cytotoxic agents, 
administration of non-steroidal anti-inflammatory drugs for analgesia, previous history of 
peptic ulcer disease, prior blood transfusions to permit entry into the study), thus making 
evaluation difficult.  No overt effect on platelet values has been identified in patients with 
advanced cancer.  No evidence of cumulative hematological toxicity has been observed 
in either healthy volunteers or patients with advanced cancer. 
 
Moderate rises in plasma creatinine by 5% to 30% have been observed in both healthy 
volunteers and patients with malignancies.  These rises appear to be dose related and 
occur after a single dose, before rapidly reversing.  With multiple dosing, the rise occurs 
rapidly following commencement of saracatinib, reaches a plateau and falls rapidly when 
dosing is stopped.  No patient or healthy volunteer experienced an initial rise in serum 
creatinine that exceeded the upper limit of normal, and no clinical sequelae have been 
apparent.  A study of renal function in healthy volunteers who have received up to 14 
days continuous saracatinib dosing has been undertaken with the aim of clarifying the 
mechanism underlying the observed moderate and reversible rise in serum creatinine.  
The report for this study is currently being prepared.  However, it is clear that saracatinib 
does not affect glomerular filtration rate (GFR), and that increases in serum creatinine 
consequent to saracatinib treatment are the result of inhibition of tubular secretion of 
creatinine.  No evidence of tubular damage has been observed and no cumulative effect 
on renal function or changes in serum creatinine have been recorded.  Such changes in 
serum creatinine have been observed with a number of medications, including cimetidine 
and trimethoprim (34). 
 
Evaluations of saracatinib monotherapy in healthy volunteers and patients with advanced 
cancer have, therefore, demonstrated that dosing of saracatinib is associated with a 
manageable safety and tolerability profile, which in patients with advanced cancer is 
generally consistent with the underlying disease state. 
 
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In addition, examination of tumor samples from patients in Phase I trials, before and after 
the initiation of saracatinib, have shown decreases in phosphorylation of the downstream 
targets of Src, namely FAK and paxillin.  Shown below are immunohistochemistry 
results in a patient with breast carcinoma, one day prior to, and 28 days after, treatment 
with saracatinib at 125mg (21).   
 
 
 
 
 
 
          Day -1                      Day 28                                   Day -1                     Day 28          
                           p-FAK                                                                 p-paxillin 
 
To date, no formal analysis of the efficacy evaluations of saracatinib have been 
performed.  In the Phase 1 multiple ascending dose and cohort expansion study 
conducted in 81 patients with advanced cancer, 11 patients experienced a best objective 
response of stable disease, with 11 others having unconfirmed stable disease.  There were 
no complete responses or confirmed partial responses.  Thirteen out of 81 (16%) patients 
who participated in the Phase 1 study received saracatinib therapy for over 12 weeks. 
 
 
1.2.9 Rationale for the Use of Saracatinib in Recurrent Osteosarcoma 
 
There is a large body of in vitro data showing Src plays an important role in the motility 
of osteosarcoma cells, a function that can be abrogated by the use of Src inhibitors.  More 
importantly, Src and other genes that are involved in the Src pathway are activated in 
95% of patients with osteosarcoma.  These data suggest that saracatinib represents a 
promising candidate for the treatment of patients with recurrence of osteosarcoma. 
 
We propose to utilize a newly described type of study, coined a Phase II.5 study (35).  
Phase II.5 studies examine outcome differences using a one-sided 0.10 alpha level 
significance test, rather than the traditional value of 0.05.  The benefits of this type of 
study include enrollment of a fewer number of patients, which is important since patients 
with recurrent osteosarcoma are rare.  In addition, it is a randomized, placebo-controlled 
trial, thus precluding the need to compare to historical controls, which is important since 
patients with recurrent osteosarcoma have previously received many different treatment 
modalities.  The purpose of this design is to provide a sufficiently large, controlled, 
comparative evaluation to determine whether a sufficient effect is noted.  Although the 
results are not definitive, if merited, they can then be used to estimate the parameters to 
design a definitive subsequent trial. 
 
The trial objective is to perform a randomized, double-blinded, placebo-controlled study 
to evaluate the addition of saracatinib to pulmonary metastasectomy, versus placebo and 
pulmonary metastasectomy, in patients with relapsed osteosarcoma, localized to the lung.  
Currently, patients who achieve a surgical second remission have a progression free 
survival rate of 33% at two years and an overall survival rate of 45% at three years.  An 
important caveat to this statement is that these patients have received a multitude of 
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different treatments, including surgery alone, and/or radiation, and/or chemotherapy, 
and/or high dose chemotherapy with stem cell rescue.  Therefore, historical data do not 
give a true indication of actual survival rates.  This study will try to determine whether 
patients who receive saracatinib will experience a 60% relative increase in progression 
free survival.  Secondary objectives will determine whether patients who receive 
saracatinib will experience a 56% relative increase in overall survival and an increase in 
the time to treatment failure.  Any adverse event, including toxicity, disease progression 
and death, that result in discontinuation of either saracatinib or placebo will be considered 
a treatment failure.  The randomized nature of this study will allow us to determine the 
actual survival rates in these two cohorts, thereby assessing the efficacy of saracatinib in 
this patient population.  Forty-four patients will need to be randomized in each arm, for a 
total of 88 patients, over a 48-month accrual period.  Follow-up for survival of the last 
patient randomized must continue for an additional year.  Patients who recur in the lung 
while on-study and who are thought to be amenable to complete surgical resection will be 
unblinded.  Those who were receiving placebo will be given the option of undergoing 
surgical resection.  If fully resected, they will be given the option to begin oral therapy 
with saracatinib. 
 
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2 
Eligibility Assessment and Enrollment 
 
 
2.1 
Eligibility Criteria 
 
 
2.1.1 Inclusion Criteria 
 
Patients who have recurrence of osteosarcoma, localized to the lungs, who have had 
complete surgical removal of all lung nodules, are eligible for enrollment. 
 
OR 
 
Patients with suspected recurrence of osteosarcoma but have not had surgery are eligible 
for enrollment but will not be randomized until inclusion criteria (a) and exclusion 
criteria (b) are confirmed after surgery.  If these are not confirmed, patient will be 
considered a screen failure and will not be randomized. 
 
Other inclusion criteria are as follows: 
 
a. 
Histological diagnosis of osteosarcoma of the recurrent sample (histology 
types must be osteoblastic, chondroblastic, fibroblastic or telangiectatic).  
For patients enrolled prior to surgery, this criterion can be confirmed after 
consent, enrollment and surgical resection. 
b. 
Recurrence of osteosarcoma in the lung following standard chemotherapy 
including: adriamycin, cisplatin, ifosphamide and methotrexate (or 
provide justification why any of these agents were not received, for 
example, previous toxicity with methotrexate, or methotrexate not 
routinely given for adult patients) 
c. 
Age >15 and <75 years of age 
d. 
Weight >34 kg 
e. 
ECOG performance score of 0, 1 or 2 (0 = asymptomatic, 1 = 
symptomatic but fully ambulatory, 2 = symptomatic in bed <50% of the 
day) 
f. 
Adequate bone marrow function (ANC >1500/uL, Hb >9.0 g/dL, platelets 
>100,000/uL) 
g. 
Adequate renal function (serum creatinine <1.5 or a creatinine clearance 
>50 mL/min/1.73m2) 
h. 
Adequate hepatic function (ALT/AST <2.5X normal, total bilirubin <2 
mg/dl with the exception of patients with Gilbert’s syndrome) 
i. 
Adequate cardiac function (ECHO or MUGA with shortening fraction 
>27% or ejection fraction >45%) and (EKG with QTc <480 msec) 
j. 
Negative pregnancy test for women of childbearing potential, <7 days 
prior to enrollment, and the willingness to use an acceptable method of 
contraception during participation in the study and for 3 months after the 
last dose 
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k. 
Randomization must occur <6 weeks after complete surgical resection of 
all tumor nodules  
l. 
Informed consent: all patients, or their legal guardian if the patient is less 
than 18 years of age, must sign a document of informed consent indicating 
their awareness of the investigational nature and the risks of this study 
 
 
2.1.2 Exclusion Criteria 
 
a. 
Presence of metastatic disease in other locations in addition to the lung 
b. 
Extensive disruption of the lung pleura by tumor.  For patients enrolled 
prior to surgery, this criterion can be confirmed after consent, enrollment 
and surgical resection.  This does not include solitary nodules that involve 
the lung pleura, but that have been completely resected, with no evidence 
of additional pleural involvement. 
c. 
Paget’s disease 
d. 
Current use, or previous use within the specified time period, of 
medications that are potent inducers, inhibitors or substrates of CYP3A4, 
(see Section 4.5) 
e. 
Known hypersensitivity to other Src/Abl non-receptor kinase inhibitors 
f. 
Any evidence of interstitial lung disease (bilateral, diffuse, parenchymal 
lung disease) 
g. 
Any concurrent condition which in the investigator’s opinion makes it 
undesirable for the patient to participate in the trial or which would 
jeopardize compliance with the protocol.  These include conditions that 
are severe and/or inadequately uncontrolled, such as severe or worsening 
hepatic, respiratory and cardiac impairment. 
h. 
Myocardial infarction within one year prior to study entry 
i. 
Bleeding diathesis, resulting in symptomatic bleeding 
j. 
Pregnant women or breast-feeding or nursing women 
k. 
Any agent (chemotherapy, biological or investigational) administered < 28 
days prior to enrollment 
l. 
Unresolved toxicity > CTCAEv3 grade 2 (except alopecia) from previous 
agents 
 
The reasoning for the above criteria is that patients who meet exclusion criteria a-c have 
an extremely poor five-year survival rate (3).  Since some patients will meet one of the 
above criteria, it is possible that a true survival advantage with adjuvant saracatinib 
treatment may go undetected if the above patients are included. 
 
 
2.2 
Screening 
 
For patients who are enrolled prior to surgery, if there is a significant change in a patient 
health status post-operatively, appropriate screening studies should be repeated based on 
the judgment of the treating investigator. 
 
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• History and Physical Examination 
• vital signs, weight, height, ECOG score 
 
• Laboratory Studies (within 7 days prior to enrollment) 
• urine or serum pregnancy test (for females of childbearing potential) 
 
• Laboratory Studies (within 14 days prior to enrollment) 
• white blood cell count with differential 
• hemoglobin and hematocrit 
• platelet count 
• prothrombin time, partial thrombin time, INR 
• sodium, potassium, chloride, bicarbonate, blood urea nitrogen, creatinine, glucose 
• calcium, magnesium, phosphorus 
• ALT, AST, total bilirubin, direct bilirubin 
• alkaline phosphatase, lactate dehydrogenase, total protein, albumin 
• urinalysis 
• urine or serum pregnancy test (for females of childbearing potential) 
 
• Functional Studies (within 14 days prior to enrollment) 
• EKG 
 
• Radiographic Studies (within 6 weeks prior to definitive resection or within 6 weeks 
prior to randomization) 
• Thoracic CT scan with contrast (unless patient cannot tolerate contrast ) */** 
• Bone scan **  
 
• Functional Studies (within 28 days prior to enrollment) 
• echocardiogram or MUGA 
• creatinine clearance (if serum creatinine is >1.5) 
 
* The thoracic CT scan must be performed at a slice thickness of 5 mm or less.  If there is 
any suspicion of interstitial lung disease, the patient must undergo high-resolution CT 
imaging to exclude interstitial lung disease.  Any evidence of interstitial lung disease will 
make the patient ineligible for the study (see Exclusion Criteria in Section 2.1.2.f).  The 
suggested parameters for the high-resolution thoracic CT scan are as follows: position 
(supine), slice thickness (≤1.25 mm), slice spacing (10 mm), start location (10 mm below 
the apices), end location (10 mm above the costophrenic angles). 
 
** There will be instances when patients have very small indeterminate nodules on the 
CT scan.  Sometimes it will be difficult to determine if these are tumor nodules or not.  
For the purposes of this protocol, the oncologist, radiologist and surgeon will have to use 
their best judgment to decide if the patient is fully resected of tumor.  The same applies 
for nonspecific uptake on bone scans. 
 
 
 
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2.3 
Patient Enrollment 
 
 
A signed informed consent document will be obtained prior to entry onto the study.  
Following consent, patient information is entered in the eCRF database.  All patients 
must have histological verification of recurrent osteosarcoma in the lung prior to 
randomization.  A copy of the pathology report documenting histologic confirmation 
should be sent to the SARC RPM prior to randomization.  
 
Enrollment will be centrally managed by the trial coordinating center, SARC.  Patient 
data will be entered electronically by the participating institutions through the study 
website: 
 
https://velos.med.umich.edu/eres/jsp/ereslogin.jsp 
 
Each patient will be assigned a patient identification number automatically following 
enrollment.  Patients can be enrolled at any time of the day, any day of the week, via the 
website.   
 
Once the patient has undergone complete surgical resection and the institutional PI 
determines that all of the criteria for inclusion have been met per protocol Section 2.1, the 
eligibility CRF will be completed in the database.   The patient can then be randomized.   
 
 
 
 
 
 
 
 
 
 
 
 
                                                                                   
 
                                                                        
                                                                         
 
                                                                                            
 
                                                                                          
                                                           
 
 
 
                                                                       
 
                                                                          
 
 
 
Patients will be registered and then stratified based on the number of recurrences (FIRST 
versus SECOND versus THIRD or MORE) and the number of recurrent nodules (ONE or 
TWO versus THREE or MORE).   
 
Consent 
Enrollment through Study website 
Surgical 
Resection 
Eligibility Confirmed 
Patient randomized 
Patient has undergone surgical resection? 
No 
Yes 
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SARC will possess separate randomization sheets for each stratum.  Patient treatment 
assignment will be kept confidential and will not be shared with the treating physician(s) 
or any other site team staff involved in the care of the patient, except in the event of a 
medical emergency where unblinding is necessary to ensure patient safety (See Operation 
Manual for details), or at the time of recurrence if the recurrence is in the lung. (See 
Section 7.4.2). 
 
Any questions regarding eligibility or the randomization process can be addressed to the 
SARC Operations Office: 
 
SARC Research Project Manager 
24 Frank Lloyd Wright Dr. 
PO Box 406 
Lobby A, 3rd Floor, Suite 3100 
Ann Arbor MI, 48105 
Phone: 734-930-7600 
Fax: 734-930-7557 
Email: sarc@sarctrials.org 
 
SARC, the study Principal Investigator and the Principal Investigators at each 
participating institution will have access to this website to review data regarding this 
clinical trial. 
 
For patients at the National Cancer Institute, in addition to the required enrollment 
procedure described above, the following are also required prior to initiation of therapy. 
Patients must register with the NCI Central Registration Office (CRO, phone number 
301-402-1732, fax number 301-480-0707).  A completed eligibility checklist and a 
signed consent form must be on file prior to entry onto the study.  Research nurses in the 
Pediatric Oncology Branch will facilitate this process. 
 
 
3 
Study Implementation 
 
 
3.1 
Study Design 
 
 
The primary objective of this study is to determine whether pulmonary metastasectomy 
and treatment with saracatinib, versus pulmonary metastasectomy and treatment with 
placebo, results in an increase in progression free survival.  A secondary objective is to 
determine whether pulmonary metastasectomy and treatment with saracatinib, versus 
pulmonary metastasectomy and treatment with placebo, results in an increase in overall 
survival.  Patients will be eligible for the study following the histological verification of 
recurrent osteosarcoma.  Patients will be stratified based on the number of recurrences 
(FIRST versus SECOND versus THIRD or MORE) and the number of recurrent nodules 
(ONE or TWO versus THREE or MORE). 
 
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Randomization will occur following complete resection of all lung nodules and the 
histological verification of recurrent osteosarcoma. 
 
Patients who are randomized to the saracatinib arm will receive saracatinib, 175 mg, 
orally, once daily, for a 28-day cycle, with no breaks between cycles.  The total duration 
of treatment with saracatinib will be thirteen 28-day cycles (364 days total).  Patients 
will receive one 125 mg tablet (9.5 mm diameter) and one 50 mg tablet (7 mm diameter). 
 
Patients who are randomized to the placebo arm will receive placebo, orally, once daily, 
for a 28-day cycle, with no breaks between cycles.  The total duration of treatment with 
placebo will be thirteen 28-day cycles (364 days total).  Patients will receive one 9.5 
mm tablet and one 7 mm tablet.  These tablets will be indistinguishable from saracatinib. 
 
Patients who recur in the lung while on-study and who are thought to be completely 
resectable will be unblinded.  Those patients who were receiving placebo will be offered 
the opportunity to undergo additional surgical resection, followed by treatment with 
Saracatinib.  If fully resected, they will then begin oral therapy with saracatinib. 
Saracatinib will be administered as a once daily, oral dose of 175 mg, for a 28-day cycle, 
with no breaks between cycles.  The duration of treatment with saracatinib will be 
thirteen 28-daycycles (364 days total). 
 
Patients will be followed for the duration that this study is open.  If accrual rates proceed 
as projected, the total duration of this study will be six years. 
 
 
3.2 
Treatment Administration 
 
 
3.2.1 Administration and Commencement of Oral Therapy 
 
Patients will receive two bottles that contain either saracatinib or placebo.  One bottle 
will contain 125 mg tablets (or a similar placebo tablet) and the other bottle will contain 
50 mg tablets (or a similar placebo tablet). 
 
Patients will take one 125 mg tablet and one 50 mg tablet, once every day, for the 
duration of the trial.  The tablets can be taken at any time of the day, with or without 
food.  See Sections 4.5, 4.6 and 4.7 for a list of medications and food products that should 
be avoided while on study.  Patients will also be asked to keep a daily diary of the time 
and dose of the drug ingested. (see Appendix B). 
 
There are three possibilities for disease burden in our study population.  First: patients 
who had very few nodules at recurrence, may have had resection of all of the nodules at 
the time of the biopsy.  Second: patients who had biopsy of one nodule and require one 
additional surgery for complete resection of any remaining nodules.  Third: patients who 
had biopsy of one nodule who have bilateral disease that requires a staged thorocotomy to 
obtain surgical remission.  The timing of enrollment, randomization and commencement 
of oral therapy, with either saracatinib or placebo, is detailed below for all three of these 
possibilities. 
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3.2.2 Distinction between Enrollment and Randomization 
 
This protocol distinguishes between enrollment and randomization.  Patients with 
suspected or confirmed recurrence of osteosarcoma localized to the lung will be enrolled 
in the study following informed consent.  This allows for the collection of tumor samples 
(for patients with suspected recurrence of osteosarcoma who have not yet undergone 
surgical resection), and their subsequent examination, which is an important objective in 
this protocol.  However, randomization will not occur until the patient has had complete 
surgical resection of all recurrent tumor nodules.  
 
There will be several patients who are deemed fully resectable based on a CT scan.  In a 
few cases, at the time of definitive surgery, the surgeon will find more tumor burden than 
was expected.  At that point, if total tumor resection is not possible, the procedure may be 
stopped due to high morbidity risk. 
 
Patients who have been enrolled in the study, but subsequently are not fully resected of 
tumor will not be randomized and therefore, they will not be included in any efficacy or 
toxicity studies.  However, their tumor samples can still be analyzed (see Section 3.6.1 
and Operations Manual).  These patients will be followed for overall survival only.  Their 
primary oncologist will manage their medical care.  The continued monitoring for overall 
survival on this study does not preclude them from any other trials or treatments that 
these patients will undergo. 
 
 
3.2.3 Regimen for Patients Who Have Been Fully Resected 
 
Patients who had resection of all tumor nodules at the time of their biopsy will be eligible 
for randomization after definitive histological diagnosis of recurrent osteosarcoma.  Once 
the treating physician decides that the patient is able to tolerate oral therapy, the patient 
will be randomized to either the saracatinib arm or the placebo arm.  Following 
randomization, tablets will be dispensed by the hospital pharmacy.   
 
Cycle 1 Day 1 must commence no later than 6 weeks after the time of the definitive 
mestastasectomy.  Patients who cannot commence oral therapy within these time frames 
will be removed from the study. 
 
 
3.2.4 Regimen for Patients Who Require Definitive Resection 
 
Patients who underwent biopsy of a nodule but have remaining nodules will be eligible 
for randomization after definitive histological diagnosis of recurrent osteosarcoma.  
These patients should undergo definitive pulmonary metastasectomy as soon as possible.  
Following definitive surgical resection of all metastatic nodules, and once the treating 
physician decides that the patient is able to tolerate oral therapy, the patient will be 
randomized to either the saracatinib arm or the placebo arm.  Following randomization, 
tablets will be dispensed by the hospital pharmacy.   
 
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Cycle 1 Day 1 must commence no later than 6 weeks after the time of the definitive 
metastasectomy.  Patients who cannot commence oral therapy within these time frames 
will be removed from the study. 
 
Biological studies to determine the etiology of recurrent osteosarcoma are an important 
component of this protocol.  Prior to metastasectomy, every attempt should be made to 
insure that the tumor sample is handled properly, so that all of the biological studies can 
be performed (see Sections 3.6.1 and Operations Manual). 
 
 
3.2.5 Regimen for Patients Who Require Staged Thoracotomies 
 
Patients with extensive bilateral disease that requires staged thoracotomies will be 
eligible for enrollment.  These patients should undergo resection of one side as soon as 
possible.  Resection of the other side should be performed at a time determined by the 
surgical oncologist.  Following definitive surgical resection of all metastatic nodules, 
histologic confirmation of osteosarcoma, and once the treating physician decides that the 
patient is able to tolerate oral therapy, the patient will be randomized to either the 
saracatinib arm or the placebo arm.  Following randomization, tablets will be dispensed 
by the hospital pharmacy.   
 
Cycle 1 Day 1 must commence no later than 6 weeks after the time of the definitive 
metastasectomy.  This will allow for the resolution of any complications that may arise as 
a result of the procedure, prior to administration of oral therapy.  Patients who cannot 
commence oral therapy within these time frames will be removed from the study. 
 
Biological studies to determine the etiology of recurrent osteosarcoma are an important 
component of this protocol.  Prior to BOTH surgeries, every attempt should be made to 
insure that the tumor sample is handled properly, so that all of the biological studies can 
be performed (see Sections 3.6.1 and Operations Manual). 
 
 
3.2.6 Cross-over Regimen for Patients Who Recur in the Lung While On-Study 
 
Patients who recur in the lung while on study, and who are thought to be amenable to 
complete surgical resection of the recurrent tumor will be unblinded.  Those patients who 
were receiving placebo will then have the option of undergoing surgical resection; if fully 
resected they will be given the option to begin oral therapy with Saracatinib.   
 
Saracatinib will be administered as a once daily, oral dose of 175 mg, for a 28-day cycle, 
with no breaks between cycles.  The duration of treatment with saracatinib will be 
thirteen 28-day cycles (364 days total).  Cycle 1 Day 1 must commence no later than 6 
weeks after the time of the definitive metastasectomy.  Patients who cannot commence 
oral therapy within 6 weeks will be removed from the study. 
 
Biological studies to determine the etiology of recurrent osteosarcoma are an important 
component of this protocol.  Prior to metastasectomy, every attempt should be made to 
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insure that the tumor sample is handled properly, so that all of the biological studies can 
be performed (see Sections 3.6.1 and Operations Manual). 
 
Patients who recur in locations other than the lung while on-study will be taken off study 
and will not be unblinded. 
 
 
3.3 
Treatment Modifications 
 
 
3.3.1 Dose Modification Criteria 
 
Dose reductions should be applied if any of the following toxicities occur 
 
 
Hematological 
 
• 
Any CTCAEv3 grade 4 hematological toxicity of any duration (With the 
exception of CTCAEv3 grade 4 neutropenia <6 days duration.  For 
CTCAEv3 grade 4 neutropenia <6 days duration, oral therapy will be held 
until the neutropenia recovers to CTCAEv3 grade 1 or less, at which time 
oral therapy will resume at the same dose) 
• 
Febrile neutropenia (CTCAEv3 grade 3 neutropenia with temperature 
>38.5°C or CTCAEv3 grade 4 neutropenia with temperature >38.0°C) 
• 
CTCAEv3 grade >3 neutropenia requiring hospitalization 
• 
CTCAEv3 grade >3 thrombocytopenia associated with non-traumatic 
bleeding (with the exception of patients on therapeutic anti-coagulation)   
 
 
Non-Hematological 
 
• 
Any CTCAEv3 grade >3, non-hematological toxicity (with the exception of 
alopecia, nausea and vomiting) 
• 
CTCAEv3 grade >3, hypophosphatemia (see section 3.3.3 for modified dose 
reduction schema) 
• 
CTCAEv3 grade >3 nausea or CTCAEv3 grade >3 vomiting, lasting >24 
hours despite IV fluids, anti-emetic therapy and adequate supportive care 
• 
Chronic CTCAEv3 grade 2 nausea or vomiting 
In the event of any toxicity, of any grade, that the treating physician suspects is due to 
disease progression, re-evaluation of tumor status is indicated, irrespective of scheduled 
clinic visits. 
 
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3.3.2 Dose Reduction of Oral Therapy 
 
If a patient experiences any of the toxicities defined in section 3.3.1, or another 
unacceptable toxicity occurs, and the investigator considers that the event is related to the 
study drug, oral therapy will be stopped for a maximum of 21 days, and supportive 
therapy will be administered as required.  If the toxicity resolves or reverts to a 
CTCAEv3 grade 0 or grade 1 or to the baseline (pre-study) grade within 21 days of onset, 
oral therapy will be restarted at a lower dose as follows: 
 
 
If a patient is currently taking 175 mg, the lower dose will be 125 mg. 
 
If a patient is currently taking 125 mg, the lower dose will be 100 mg. 
 
A maximum of two dose decreases, for any individual patient, can be made during the 
study period, down to the lowest dose of 100 mg of saracatinib or placebo. 
 
If a patient experiences any of the toxicities defined in Section 3.3.1, or another 
unacceptable toxicity occurs, while taking 100 mg, then the patient must be withdrawn 
from the study.  For all patients who experience any of the toxicities defined in Section 
3.3.1, or another unacceptable toxicity occurs during the study, if the toxicity does not 
resolve to CTCAEv3 grade 0 or grade 1 or to the baseline (pre-study) grade within 21 
days of onset, then the patient must be withdrawn from the study.  Patients will continue 
to be monitored until the toxicity has resolved. 
 
Patients will continue to be monitored for overall survival for the duration of the study.  
If patients have toxicity that requires their removal from the study prior to ascertainment 
of disease progression, then these patients will be considered treatment failures in the 
time to treatment failure analysis and the duration of total treatment will be included in 
the time to treatment failure.  However, for the progression free survival analysis, 
withdrawals due to toxicity will be censored, as the subject has not progressed. 
 
 
3.3.3 Dose Reduction of Oral Therapy for Hypophosphatemia 
 
Hypophosphatemia may be encountered for reasons that are unrelated to the study drug, 
such as vitamin D deficiency.  Prior to beginning oral therapy, treating physicians should 
obtain a full work-up to evaluate low or borderline low levels of phosphorus.  In addition, 
additional time to allow hypophosphatemia to normalize will be allowed. 
 
If a patient experiences CTCAEv3 grade 3 hypophosphatemia, dose reduction will occur 
as per section 3.3.2.  However, oral therapy may be stopped for a maximum of 35 days, 
and supportive therapy will be administered as required.  If the toxicity resolves or 
reverts to a CTCAEv3 grade 0 or grade 1 or to baseline (pre-study) grade within 35 days 
of onset, oral therapy will be restarted at a lower dose.  If the toxicity does not resolve to 
CTCAEv3 grade 0 or grade 1 or to baseline within 35 days of onset, then the patient must 
be withdrawn from the study. 
 
 
 
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3.4 
On Study Evaluations 
 
Treatment with saracatinib or placebo will be given for thirteen 28-day cycles (364 
days).  Patients will be required to return for routine follow-up visits as indicated in the 
chart below.   
 
For patients enrolled on this study, evaluations must be administered at the study site for 
the pre-treatment evaluation and for the 3, 6, 9, and 13 cycle visits.   For all other study 
evaluations (including specified follow up evaluations), the investigator may determine in 
the best interest of the patient that those evaluations may be safely conducted at a local, 
competent, referring oncologist’s office.  The institutional principal investigator is 
responsible for the timely and accurate reporting of data to the SARC Operations Center.  
 
Treatment Evaluations (also available in table form, see Appendix A) 
 
All treatment evaluations/procedures should be performed within a +/- 7 day window, 
with the exception of week 1 and week 3-4 which should be done within +/- 3 day 
window. 
 
Pre-treatment 
 history, physical, vital signs, laboratory tests 
Day 1 
 BEGIN oral therapy of saracatinib or placebo 
Week 1 
 history, physical, vital signs, laboratory tests * 
Week 3-4 
 history, physical, vital signs, laboratory tests * 
 
 thoracic CT */** 
Week 6-8 
 history, physical, vital signs, laboratory tests * 
 
 thoracic CT */** 
 Week 9 
 history, physical, vital signs, laboratory tests * 
 3 months/Cycle 3  history, physical, vital signs, laboratory tests 
 
 thoracic CT 
 
 EKG *** 
 4 months/Cycle 4  history, physical, vital signs, laboratory tests * 
 5 months/Cycle 5  history, physical, vital signs, laboratory tests * 
 6 months/Cycle 6  history, physical, vital signs, laboratory tests 
 
 thoracic CT 
 7 months/Cycle 7  history, physical, vital signs, laboratory tests * 
 8 months/Cycle 8  history, physical, vital signs, laboratory tests * 
 9 months/Cycle 9  history, physical, vital signs, laboratory tests 
 
 thoracic CT 
10 months/Cycle 10  history, physical, vital signs, laboratory tests * 
11 months/Cycle 11  history, physical, vital signs, laboratory tests * 
12 months/Cycle 12  history, physical, vital signs, laboratory tests 
13 months/Cycle 13  perform thoracic CT and bone scan within 14 days after the last 
dose  
 
DISCONTINUE oral therapy of saracatinib or placebo after 
thirteen 28-day cycles (364 days of therapy) **** 
 
 
15 months 
history, physical, vital signs * 
18 months 
history, physical, vital signs, laboratory tests 
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thoracic CT 
21 months 
history, physical, vital signs * 
24 months 
history, physical, vital signs, laboratory tests 
 
thoracic CT 
30 months 
history, physical, vital signs * 
36 months 
history, physical, vital signs, laboratory tests 
 
thoracic CT 
 
Laboratory tests are as follows: 
• white blood cell count with differential 
• hemoglobin and hematocrit 
• platelet count 
• sodium, potassium, chloride, bicarbonate, blood urea nitrogen, creatinine, glucose 
• calcium, magnesium, phosphorus 
• ALT, AST, total bilirubin,  
• alkaline phosphatase, lactate dehydrogenase, total protein, albumin 
 
 
* At the discretion of the treating physician, these visits do not need to be performed at 
the study center.  However, a document containing the interim history, physical 
examination, weight and height, vital signs, laboratory tests, and CT scan results when 
appropriate, must be sent to the treating physician at the study center as soon as they are 
available. 
 
** The purpose of the two additional thoracic CT scans is to monitor for interstitial lung 
disease, which has been seen in 2% of patients taking saracatinib.  If there is any 
suspicion of interstitial lung disease on any CT scan, the patient must undergo high-
resolution CT imaging to exclude interstitial lung disease.  Any evidence of interstitial 
lung disease will lead to removal of the patient from the study (defined in the Exclusion 
Criteria in Section 2.1.2.f).  The suggested parameters for the high-resolution thoracic CT 
scan are as follows: position (supine), slice thickness (≤1.25 mm), slice spacing (10 mm), 
start location (10 mm below the apices), end location (10 mm above the costophrenic 
angles). 
 
*** Previous studies have not demonstrated prolonged QTc intervals in patients treated 
with saracatinib.  A 12-lead EKG should be obtained after the patient has rested in a 
supine position for at least five minutes.  The treating physician should review the EKG.  
Any abnormality of clinical significance should result in medical management of the 
patient as clinically indicated.  The abnormality should be reported as an adverse event or 
a serious adverse event (see Section 7.2). 
 
**** Saracatinib or placebo will be discontinued after thirteen 28-day cycles (364 days) 
of therapy.   
 
 
3.5 
Concurrent Therapies 
 
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Chemotherapeutic agents, radiation therapy, immunotherapy or investigational anti-
cancer agents cannot be administered to patients enrolled on this protocol.  If these 
therapies are administered, the patient will be removed from the study. 
 
 
3.5.1 Surgical Guidelines 
 
Surgery will play an important role in the management of patients enrolled on this 
protocol.  Only patients who have been fully resected, or who are deemed fully 
resectable, will be eligible to enroll.  The surgical oncologist will determine the approach 
for resection.  Oral therapy with saracatinib or placebo will begin following complete 
resection of all recurrent lung nodules.  For patients with bilateral disease who require 
staged thoracotomies, oral therapy will begin only after the second thoracotomy and only 
if all nodules have been resected.  Patients who recur in the lung while on study and who 
are thought to be amenable to complete surgical resection will be unblinded.  Those 
patients who were receiving placebo may then have the option of undergoing surgical 
resection.  If fully resected, they will be given the option to begin oral therapy with 
Saracatinib.   
 
Biological studies to determine the etiology of recurrent osteosarcoma are an important 
component of this protocol.  Prior to any surgery, every attempt should be made to insure 
that the tumor sample is handled properly, so that all of the studies can be performed (see 
Sections 3.6.1 and Operations Manual). 
 
 
3.6 
Biological Studies 
 
 
All institutions will send fresh frozen tissue, a corresponding H+E slide, and a blood 
sample for microarray and sequencing analysis from biopsy and/or time of surgery for 
patients who have consented, if available (see Sections 3.6.1, 3.6.4, and Operations 
Manual).  Other biological studies will be performed only at the NIH (see Sections 3.6.2 
and 3.6.3). 
 
The molecular changes that underlie tumorigenesis have been well studied in many tumor 
types due to the availability of tumor samples.  For pediatric cancers such as leukemia 
and neuroblastoma, this has resulted in a dramatic improvement in overall survival and 
marked decrease in treatment related toxicities.  The latter is a direct consequence of 
molecular studies that have resulted in the ability to stratify patients into high-risk, 
standard-risk and low-risk groups.  Overall survival rates in osteosarcoma have also 
increased remarkably in the last 40 years.  However, the identification of biological and 
genetic surrogates for prognosis, progression and metastasis has been lacking.  One of the 
major reasons for this has been the overwhelming use of neo-adjuvant chemotherapy to 
treat patients.  Initial biopsy samples are so small that the entire sample is usually needed 
for diagnosis.  Samples taken at the time of definitive surgery are large.  However, very 
few samples contain high numbers of viable tumor cells due to the effects of 
chemotherapy, and many times the sample consists only of a dense non-cellular stroma.  
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This has greatly hindered the ability to study molecular changes associated with 
osteosarcoma. 
 
The tumor samples that we expect to analyze will form the largest collection of recurrent 
osteosarcoma patient samples that have not been subjected to any form of therapy.  Many 
of the studies we have planned can only be performed if the sample is freshly frozen.  We 
therefore request, that treating physicians use the guidelines in this protocol for sample 
preparation and shipping whenever possible (see Operations Manual). 
 
 
3.6.1 Microarray Analysis 
 
The expression pattern of genes in tumors can provide a wealth of knowledge, especially 
when they are tied to outcome data.  Microarray analysis makes it possible to study the 
expression of tens of thousands of transcripts.  This study will provide the opportunity to 
increase the biological data for patients with osteosarcoma.  Specifically, the large 
number of untreated samples will make it easier to identify a gene signature to predict for 
recurrence of osteosarcoma.  In addition, the outcome of patients, irrespective of whether 
they received saracatinib or placebo, will also be known.  This allows for the possibility 
of determining an additional gene signature that predicts for survival.  Understanding 
gene signatures using a large population will help elucidate the pathophysiology of 
recurrent osteosarcoma and may lead to improvements in the treatment of this disease. 
 
In general, the methodology relies on preparation of RNA, followed by cDNA.  
Fluorescent labeling followed by hybridization to a DNA chip allows for quantitative 
scanning for hybridized complexes.  The complexity and density of the microarray chips 
is increasing exponentially, as are the software programs used to analyze these large 
result files.  Therefore, specifics of this experiment will not be addressed, since the 
technology may improve markedly prior to the point that samples are available for 
analysis. 
 
For all patients who have consented, samples will be collected, consisting of flash frozen 
tumor (see Operations Manual, for preparation and shipping instructions) and a 
corresponding H+E slide.  In addition, peripheral blood will also be collected for the 
preparation of normal DNA from leukocytes.  These assays will be performed at the NCI 
under the guidance of Dr. Paul Meltzer.  To maintain the integrity of the blind, at no 
point, will clinical investigators have access to the results of these studies. 
 
 
 
 
 
3.6.2 Biomarkers Related to Activation of Src and Src Substrates 
 
For patients who are treated at the NIH, immunohistochemistry will be utilized to study 
the expression of Src and phosphorylated Src in tumor samples.  More importantly, the 
downstream targets of Src will also be examined.  These include FAK and paxillin and 
their phosphorylated forms. Samples will consist of paraffin blocks of tumor tissue.  The 
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assay will be performed under the direction of Dr. Mark Raffeld at the NCI.  To maintain 
the integrity of the blind, at no point, will clinical investigators have access to the results 
of these studies. 
 
 
3.6.3 Establishment of Cell Lines and Murine Xenografts 
 
For patients who are treated at the NIH, the establishment of cell lines and murine 
xenografts will be attempted when there is a sufficient amount of tumor sample.  Cell 
lines are a valuable reagent that allow for in vitro and in vivo experiments.  These cell 
lines can be targeted for introduction of exogenous DNA sequences or disruption of 
endogenous DNA sequences, allowing investigators to verify that distinct genetic 
changes are causative for tumor progression and metastases.  The paucity of human 
osteosarcoma cell lines testifies to the difficulty in establishing them.  In addition, only a 
handful of osteosarcoma cell lines that grow in cell culture form primary tumors in 
immunocompromised mice. 
 
The successful generation of a cell line requires immediate processing of the sample.  At 
the NIH, as soon as a surgical sample is removed from the operating room, a pathologist 
places the sample in media and delivers it to a laboratory technician who has expertise in 
tissue culture.  The sample is minced and added to a tissue culture flask and allowed to 
propagate.  Overgrowing fibroblasts are allowed to grow and detach as they become 
over-confluent.  In several instances, osteosarcoma cells begin to grow rapidly, but this 
may take up to one year of tissue culture. 
 
Another useful reagent is a primary tumor that forms following surgical implantation of 
tumor fragments into immunocompromised mice.  At the NIH, a protocol has been 
approved by the animal care committee, allowing for such studies.  Tumor samples will 
be minced and added to a tissue culture flask containing tissue culture media for 
overnight propagation.  The following day, tumor samples will be surgically implanted in 
the area of the tibia.  In several instances, a primary tumor will form at the implantation 
site.  Although it will be impossible to determine the type of treatment that a patient is 
receiving based these results, at no point will clinical investigators have access to the 
results of these studies. 
 
 
3.6.4 Sequencing Analysis 
 
Technology is improving so rapidly, that we now have the capability to perform 
sequencing analysis with the samples that are left over following microarray analysis (see 
section 3.6.1).  In addition to RNA, DNA will also be prepared after comparison to an 
H+E slide of the corresponding tumor.  We will then perform transcriptome sequencing, 
exon re-sequencing and mate-pair end sequencing, allowing us to detect translocations.  
The availability of matched normal DNA in the blood will allow us to determine which 
changes are unique to the tumor.  The rapid improvements in genomic sequencing 
technology makes it impossible to predict what will be the state of the art methodology at 
the time that the samples are actually tested.  Therefore, specifics of this experiment are 
not addressed. 
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These tests will be performed for research purposes.  All samples will be de-identified 
prior to submission.  Although it is impossible to determine the type of treatment that a 
patient is receiving based on these results, to maintain the integrity of the blind, at no 
point will clinical investigators have access to the results of these studies.  The results of 
these tests will not be divulged to the patient or any physician who is involved in clinical 
care. 
 
 
3.7 
Off Study Criteria 
 
 
3.7.1 Definition of Disease Progression 
 
Disease progression is defined as recurrence of osteosarcoma based on radiographic 
evidence or histologic verification of the recurrent lesion.  Disease progression is one of 
the criteria that results in removal from the protocol. 
 
Patients who recur in the lung while on study and who are thought to be amenable to 
complete surgical resection will be unblinded.   
 (see Section 7.4.2). 
 
Those who were receiving Saracatinib will be taken off study due to disease progression. 
 
Those patients who were receiving placebo, whose recurrence is localized to the lung and 
who are thought to be completely resectable, will be offered the option of undergoing 
further surgery followed by therapy with Saracatinib (see Section 3.2.6). 
 
The only curative therapy for patients who have progression of disease, which in this 
case, is recurrence of tumor, while on saracatinib or placebo, is surgical resection of all 
recurrent nodules.  Therefore, every attempt at complete surgical resection should be 
attempted in any patient who progresses/recurs.  Biological analysis of these tumor 
samples may prove very informative in determining the etiology of osteosarcoma 
recurrence.  Therefore, at the time of surgery every attempt should be made to send the 
recurrent tumor sample for biological studies (see Operations Manual). Blood sample for 
microarray analysis should be collected at time of recurrence only if it was not obtained 
at baseline.  Even though patients who were receiving Saracatinib will be off study due to 
disease progression, if the patient consents the recurrent tumor sample should still be 
collected for biological studies if possible. 
 
The date that the patient is randomized will be used as the starting date for measurements 
of overall survival, progression free survival and time to treatment failure.  For cross-over 
patients, the date that Saracatinib is started will be used as the starting date for 
measurements of overall survival, progression free survival and time to treatment failure.  
Progressive disease will be defined as recurrence of osteosarcoma based on radiographic 
evidence of recurrent nodules.  In many cases, initial radiographic scans may not provide 
clear evidence of recurrence, especially if an infectious etiology is also possible.  Once 
recurrence is verified, either by conclusive radiographic evidence or by histologic 
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diagnosis, the earliest date of the abnormal radiologic finding will be used as the ending 
date for measurement of progression free survival and time to treatment failure.  Any 
adverse event that results in discontinuation of either saracatinib or placebo will be 
considered a treatment failure.  This includes toxicity, disease progression or death.  The 
time to treatment failure will begin on the day of randomization, and end on the day of 
discontinuation of either saracatinib or placebo. 
 
 
3.7.2 Criteria for Removal from Protocol 
 
Patients will be taken off study for any of the reasons listed below.  The reason for 
removal from the protocol must be noted in that patient's medical record, the case report 
form and the SARC Operations Office must be notified. 
 
SARC Research Project Manager 
24 Frank Lloyd Wright Dr. 
PO Box 406 
Lobby A, 3rd Floor, Suite 3100 
Ann Arbor MI, 48105 
Phone: 734-930-7600 
Fax: 734-930-7557 
Email: sarc@sarctrials.org 
 
 
Criteria for Removal from Protocol: 
 
Administrative 
• 
Protocol violations, such as non-compliance with treatment, or required 
follow-up evaluation, as determined by the Principal Investigator (Contact 
SARC for non-compliance issues; study PI will review on a case-by-case 
basis) 
• 
Refusal of further treatment or withdrawal of consent by the patient 
• 
Patient is lost to follow-up 
 
 
Medical 
• 
Patients with radiographic or histologic evidence of disease progression who 
were receiving Saracatinib (see section 7.4.2) 
• 
All patients with radiographic or histologic evidence of disease progression 
that is not confined to the lung(s) 
• 
Patients with radiographic or histologic evidence of disease progression who 
were receiving placebo and are not amenable to surgical resection 
• 
If the treating physician decides that it is in the best interest of the patient to 
be taken off the study 
• 
Development of any concurrent medical condition that might preclude or 
contra-indicate the further administration of saracatinib/placebo 
• 
Pregnancy 
• 
Death 
 
 
 
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Toxicity 
• 
Life threatening toxicity as a result of saracatinib/placebo 
• 
Patients who have persistent toxicity despite appropriate dose modifications 
• 
Any unacceptable toxicity in the opinion of the Principal Investigator 
 
Patients who are taken off study will continue to be monitored for survival determination, 
annually by contacting the referring/treating physician, for the duration that this study is 
open or a maximum of 3 years follow up. 
 
 
3.8 
Post-Study Evaluation 
 
 
The following tests or procedures should be performed, if possible, at the time a patient is 
taken off of the study, regardless of the reason, unless the test or procedures have been 
performed within a period of four weeks. 
 
• Physical examination 
• ECOG performance status 
• Assessment of clinical toxicity or adverse events 
• Radiologic evaluation of progressive disease 
• Laboratory studies 
• white blood cell count with differential 
• hemoglobin and hematocrit 
• platelet count 
• sodium, potassium, chloride, bicarbonate, blood urea nitrogen, creatinine, glucose 
• calcium, magnesium, phosphorous 
• ALT, AST, total bilirubin 
• alkaline phosphatase, lactate dehydrogenase, total protein, albumin 
 
 
4 
Supportive Care 
 
 
4.1 
General 
 
 
The appropriate surgical care, antibiotics, blood product support and general supportive 
care measures will be administered by the treating physician, as clinically indicated. 
 
 
4.2 
Management of an Overdose with Saracatinib 
 
 
There is no known antidote for saracatinib and management of overdose should consist of 
symptomatic and supportive treatment.  In view of the slow absorption rate of saracatinib, 
measures such as gastrointestinal lavage or administration of an emetic agent such as 
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activated charcoal or Ipecac syrup may be helpful if a patient is seen within two hours of 
taking an overdose. 
 
Should an overdose occur, it must be recorded in accordance with the procedures 
described (see Section 7.2) regardless of whether the overdose was associated with any 
symptoms or not.  All symptoms associated with the overdose should be recorded as 
adverse events.  Oral therapy with saracatinib or placebo will re-commence at a time 
decided by the treating physician. 
 
 
4.3 
Procedures in Case of Pregnancy 
 
 
All patients must use adequate contraception during the study.  However, should 
pregnancy occur, the patient will be removed from the study.  Patients will be advised 
that the possible effects of saracatinib on the fetus are unknown. 
 
Rodent reproductive toxicology studies have found that the administration of saracatinib 
resulted in effects on embryonic survival and fetal malformations at dose levels that were 
similar or lower than those likely to be achieved in humans.  Some of the malformations 
included anophthalmia, microphthalmia, aglossia, micrognathia, cleft palate, kinked tail 
and hind paw hyperextension (33). 
 
Should a pregnancy occur, it must be recorded in accordance with the procedures 
described (see Section 7.2).  Pregnancy in itself is not regarded as an adverse event, 
unless there is a suspicion that an investigational product may have interfered with the 
effectiveness of a contraceptive medication. 
 
 
4.4 
Respiratory Care 
 
 
As described previously (Section 1.2.8), four adult patients developed pulmonary adverse 
events, possibly due to concurrent treatment with saracatinib.  The development of any 
pulmonary symptom, no matter how minimal it may be, must be investigated 
immediately.  Patients who have cough or slight discomfort in association with an upper 
respiratory infection may be monitored clinically, if the symptoms resolve or improve 
within a period of seven days. 
 
Any patient who develops a pulmonary symptom, or has worsening of symptoms, will 
undergo thoracic CT as soon as possible.  Pulmonary symptoms include, but are not 
limited to the following: cough, dyspnea, pain, hemoptysis, or oxygen saturation <94%.  
Oral therapy will be stopped immediately and the algorithm below should be followed. 
 
 
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*CT scan of thorax to be performed with slice thickness < 5mm 
*HRCT scan recommended parameters: 
 
 
position  
supine 
 
 
 
 
slice thickness 
≤1.25 mm 
 
 
 
 
slice spacing 
10 mm 
 
 
 
 
start location 
10 mm below the apices 
 
 
 
 
end location  
10 mm above costophrenic angles 
 
 
4.5 
List of Contra-Indicated Medications 
 
 
Saracatinib is substrate of CYP3A4 in humans.  There are many drugs that either inhibit 
or induce CYP3A4 metabolism.  This may result in increased or decreased exposure to 
saracatinib.  The following tables list the drugs that are contra-indicated.  In addition, the 
tables also list the minimum time period that the contra-indicated drug must be stopped, 
prior to the initiation of oral therapy with saracatinib or placebo. 
 
 
Potent CYP3A4 inhibitors (may result in a 3-fold increase in exposure to saracatinib) 
 
 
If any of the following (cough, dyspnea, new pulmonary radiologic abnormality) occur 
or worsen while on study and cannot categorically be clinically ascribed to a cause 
other than saracatinib dosing, then 
Interrupt saracatinib dosing 
 
Perform a *CT scan of the thorax 
Consider *HRCT if necessary to rule out interstitial lung disease 
(defined as bilateral, diffuse, parenchymal lung disease) 
 
 
 
 
 
 
CT scan of the thorax 
DOES NOT show interstitial lung disease 
(bilateral, diffuse, parenchymal lung disease) 
CT scan of the thorax 
DOES show interstitial lung disease 
(bilateral, diffuse, parenchymal lung disease) 
Consider re-commencing saracatinib dosing 
 
Permanently discontinue saracatinib dosing 
 
Begin appropriate management 
(Consider initiation of steroid therapy if non-
drug related etiologies have been excluded) 
(Referral to a pulmonologist is recommended) 
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Contraindicated Drugs 
 
Minimum period of discontinuation 
Diltiazem 
14 days 
Clarithromycin (250 mg or 
500 mg bid) 
  7 days 
Erythromycin 
  7 days 
Fluconazole 400 mg 
- lower doses (200 mg and 
  100 mg) are allowed 
  7 days 
Itraconazole 
  7 days 
Voriconazole 
  7 days 
Ketoconazole 
  7 days  
Indanavir 
  2 days 
Nefazodone 
  2 days 
Ritonavir 
  2 days 
Saquinavir 
  2 days 
 
 
Potent CYP3A4 inducers (may result in a 3-fold decrease in exposure to saracatinib) 
 
 
Contraindicated Drugs 
 
Minimum period of discontinuation 
Barbiturates 
14 days 
Carbamazepine 
14 days 
Phenytoin 
14 days 
Rifabutin 
14 days 
Rifampicin 
14 days 
St John's Wort 
14 days 
 
 
 
 
Saracatinib is a moderate inhibitor of CYP3A4 in humans.  There are many drugs that are 
CYP3A4 substrates.  Therefore, patients who are receiving saracatinib may have 
increased exposure, pharmacological action or toxicity to CYP3A4 substrate medications 
due to inhibition of CYP3A4 by saracatinib.  The following table lists the drugs that are 
contra-indicated.  In addition, the table also lists the minimum time period that the contra-
indicated drug must be stopped, prior to the initiation of oral therapy with saracatinib or 
placebo. 
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Contraindicated Drugs 
 
Minimum period of discontinuation 
Carbamazepine 
14 days 
Alfentanil 
  7 days 
Cyclosporin 
  7 days 
Tacrolimus 
  7 days 
Atorvastatin 
  7 days 
Lovastatin 
  7 days 
Simvastatin 
  7 days 
 
In addition, all of the medications listed above should not be restarted until 14 days after 
the last dose of oral therapy with saracatinib or placebo.  They should never be restarted 
as long as the patient remains on oral drug therapy.  
 
 
4.6 
Use of Concomitant Medications 
 
 
The following table is a list of medications that are moderate inhibitors of CYP3A4.  It is 
possible that the concomitant use of these items may result in an increase in exposure to 
saracatinib.  If possible, these medications should be avoided.  However, they are not 
contra-indicated, but care must be taken to monitor closely for possible drug interactions.   
 
 
Moderate CYP3A4 inhibitors (may result in an increase in exposure to saracatinib) 
 
 
Drugs with possible interactions 
 
 
Fluconazole (200 mg or 100 mg) 
- 400 mg is contraindicated 
Monitor closely 
Verapamil 
Monitor closely 
Nelfinavir 
Monitor closely 
 
 
 
The following table is a list of medications that are CYP3A4 substrates, but are allowed 
to be taken in conjunction with oral therapy with saracatinib or placebo.  Again, when at 
all possible, these drugs should be avoided, due to the possibility of increased exposure to 
these drugs.  The following is a list of some medications that may be affected by 
saracatinib that may be more commonly used in this study population. 
 
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Drugs with possible interactions 
 
 
Alprazolam 
Midazolam 
Triazolam 
Monitor closely 
Felodipine 
Isradipine 
Nifedipine 
Other calcium antagonists 
Monitor closely 
Methylprednisolone 
Monitor closely 
Pimozide 
Monitor closely 
Quinidine 
Monitor closely 
 
This list is by no means complete.  Treating physicians should determine the toxicity and 
interaction profile of all medications that her/his patient is taking. 
 
 
4.7 
List of Contra-Indicated Foods 
 
 
The following is a list of food products that are moderate inhibitors of CYP3A4.  It is 
possible that the concomitant use of these items may result in an increase in exposure to 
saracatinib.  The following food products must not be taken while the patient is on study: 
grapefruits, grapefruit juice, star fruits, Seville oranges (also known as Chinese Bitter 
Oranges) and Seville orange marmalade. 
 
 
5 
Data Collection and Evaluation 
 
 
5.1 
Data Collection 
 
 
This is a multi-institutional study.  The data from all participating institutions will be 
stored electronically at the Michigan Institute for Clinical and Health Research (MICHR) 
Specific forms for registration, adverse event reporting, non-adverse event data 
collection, and documentation of shipment and receipt of biological specimens will be 
developed by SARC and the study Principal Investigator.  The data manager at 
participating institutions will complete these online forms.  Patients will be identified by 
their unique patient identification number on these forms.  Only persons directly involved 
in this clinical trial will have access to the data stored at MICHR. 
 
Electronic case reports are available at: https://velos.med.umich.edu/eres/jsp/ereslogin.jsp 
 
Please contact the SARC Operations Office with any questions. 
 
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SARC Research Project Manager 
24 Frank Lloyd Wright Dr. 
PO Box 406 
Lobby A, 3rd Floor, Suite 3100 
Ann Arbor MI, 48105 
Phone: 734-930-7600 
Fax: 734-930-7557 
Email: sarc@sarctrials.org 
 
Required forms should be submitted electronically within two weeks of the required visit 
(see Section 3.4).  The SARC Research Project Manager will review the receipt of all 
required forms and contact any institution directly if data entry is delinquent. 
 
In addition to electronic data submission, participating institutions will print copies of 
completed forms, which will be kept with source documentation, in the patient study 
binder. 
 
 
5.2 
Toxicity Criteria 
 
 
Toxicity will be graded according to the CTEP CTCAE version 3.0 for toxicity and 
adverse event reporting.  A copy of the Common Terminology Criteria for Adverse 
Events Version 3.0 (http://ctep.cancer.gov/forms/CTCAEV3v3.pdf) is available and is 
included in the study database.  All appropriate treatment areas should have access to a 
copy of this document.  Dose modifications will be made based upon the parameters 
defined previously (see Section 3.3.1). 
 
 
5.3 
Statistical Considerations 
 
 
The primary goal of this study is to determine whether the addition of saracatinib to 
surgery will result in an improvement in progression free survival (PFS).  The sample 
size will be based on being able to detect a 60% relative improvement (from 33% to 
53%) in PFS probability at two years.  The current 2-year PFS probability is 33%, when a 
second surgical complete remission is achieved (3).  Assuming exponential survival 
curves, the hazard rate corresponding to this 2-year PFS probability for the control arm is 
0.0462, which is defined as approximately a 0.0462 probability of failing each month 
when the 2-year PFS probability is 33%.  If we assume that the 2-year PFS probability 
may be 53% for the saracatinib arm, the hazard is 0.0265, which then results in a hazard 
ratio of 1.75.  Forty-four patients will need to be randomized in each arm of the study, for 
a total of 88 patients, over a 48-month accrual period.  Follow-up of the last patient 
randomized must continue for an additional year.  Since this study follows a phase II.5 
design (35), this provides 80% power to detect a difference between the two resulting 
actuarial curves with a one-sided 0.10 alpha level log-rank test. 
 
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A secondary goal of this study is to determine whether the addition of saracatinib to 
surgery will result in an improvement in overall survival (OS).  The sample size selected 
to evaluate PFS will also be adequate to detect a 56% relative improvement (from 45% to 
70%) in OS probability at three years.  The current 3-year OS probability is 45%, when a 
second surgical complete remission is achieved (3).  Assuming exponential survival 
curves, the hazard rate corresponding to this 3-year OS probability for the control arm is 
0.0222, which is defined as approximately a 0.0222 probability of failing each month 
when the 3-year OS probability is 45%.  If we assume that the 3-year OS probability may 
be 70% for the saracatinib arm, the hazard is 0.0099, which then results in a hazard ratio 
of 2.24.  Evaluation of the 88 patients who are randomized, over the same time frame, 
will provide 85% power to detect a difference between the two resulting actuarial curves 
with a one-sided 0.10 alpha level log-rank test. 
 
As explained in section 3.2.6, a subset of patients who recur while receiving placebo will 
be given the opportunity to receive saracatinib. Since patients on both arms will have 
received this agent, although at different times in the natural history of their disease, this 
may result in a lessening of the difference in survival between the arms compared to the 
case when only patients on one arm received the agent. However, since development of a 
recurrence may still be associated with overall survival duration, the magnitude of the 
impact may be limited.  
 
An additional secondary goal is to determine if the addition of saracatinib to pulmonary 
metastasectomy, versus placebo and pulmonary metastasectomy, results in an increase in 
the time to treatment failure (TTF).  Any adverse event that results in discontinuation of 
either saracatinib or placebo will be considered a treatment failure.  This includes 
toxicity, disease progression or death. 
 
Again, the randomized nature of the Phase II.5 study will allow us to determine the actual 
2-year PFS and 3-year OS rates in patients who receive surgery and placebo, or surgery 
in combination with saracatinib. 
 
Patients will be stratified based on the following criteria: 
 
Number of Recurrences: FIRST versus SECOND versus THIRD or MORE 
 
Number of Recurrent Nodules: ONE or TWO versus THREE or MORE 
 
The date that the patient is randomized will be used as the starting date for measurements 
of overall survival, progression free survival and time to treatment failure.  Progressive 
disease will be defined as recurrence of osteosarcoma based on radiographic evidence or 
histologic verification of the recurrent lesion. 
 
At the first annual opportunity following the point at which 20 patients per arm have been 
randomized (40 total) and potentially followed for at least 12 months, an interim 
evaluation for futility will be performed.  
 
The futility evaluation will be performed as follows.  Based upon the full data available at 
that time, a conditional power analysis will be performed to determine if the trial is 
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unlikely to find an effect at the 0.10 one-sided level with continued accrual, based on the 
PFS endpoint.  Since the goal is to detect a difference between two year PFS of 33% and 
53%, an early evaluation will be performed based on the binomial probabilities at the 12-
month point, which reflect the same objective.  A PFS of 33% at 2 years would be 
equivalent to a 1 year PFS of 57.4% and a PFS of 53% at two years is equivalent to a 1 
year PFS of 72.8%.  Using these as the values under the alternative, and using the actual 
proportions without progression at 1 year based on the observed fractions based on the 
expected sample size at 1 year, the conditional power of the trial assuming accrual of 
however many patients would remain to be entered will be computed.  If the conditional 
probability of finding a difference at the one-sided 0.10 level at the end of the trial is less 
than 20%, then it will be reasonable to recommend that no further patients will be 
enrolled.  Alternatively, an evaluation based on exponential distribution of PFS may be 
substituted for the binomial evaluation. 
 
At the first annual point after which 30 patients per arm (60 total) have been accrued and 
potentially followed for at least 12 months, a very stringent interim monitoring rule will 
be used to determine if superiority is identified early.  If at this single interim efficacy 
evaluation for superiority, the log-rank p-value for the difference (one-tailed) is <0.001, 
then accrual will stop.  Otherwise, enrollment will continue as planned. 
 
 
5.3.1 Patient Randomization 
 
Details of patient randomization are described in the Operations Manual. 
 
Dr. Seth Steinberg, the NCI statistician, will generate randomization assignment sheets.  
The sheets will be based on a stratified randomization, which will be created using 
software that generates randomized blocks of varying sizes as directed by Dr. Steinberg.  
He will provide these sheets directly to the SARC Operations Office, where they will be 
maintained in a confidential manner.   
 
After the patient is registered and enrolled electronically by the site through the SARC 
study website, the site will contact the SARC Operations Office to obtain patient 
randomization treatment assignment. 
 
The site pharmacy will be notified of the assigned randomization treatment (i.e. 
saracatinib or placebo). After confirmation of receipt of treatment assignment by the site 
pharmacy, labeled, blinded medication will be dispensed for the patient.  This will consist 
of saracatinib in 125 mg and 50 mg tablets, or placebo 125-like and 50-like tablets, in 
accordance with the protocol. 
 
The randomization assignment should be kept confidential and should not be shared with 
the treating physician(s) or any other site team staff involved in the care of the patient, 
except in the event of a medical emergency where unblinding is necessary for patient care 
(see section 7.4) or for disease recurrence (see section 7.4.2) 
 
 
 
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5.4 
Multi-Institutional Guidelines 
 
 
The trial coordinating center will be SARC.  Patients will be registered electronically via 
the study website (see Section 2.3) and adverse events (see Section 7.2) will be reported 
to SARC. 
 
SARC Research Project Manager 
24 Frank Lloyd Wright Dr. 
PO Box 406 
Lobby A, 3rd Floor, Suite 3100 
Ann Arbor MI, 48105 
Phone: 734-930-7600 
Fax: 734-930-7557 
Email: sarc@sarctrials.org 
 
 
5.4.1 IRB Approvals 
 
The protocol must be approved at the participating institution prior to enrolling patients.  
Documentation of individual institutional IRB approval for the current protocol must be 
sent to SARC along with IRB approved consent. 
 
 
5.4.2 Amendments and Consents 
 
Institution informed consent form must be sent to SARC for review and approval prior to 
submission to their IRB.  All amendments must be submitted to institutional IRB for 
review and approval.  Documentation of approval of amendments and of yearly 
continuing review must be sent to SARC to permit site continued enrollment and 
treatment of patients on this study.   
 
5.4.3 Data Collection and Toxicity Reporting 
 
Weekly registration and reports will be generated by SARC to monitor patient accrual 
and completeness of registration data.  Routine data quality reports will be generated to 
assess missing data and inconsistencies by the Research Project Manager at SARC. 
 
A monthly telephone conference will be held between the study Principal Investigator 
and the research project manager at SARC to address any issues that arise pertaining to 
this study.   
 
Unexpected CTCAEv3 grade 3 or grade 4 toxicities (see Section 8.1.5 for known 
toxicities of saracatinib) and all grade 5 toxicities must be reported to the research project 
manager at SARC within 24 hours of the occurrence (see Section 7.3.1).  All serious 
adverse events will be submitted to the National Heart, Lung and Blood Institute 
(NHLBI) IRB (see Section 7.3.2). 
 
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5.4.4 Data and Participating Institution Audits 
 
SARC research project manager will review data entered into the electronic data capture 
system on a weekly basis and generate queries as needed.  No on site audit will be 
performed for this study. Selected source documents will periodically be requested by 
SARC for verification of data entered into the electronic data capture system.  All source 
documents submitted to SARC will be marked with the patient initials and patient unique 
study number.  All other patient identifiers will be redacted.   
 
 
5.5 
Data and Safety Monitoring Plan 
 
 
The SARC Executive Committee will convene monthly via teleconference to review with 
the study principal investigator the study accrual, adverse events, serious adverse events, 
protocol violations and/or deviations.  Data provided to this committee will be blinded as 
to the treatment arm for the events reported.  Any concerns related to patient safety will 
be referred to the NCI DSMB as they will have access to unblinded data.  
 
A NCI-created DSMB will monitor this trial for toxicity, as well as clinical endpoints 
relative to early termination, in its annual meetings.  As noted above (see Section 5.3), 
clinical evaluations of endpoints will be formally evaluated beginning after 40 to 60 total 
patients have accrued and potentially followed for 12 months. 
 
 
 
6  
Human Subjects Protections 
 
 
 
6.1 
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 (see Section 2.1).  No groups are being excluded from 
participation in this trial.  To date, there is no information that suggests differences in the 
effectiveness of saracatinib between genders or among racial or ethnic groups in any 
patient with cancer, indicating that the results of this trial will be applicable to all groups.  
Efforts will be made to extend the accrual to a representative population.  Patients with 
recurrent osteosarcoma are rare and our hope is to enroll every patient in the United 
States.  Since recurrent osteosarcoma affects both genders and all racial and ethnic 
groups, almost equally, this trial should be composed of a representative population.  All 
participating institutions will need to have IRB approval prior to registering a subject for 
this trial. 
 
 
6.2 
Participation of Children 
 
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Pediatric subjects >15 years of age are eligible for this trial.  Patients with recurrent 
osteosarcoma are typically adolescents or older.  Until the safety/efficacy of this 
approach is established, children <15 years of age will not be included in this study.   
 
 
 
6.3 
Evaluation of Benefits and Risks/Discomforts 
 
 
The primary risk to patients participating in this research study is from toxicity of 
anticancer drugs and the agents used to alleviate the toxicities of the anticancer drugs.  
For patients with recurrent osteosarcoma, there is no salvage regimen that offers a good 
response rate.  The current standard of care is to resect all recurrent nodules, if this is 
possible.  The primary objective of this study is to assess the ability of saracatinib, versus 
placebo, to increase progression free survival in patients who have undergone complete 
resection of recurrent nodules.  Saracatinib has been tolerated in patients with advanced 
cancers, but it is still an investigational agent.  As such, an additional risk to patients 
participating in this trial may be that saracatinib may have an increased incidence of side 
effects.  Potential benefits for patients who participate in this study include a possible 
increase in progression free survival.  Since the standard of care is surgical resection, 
patients who are randomized to receive placebo, will be receiving the standard of care. 
 
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 any reports or publications concerning this study.  Patient records may be 
inspected by auditing agencies, including the NCI, the FDA, SARC (the study sponsor) 
and AstraZeneca (the distributor of saracatinib) to satisfy regulatory requirements. 
 
 
6.4 
Risks/Benefits Analysis 
 
 
This 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 to improve progression free survival.  Therefore, this protocol involves greater than 
minimal risk to subjects, but presents the potential for direct benefit to individual 
subjects.   
 
 
6.5 
Consent and Assent Processes and Documentation 
 
 
A signed informed consent document will be obtained prior to entry onto the study.  The 
investigational nature and research objectives of this trial, the procedures and treatments 
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involved and their attendant risks and discomforts and potential benefits, and alternative 
therapies will be carefully explained to the patient and/or the patient’s parents or 
guardians if she/he is a child.  The investigators are requesting a waiver from the NCI 
IRB to allow only one parent or guardian to sign the informed consent to enter a child on 
the protocol.  Because many patients must travel to the NIH from long distances at 
substantial expense, requiring both parents to be present for the consent process may 
adversely impact other children at home and pose financial hardship due to loss of work-
related income.  Other participating centers will have patients in similar circumstances 
and may request a similar waiver from their IRB. 
 
The institutional Principal Investigator, or their designee, will meet with the patient, or 
the patient’s parents or guardian, and other family members, to discuss the protocol 
treatment and alternative options.  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 if necessary.  The institutional Principal Investigator, or their designee, 
will then obtain consent from the patient.  For patients who are <18 years of age, where 
deemed appropriate by the clinician and the child’s parents or guardian, the child will 
also be included in all discussions about the trial and verbal or written assent will be 
obtained.  The parent or guardian will sign the designated line on the informed consent 
form attesting to the fact that the child has given assent. 
 
 
6.6 
Handling of Research Samples 
 
 
This study is being conducted and coordinated by SARC.  Collection of blood can occur 
any time prior to the first dose of oral therapy.  A blood specimen should be collected 
regardless of whether there is tissue to be submitted.  Collection of tumor tissue for 
research purposes will occur at the time the tumor is resected (see Sections 3.6.1 and 
Operations Manual).  A corresponding H+E should also be prepared and sent to the NIH.  
Every attempt will be made to obtain tissue samples and to combine the collection of 
research samples with the collection of specimens for clinical care purposes.  If there is 
not a tissue sample available the patient is still eligible to participate in the trial. 
Research specimens will be evaluated for the following: 
 
 
Microarray analysis (for all patients) 
 
Biomarkers related to activation of Src and Src substrates (for NIH patients) 
 
Establishment of cell lines and murine xenografts (for NIH patients) 
 
Sequencing analysis (for all patients) 
 
Samples will be transported in a manner that complies with current regulatory guidelines 
for transport of specimens.  All samples will be labeled with a protocol-specific patient 
tracking number that was generated for the patient at the time of randomization.  Sample 
labeling, collection and initial processing will be conducted as described in the 
Operations Manual.  Unintentional loss or destruction of any sample will be reported to 
the National Cancer Institute (NCI) IRB and the IRB of the responsible Institutional 
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Principal Investigator as part of annual continuing reviews.  Unexpected problems such 
as, but not limited to, natural disaster, equipment malfunction, and human error, will be 
reported to the IRB in written form.  Any use of these samples for purposes not described 
in this section will require prospective NCI IRB review and approval. 
 
For all fresh frozen tumor samples submitted, microarray studies and corresponding 
normal lymphocytes will be performed in the laboratory of Dr. Paul Meltzer (see Sections 
3.6.1 and Operations Manual for details).  Participating institutions are requested to send 
fresh frozen tissue, a corresponding H+E slide, and peripheral blood to the NIH.  Samples 
will be tracked and considered the responsibility of the Institutional Principal 
Investigator, until they are received by the designated recipient at the NIH.  Samples will 
then be logged into a database on a secured computer.  Tumor samples will be stored in a 
designated monitored -80°C freezer.  Peripheral blood will be processed for isolation of 
white blood cells which will then be stored in a designated monitored -80°C freezer 
associated with Dr. Paul Meltzer’s laboratory until analyzed.  After the samples have 
been analyzed and the results published, any remaining samples will be transferred 
anonymously to a research sample protocol.  To maintain the integrity of the blind, at no 
point, will clinical investigators have access to the results of these studies.  
 
For all fresh frozen tissue samples received from patients who are treated at the NIH, 
activation of Src and Src substrates will be determined by immunohistochemistry in the 
laboratory of Dr. Mark Raffeld (see Sections 3.6.2 for details).  Samples will be logged 
into a database on a secured computer, and stored at room temperature and secured in Dr. 
Mark Raffeld’s laboratory.  After the samples have been analyzed and the results 
published, any remaining samples will be transferred anonymously to a research sample 
protocol.  To maintain the integrity of the blind, at no point, will clinical investigators 
have access to the results of these studies. 
 
For all tissue samples received from patients who are treated at the NIH, tumor samples 
will be minced and cultured in media in an effort to obtain a stable cell line in the 
laboratory of Dr. Chand Khanna (see Sections 3.6.3 for details).  These samples will only 
be obtained if extra samples are available.  Sterile resection samples are sent to 
pathology.  After samples are sent for clinical analysis and other requirements of this 
protocol, any extra tumor samples will be added sterilely into a 50 cc conical tube 
containing 20 ml of tissue culture media.  The sample will be minced and added to a 
tissue culture flask containing tissue culture media.  Samples will then be logged into the 
NCI LabMatrix database on a secured computer.  Tissue culture samples will be 
propagated in a tissue culture incubator associated with Dr. Chand Khanna’s laboratory.  
In most cases, a cell line will not result and the sample will be destroyed.  In the rare 
event that a cell line does result, the cell line will be renamed in the following format 
(NCI-OST-last two digits of the year-random one digit check number).  The cell line will 
then be aliquoted and frozen in liquid nitrogen.  Two aliquots will be deposited with 
ATCC with only the renamed identifier and the following description: “recurrent 
osteosarcoma tumor isolated from the lung.”  At no point will any other clinical 
information be given to ATCC.  Although it will be impossible to determine the type of 
treatment that a patient is receiving based these results, at no point will clinical 
investigators have access to the results of these studies. 
 
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For all tissue samples received from patients who are treated at the NIH, tumor samples 
will be minced and injected into immuno-compromised mice to obtain xenografts in the 
laboratory of Dr. Chand Khanna (see Sections 3.6.3 for details).  These samples will only 
be obtained if extra samples are available.  Sterile resection samples are sent to 
pathology.  After samples are sent for clinical analysis and other requirements of this 
protocol, any extra tumor samples will be added sterilely into a 50 cc conical tube 
containing 20 ml of tissue culture media.  The sample will be minced and added to a 
tissue culture flask containing tissue culture media.  Samples will then be logged into the 
NCI LabMatrix database on a secured computer.  Tissue culture samples will be 
propagated overnight in a tissue culture incubator associated with Dr. Chand Khanna’s 
laboratory.  The following day, tumor samples will be surgically implanted in the area of 
the tibia.  In most cases, a primary tumor will not form and the mouse will be euthanized.  
In the rare event that a primary tumor does form, the resulting tumor will be renamed in 
the following format (XEN-OST-last two digits of the year-random one digit check 
number).  The tumor will be harvested, minced and frozen in liquid nitrogen.  Although it 
will be impossible to determine the type of treatment that a patient is receiving based 
these results, at no point will clinical investigators have access to the results of these 
studies. 
 
For all patients for whom frozen tissue is available, sequencing analysis of DNA and 
RNA from tumor samples and corresponding normal lymphocytes will be performed in 
the laboratory of Dr. Paul Meltzer.  This will include transcriptome sequencing, exon re-
sequencing and mate-pair end sequencing.  These studies will be performed on material 
that is left over following microarray analyses (see Sections 3.6.1, 6.6 and Operations 
Manual for details).  The logistics have been described previously. 
 
 
7 
Data Reporting 
 
7.1 
Patient Registration and Case Report Forms 
 
This is a multi-institutional study.  The data from all institutions will be stored in the 
database at the Michigan Institute for Clinical and Health Research (MICHR).  All case 
report forms (CRFs) should be filed electronically within two weeks of the scheduled 
visit 
 
Electronic case reports are available at: https://velos.med.umich.edu/eres/jsp/ereslogin.jsp 
 
Please contact the SARC Operations Office with any questions. 
 
SARC Research Project Manager 
24 Frank Lloyd Wright Dr. 
PO Box 406 
Lobby A, 3rd Floor, Suite 3100 
Ann Arbor MI, 48105 
Phone: 734-930-7600 
Fax: 734-930-7557 
Email: sarc@sarctrials.org 
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7.2 
Adverse Event Recording 
 
 
 
7.2.1 Definitions 
 
ADVERSE EVENT: An adverse event (AE) is any untoward medical occurrence associated 
with the use of a drug in humans, whether or not considered drug related.  An adverse 
event 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 the event is considered causally 
related to the use of the product.  Such an event can result from use of the drug as 
stipulated in the protocol or labeling, as well as from accidental or intentional overdose, 
drug abuse, or drug withdrawal.  Any worsening of a pre-existing condition or illness is 
considered an adverse event.   
 
Life-threatening adverse event or life-threatening suspected adverse reaction:  An adverse 
event or suspected adverse reaction is considered "life-threatening" if, in the view of 
either the investigator or sponsor, its occurrence places the patient or subject at 
immediate risk of death. It does not include an adverse event or suspected adverse 
reaction that, had it occurred in a more severe form, might have caused death.  
 
SERIOUS ADVERSE EVENT OR SERIOUS SUSPECTED ADVERSE REACTION: A serious adverse 
event (SAE) is considered ‘serious’ if, in the view of the investigator or sponsor it results 
in any of the following outcomes: 
• Death 
• is life-threatening 
• requires inpatient hospitalization, or prolongs an existing hospitalization 
• causes persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions 
• results in congenital anomalies or birth defects 
• Important medical events which in the judgment of the investigators may jeopardize 
the patient and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition. 
 
SUSPECTED ADVERSE REACTION: Any adverse event for which there is a reasonable 
possibility that the drug caused the adverse event.  For purpose of safety reporting, 
“reasonable possibility’ means there is evidence to suggest causal relationship between 
the drug and the adverse event.   SUSPECTED ADVERSE REACTION implies a lesser degree 
of certainty about causality than adverse reaction, which means any adverse event caused 
by a drug. 
 
EXPECTED ADVERSE EVENT: An expected adverse event (EAE) is an adverse event with a 
non-fatal outcome that is described in section 5.4 of the Investigator’s Brochure or in 
section 8.1.5 of this protocol. 
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UNEXPECTED ADVERSE EVENT: An unexpected adverse event (UAE) is any adverse event 
that is not described at the specificity and severity that has been observed and described 
in section 5.4 of the Investigator’s Brochure or in section 8.1.5 of this protocol, or an 
event described in these sections that has a fatal outcome. 
 
ATTRIBUTION: The relationship of adverse events to the study medication will be assessed 
by means of the question: “Is there a reasonable possibility that the event may have been 
caused by the study medication?”  The Institutional Principal Investigator well answer: 
Yes or No.  If there is a reasonable possibility that the event is related to study drug, then 
Yes would be designated for causality to study drug.  If there is clearly no possibility that 
the event is related to the study drug then No would be designated for causality to study 
drug.    
 
 
7.2.2 Recording Procedures for All Adverse Events 
 
All observed or volunteered adverse events, regardless of treatment group or suspected 
causal relationship to study drug, will be recorded as an Adverse Event in the case report 
forms at each study visit.  Adverse events should be collected from the time the patient 
provides informed consent to participate in the study until 30 days after the last dose of 
study medication.  Events involving adverse drug reactions, illnesses with onset during 
the study, or exacerbation of pre-existing illnesses should be recorded.  Objective test 
findings (e.g., abnormal laboratory test results) that result in a change in study drug 
dosage should also be recorded. 
 
All AEs will be recorded on the CRFs provided.  A description of the event, including its 
date of onset and resolution, whether it constitutes a SAE or not, the date it became 
serious, seriousness criteria (e.g fatal, life-threatening, hospitalization, disability, 
congenital anomalies), any action taken (e.g., changes to study treatment, other treatment 
given and follow-up tests) and outcome should be provided along with the Investigator’s 
assessment of causality to the study drug, study medication and study procedure.  
 
It will be left to the treating physician’s clinical judgment whether or not an adverse 
event is of sufficient severity to require that the subject should be removed from 
treatment.  A subject may also voluntarily withdraw from treatment due to what she/he 
perceives as an intolerable adverse event.  If either of these occurs, the subject will be 
given appropriate care under medical supervision until the symptoms cease or until the 
condition becomes stable. 
 
The severity of toxicities will be graded in accordance with the Common Terminology 
Criteria for Adverse Events Version 3.0 (http://ctep.cancer.gov/forms/CTCAEv3.pdf).  A 
link to CTCAE v3 is also provided in the study database in the adverse event CRFs. 
 
 
7.3 
Adverse Event Reporting 
 
 
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7.3.1 Reporting Procedures for Serious Adverse Events 
 
Reporting of SAEs will be managed by SARC.  Full details for the procedures to be 
adopted will be documented in the Safety Reporting Plan approved by the responsible 
parties. 
 
Initial notification of serious adverse events 
 
The treating physician or other site personnel must report all serious adverse events 
within 24 hours to the study coordinator at SARC. 
 
All SAEs must be reported, whether or not considered causally related to the 
investigational product or to the study procedure/s.  All SAEs will be recorded in the 
CRF. 
 
All serious AEs (SAEs), whether considered related or unrelated to investigational 
product, must be reported immediately (within 24 hours of awareness) by the 
investigational site to SARC, the Study Principal Investigator, and AstraZeneca Patient 
Safety by confirmed facsimile transmission.  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. 
 
SAEs should be reported on the MedWatch Form 3500A, which can be accessed at: 
http://www.accessdata.fda.gov/scripts/MedWatch/. The MedWatch form must be 
completed using the following guidelines: 
 
• The date the site notified SARC and AstraZeneca of the SAE must be specified in 
the “Describe event” narrative section. 
• Initial and follow-up MedWatch reports should be numbered either in the 
narrative section or in section G.7 of the MedWatch form. 
• If more than one SAE is listed on the MedWatch form, each event should be 
numbered. 
• Institutional Principal Investigator must designate causality to study drug for each 
SAE and must be specified in both the “Describe event” narrative section of the 
MedWatch form and the SARC012 SAE Fax Coversheet.   
• There will be 2 causality designations: Yes = Related to study drug, No = 
Unrelated to study drug 
o If there is any possibility that the SAE is related to study drug, then 
designate Yes for causality.   
o If there is clearly no possibility that the SAE is related to study drug, then 
designate No for causality. 
• If the SAE is considered to be related to a study procedure, this should also be 
indicated in the narrative section 
For all SAEs, completed MedWatch forms along with a completed SAE Fax Coversheet 
(Appendix C) should be faxed to SARC, the Study Principal Investigator, and 
AstraZeneca Patient Safety within 24 hours of awareness of the event.  The SAE Fax 
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Coversheet must be completed with Site and Subject Identifiers, SAE CTCAE version 
3.0 terms with a causality assessment to study drug, to other medication and to study 
procedure for each SAE term, Grade, and whether the notification concerns any event 
that is fatal or life-threatening.  The fax date and whether the notification constitutes an 
initial or follow-up report (with follow-up number) should also be noted on the SAE Fax 
Coversheet. 
 
Contact details for reporting SAEs are documented on the SAE Fax Coversheet and are 
as follows: 
 
o SARC 
SARC Research Project Manager 
Fax Number: (734) 930-7557 
o Study Principal Investigator, Scott Okuno, MD 
Email: okuno.scott@mayo.edu 
o AstraZeneca, Patient Safety 
Fax Number: +1 302 886 4114 
Back up Fax Number: +1 302 886 5886 
Email back-up in the event of fax failure (this is not a secure e-mail 
connection): PatientSafety.ClinicalTrialTemplatesWilm@astrazeneca.com 
(include in subject line: Study D8180C00039, SARC012, Patient number) 
 
SARC will review the SAE report for completeness and accuracy and will work with the 
Investigator to compile all the necessary support information to provide full written 
reports, and will record the SAE on the safety database. 
 
 
Reporting of serious adverse events 
 
SARC will determine the reportability of the event and will send expeditable reports to 
the FDA within the required timelines.  The Research Project Manager at SARC will be 
responsible for sending these expeditable reports to the Study Leader at AstraZeneca at 
the same time that they are reported to the FDA. 
 
SARC will also provide full written reports of all SAEs to: 
 
• STUDY PRINCIPAL INVESTIGATOR.  Scott Okuno (okuno.scott@mayo.edu). 
• INSTITUTIONAL PRINCIPAL INVESTIGATOR.   
• SARC will email expedited reports to all local sites involved in the study within 2 
business days of receipt, and local sites will process per institutional policy. 
 
SARC will send Safety Reports received from AstraZeneca to all sites involved in the 
study within the timelines required by the FDA, and local sites will process per 
institutional policy. 
 
 
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7.3.2 Adverse Event Reporting Procedures to the Investigator’s IRB 
 
The Principal Investigator of each participating site is responsible for reporting to their 
local IRB all events that occur in participants enrolled at the site according to the policies 
and procedures of the institutional IRB. 
 
7.4 
Treatment Regimen Unblinding 
 
 
See Operations Manual for process to request patient treatment regimen unblinding. 
 
 
7.4.1  Criteria for Unblinding for Serious Adverse Events 
 
The following events require unblinding of treatment assignments in this study: 
 
1. The occurrence of a serious adverse event that is both unexpected and 
considered by the reporting investigator to be associated with the use of study 
drug, and the knowledge of the treatment assignment is deemed essential for 
the patient’s care. 
2. An unexpected serious adverse event occurs and the intervention must be 
made known for purposes of reporting to the FDA (SARC responsibility as 
Study Sponsor).  
 
Unblinding of treatment assignments for patients on this study will be performed by 
authorized SARC personnel, upon approval from the SARC Medical Officer or designee. 
 
Requests for unblinding by the site should be only for urgent patient safety issues. 
 
Note: To ensure patient safety, if need be, all discussions can be done verbally with 
written documentation to follow once patient safety secured. 
 
Any patient whose treatment assignment is unblinded because of a serious adverse 
event(s) will be removed from study treatment and followed only for survival.  The site 
should continue to follow the patient status regarding the serious adverse event(s) for 
which the patient’s treatment was unblinded until resolved or improved to baseline and 
the patient can receive additional off-study treatment as necessary. 
 
7.4.2 Unblinding for Disease Recurrence in the Lung 
 
Patients who recur in the lung while on-study and who are thought to be amenable to 
complete surgical resection will be unblinded.  Those patients who were receiving 
placebo may then have the option of undergoing surgical resection.  If fully resected,  
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the patient will be given the option to begin oral therapy with Saracatinib.  Patients who 
recur in sites other than the lung while on-study will be taken off study and will not be 
offered the opportunity to be unblinded. 
 
Requests for unblinding by the site should be made at the time of recurrence, only if the 
recurrence is in the lung, and only if the recurrence is thought to be amenable to complete 
surgical resection. Authorized SARC personnel will perform unblinding of the treatment 
assignment.  Those patients who were receiving Saracatinib will be taken off-study for 
disease progression (see Section 3.7).  Those patients who were receiving placebo will be 
offered the option of undergoing surgical resection.  If complete resection is achieved, the 
patient will be given the opportunity to receive Saracatinib (see Section 3.2.6). 
 
 
8 
Pharmaceutical Information 
 
 
8.1 
Saracatinib (AZD0530) 
 
 
8.1.1 Chemical Information 
 
Chemical Name : 
N-(5-Chloro-1,3-benzodioxol-4-yl)-7-[2-(4-methylpiperazin-1- 
 
 
 
yl)ethoxy]-5-(tetrahydro-2H-pyran-4-yloxy)quinazolin-4-amine 
 
Chemical Structure : 
 
 
 
 
 
 
 
Molecular Formula : C27H32ClN5O5 
 
Molecular Weight : 
542.04 as free base 
 
Half-life 
 
40 hours in humans 
 
8.1.2 Supplier and Trial Sponsor 
 
AstraZeneca will supply saracatinib and placebo for this trial.  SARC (Sarcoma Alliance 
for Research through Collaboration) will sponsor this trial, which will be conducted 
under an IND held by SARC (IND #103,268). 
 
 
8.1.3 Preparation and Storage 
 
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Saracatinib tablets will be prepared by AstraZeneca and supplied by a third party vendor 
to the hospital pharmacy for subsequent distribution to the patient.  The tablets are round, 
pink, film-coated and come in 50 mg and 125 mg doses.  Tablets will be packed in child-
resistant, tamper-evident, high-density, polyethylene (HDPE) bottles with child-resistant 
closures.  Packaging includes bottles, caps and labels. 
 
Bottle labels will be available for the two different strengths of saracatinib.  Saracatinib is 
presented in plain, round, biconvex, pink, film-coated tablets that contain 50 mg or 125 
mg of saracatinib in free base form.  The 50 mg tablets have a diameter of 7 mm and the 
125 mg tablets have a diameter of 9.5 mm. 
 
Both 50 mg and 125 mg tablets contain saracatinib, mannitol, dibasic calcium phosphate 
anhydrous, crospovidone, hypromellose and magnesium stearate.  The film-coat contains 
hypromellose, macrogol 400, red iron oxide, black iron oxide and titanium dioxide. 
 
The tablets should be stored at room temperature in the pack provided.  The expiration 
date will be listed on the product label.  For further information, investigators should 
refer to the investigational product label. 
 
 
8.1.4 Administration of Saracatinib 
 
Saracatinib will be administered orally, once daily, every day, until the patient comes off 
study.  The tablets can be taken at any time of the day, with or without food.  See sections 
4.5, 4.6 and 4.7 for a list of medications and food products that should be avoided while 
on study. 
 
Each cycle will consist of 28 days, but there will be no breaks between cycles. 
 
Should emesis occur after swallowing the saracatinib tablet, an additional dose is not to 
be given.  The only exception is when emesis occurs immediately after swallowing the 
saracatinib tablet, and a fully intact, regurgitated, tablet is recovered. 
 
For patients who cannot swallow tablets, the following guideline must be followed to 
crush either the 50 mg or the 125 mg tablets. 
 
• Ensure that the crusher is clean and thoroughly dry (Ezy Dose Tablet Crusher with 
Pill Container, stock number 71091 from Apothecary Products Inc, Minneapolis or 
equivalent). 
• Place the crusher on its base on a flat surface, insert the tablet and screw down the 
crusher cap to crush the tablet. 
• Rotate the crusher cap repeatedly backwards and forwards (about one quarter turn in 
each direction). 
• Unscrew the cap by about one half turn, then tap the crusher sharply on the table, to 
redistribute the powder.  Do not shake or invert the crusher. 
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• Repeat the crushing process until a fine powder has been produced.  Note that the 
pink coating on the tablet may remain as flakes.  This is not critical.  As long as the 
inside of the tablet has been ground to a fine powder, this is sufficient. 
• Unscrew the crusher cap and transfer the powder into an appropriate glass container.  
If any significant amounts of tablet remain stuck to the crusher, these should be 
scraped or tapped out and added to the container. 
• Add 50 ml of water to the crushed tablet in the glass container and drink immediately. 
• Clean and dry the tablet crusher in preparation for the next dose. 
Should emesis occur after swallowing the saracatinib suspension, an additional dose 
is not to be given, since it is impossible to estimate the amount of saracatinib that has 
been delivered. 
For patients who require administration of saracatinib through a gastrostomy tube, the 
following guideline must be followed. 
 
• Note: The elapsed time from the first addition of water to the crushed tablet to the 
administration of rinse through the gastrostomy tube should not exceed 4 hours. 
• Stir the water and tablet powder together for 15 seconds.  Then promptly draw the 
suspension into the syringe. 
• Administer through the gastrostomy tube. 
• Add 50 ml water to the glass container as a rinse, stir for 15 seconds and draw into 
the syringe. 
• Administer through the gastrostomy tube. 
• Clean and dry the tablet crusher in preparation for the next dose. 
• Rinse the syringe with water. 
 
 
8.1.5 Known toxicities of Saracatinib 
 
For further information regarding saracatinib, please refer to the Investigator's Brochure. 
 
The following events are to be regarded as expected for regulatory reporting purposes: 
 
General symptoms 
 
flu-like symptoms 
 
 
 
 
- including fever, fatigue, musculoskeletal pain, headache 
 
 
 
 
fatigue 
 
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Hematological symptoms 
mild bleeding (such as epistaxis) 
 
 
 
 
mild bruising (such as bruising at a venipuncture site) 
 
Respiratory symptoms 
pneumonitis 
 
Gastrointestinal symptoms 
nausea 
 
 
 
 
vomiting 
 
 
 
 
diarrhea 
 
Skin symptoms 
 
rash, generally papular 
 
Laboratory findings  
decrease in neutrophil count including neutropenia 
 
 
 
 
decrease in platelet count including thrombocytopenia 
 
 
 
 
increase in serum creatinine 
 
 
 
 
increase in serum C-reactive protein 
 
 
 
 
positive protein on urinalysis 
 
 
 
 
positive heme or RBCs on urinalysis 
 
 
8.2 
Placebo 
 
 
Placebo tablets contain mannitol, microcrystalline cellulose, sodium starch glycolate and 
magnesium stearate.  The drug substance is substituted with an equal quantity of 
mannitol.  Placebo tablets are provided to match the active tablets in size, shape and 
color.  The tablets should be stored at room temperature in the pack provided.  The 
expiration date will be listed on the product label.  For further information, investigators 
should refer to the investigational product label.  Placebo tablets will be prepared by 
AstraZeneca and supplied by a third party vendor to the hospital pharmacy for 
subsequent distribution to the patient.  The same instructions as described above (see 
Section 8.1.4), should be used for patients who are not able to swallow the tablets whole, 
or who require administration through a gastrostomy tube. 
 
Since this is a double-blinded, placebo-controlled study, patients must refrain from taking 
certain medications and food products (see Sections 4.5, 4.6 and 4.7). 
 
 
8.3 
Drug Ordering 
 
See Operations Manual for details of Drug supply/ordering. 
 
 
8.3.1 Initial Supply 
 
The investigational drug will be supplied by AstraZeneca and will be distributed to 
individual sites by a third party vendor. 
 
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Initial drug supply is provided to maintain a minimum inventory at the site to avoid 
delays in starting patient treatment.   
 
The drug order supply form must be faxed or emailed to SARC.  Upon confirmation that 
SARC has received all necessary regulatory documents, the contract is fully executed, 
and the site initiation meeting completed, SARC will authorize the initial drug supply 
shipment. 
 
Requests should be submitted at least 5-7 business days before the expected delivery 
date.  Deliveries will be made Tuesday through Friday. 
 
Please complete the Saracatinib (AZD0530) Drug Supply Form (see Appendix D for drug 
supply form).  Fax or email the form to SARC Operations Office: 
 
SARC Research Project Manager 
SARC operations office fax: 734-930-7557 or 
Email: sarc@sarctrials.org 
 
 
8.3.2 Re-Supply 
 
Re-supply requests can be obtained by completing the saracatinib Drug Supply Form (see 
Appendix D for drug supply form).  Fax or email the form to SARC as above. 
 
Requests should be submitted at least 5-7 business days before the expected delivery 
date.  Deliveries will be made Tuesday through Friday. 
 
 
8.4 
Investigational Product Records at Investigational Site(s) 
 
 
It is the responsibility of the Investigator to ensure that a current record of investigational 
product disposition is maintained at each study site where investigational product is 
inventoried and disposed.  Records or logs must comply with applicable regulations and 
guidelines, and should include: 
• Amount received and placed in storage area.  
• Amount currently in storage area. 
• Label ID number or batch number and use date or expiry date. 
• Dates and initials of person responsible for each investigational product 
inventory entry/movement. 
• Amount dispensed to and returned by each subject, including unique 
subject identifiers. 
• Amount transferred to another area/site for dispensing or storage. 
• Non-study disposition (e.g., lost, wasted, broken). 
• Amount destroyed at study site. 
 
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Investigational product dispensing record/inventory logs and copies of signed packing 
lists must be maintained at the investigational site.  Batch numbers for saracatinib must 
be recorded in the drug accountability records. 
 
 
8.5 
Destruction of Investigational Product 
 
 
It is the Institutional Principal Investigator’s responsibility to ensure that arrangements 
have been made for disposal and that procedures for proper disposal have been 
established according to applicable regulations, guidelines, and institutional procedures.  
Appropriate records of the disposal must be maintained. Unused drug and empty bottles 
will not be returned to AstraZeneca. 
 
A copy of the institutional drug disposal policy should be sent to SARC for retention in 
the Trial Master File. 
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healthy males.  J Clin Oncol.  23supp:#3041 (2005) 
32 
Tabernero J, Cervantes A, Hoekman K, et al.  Phase I study of AZD0530, an oral 
potent inhibitor of Src kinase: first demonstration of inhibition of Src activity in 
human cancers.  J Clin Oncol.  25supp:#3520 (2007) 
33 
AstraZeneca, AZD0530 Investigator’s Brochure. 
34 
Andreev E, Koopman M, Arisz L.  A rise in plasma creatinine that is not a sign of 
renal failure: which drugs can be responsible.  J Intern Med.  246:247-252 (1999) 
35 
Simon RM, Steinberg SM, Hamilton M, et al.  Clinical trial designs for the early 
clinical development of therapeutic cancer vaccines.  J Clin Oncol.  19:1848-1854 
(2001) 
 
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10 
Appendices   
 
Appendix A – On Study Evaluations  
 
Study Month 
screening 
pre dose 
day 1 
week 
1(g) 
week 3-4 
(g) 
week 6-8 
(h) 
week 9 
(h) 
 
Interim History 
X 
X (d) 
 
X (d) 
X 
X 
X (d) 
Physical Examination 
X 
X (d) 
 
X (d) 
X 
X 
X (d) 
Weight, Height, Vital Signs 
X 
X (d) 
 
X (d) 
X 
X 
X (d) 
Laboratory Tests (a, f) 
X 
X (d) 
 
X (d) 
X 
X 
X (d) 
Thoracic CT (b) 
X 
 
 
 
X 
X 
 
Bone Scan 
X 
 
 
 
 
 
 
EKG 
X 
 
 
 
 
 
 
Echocardiogram or MUGA 
X 
 
 
 
 
 
 
Creatinine Clearance (c) 
X 
 
 
 
 
 
 
Pregnancy Test 
X 
 
 
 
 
 
 
ECOG Score 
X 
 
 
 
 
 
 
Begin Oral Therapy 
 
 
X ----------------------------------------------------------------- > 
 
 
 
Study Month 
3 
Mo 
Cycle 
3 (h) 
4 
Mo 
Cycle 
4 (h) 
5 
Mo 
Cycle 
5 (h) 
6 
Mo 
Cycle 
6 (h) 
7 
Mo 
Cycle 
7 (h) 
8 
Mo 
Cycle 
8 (h) 
9 
Mo 
Cycle 
9 (h) 
10 
Mo 
Cycle 
10 (h) 
11 
Mo 
Cycle 
11 (h) 
12 
Mo 
Cycle 
12 
 
Interim History 
X 
X (d) 
X (d) 
X 
X (d) 
X (d) 
X 
X (d) 
X (d) 
X 
Physical Examination 
X 
X (d) 
X (d) 
X 
X (d) 
X (d) 
X 
X (d) 
X (d) 
X 
Weight, Height, Vital Signs 
X 
X (d) 
X (d) 
X 
X (d) 
X (d) 
X 
X (d) 
X (d) 
X 
Laboratory Tests (a) 
X 
X (d) 
X (d) 
X 
X (d) 
X (d) 
X 
X (d) 
X (d) 
X 
Thoracic CT (b) 
X 
 
 
X 
 
 
X 
 
 
X 
EKG 
X 
 
 
 
 
 
 
 
 
 
Continue Oral Therapy 
X ---------------------------------------------------------------------------------------------- > 
 
 
Suggested Follow-up 
Study Month 
End of 
Trmt 
13 mo 
15 
mo 
18 
mo 
21 
mo 
24 
mo 
30 
mo 
36 
mo 
 
Interim History 
X 
X (d) 
X 
X (d) 
X 
X (d) 
X 
Physical Examination 
X 
X (d) 
X 
X (d) 
X 
X (d) 
X 
Weight, Height, Vital Signs 
X 
X (d) 
X 
X (d) 
X 
X (d) 
X 
Laboratory Tests 
X 
 
X 
 
X 
 
X 
Thoracic CT 
X 
 
X 
 
X 
 
X 
Bone Scan 
X 
 
 
 
 
 
 
EKG 
X 
 
 
 
 
 
 
End Oral Therapy 
X (e) 
 
 
 
 
 
 
 
(a) 
White blood cell count with differential, hemoglobin, hematocrit, platelet count, sodium, potassium, chloride, bicarbonate, blood 
urea nitrogen, creatinine, glucose, calcium, magnesium, phosphorus, ALT, AST, total bilirubin, alkaline phosphatase, lactate 
dehydrogenase, total protein, albumin 
(b) 
Thoracic CT scan must be performed at a slice thickness of 5 mm or less 
(c) 
For patients with serum creatinine >1.5 
(d) 
These visits do not need to be performed at the study center, however, documentation of the required items must be sent to the 
study center as soon as they are available 
(e) 
Saracatinib or placebo will be discontinued after 13 cycles (364 days) of therapy 
(f)   Prior to beginning oral therapy, treating physicians should obtain a full work-up to evaluate low or borderline low levels of 
phosphorus. (See section 3.3.3) 
(g)  Treatment evaluations/procedures should be performed within +/- 3 days. 
(h)   Treatment evaluations/procedures should be performed within +/- 3 days. 
 
 
 
 
 
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Appendix B – SARC 012 Patient Pill diary 
PATIENT INITIALS: _________   SUBJECT UNIQUE STUDY #__________________ 
Please complete this chart each time you take study drug. You may take the study drug at any time 
of the day with or without food. Please contact the study staff before changing the dose of the study 
drug.  Once completed, please return this chart to the study staff.                                                      
Study Drug Dose: 175 mg daily, 125 mg daily, or 100 mg daily 
Note:  Should vomiting occur after swallowing the saracatinib tablet, an additional dose is not to be taken.  The only exception is 
when vomiting occurs immediately after swallowing the Saracatinib tablet, and a fully intact, regurgitated tablet is recovered.  The 
following food products must not be taken while the patient is on study: grapefruits, grapefruit juice, star fruits, Seville oranges 
(also known as Chinese Bitter Oranges) and Seville orange marmalade. 
Patient Signature___________________________________    Date ____________________________ 
 
 
Day 
 
Date 
 
Time 
 
AM / PM 
Dose of 
Study Drug 
 
Comments 
Day 1 
/     / 
 
 
mg 
 
Day 2 
/     / 
 
 
mg 
 
Day 3 
/     / 
 
 
mg 
 
Day 4 
/     / 
 
 
mg 
 
Day 5 
/     / 
 
 
mg 
 
Day 6 
/     / 
 
 
mg 
 
Day 7 
/     / 
 
 
mg 
 
Day 8 
/     / 
 
 
mg 
 
Day 9 
/     / 
 
 
mg 
 
Day 10 
/     / 
 
 
mg 
 
Day 11 
/     / 
 
 
mg 
 
Day 12 
/     / 
 
 
mg 
 
Day 13 
/     / 
 
 
mg 
 
Day 14 
/     / 
 
 
mg 
 
Day 15 
/     / 
 
 
mg 
 
Day 16 
/     / 
 
 
mg 
 
Day 17 
/     / 
 
 
mg 
 
Day 18 
/     / 
 
 
mg 
 
Day 19 
/     / 
 
 
mg 
 
Day 20  
/     / 
 
 
mg 
 
Day 21 
/     / 
 
 
mg 
 
Day 22 
/     / 
 
 
mg 
 
Day 23 
/     / 
 
 
mg 
 
Day 24 
/     / 
 
 
mg 
 
Day 25 
/     / 
 
 
mg 
 
Day 26 
/     / 
 
 
mg 
 
Day 27 
/     / 
 
 
mg 
 
Day 28 
/     / 
 
 
mg 
 
To be completed by Study Staff:  Drug Bottle(s) Return Date:___________ 
# of 125 mg tablets dispensed ___________  /  returned ___________ 
# of 50 mg tablets dispensed ___________   /  returned ___________ 
Study Staff Signature_________________________     Date ______________ 
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Appendix C – SAE Fax Coversheet 
SARC 012 SAE FAX COVERSHEET(To be retained with MedWatch form)             
IND number: 103,268                                             AZ Study Code D8180C000039 
Investigational Prooduct: Saracatinib (AZD0530)Please place a check mark below to indicate 
that you have faxed this form to all parties: 
  SARC Research Project Manager: (734) 930-7557 
 
# of pages 
Fax Date 
  Scott Okuno, MD, Study PI: (507) 266-9161 
 
(incl. this page) 
(dd-mmm-yyyy) 
  AstraZeneca, Patient Safety:  (302) 886-4114 
 
 
 
Sender: 
 
 
Investigator: 
 
Site: 
Study Title: A Randomized, Double-Blinded, Placebo-Controlled, Multi-Institutional, Phase II.5 Study of 
Saracatinib (AZD0530), a Selective Src Kinase Inhibitor, In Patients with Recurrent Osteosarcoma 
Localized to the Lung 
Subject Study ID:  
Subject Study Initials: 
Type of Report:   Initial       Follow-up # ______ 
Please list all AEs by unique term and CTCAE v3.0 grade.  Use additional cover sheets if necessary: 
AE term 1: 
Grade 
 
 
Causality to study drug? 
Yes  /  No 
Causality to other medication? 
Yes  /  No 
Causality to study procedure? 
Yes  /  No 
AE term 2: 
Grade 
 
 
Causality to study drug? 
Yes  /  No 
Causality to other medication? 
Yes  /  No 
Causality to study procedure? 
Yes  /  No 
AE term 3: 
Grade 
 
 
Causality to study drug? 
Yes  /  No 
Causality to other medication? 
Yes  /  No 
Causality to study procedure? 
Yes  /  No 
AE term 4: 
Grade 
 
 
Causality to study drug? 
Yes  /  No 
Causality to other medication? 
Yes  /  No 
Causality to study procedure? 
Yes  /  No 
Is any AE listed above fatal or life-threatening?      Yes         No 
Photocopies of supportive documents; attach if relevant, tick those attached 
 Lab report(s)      Autopsy report      Other: details ____________________________ 
All serious adverse events will be reported and documented on MedWatch Form FDA 3500 A as follows: 
• 
If more than one SAE is listed each event should be numbered. 
• 
Investigator must designate causality as YES or NO for each SAE in the “Describe event” narrative 
section of the MedWatch form. If there is any possibility that the SAE is related to study drug, then 
designate Yes for causality.  If there is clearly no possibility that the SAE is related to study drug, then 
designate No for causality. 
• 
If causality is due to other medication or study procedure, please provide a clear description and 
reasoning in the narrative section of the MedWatch form.  
• 
The date the site notified SARC and AstraZeneca of the SAE must be specified in the “Describe event” 
narrative section of the MedWatch form. Initial and follow-up MedWatch reports should be numbered 
either in the narrative section or in section G.7 of the MedWatch form. 
 
 
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Appendix D – Drug Supply Form 
 
ASTRAZENECA 
Saracatinib (AZD0530) DRUG SUPPLY FORM  
FOR INVESTIGATOR SPONSORED STUDY - SARC 012 (D8180C00039) 
 
REQUEST FOR DRUG SHIPMENT TO SITE (AZ) 
 
AZ Protocol 
Number 
D8180C00039 
Group 
Protocol 
Number 
SARC012 
Site Name (as Institution) and Number:                                               
Investigator Name:  
  
Dr.        
 
Shipment Must Reach Destination By:  
      
 
 
 
 
 
DD/MM/YYYY 
(Deliveries are not made on Monday: allow five (5) working days for resupply)
Investigator Address: 
      
 
 
Telephone Number:        
 
 
Pharmacy Address - Where Supplies Should Be Delivered: 
(If Different From Investigator Address and Contact) 
      
Pharmacy Contact:        
 
Telephone Number:        
 
E-mail (if available):        
DRUG REQUIRED: 
Study Drug:  
Saracatinib (AZD0530) 
Saracatinib (AZD0530) 
Strength/ Dose Form:  
50mg tablets/ 35 per bottle 
125mg tablets/35 per bottle 
QUANTITY NEEDED 
No. of bottles: 
      
No. of bottles: 
      
Study Drug:  
Placebo Saracatinib (AZD0530) 
Placebo Saracatinib (AZD0530) 
Strength/ Dose Form:  
50mg tablets/ 35 per bottle 
125mg tablets/35 per bottle 
QUANTITY NEEDED 
No. of bottles: 
      
No. of bottles: 
      
Comments:       
 
Please fax or e-mail this document to the following: 
Via email: sarc@sarctrials.org 
Via FAX: 734-930-7557 
 
For SARC Office use only: 
 
SARC verifies that all required regulatory and contractual documentation for this Site/Study is complete: 
 
Signature:_____________________________________________              Date:_____________________ 
 
 
 
 
 
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Appendix E – Local MD Guidelines 
 
For patients enrolled on this study, evaluations must be administered at the study site for 
the pre-treatment evaluation and for the 3, 6, 9, and 13month visits (cycle 3, 6, 9 and end 
of cycle 13).   For all other study evaluations, the investigator may determine in the best 
interest of the patient that those evaluations may be safely conducted at a local, 
competent, referring oncologist’s office.  The institutional principal investigator is 
responsible for the timely and accurate reporting of data to the SARC Operations Center.  
 
• SARC institutional PI communication with the outside physician is required 
prior to the patient returning to the local physician. This will be documented 
in the patient record. 
• A letter to the local physician outlining the patient’s participation in a clinical 
trial will request local physician agreement to supervise the patient’s care. 
(Sample letter- Appendix F). 
• Protocol required evaluations outside the consortium site will be documented 
by telephone, fax, or e-mail. Fax or e-mail will be dated and signed by the 
SARC institutional PI, indicating that they have reviewed it. 
• Documentation to be provided by the local physician will include all drug 
administration records, progress notes, reports of protocol required laboratory 
and diagnostic studies and documentation of any hospitalizations. 
• SARC institutional PI is responsible for all adverse event reporting, timely 
and accurate submission of serious adverse events reporting as outlined in 
Section 7.3 
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Appendix F – Local MD Agreement Letter 
 
Date 
 
Dear Doctor, 
 
“Name” is a mutual patient of ours with sarcoma. He/she is participating in a multi-
center randomized trial of Saracatinib (AZD0530). The study involves continuous study 
drug administration with interval lab studies, physical exams and CT scans. The cycle is 
repeated every 28 days, without any breaks between cycles. We are inquiring as to your 
willingness to supervise a portion of this patient’s care while on the trial. 
 
“Name” would like to be evaluated at XXXX and obtain the lab studies at your office. In 
order for this to be done, we will need the following: 
• confirmation of your willingness to obtain lab studies 
• ability to obtain thoracic CT scans and relay reports and images, if required, to 
the study center  
• agreement to report all serious adverse events within 24 hours 
• agreement to discuss and obtain approval prior to any change in drug dose 
and/or schedule 
• a copy of your lab’s certification 
• a fax copy of the documented, dictated or handwritten, findings of patient 
visits, record of study doses and administration, lab results and documentation 
of any hospitalizations 
 
If you agree to the above, we would ask you to sign and return this letter as confirmation 
that you will comply with the items as outlined above. 
 
 
By signing below, I agree to perform all tests and evaluations as noted above, and fax all 
documentation to name and fax number. 
 
___________________________________ _________________________ 
Signature date 
 
 
A copy of the abstract, study schema, and study calendar are included with this letter. 
Should you have any questions or need additional information, please do not hesitate to 
contact: Name and Contact Information 
 
Sincerely, 
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