Clinical trial NCT03592641
Conditions: Colorectal Carcinoma Metastatic Colon Adenocarcinoma Metastatic Rectal Adenocarcinoma Stage III Colon Cancer AJCC v8 Stage III Rectal Cancer AJCC v8 Stage IIIA Colon Cancer AJCC v8 Stage IIIA Rectal Cancer AJCC v8 Stage IIIB Colon Cancer AJCC v8 Stage IIIB Rectal Cancer AJCC v8 Stage IIIC Colon Cancer AJCC v8 Stage IIIC Rectal Cancer AJCC v8 Stage IV Colon Cancer AJCC v8 Stage IV Rectal Cancer AJCC v8 Stage IVA Colon Cancer AJCC v8 Stage IVA Rectal Cancer AJCC v8 Stage IVB Colon Cancer AJCC v8 Stage IVB Rectal Cancer AJCC v8 Stage IVC Colon Cancer AJCC v8 Stage IVC Rectal Cancer AJCC v8 Unresectable Colon Adenocarcinoma Unresectable Rectal Adenocarcinoma
Sponsor: National Cancer Institute (NCI)
Start date: 2019-07-25; Completion date: 2021-12-30
Enrollment: 5 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This phase II trial studies how well savolitinib works in treating patients with MET amplified colorectal cancer that has spread to other places in the body (metastatic) or cannot be removed by surgery (unresectable). Savolitinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Detailed description:
PRIMARY OBJECTIVE:

I. To estimate the objective response rate (ORR) of savolitinib in patients with MET amplified metastatic colorectal cancer (CRC).

SECONDARY OBJECTIVES:

I. To describe the clinical activity (duration of response, progression free survival \[PFS\]) of savolitinib in patients with MET amplified metastatic CRC.

II. To describe the toxicities of savolitinib in patients with MET amplified metastatic CRC.

III. To explore the effect of RAS mutation status on response to savolitinib. IV. To explore any correlation between tissue and blood based biomarkers and clinical outcomes.

OUTLINE:

Patients receive savolitinib orally (PO) once daily (QD) on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days, and then every 12 weeks thereafter for up to 2 years.

Arms: arm 1: Patients receive savolitinib PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Interventions: intervention 1: Savolitinib
Intervention descriptions: intervention 1: Given PO

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
A Phase 2 Study of Savolitinib in Subjects with MET Amplified Metastatic 
Colorectal Cancer 
 
 
Trial: NCT03592641 
 
 
Protocol 
 
December 3, 2020 


1 
 
NCI Protocol #: 
10181 
 
Local Protocol #: 
NCI-10181 
 
ClinicalTrials.gov Identifier: 
NCT03592641 
 
TITLE: A Phase 2 Study of Savolitinib in Subjects with MET Amplified Metastatic Colorectal 
Cancer 
 
Corresponding Organization: LAO-NC010 / Duke University - Duke Cancer Institute LAO 
 
Principal Investigator: 
John Strickler, MD 
Duke University Medical Center 
Division of Medical Oncology, GI Oncology Unit 
10 Bryan Searle Drive, Room 349 Seeley Mudd Building, 
DUMC Box 3052, Durham, NC 27710 
Phone: 919-681-6006 
Fax: 919-613-5228 
Email: john.strickler@dm.duke.edu 
 
 
Participating Organizations  
LAO-11030 / University Health Network Princess Margaret Cancer Center LAO 
LAO-CA043 / City of Hope Comprehensive Cancer Center LAO 
LAO-CT018 / Yale University Cancer Center LAO 
LAO-MA036 / Dana-Farber - Harvard Cancer Center LAO 
LAO-MD017 / JHU Sidney Kimmel Comprehensive Cancer Center LAO 
LAO-MN026 / Mayo Clinic Cancer Center LAO 
LAO-NJ066 / Rutgers University - Cancer Institute of New Jersey LAO 
LAO-OH007 / Ohio State University Comprehensive Cancer Center LAO 
LAO-PA015 / University of Pittsburgh Cancer Institute LAO 
LAO-TX035 / University of Texas MD Anderson Cancer Center LAO 
LAO-NCI / National Cancer Institute LAO 
EDDOP / Early Drug Development Opportunity Program 
CATCHUP/ Creating Access to Targeted Cancer Therapy for Underserved Populations 
 
Statistician: 
Donna Niedzwiecki, PhD 
 
Duke Cancer Institute 
Biostatistics 
 
2424 Erwin Rd, Hock Plaza I Rm 8040, 
Durham, NC 27710 


NCI Protocol #: 10181 
Version Date: December 3, 2020 
 
2 
Office: 919-681-5030 
Fax: 919-668-9335   
Email: donna.niedzwiecki@duke.edu 
 
 
Study Coordinator: 
Ashley Moyer 
Duke Cancer Institute 
Oncology CRU 
 
30 Duke Medicine Circle, Morris Building Rm 00540 
DUMC Box 3216  
Durham, NC 27710 
Office: 919-684-6268 
Email: ashley.n.moyer@duke.edu 
 
 
NCI-Supplied Agent:  Savolitinib (AZD6094), NSC #785348 
 
IND #:  140202 
IND Sponsor:  DCTD, NCI   
 
Protocol Type / Version # / Version Date: 
Original / Version #1 / January 11, 2018 
 
 
 
 
 
 
 
     Version #2 / April 23, 2018 
 
 
 
 
 
 
 
 
Version #3 / June 11, 2018 
         Responses to CIRB, FDA, CTEP, and Biorepository / Version #4 / October 1, 2018 
 
 
 
 
 
 
 
 
Version #5 / November 15, 2018 
  
 
 
 
 
 
 
 
Version #6 / December 2, 2018 
                 Request for Rapid Protocol Amendment (RRA) / Version #7 / March 11, 2019 
                 Request for Rapid Protocol Amendment (RRA) / Version #8 / May 19, 2020 
                 Request for Rapid Protocol Amendment (RRA) / Version #9/ December 3, 2020 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


NCI Protocol #: 10181 
Version Date: December 3, 2020 
 
3 
 
 
 
SCHEMA 
 
 
Patient Selection 
Patients with metastatic CRC who have received prior anti-EGFR monoclonal antibody therapy 
(cetuximab or panitumumab) will be prospectively screened for MET amplification using a cell 
free DNA assay (Guardant 360TM). Patients with MET amplification will be enrolled and treated 
with savolitinib.  
NOTE:  There are two consent forms for this study.  Patients will sign the Screening Consent 
Form prior to the Guardant 360.  If MET amplification is detected in the Guardant 360, the 
patient will sign the Main Consent Form prior to screening for the study treatment portion of the 
study. 
Treatment Plan 
Study Drug Regimen: After satisfying eligibility and screening criteria, subjects will be treated 
with savolitinib on 28-day cycles. Treatment will continue until unacceptable drug-related 
toxicity or disease progression. Savolitinib dosing may be modified, suspended, or discontinued 
due to unacceptable treatment-related side effects.  
Follow-Up: While on study treatment, subjects will be followed for progression every 2 cycles 
until documented progression, start of a new anti-cancer therapy, death, loss to follow-up, or 
study completion. Subjects who discontinue study treatment for any reason (e.g., toxicity) other 
than disease progression will be followed with tumor evaluations every 12 weeks until 
documented disease progression or start of a new anti-cancer therapy. Study completion is 2 
years after the last subject starts study drug regimen.  
Study Assessments  
All subjects will complete an extensive medical history, physical examination and clinical 
assessment prior to starting study treatment to ensure subject eligibility requirement, during 
study treatment to monitor the efficacy and toxicity and safety, as well as during follow up 
period after discontinuation of the study treatment. 


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Toxicity and Safety Assessments: Toxicity will be assessed at every visit using NCI-CTCAE 
version 5.0. Safety assessments will be performed weekly during the first cycle, then every two 
weeks for 3 cycles, then monthly thereafter. Safety assessments will include vital signs, ECOG 
performance status, medical history, physical examination, review of concomitant medications, 
complete blood count (CBC), and chemistries with liver function tests. Symptom management 
and supportive care will be provided as clinically indicated to ensure optimal patient care. After 
discontinuation of study treatment, subjects will have safety assessments 30 days after the last 
dose of study drug.  
Efficacy: Restaging scans and tumor markers will be repeated every two cycles while on protocol 
therapy. Tumor response will be assessed using Response Evaluation Criteria in Solid Tumors 
Version 1.1 (RECIST 1.1).  
Correlatives Studies 
Blood-based studies. Peripheral blood samples will be obtained at specified time points from all 
treated subjects. Blood- based correlative studies include the following:  
• Cell free tumor DNA (cfDNA). Plasma obtained at baseline, Cycle 1 Day 15, each restaging, 
and end of study treatment will be analyzed for mutations of interest.  
 
• Circulating protein studies. Plasma obtained at baseline, Cycle 1 Day 15, each restaging, and 
end of study treatment will be analyzed for multiple soluble protein analytes. 
 
• Pharmacogenomics. Whole blood obtained at baseline for pharmacogenomics.   
 
Tumor tissue studies. Archival tumor tissue will be collected from all evaluable subjects. Tissue-
based correlative studies include the following:  
 
• Tumor protein expression. All tumors (archival) will be tested for c-MET expression by IHC 
and MET amplification by FISH.  
 
• Tumor mutation analysis. Comprehensive mutational analysis will be performed on archived 
formalin fixed paraffin embedded (FFPE) tumor samples. This analysis will include Next 
Generation Sequencing and FISH for MET gene amplification.  


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TABLE OF CONTENTS 
 
1. 
OBJECTIVES  ……………………………………………………….................................7 
1.1 
Primary Objective s..................................................................................................7 
1.2 
Secondary Objectives...............................................................................................7 
2. 
BACKGROUND .................................................................................................................7 
2.1 
Colorectal Cancer.....................................................................................................7 
2.2 
Savolitinib ................................................................................................................7 
2.3 
Rationale ................................................................................................................10 
2.4 
Correlative Studies Background ............................................................................11 
3. 
PATIENT SELECTION ....................................................................................................12 
3.1 
Inclusion Criteria ...................................................................................................12 
3.2 
Exclusion Criteria ..................................................................................................13 
3.3 
Inclusion of Women and Minorities ......................................................................16 
4. 
REGISTRATION PROCEDURES ...................................................................................16 
4.1 
Investigator and Research Associate Registration with CTEP ..............................16 
4.2 
Site Registration .....................................................................................................17 
4.3 
Patient Registration ................................................................................................20 
5. 
TREATMENT PLAN ........................................................................................................21 
5.1 
Agent Administration.............................................................................................21 
5.2 
General Concomitant Medication and Supportive Care Guidelines ......................22 
5.3 
Duration of Therapy ...............................................................................................24 
5.4 
Duration of Follow Up ...........................................................................................25 
6. 
DOSING DELAYS/DOSE MODIFICATIONS ...............................................................25 
6.1 
Hepatic Toxicities ..................................................................................................25 
6.2 
Non-hepatic Toxicities ...........................................................................................26 
7. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ............................29 
7.1 
Comprehensive Adverse Events and Potential Risks List(s) (CAEPRs) ...............29 
7.2 
Adverse Event Characteristics ...............................................................................31 
7.3 
Expedited Adverse Event Reporting ......................................................................32 
7.4 
Routine Adverse Event Reporting .........................................................................33 
7.5 
Pregnancy ...............................................................................................................34 
7.6 
Secondary Malignancy...........................................................................................34 
7.7 
Second Malignancy ................................................................................................34 
8. 
PHARMACEUTICAL INFORMATION ..........................................................................34 
8.1 
Savolitinib (NSC #785348)....................................................................................35 
9. 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ........................................38 


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9.1 
Summary Table for Specimen Collection ..............................................................38 
9.2 
Specimen Procurement Kits and Scheduling .........................................................39 
9.3 
Specimen Collection ..............................................................................................40 
9.4 
Specimen Tracking System Instructions ................................................................42 
9.5 
Shipping Specimens from Clinical Site to the ETCTN Biorepository ..................45 
9.6 
Shipping of Specimens to Other Laboratories .......................................................47 
9.7 
Integral/Integrated Laboratory Studies ..................................................................47 
9.8 
Exploratory/Ancillary Correlative Studies ............................................................51 
10. 
STUDY CALENDAR .......................................................................................................53 
11. 
MEASUREMENT OF EFFECT........................................................................................55 
11.1 
Antitumor Effect – Solid Tumors ..........................................................................55 
12. 
STUDY OVERSIGHT AND DATA REPORTING / REGULATORY 
REQUIREMENTS .............................................................................................................62 
12.1 
Study Oversight .....................................................................................................62 
12.2 
Data Reporting .......................................................................................................62 
12.3 
CTEP Multicenter Guidelines ................................................................................64 
12.4 
Collaborative Agreements Language .....................................................................64 
12.5 
Genomic Data Sharing Plan ...................................................................................66 
13. 
STATISTICAL CONSIDERATIONS...............................................................................66 
13.1 
Study Design/Endpoints.........................................................................................66 
13.2 
Sample Size/Accrual Rate ......................................................................................67 
13.3 
Stratification Factors ..............................................................................................68 
13.4 
Analysis of Secondary Endpoints ..........................................................................68 
13.5 
Reporting and Exclusions ......................................................................................68 
REFERENCES 
…………………………………………………………70 
APPENDIX A 
PERFORMANCE STATUS CRITERIA ..................................................72 
APPENDIX B 
PATIENT DRUG DIARY CARD .............................................................73 
APPENDIX C 
PATIENT DRUG INFORMATION HANDOUT AND 
WALLET CARD ...............................................................................................................74 
APPENDIX D 
NEW YORK Heart ASSOCIATION FuNCTIONAL 
CLASSIFICATION ...........................................................................................................76 
APPENDIX E 
GUARDANT360 BLOOD COLLECTION AND 
SHIPPING INSTRUCTIONS ............................................................................................77 
APPENDIX F 
GUIDANCE REGARDING POTENTIAL 
INTERACTIONS WITH CONCOMITANT MEDICATIONS KNOWN 
TO PROLONG QT INTERVAL .......................................................................................78 
 


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1. OBJECTIVES 
 
1.1 
Primary Objectives 
 
1.1.1 To estimate the objective response rate (ORR) of savolitinib in patients with MET 
amplified metastatic CRC. 
 
1.2 
Secondary Objectives 
 
1.2.1 To describe the clinical activity (duration of response, progression free survival [PFS]) 
of savolitinib in patients with MET amplified metastatic CRC. 
1.2.2 To describe the toxicities of savolitinib in patients with MET amplified metastatic CRC. 
1.2.3 To explore the effect of RAS mutation status on response to savolitinib.  
1.2.4 To explore any correlation between tissue and blood based biomarkers and clinical 
outcomes.  
 
2. BACKGROUND 
 
2.1 
Colorectal Cancer 
 
Colorectal cancer (CRC) is the second leading cause of cancer death in the United States [1]. 
Approximately half of all patients with metastatic CRC have KRAS or NRAS (RAS) wild-type 
tumors [2], and these patients are eligible to receive the epidermal growth factor receptor 
(EGFR) monoclonal antibodies panitumumab or cetuximab. To further improve the benefit of 
anti-EGFR therapies, efforts are needed to better understand and treat the molecular drivers of 
acquired resistance. This study will prospectively identify and treat patients whose tumors harbor 
MET gene amplification – an important driver of acquired EGFR resistance.  
2.2 
Savolitinib 
 
AZD6094 (also known as HMPL-504, volitinib [Chinese accepted name] and savolitinib 
[international non-proprietary name]) is a potent and selective small molecule MET kinase 
inhibitor with significant antitumour activity.  Savolitinib is active against MET amplified 
gastrointestinal malignancies, and is well tolerated [3]. The maximum tolerated dose (MTD) of 
the once-daily dosing is 800 mg. The most common adverse events are constipation, diarrhea, 
fatigue, nausea, vomiting, dizziness and peripheral edema, but these adverse events are usually 
mild to moderate in severity (grades 1 or 2). To maximize efficacy and tolerability, current 
monotherapy and combination clinical trials are using a dose of 600mg for weight ≥ 55 kg and 
300 mg if weight < 55kg [4-6] (www.clinicaltrials.gov).  
Non-clinical Information 
The nonclinical safety of AZD6094 has been evaluated in general toxicology studies in rats 
and dogs. Maximum tolerated doses have been explored and target organs/tissues for toxicity 


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identified. In repeat-dose oral studies, a key target for toxicity was the lymphoreticular 
system. Decreased cellularity was observed in various tissues, including lymph nodes, 
thymus, spleen and Peyer’s patches. There were also various changes in the GI tract in both 
species, including stomach erosions in rats and oral ulceration in dogs, and effects on the 
kidney and urinary tract in rats. 
 
After dosing for 4 weeks, in addition to GI tract and lymphoreticular effects, there were 
findings in the heart, liver, thyroid, adrenals, eyes, prostate and female reproductive tract. All 
toxicities had recovered 28 days after the cessation of dosing with the exception of eye 
changes in dogs, and stomach epithelial hyperplasia, hepatocyte hypertrophy and thyroid 
follicular cell hypertrophy in rats, where low-grade effects were noted. 
 
After dosing for 13 weeks, in addition to GI and lymphoreticular effects, there were findings 
in the liver and adrenals. In rats only, there were findings in the thyroid gland, kidney, urinary 
bladder, urinary tract and heart. In dogs, there was evidence of testicular toxicity. 
In rats, there was evidence of reproductive toxicity, including adverse effects on embryofoetal 
survival and development. 
 
In safety pharmacology studies, there were no noteworthy effects on cardiovascular, 
neurobehavioral or respiratory parameters. Some transient increases in heart rate were noted 
following repeated dosing in dogs. 
 
AZD6094 was not genotoxic in vitro or in vivo. 
 
In vitro data suggest a potential for phototoxicity. A tissue distribution study in the rat 
showed distribution of AZD6094 was limited, though there was evidence of distribution to the 
skin. 
 
Efficacy 
Efficacy data are based on data from completed studies at a data cut-off date of 27 February 
2017. 
 
• In Study D5081C00001, there were 48 patients in the All Subjects population, and of 
these, 3 patients experienced a partial response. Hence the best overall response rate 
(ORR) (either complete response or partial response) for all patients overall was 6.3% 
(95% confidence interval [CI] 1.3%, 17.2%). All 3 responders were PRCC patients with 
Stage IV disease. 
 
• In Study D5082C00002, the Phase II study of PRCC, 8 of 109 patients dosed with 
AZD6094 have experienced partial responses. In the safety analysis population, 8 of 44 
(18.2%) c-MET positive patients achieved a partial response. All of the responders had a 
local pathology report showing PRCC, although central laboratory review was hampered 
by small amounts of tumour tissue on occasion. Thirty-eight (34.9%) patients in the 
safety analysis maintained stable disease ≥5 weeks. 
 
In summary, AZD6094 has shown promising efficacy in patients with tumour MET alterations. 


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Pharmacokinetics and Drug metabolism in Humans 
The PK in humans has been studied, following dosing of AZD6094 in the fed state, in the 
dose escalation phase of Study D5081C00001 and Study D5081C00002. Both QD and BID 
dosing have been investigated across a dose range of 100 mg to 1200 mg (total dose). In 
addition, preliminary unvalidated PK data from D5082C00002 (600 mg QD; patients in the 
fed state) is available. 
 
In general, AZD6094 is rapidly absorbed with a relatively short tmax. Maximum plasma 
concentration and AUC appear to show dose proportionality across the dose ranges 
investigated. The apparent t½ is short and as a result there is no accumulation of AZD6094 
after QD or BID dosing. Interpatient variability is moderate-to-high with a CV of over 30%. 
Two metabolites (M2 and M3), thought to be major metabolites in humans based on 
nonclinical and in vitro work, have also been characterised. Both metabolites are rapidly 
formed and have short half-lives similar to that of the parent. Both metabolites appear to have 
a constant parent:metabolite ratio independent of dose. 
 
The food effect study showed a small but statistically significant difference between the PK 
after dosing in the fed compared to the fasted state. Due to the higher AE incidence following 
dosing in the fasted state, it is recommended that all patients should take AZD6094 in the fed 
state. 
 
Safety 
As of the data cut-off date (27 February 2017), 4 clinical studies had completed and 4 were 
ongoing; all completed and ongoing studies at the time of the data cut-off are open label 
studies. Safety data were available for 245 patients who received monotherapy AZD6094 (in 
Studies D5081C00001, D5081C00002, D5160C00006C or D5082C00002). In addition, data 
are presented from 124 patients who received combination therapy in Studies D5081C00003, 
D5080C00001, D5160C00006 and D5160C0006B, and 25 healthy volunteers who received a 
single dose of AZD6094 in the completed food-effect study (Study D5081C00004). The 
food-effect study is not included in the pooled data and is summarised in Investigator’s 
Brochure. 
 
The majority of patients receiving monotherapy AZD6094 had at least 1 AE (237/245 patients 
[96.7%]), and most patients (211/245 [86.1%]) had an AE that was considered by the 
Investigator to be causally related to AZD6094 treatment. A total of 126/245 patients (51.4%) 
had an AE of CTCAE Grade ≥3. A total of 30.6% patients (75/245) had SAEs and 13.9% 
patients (34/245) had a causally related SAE. There were 6 patients who died, but there are 7 
AEs leading to death, as 1 patient had 2 AEs with a fatal outcome. Forty-five patients 
(18.4%) had an AE that resulted in discontinuation from treatment. 
 
The majority of patients receiving AZD6094 in combination had at least 1 AE (118/124 
patients, 95.2%). A total of 100/124 patients (80.6%) had an AE that was considered by the 
Investigator to be related to treatment. Forty-two patients (33.9%) had SAEs and 17 patients 
(13.7%) had a treatment related SAE. Nine patients (7.3%) had an AE resulting in death, and 
1 patient (0.8%) had a fatal AE that was considered to be related to AZD6094 treatment by the 


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Investigator. Twenty-one patients (16.9%) had an AE that resulted in discontinuation from 
treatment. 
 
2.3 
Rationale 
 
The receptor tyrosine kinase c-MET (mesenchymal-epithelial transition factor) is associated with 
tumor cell invasiveness, metastasis, proliferation, and treatment resistance. In patients with 
treatment-naive CRC, MET amplification is rare, occurring in less than 3% of tumors [7-9]. On 
the other hand, several studies indicate that MET amplification increases under the selective 
pressure of anti-EGFR therapy [10-14]. As a result, tumor profiling studies performed on 
primary tumors underestimate the prevalence of MET amplification in the treatment refractory 
setting, where MET amplification may not only be more common, but also more biologically and 
clinically relevant.  
Functional crosstalk between c-MET and EGFR provides compensatory signal transduction, 
leading downstream MAPK and PI3K pathway activation in the presence of upstream EGFR 
blockade [15]. MET amplification emerged in post-treatment tumor biopsies in 3 out of 7 
patients with metastatic CRC who developed acquired resistance to anti-EGFR antibody. 
Furthermore, MET-amplified CRC tumors did not respond to cetuximab treatment in mouse 
xenograft model, suggesting MET amplification is associated with resistance to anti-EGFR 
therapy in patients with metastatic CRC [14].  
Access to treatment-refractory tumor tissue is a significant barrier to the identification of 
acquired MET amplification. Technology now exists to identify patients with MET amplified 
tumors from a routine blood draw. In several studies assessing simultaneously obtained “liquid” 
and tissue biopsies, concordance between mutation profiles approached 90% [16-19]. For 
patients with metastatic CRC, a peripheral blood draw for acquired mutations may be 
particularly valuable. In a case series of 56 patients with KRAS wild-type/ MET non-amplified 
tumors treated with anti-EGFR therapy, 14% of patients had acquired MET amplification in 
peripheral blood upon progression [13]. Fifty percent (50%) of these patients with acquired MET 
amplification also had acquired KRAS or NRAS (RAS) co-mutations. These results have been 
reproduced in an ongoing clinical trial of cabozantinib plus panitumumab (NCT02008383). 
Among the first 64 patients with EGFR-refractory metastatic CRC receiving blood-based 
genomic profiling, 11 patients (17%) had MET amplified tumors [20]. Concurrent BRAF and/or 
RAS somatic mutations were detected in 5 out of these 11 patients. These results illustrate the 
genomic complexity of acquired resistance.  
MET inhibitors have significant single-agent activity against MET amplified advanced solid 
tumors. In a case series of 6 patients with MET amplified, treatment refractory non-small cell 
lung cancer (NSCLC), the c-MET inhibitor crizotinib had an ORR of 67% [21]. This included 3 
patients with a partial response, and 1 patient with a complete response. The median duration of 
response was 1.4 years. In addition, several selective MET inhibitors have monotherapy response 
rates exceeding 50%, including ABT-700 [21], SAR125844 [23], and AMG337 [24]. In patient-
derived tumor xenograft models, savolitinib has demonstrated anti-tumor efficacy in MET 
amplified gastric cancer [25] and papillary renal cell carcinoma [26]. More recently, in a phase 2 
trial of savolitinib in patients with advanced papillary renal cell carcinoma (pRCC), MET 


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activation  was strongly associated with response [5]. In a subgroup analysis, eight patients 
(18%) with MET-driven pRCC had partial response to savolitinib treatment, whereas none of the 
patients with MET-independent pRCC had a response. The median PFS for patients with MET-
driven pRCC was 6.2 months, significantly higher than that for patients with MET-independent 
pRCC (1.4 months).   
The activity of MET inhibitors in anti-EGFR antibody refractory metastatic CRC has been 
demonstrated in preclinical and clinical studies. In mice engrafted with a CRC tumor that was 
anti-EGFR antibody refractory, tumor growth was inhibited by treatment with a MET tyrosine 
kinase inhibitor [14]. Similarly, tumor regression was seen with MET inhibitor in a CRC 
xenograft mouse model genetically engineered to overexpress human HGF [27]. Although the 
clinical activity of MET inhibitors in patients with MET amplified CRC is not well established, a 
recent case report suggests clinical activity [28].  In this report, a patient with RAS wild-type 
metastatic CRC who experienced disease progression on chemotherapy and panitumumab was 
enrolled in a clinical trial evaluating the combination of the c-MET inhibitor cabozantinib plus 
panitumumab. The patient experienced a significant response . Although tissue was negative for 
MET amplification, cfDNA revealed MET amplification. This case suggests that MET 
amplification in cfDNA may predict sensitivity to MET inhibitors in patients with MET 
amplified metastatic CRC. 
This trial will evaluate the clinical activity and tolerability of savolitinib, an oral, potent and 
selective c-MET inhibitor, in patients with MET amplified metastatic CRC. Additionally, this 
study will include tissue and blood-based correlative studies to better understand biomarkers of 
sensitivity and resistance.  
2.4 
Correlative Studies Background 
 
2.4.1 Cell free DNA (cfDNA).  Plasma obtained at baseline, each restaging, and end of study 
treatment will be analyzed for the presence of mutations and amplifications of genes of 
interest. Mutations of interest include KRAS and NRAS exons 2, 3, and 4, BRAF, 
PIK3CA, EGFR, AKT, PTEN, and MET. Amplifications of interest include MET, EGFR, 
and ERBB2. The allele frequency and copy number of these mutations and 
amplifications will be followed until progression (or end of study treatment). These 
analyses will help to characterize genomic contributions to treatment outcome and 
analyze genomic changes over time on treatment.  
 
2.4.2 Circulating protein studies. Plasma obtained at baseline, each restaging, and end of 
study treatment will be analyzed for multiple soluble protein analytes, including (but not 
limited to) HGF, c-MET, EGF, HBEGF, TGF-α, EGFR, VEGFA-D, HER2, HER3, 
GAS6, and AXL. Additional biomarkers may also be explored using multiplex array 
technology. The results will help to characterize the relationship between soluble protein 
analyte expression and response to treatment. This analysis will also explore the 
association between soluble protein c-MET expression and gene amplification in tumor 
tissue. 
 


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2.4.3 c-MET expression and MET amplification in tumor tissue. Archival tumor tissue will 
be analyzed by IHC and FISH to assess c-MET protein expression and MET gene 
amplification in tumor tissue. The results will help to explore the association between c-
MET protein expression and amplification, the association between soluble c-MET 
expression in whole blood and c-MET protein expression in tumor tissue, as well as the 
association between MET gene amplification in cfDNA and amplification in tumor 
tissue.  
 
2.4.4 Comprehensive mutational analysis in tumor tissue. Archival tumor tissue will be 
analyzed by Next Generation Sequencing (NGS) to characterize genomic alterations, 
including MET gene amplification, in tumor tissue. These results will help to explore the 
contribution of these alterations to treatment outcome and prognosis.  
 
 
3. PATIENT SELECTION 
 
3.1 
Inclusion Criteria  
 
3.1.1 Histologically or cytologically confirmed adenocarcinoma of the colon or rectum that is 
metastatic and/or unresectable.  
 
3.1.2 Documented wild-type in KRAS and NRAS (codons 12, 13, 59, 61, 117, and 146) and in 
BRAF codon 600, based on tumor tissue taken from primary or metastatic site prior to 
anti-EGFR antibody treatment.   
 
3.1.3 At least one site of disease that is measurable by RECIST criteria as defined in Section 
11.1.2. 
 
3.1.4 MET amplification detected by the Guardant360 cfDNA screening assay (MET copy 
number ≥ 2.2). 
 
3.1.5 Clinical or radiographic progression on treatments containing a fluoropyrimidine (e.g., 
5- fluorouracil or capecitabine), oxaliplatin, irinotecan, an anti-VEGF monoclonal 
antibody (bevacizumab, ziv-aflibercept) or anti-VEGFR monoclonal antibody 
(ramucirumab), and an anti-PD1 monoclonal antibody (nivolumab or pembrolizumab) 
for patients with MSI-high/MMR deficient tumors, or the treatments were not tolerated 
or contraindicated.  
 
3.1.6 Clinical or radiographic progression on prior anti-EGFR antibody therapy (either 
panitumumab or cetuximab).  
 
3.1.7  Age ≥18 years. 
 
3.1.8 ECOG performance status 0-1 (Karnofsky ≥80%, see Appendix A). 
 


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13 
3.1.9 Adequate hematological function defined as: 
− 
Absolute neutrophil count (ANC) ≥1,500/mcL 
− 
Hemoglobin (Hgb) ≥9 g/dL (no transfusion in the past 2 weeks)                                          
− 
Platelets ≥100,000/mcL (no transfusion in the past 10 days) 
 
3.1.10 Adequate liver function defined as: 
− 
Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 x the 
institutional upper limit of normal (ULN) with total bilirubin (TBL) ≤1 x ULN 
OR 
− 
Total bilirubin (TBL) >ULN ≤1.5 × ULN with ALT and AST ≤ 1x ULN 
 
3.1.11 Adequate renal function defined as: 
− GFR ≥60 mL/min/1.73m2 unless data exists supporting safe use at lower kidney 
function values, no lower than 30 mL/min/1.73m2 
 
3.1.12 Adequate coagulation parameters, defined as: 
− 
International Normalization Ratio (INR) <1.5 x ULN and activated partial 
thromboplastin time (aPTT) <1.5 x ULN unless patients are receiving therapeutic 
anticoagulation which affects these parameters 
 
3.1.13 Females of childbearing potential should be willing to use adequate contraceptive 
measures (see Section 5.2.2), should not be breast feeding, and must have a negative 
pregnancy test if of childbearing potential or must have evidence of non-childbearing 
potential by fulfilling one of the following criteria at screening: 
− 
post-menopausal is defined as aged more than 50 years and amenorrheic for at least 
12 months following cessation of all exogenous hormonal treatments; women under 
the age of 50 years would be considered postmenopausal if they have been 
amenorrheic for 12 months or more following cessation of exogenous hormonal 
treatments and with LH and FSH levels in the post-menopausal range for the 
institution; or women with documentation of irreversible surgical sterilization by 
hysterectomy, bilateral oophorectomy or bilateral salpingectomy but not tubal 
ligation. 
 
3.1.14 Male patients with female partner of childbearing potential should be willing to use 
barrier contraception during the study and for 6 months following discontinuation of 
study drug.  
 
3.1.15 Ability to swallow and retain oral medications. 
 
3.1.16 Ability to understand and the willingness to sign a written informed consent document. 
 
3.2 
Exclusion Criteria 
 
3.2.1 Cytotoxic chemotherapy (including investigational cytotoxic chemotherapy) or biologic 
agents (eg. Cytokines or antibodies) within 3 weeks of first dose of study treatment.  
 


NCI Protocol #: 10181 
Version Date: December 3, 2020 
 
14 
3.2.2 Not recovered to baseline or CTCAE ≤ Grade 1 from adverse events due to all prior 
anti-cancer therapies except alopecia, oxaliplatin-related neuropathy, and other non-
clinically significant adverse events.  
 
3.2.3 Any other investigational agents within 21 days before the first dose of study treatment. 
 
3.2.4 Wide field radiotherapy (including therapeutic radioisotopes such as strontium 89) 
administered ≤28 days or limited field radiation for palliation ≤7 days prior to starting 
study drug or has not recovered from side effects of such therapy. 
 
3.2.5 Known brain metastases. (Radiated or resected lesions are permitted, provided the 
lesions are fully treated and inactive, patient is asymptomatic, and no steroids have been 
administered for at least 30 days). 
 
3.2.6 History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to savolitinib. 
 
3.2.7 Prior treatment with a small molecule inhibitor of c-MET or monoclonal antibody 
against c-MET or HGF. 
 
3.2.8 Any of the following concurrent medication use: 
a. Herbal preparations/medications are not allowed throughout the study.  These 
herbal medications include, but are not limited to: St. John’s wort, kava, ephedra 
(ma huang), gingko biloba, dehydroepiandrosterone (dhea), yohimbe, saw 
palmetto, and ginseng.  Patients should stop using these herbal medications 7 
days prior to first dose of study drug (three weeks for St. John’s wort). 
b. Patients receiving or requiring strong inducers or strong inhibitors of CYP3A4, 
strong inhibitors of CYP1A2, or CYP3A4 substrates which have a narrow 
therapeutic range within 2 weeks of the first dose of study treatment (3 weeks for 
st john’s wort) will be excluded.   
c. Concomitant use of drugs that are known to be strong inhibitors of CYP3A4 or 
CYP1A2 is not permitted during the trial or must be stopped at least 2 weeks 
prior to receiving the first dose of savolitinib.   
 
3.2.9 Any of the following cardiac disease currently or within the last 6 months: 
a. Unstable angina pectoris 
b. Congestive heart failure (New York Heart Association (NYHA) ≥ Grade II; See 
Appendix D for details of NYHA grading system)  
c. Acute myocardial infarction 
d. Stroke or transient ischemic attack 
3.2.10 Known hypersensitivity to the active or inactive excipients of AZD6094. 
 


NCI Protocol #: 10181 
Version Date: December 3, 2020 
 
15 
3.2.11 Uncontrolled hypertension (BP ≥150/95 mmHg despite medical therapy) 
 
3.2.12 Active gastrointestinal disease or other condition that will interfere significantly with the 
absorption, distribution, metabolism, or excretion of oral therapy (e.g. ulcerative disease, 
uncontrolled nausea, vomiting, diarrhea Grade ≥2, and malabsorption syndrome). 
 
3.2.13 Mean resting correct QT interval (QTcF) >470 msec for women and >450 msec for men 
on screening obtained from 3 electrocardiograms (ECGs). 
 
3.2.14 Any factors that may increase the risk of QTc prolongation such as chronic 
hypokalaemia not correctable with supplements, congenital or familial long QT 
syndrome; or family history of unexplained sudden death under 40 years of age in first-
degree relatives or any concomitant medications known to prolong QT interval and 
cause Torsade de Pointes (TdP). 
 
3.2.15 Any clinically important abnormalities in rhythm, conduction or morphology of resting 
electrocardiograms (ECGs), e.g. complete left bundle branch block, third degree heart 
block, second degree heart block, PR interval >250 msec.  
 
3.2.16 Major surgical procedures ≤28 days of beginning study drug or minor surgical 
procedures ≤7 days. No waiting is required following port-a-cath placement. 
 
3.2.17 Serious underlying medical condition at the time of treatment that would impair the 
ability of the patient to receive protocol treatment.  
 
3.2.18 Active hepatitis B (positive HBV surface antigen (HBsAg) result) or hepatitis C (HCV) 
infection. Patients with positive HCV antibody are eligible only if the polymerase chain 
reaction is negative for HCV RNA.  Patients with a past or resolved HBV infection are 
eligible if: 
− negative for HBsAg and positive for hepatitis B core antibody [anti-HBc] 
 
OR  
− positive for HBsAg, but for > 6 months have had normal transaminases and HBV 
DNA levels between 0 – 2000 IU/ml (inactive carrier state) and willing to start and 
maintain antiviral treatment for at least the duration of the study 
OR 
− HBV DNA levels  >2000 IU/ml but on prophylactic antiviral treatment for the past 3 
months and will maintain the antiviral treatment during the study 
 
3.2.19 Known serious active infection requiring antibiotic, antiviral or antifungal therapy. HIV-
positive patients are eligible only if meeting ALL criteria below: 
− 
No history of AIDS-defining conditions 
− 
Has been on the current HARRT regimen for the past 3 months and will remain on 
the same regimen during the study 
− 
Current HARRT regimen has a low potential for drug-drug interaction with the study 
drug 
− HIV viral load consistently below detectable limit for the past 3 months 


NCI Protocol #: 10181 
Version Date: December 3, 2020 
 
16 
− CD4 count consistently >200 cells/mm3 for the past 3 months 
 
3.2.20 Presence of other active cancers, or history of treatment for invasive cancer, within the 
last 5 years.  Patients with Stage I cancer who have received definitive local treatment at 
least 3 years previously, and are considered unlikely (less than 5% probability) to recur 
are eligible.  All patients with previously treated in situ carcinoma (i.e., non-invasive) 
are eligible, as are patients with history of non-melanoma skin cancer. 
 
3.2.21 Psychiatric illness/social situations that would limit compliance with study requirements.  
Patients with impaired decision-making capacity who have a close caregiver or legal 
guardian are also eligible with the consent of the caregiver/guardian. 
 
3.2.22 Judgment by the investigator that the patients should not participate in the study if the 
patient is unlikely to comply with study procedures, restrictions and requirements. 
 
3.3 
Inclusion of Women and Minorities 
 
Men and women of all races and ethnic groups are eligible for this study. 
 
NIH policy requires that women and members of minority groups and their subpopulations be 
included in all NIH-supported biomedical and behavioral research projects involving NIH-
defined clinical research unless a clear and compelling rationale and justification establishes to 
the satisfaction of the funding Institute & Center (IC) Director that inclusion is inappropriate 
with respect to the health of the subjects or the purpose of the research.  Exclusion under other 
circumstances must be designated by the Director, NIH, upon the recommendation of an IC 
Director based on a compelling rationale and justification.  Cost is not an acceptable reason for 
exclusion except when the study would duplicate data from other sources.  Women of 
childbearing potential should not be routinely excluded from participation in clinical research.   
 
Please see http://grants.nih.gov/grants/funding/phs398/phs398.pdf. 
 
 
4. REGISTRATION PROCEDURES 
 
4.1 
Investigator and Research Associate Registration with CTEP 
 
Food and Drug Administration (FDA) regulations require IND sponsors to select qualified 
investigators. NCI policy requires all persons participating in any NCI-sponsored clinical trial to 
register and renew their registration annually.  To register, all individuals must obtain a CTEP 
Identity and Access Management (IAM) account (https://ctepcore.nci.nih.gov/iam).  In addition, 
persons with a registration type of Investigator (IVR), Non-Physician Investigator (NPIVR), or 
Associate Plus (AP) (i.e., clinical site staff requiring write access to OPEN or RAVE or acting as 
a primary site contact) must complete their annual registration using CTEP’s web-based 
Registration and Credential Repository (RCR) (https://ctepcore.nci.nih.gov/rcr).  Documentation 
requirements per registration type are outlined in the table below. 
 


NCI Protocol #: 10181 
Version Date: December 3, 2020 
 
17 
Documentation Required 
IVR 
NPIV
R 
AP 
A 
FDA Form 1572 
 
 
Financial Disclosure Form 
 
 
 
NCI Biosketch (education, training, employment, 
license, and certification) 
 
 
 
HSP/GCP training 
 
 
 
Agent Shipment Form (if applicable) 
 
CV (optional) 
 
 
 
 
An active CTEP-IAM user account and appropriate RCR registration is required to access all 
CTEP and CTSU (Cancer Trials Support Unit) websites and applications.  In addition, IVRs and 
NPIVRs must list all clinical practice sites and IRBs covering their practice sites on the FDA 
Form 1572 in RCR to allow the following: 
• Added to a site roster 
• Assigned the treating, credit, consenting, or drug shipment (IVR only) tasks in OPEN 
• Act as the site-protocol PI on the IRB approval 
• Assigned the Clinical Investigator (CI) role on the Delegation of Tasks Log (DTL).     
 
Additional information can be found on the CTEP website at 
https://ctep.cancer.gov/investigatorResources/default.htm. For questions, please contact the RCR 
Help Desk by email at RCRHelpDesk@nih.gov 
 
4.2 
Site Registration 
 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
 
Each investigator or group of investigators at a clinical site must obtain IRB approval for this 
protocol and submit IRB approval and supporting documentation to the CTSU Regulatory Office 
before they can be approved to enroll patients.  Assignment of site registration status in the 
CTSU Regulatory Support System (RSS) uses extensive data to make a determination of whether 
a site has fulfilled all regulatory criteria including but not limited to the following:  
• An active Federal Wide Assurance (FWA) number 
• An active roster affiliation with the Lead Network or a participating organization 
• A valid IRB approval 
• Compliance with all protocol specific requirements. 
 
In addition, the site-protocol Principal Investigator (PI) must meet the following criteria: 


NCI Protocol #: 10181 
Version Date: December 3, 2020 
 
18 
• Active registration status 
• The IRB number of the site IRB of record listed on their Form FDA 1572 
• An active status on a participating roster at the registering site 
 
Sites participating on the NCI CIRB initiative that are approved by the CIRB for this study are 
not required to submit IRB approval documentation to the CTSU Regulatory Office. For sites 
using the CIRB, IRB approval information is received from the CIRB and applied to the RSS in 
an automated process.  Signatory Institutions must submit a Study Specific Worksheet for Local 
Context (SSW) to the CIRB via IRBManager to indicate their intent to open the study locally.  
The CIRB’s approval of the SSW is then communicated to the CTSU Regulatory Office.  In 
order for the SSW approval to be processed, the Signatory Institution must inform the CTSU 
which CIRB-approved institutions aligned with the Signatory Institution are participating in the 
study. 
 
4.2.1 Downloading Regulatory Documents 
 
Site registration forms may be downloaded from the 10181 protocol page located on the 
CTSU Web site.  Permission to view and download this protocol is restricted and is based 
on person and site roster data housed in the CTSU RSS.  To participate, Investigators and 
Associates must be associated with the Corresponding or Participating protocol 
organization in the RSS.  
 
• Go to https://www.ctsu.org and log in using your CTEP-IAM username and 
password. 
• Click on the Protocols tab in the upper left of your screen.  
• Either enter the protocol # in the search field at the top of the protocol tree, or 
• Click on the By Lead Organization folder to expand, then select LAO-NC010, 
and protocol #10181. 
• Click on LPO Documents, select the Site Registration documents link, and 
download and complete the forms provided.  (Note: For sites under the CIRB 
initiative, IRB data will load to RSS as described above.) 
 
4.2.2 Requirements For 10181 Site Registration: 
 
• IRB approval (For sites not participating via the NCI CIRB; local IRB 
documentation, an IRB-signed CTSU IRB Certification Form, Protocol of Human 
Subjects Assurance Identification/IRB Certification/Declaration of Exemption 
Form, or combination is accepted) 
• Site Initiation Meeting (SIM) by the Study Chair/Lead Principal Investigator 
(Prior to the start of subject enrollment, participating sites must contact Duke 
Cancer Institute LAO by emailing ETCTN-LAO-NC010@dm.duke.edu to 
schedule a SIM.  In cooperation with the participating site, Duke Cancer Institute 
LAO will arrange a web conference meeting. Once the SIM is completed, Duke 
Cancer Institute LAO will notify the CTSU of participating site’s training 
fulfillment.) 


NCI Protocol #: 10181 
Version Date: December 3, 2020 
 
19 
• ETCTN Specimen Tracking Training 
• At least one individual at each participating site will need to complete the 
Theradex-led training. 
• Theradex will provide a certificate of completion, which will need to be 
submitted to the CTSU through the Regulatory Submission Portal. 
• The training is a one-time only requirement per individual. If an individual 
has previously completed the training for another ETCTN study, the 
training does not need to be completed again nor does the certificate of 
completion need to be resubmitted to the CTSU. 
• This training will need to be completed before first/further patient 
enrollment at a given site 
• Peter Clark is the main point of contact at Theradex for the training (802-
456-8735, PClark@theradex.com). Nafeesa Sarakhawas is the backup 
contact (609.480.2693, NSarakhawas@theradex.com). 
 
4.2.3 Submitting Regulatory Documents 
 
Submit required forms and documents to the CTSU Regulatory Office, where they will 
be entered and tracked in the CTSU RSS.   
Regulatory Submission Portal: www.ctsu.org  (members’ area) → Regulatory Tab 
→Regulatory Submission  
 
When applicable, original documents should be mailed to: 
CTSU Regulatory Office 
1818 Market Street, Suite 3000 
Philadelphia, PA 19103 
 
Institutions with patients waiting that are unable to use the Portal should alert the CTSU 
Regulatory Office immediately at 1-866-651-2878 in order to receive further instruction 
and support. 
 
4.2.4 Checking Site Registration Status 
 
You can verify your site registration status on the members’ section of the CTSU 
website.   
 
• Go to https://www.ctsu.org and log in to the members’ area using your CTEP-IAM 
username and password 
• Click on the Regulatory tab at the top of your screen 
• Click on the Site Registration tab 
• Enter your 5-character CTEP Institution Code and click on Go 
 


NCI Protocol #: 10181 
Version Date: December 3, 2020 
 
20 
Note: The status given only reflects compliance with IRB documentation and institutional 
compliance with protocol-specific requirements as outlined by the Lead Network. It does 
not reflect compliance with protocol requirements for individuals participating on the 
protocol or the enrolling investigator’s status with the NCI or their affiliated networks. 
 
4.3 
Patient Registration 
 
NOTE:  There are two consent forms for this study.  Patients will sign the Screening Consent 
Form prior to the Guardant360 test.  If MET amplification is detected from the Guardant360 test, 
the patient will sign the Main Consent Form prior to screening for the study treatment portion of 
the study. 
4.3.1 OPEN / IWRS 
 
Patient enrollment will be facilitated using the Oncology Patient Enrollment Network 
(OPEN).  OPEN is a web-based registration system available to users on a 24/7 basis.  It 
is integrated with the CTSU Enterprise System for regulatory and roster data interchange 
and with the Theradex Interactive Web Response System (IWRS) for retrieval of patient 
registration/randomization assignment.  Patient enrollment data entered by Registrars in 
OPEN / IWRS will automatically transfer to the NCI’s clinical data management system, 
Medidata Rave.  
 
4.3.2 OPEN/IWRS User Requirements 
 
OPEN/IWRS users must meet the following requirements: 
• Have a valid CTEP-IAM account (i.e., CTEP username and password). 
• To enroll patients or request slot reservations:  Be on an ETCTN Corresponding 
or Participating Organization roster with the role of Registrar. Registrars must 
hold a minimum of an AP registration type. 
• To approve slot reservations or access cohort management:  Be identified to 
Theradex as the “Client Admin” for the study.  
• Have regulatory approval for the conduct of the study at their site. 
 
Prior to accessing OPEN/IWRS, site staff should verify the following: 
• All eligibility criteria have been met within the protocol stated timeframes.   
• If applicable, all patients have signed an appropriate consent form and HIPAA 
authorization form. 
 
4.3.3 Special Instructions for Patient Enrollment  
 
The following information will be requested: 
• Protocol Number 
• Investigator Identification  
o Institution and affiliate name 


NCI Protocol #: 10181 
Version Date: December 3, 2020 
 
21 
o Investigator’s name 
• Eligibility Verification:  Patients must meet all the eligibility requirements 
listed in Section 3.1. 
• Additional Requirements: 
o Patients must provide a signed and dated, written informed consent 
form. 
 
Upon enrolling a patient, IWRS will communicate with OPEN, assigning two separate 
and unique identification numbers to the patient, a Universal patient ID (UPID) and a 
Treatment patient ID.  The UPID is associated with the patient and used each and every 
time the patient engages with the ETCTN Biobanking and Molecular Characterization 
portion of this protocol.  The UPID contains no information or link to the treatment 
protocol.  IWRS will maintain an association between the UPID for ETCTN biobanking 
and molecular characterization and any treatment protocols the patient participates in, 
thereby allowing analysis of the molecular characterization results with the clinical data.   
 
Immediately following enrollment, the institutional anatomical pathology report for the 
diagnosis under which the patient is being enrolled must be uploaded into Rave.  The 
report must include the surgical pathology ID (SPID) and the IWRS-assigned UPID for 
this trial.  Important:  Remove any personally identifying information, including, 
but not limited to, the patient’s name, initials, and patient ID# for this treatment 
trial, from the institutional pathology report prior to submission. 
 
4.3.4 OPEN/IWRS Questions? 
 
Further instructional information on OPEN is provided on the OPEN tab of the CTSU 
website at https://www.ctsu.org or at https://open.ctsu.org.  For any additional questions 
contact the CTSU Help Desk at 1-888-823-5923 or ctsucontact@westat.com.  
 
 
5. TREATMENT PLAN 
 
5.1 
Agent Administration 
 
Treatment will be administered on an outpatient basis.  Reported adverse events and potential 
risks are described in Section 7.  Appropriate dose modifications are described in Section 6.  No 
investigational or commercial agents or therapies other than those described below may be 
administered with the intent to treat the patient's malignancy. 
 
Regimen Description 
Agent 
Premedications; 
Precautions 
Dose 
Route 
Schedule 
Cycle 
Length 
Savolitinib 
N/A 
600 mg 
once daily 
for weight 
Orally 
Days 1-28 
28 days 
(4 weeks) 


NCI Protocol #: 10181 
Version Date: December 3, 2020 
 
22 
Regimen Description 
Agent 
Premedications; 
Precautions 
Dose 
Route 
Schedule 
Cycle 
Length 
≥ 50 kg 
and 400 
mg once 
daily if 
weight < 
50kg once 
daily 
 
Savolitinib must be taken with food.  Tablet must be swallowed whole with water.  Savolitinib 
dosing may be modified, suspended or discontinued due to unacceptable treatment-related side 
effects. The patient will be requested to maintain a medication diary of each dose of medication 
to assess compliance with treatment.  Appendix B (Patient Drug Diary Card) should be provided 
to patients at each cycle.  The medication diary will be returned to clinic staff at the end of each 
course. 
 
5.2 
General Concomitant Medication and Supportive Care Guidelines 
 
Studies indicate that savolitinib has little induction potential for major CYP isoforms. Because 
there is a potential for interaction of savolitinib with other concomitantly administered drugs, the 
case report form must capture the concurrent use of all other drugs, over-the-counter 
medications, or alternative therapies. Regulator guidelines suggested that the exposure to 
medications whose disposition is dependent on CYPs 2C8, 3A4/5, P-gp may be increased when 
co-administered with savolitinib. The likelihood of a clinically meaningful drug-drug interaction 
with savolitinib substrates whose disposition is depended on drug transporters BCRP, OATPIB1, 
MATE1 and MATE2-K cannot be discounted. The potential of savolitinib to inhibit the 
metabolism of substrates of UGT1A1 cannot be ruled out but is considered unlikely. The 
Principal Investigator should be alerted if the patient is taking any agent known to affect or with 
the potential for drug interactions. The study team should check a frequently-updated medical 
reference for a list of drugs to avoid or minimize use of.  Appendix C (Patient Drug Information 
Handout and Wallet Card) should be provided to patients if available. 
 
5.2.1 Concomitant Medications 
 
Statins 
Discontinuation of statins is advised unless considered essential, in which case, the patients 
should be prescribed the lowest dose available and monitored for the effects of increased statin 
exposure. 
 
Acetaminophen (paracetamol) 
The administration of acetaminophen (paracetamol) to a patient is restricted to 3 grams per day 
or the maximum dose approved locally (if less than 3 gm/day) during the study.    
 


NCI Protocol #: 10181 
Version Date: December 3, 2020 
 
23 
Metformin  
Metformin should be used with caution and patients monitored for the effect of increased 
metformin exposure. 
 
Antivirals 
Adefovir, lamivudine and tenofovir should be used with caution and patients monitored for the 
effects of increased exposure. 
 
Other Medication Restrictions 
Discontinuation of strong inducers of CYP3A4 and CYP3A4 substrates which have a narrow 
therapeutic range or CYP3A4 sensitive is advised unless considered essential by the investigator, 
in which case patients must be monitored closely for potentially reduced efficacy or increased 
toxicity due to drug-drug interactions. 
 
Those drugs defined as strong CYP2C8 substrates (almost exclusively metabolised by CYP2C8, 
such as repaglinide and rosiglitazone) should be used with caution.   
 
Drugs that are known to be affected by P-gp such as digoxin, quinidine, loperamide, ritonavir 
and saquinavir should be used with caution.  
 
Drugs that prolong QT interval 
The concomitant administration of drugs known to prolong QT interval is restricted unless 
considered essential due to patient management, in which case, patients should be closely 
monitored with frequent ECGs. Additional guidance on drugs known to prolong QT interval is 
provided in the protocol appendix “GUIDANCE REGARDING POTENTIAL INTERACTIONS 
WITH CONCOMITANT MEDICATIONS KNOWN TO PROLONG QT INTERVAL.” 
 
 
5.2.2 Pregnancy and Contraception 
 
Females of childbearing potential must agree to use two medically acceptable contraceptive 
methods from the time of screening until 4 weeks after last dose of study drug. One 
contraceptive method must be a barrier method. Medically acceptable contraceptives include: (1) 
surgical sterilization (such as a tubal ligation or hysterectomy), (2) approved hormonal 
contraceptives (such as birth control pills, patches, implants or injections), (3) barrier methods 
(such as a condom or diaphragm) used with a spermicide, or (4) an intrauterine device (IUD). 
Female condoms and male condoms should never be used at the same time. Contraceptive 
measures such as Plan BTM, sold for emergency use after unprotected sex, are not acceptable 
methods for routine use.  
 
Male patients sexually active with a female partner of childbearing potential must agree to use 
two medically acceptable forms of birth control, one of which is a barrier method, at the same 
time in order to be in this study and until 6 months after the last dose of study drug. Medically 
acceptable contraceptives include: (1) surgical sterilization (such as a vasectomy), or (2) a 
condom used with a spermicide. Acceptable contraceptive methods for women include: (1) 
surgical sterilization (such as a tubal ligation or hysterectomy), (2) approved hormonal 


NCI Protocol #: 10181 
Version Date: December 3, 2020 
 
24 
contraceptives (such as birth control pills, patches, implants or injections), (3) barrier methods 
(such as a condom or diaphragm) used with a spermicide, or (4) an intrauterine device (IUD). 
Female condoms and male condoms should never be used at the same time. Contraceptive 
measures such as Plan B ™, sold for emergency use after unprotected sex, are not acceptable 
methods for routine use. 
 
Male patients should refrain from donating sperm from the start of dosing until 6 months after 
discontinuing study treatment. 
 
5.2.3 Food Restrictions 
 
Patients should abstain from eating large amounts of grapefruit and seville oranges (and other 
products containing these fruits eg, grapefruit juice or marmalade) during the study (e.g., no 
more than a small glass of grapefruit juice (120 ml) or half a grapefruit or 1-2 teaspoons (15g) of 
seville orange marmalade daily). 
 
5.2.4 UV Exposure 
 
During savolitinib therapy and for 4 weeks after the last dose patients should be advised to avoid 
prolonged exposure to the sun, wear protective clothing, a hat and seek shade from the sun as far 
as possible; in addition SPF30+ sunscreen should be used. Exposure to other sources of UV light 
including sun beds and tanning booths, etc. should be avoided. 
 
5.3 
Duration of Therapy 
 
In the absence of treatment delays due to adverse event(s), treatment may continue until one of 
the following criteria applies: 
 
• 
Radiographic disease progression as defined by RECIST criteria. 
• 
Clinical disease progression indicated by worsening signs and symptoms related to 
disease with or without radiographic disease progression. 
• 
Intercurrent illness that prevents further administration of treatment 
• 
Unacceptable adverse event(s) 
• 
Patient decides to withdraw from the study 
• 
General or specific changes in the patient's condition render the patient unacceptable 
for further treatment in the judgment of the investigator 
• 
Patient non-compliance 
• 
Pregnancy 
o All women of child bearing potential should be instructed to contact the 
investigator immediately if they suspect they might be pregnant (e.g., missed 
or late menstrual period) at any time during study participation. 


NCI Protocol #: 10181 
Version Date: December 3, 2020 
 
25 
o The investigator must immediately notify CTEP in the event of a confirmed 
pregnancy in a patient participating in the study. 
• 
Termination of the study by sponsor 
• 
The drug manufacturer can no longer provide the study agent 
 
The reason(s) for protocol therapy discontinuation, the reason(s) for study removal, and the 
corresponding dates must be documented in the Case Report Form (CRF). 
 
5.4 
Duration of Follow Up 
 
Patients who discontinue study treatment for any reason (e.g. toxicity) other than disease 
progression will be followed until disease progression, or start of a new anti-cancer therapy, or 
until death, loss to follow-up, or study completion, whichever occurs first. Study completion is 2 
years after the last subject starts study treatment.  
 
6. DOSING DELAYS/DOSE MODIFICATIONS 
 
Substantial acute toxicities should be managed as medically indicated and with temporary 
suspension of study drug, as appropriate. 
 
Dose reductions or holds are allowed as clinically indicated by the treating physician and in line 
with Table 1. For each patient, a maximum of 2 dose reductions will be allowed unless the 
patient has started at 400 mg savolitinib due to weight < 50 kg, where only one dose reduction is 
allowed.  No dose re-escalations are allowed.  Guidance on dose level reduction is presented in 
the table below. 
 
Table 1    Savolitinib dose level modification 
Dose Level 
Savolitinib Daily Dose 
Starting 
600 mg QD (weight ≥ 50 kg) 
400 mg QD (weight < 50kg) 
-1 
400 mg QD 
200 mg QD 
-2 
200 mg QD 
 
 
Below are dose modification guidance for hepatic and non-hepatic drug-related toxicities.  Please 
use as appropriate.  If a patient experiences several adverse events and there are conflicting 
recommendations, the investigator should use the recommended dose adjustment that reduces the 
dose to the lowest level. 
 
6.1 
Hepatic Toxicities 
 
Promptly evaluate patients with elevated LFTs during study treatment for alternative etiologies 
and potential Hy’s law criteria, and discontinue potential contributing concomitant medications 
or alternative causal agents, as well as anti-coagulants, if appropriate. 
 
If a patient discontinues due to LFT abnormality, LFT monitoring should continue until resolved 
to grade 1 or baseline or an apparent plateau has been reached. 


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26 
 
Paracetamol/acetaminophen dose should not exceed 3 g per day or the maximum dose approved 
locally (if this was less than 3 g/day) during the study. 
 
Investigators should review the patient’s current concomitant medications and evaluate the need 
for the patient to continue on hepatic metabolism modifying agents, such as statins. 
 
Follow the general guidance below for dose interruptions/reductions: 
 
Dose modifications for hepatic study drug-related toxicities 
·       Discontinue drug if 
-        ALT or AST >8xULN, or 
-        ALT or AST >5xULN for >2 weeks, or 
-        ALT or AST >3xULN and (TB >2xULN or INR >1.5 if not on 
anticoagulants that elevate the INR) 
-        AST or ALT >3xULN with the appearance of fatigue, nausea, vomiting, 
right upper quadrant pain or tenderness, fever, rash, and/or eosinophilia >5% 
·       Withhold dosing if ALT or AST >5-8xULN without TB elevation above baseline 
or ULN, repeat LFT testing twice a week for 1 week; 
-        If improved to Grade 1 or baseline in 1 week, resume at reduced dose with 
LFT testing twice a week for 6 weeks; 
-        If not, discontinue 
·       Withhold dosing if ALT or AST >3xULN and concurrent TB 1.5~2xULN, repeat 
LFT testing twice a week for 1 week, 
-        If both ALT/AST and TB improved to Grade 1 or baseline in 1 week, 
resume at reduced dose with LFT testing twice a week for 6 weeks 
-        If not, discontinue 
·       Continue dosing if ALT or AST >3-5xULN without TB elevation above baseline or 
ULN, repeat LFT testing every week 
-        If ALT or AST trending upward, withhold dosing and repeat LFT twice a 
week for 1 week; 
-        If improve to Grade 1 or baseline in 1 week, resume at same dose with LFT 
testing every week for 6 weeks 
-        If improve to Grade 1 or baseline in 2 weeks, resume at reduced dose with 
LFT testing every week for 6 weeks 
-        If not, discontinue 
·       Discontinue for recurrent ALT or AST >5xULN 
·       Discontinue for recurrent ALT or AST >3-5xULN and TB >1.5~2xULN 
·       Withhold dosing for recurrent ALT or AST >3-5xULN without TB elevation 
above baseline or ULN, repeat LFT testing twice a week for 1 week 
-        if improve to grade 1 or baseline in 1 week, resume at reduced dose with 
LFT testing every week for 6 weeks; if not, discontinue 
 
6.2 
Non-hepatic Toxicities 
 


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27 
Dose modification guidelines for non-hepatic study drug-related toxicities are shown 
below.  Appropriate and optimal treatment of the toxicity is assumed prior to considering dose 
modifications. Prior to discontinuation of study drug due to toxicities please consult with the 
study physician. 
 
Dose modifications for non-hepatic study drug-related toxicities 
NCI CTCAE v5.0 Toxicity Grade 
Action 
Grade 0, 1, or 2 
Hold dosing or reduce dose following 
algorithm below for persistent and/or 
intolerable grade 2 toxicities. 
 
Grade 3 a 
Hold dosing and follow algorithm below 
·         Grade 3 toxicity for ≤7 days and resolves 
to ≤Grade 1 or baseline 
·         Grade 3 toxicity for >7 days 
·         Resume dosing at one reduced dose 
level (maximum of 2 dose reductions unless 
the patient has started at 400 mg savolitinib 
due to weight < 50 kg, where only one dose 
reduction is allowed) 
·         Discontinue study drug 
 
Grade 4 
  
·         Expected to be manageable/reversible 
with dose reduction 
·         Not expected to be 
manageable/reversible with dose reduction 
 
·         Hold dose and consult with study 
medical monitor 
·         Discontinue study drug 
Recurrence of Grade 3 
  
·         Grade 3 toxicity for ≤7 days and resolves 
to ≤Grade 1 or baseline 
·         Grade 3 toxicity for >7 days 
 
·         Resume dosing at one reduced dose 
level (maximum of 2 dose reductions 
maximum of 2 dose reductions unless the 
patient has started at 400 mg savolitinib due 
to weight < 50 kg, where only one dose 
reduction is allowed) 
·         Discontinue study drug 
Recurrence of Grade 4 
Discontinue study drug 
No more than 2 dose reductions will be allowed for any patient. Patients requiring additional dose modifications 
due to toxicity will discontinue study treatment. 
a Despite appropriate supportive care 
CTCAE Common Terminology Criteria for Adverse Events; NCI National Cancer Institute 
 
Dermatologic 
A case of Stevens-Johnson syndrome (SJS) has been reported in temporal association with 
savolitinib. Patients who show symptoms or signs suggesting emerging Stevens-Johnson 
syndrome (SJS) while on study treatment (e.g., progressive skin rash often with blisters or 
mucosal lesions), must discontinue savolitinib immediately and receive appropriate treatment. If 
emerging SJS is suspected, re-challenge with savolitinib must be avoided. 
 


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28 
Hypersensitivity 
Hypersensitivity, which may manifest as drug eruption, hypotension or myalgia has been 
reported after savolitinib dosing. Patients who show symptoms of suspected savolitinib related 
hypersensitivity must follow the dose modifications for non-hepatic study drug-related toxicities. 
Dosing with savolitinib can resume only after consultation with the study physician. 
 
Pyrexia 
If fever occurs savolitinib must be interrupted until etiology is established after thorough 
investigation. In cases where fever is considered causally related to savolitinib, then savolitinib 
must be discontinued. 
 
Nausea/Vomiting 
If vomiting occurs after taking savolitinib, the patient should be instructed not to retake the dose. 
Patients should take the next scheduled dose of savolitinib. Patient reports of nausea and 
vomiting are expected to be evaluated and treated by investigators according to local practice 
(eg, use of antiemetic therapy, intravenous fluid replacement). 
 
Peripheral edema/Edema 
Treatment interruption may be considered. Diuretic therapy should be considered at the 
discretion of the Investigator. Renal function should be carefully monitored. 
 
Fatigue 
Follow the general guidance in table titled, Dose modifications for non-hepatic study drug-
related toxicities, in Section 6.2 the protocol for dose interruptions/reductions/discontinuations in 
response to this AE. 
 
QTc prolongation 
If there is a marked prolongation of the QT/QTcF interval, QT/QTcF >500 msec or of >60 msec 
over baseline, during treatment with savolitinib, the patient must hold dosing and must be 
evaluated by a cardiologist to validate ECG finding and determine further management as 
clinically indicated. 
 
 
Dose modifications for savolitinib-related QTc prolongation  
NCI CTCAE Toxicity Grade 
Action 
Grade 0, 1, or 2 
None 
Grade 3 
Hold dosing and follow algorithm below  


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29 
Dose modifications for savolitinib-related QTc prolongation  
NCI CTCAE Toxicity Grade 
Action 
o 
Patients with QTcF prolongation to >500 
msec on at least two separate ECGs  
 
 
 
 
o 
If the toxicity does not resolve to QTcF < 
481msec within 21 days 
o 
Consult with cardiologist to validate 
ECG finding. Ensure cardiac 
surveillance and take actions in 
accordance with clinical standards. 
Regular ECGs performed until 
resolution to QTcF <481 msec. 
Restart drug at one reduced dose 
level 
o 
Discontinue study drug and consult 
with a cardiologist to validate ECG 
finding and management as 
clinically indicated  
Grade 4  
 
o 
QTcF >= 501 or >60 msec change from 
baseline and Torsade de pointes or 
polymorphic ventricular tachycardia or 
signs/symptoms of serious arrhythmia 
o 
Discontinue study drug and consult 
with a cardiologist for further 
management as clinically indicated 
 
7. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS  
 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The 
following list of AEs (Section 7.1) and the characteristics of an observed AE (Sections 7.2 and 
7.3) will determine whether the event requires expedited reporting via the CTEP Adverse Event 
Reporting System (CTEP-AERS) in addition to routine reporting. 
 
7.1 
Comprehensive Adverse Events and Potential Risks List(s) (CAEPRs) 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single list of reported and/or 
potential adverse events (AE) associated with an agent using a uniform presentation of events by body system. In 
addition to the comprehensive list, a subset, the Specific Protocol Exceptions to Expedited Reporting (SPEER), 
appears in a separate column and is identified with bold and italicized text. This subset of AEs (SPEER) is a list of 
events that are protocol specific exceptions to expedited reporting to NCI (except as noted below). Refer to the 
'CTEP, NCI Guidelines: Adverse Event Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf for further clarification. 
Frequency is provided based on 381 patients. Below is the CAEPR for Savolitinib (AZD6094). 
 
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses next to the AE in the 
SPEER.  If this CAEPR is part of a combination protocol using multiple investigational agents and has an AE 
listed on different SPEERs, use the lower of the grades to determine if expedited reporting is required. 
 
 
 
 


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30 
Version 2.4, April 2, 20201 
 
 Adverse Events with Possible  
 Relationship to Savolitinib (AZD6094) 
 (CTCAE 5.0 Term) 
[n= 381] 
 
 
 Specific Protocol Exceptions 
to Expedited Reporting 
(SPEER)  
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
  
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
  
 
Anemia 
 
 Anemia (Gr 2) 
GASTROINTESTINAL DISORDERS 
  
 
Constipation 
 
 Constipation (Gr 2) 
 
Diarrhea 
 
 Diarrhea (Gr 2) 
Nausea 
 
 
 Nausea (Gr 2) 
Vomiting 
 
 
 Vomiting (Gr 2) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
Edema limbs 
 
 
 Edema limbs (Gr 2) 
Fatigue 
 
 
 Fatigue (Gr 2) 
 
Fever 
 
 Fever (Gr 2) 
HEPATOBILIARY DISORDERS 
  
 
Hepatobiliary disorders - Other 
(hepatotoxicity)2 
 
  
IMMUNE SYSTEM DISORDERS 
  
 
 
Allergic reaction 
  
INVESTIGATIONS 
  
 
Alanine aminotransferase increased  
 Alanine aminotransferase 
increased (Gr 2) 
 
Alkaline phosphatase increased 
 
  
 
Aspartate aminotransferase 
increased 
 
 Aspartate aminotransferase 
increased (Gr 2) 
 
Blood bilirubin increased 
 
  
 
Creatinine increased 
 
  
 
 
Electrocardiogram QT corrected 
interval prolonged 
  
METABOLISM AND NUTRITION DISORDERS 
  
 
Anorexia 
 
 Anorexia (Gr 2) 
 
Hypoalbuminemia 
 
 Hypoalbuminemia (Gr 2) 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
Cough 
 
  
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
 
Stevens-Johnson syndrome 
  
 
1This table will be updated as the toxicity profile of the agent is revised. Updates will be distributed to all Principal 
Investigators at the time of revision.  The current version can be obtained by contacting 
PIO@CTEP.NCI.NIH.GOV.  Your name, the name of the investigator, the protocol and the agent should be 
included in the e-mail. 
 
2Hepatoxicity may manifest as increased liver enzymes (e.g., Alanine aminotransferase increased, Aspartate 
aminotransferase increased, Alkaline phosphatase increased, Blood bilirubin increased), hepatic function abnormal, 
and drug-induced liver injury (DILI).  
 
Adverse events reported on savolitinib (AZD6094) trials, but for which there is insufficient evidence to 
suggest that there was a reasonable possibility that savolitinib (AZD6094) caused the adverse event: 
 


NCI Protocol #: 10181 
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31 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Disseminated intravascular coagulation; Febrile 
neutropenia 
CARDIAC DISORDERS - Heart failure 
ENDOCRINE DISORDERS - Adrenal insufficiency 
EYE DISORDERS - Blurred vision; Eye disorders - Other (diplopia) 
GASTROINTESTINAL DISORDERS - Abdominal pain; Ascites; Dyspepsia; Gastritis; Gastrointestinal disorders 
- Other (abdominal incarcerated hernia); Gastrointestinal disorders - Other (GI [anastomotic] perforation); Ileus; 
Mucositis oral; Small intestinal obstruction; Upper gastrointestinal hemorrhage 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Death NOS; Edema face; 
Generalized edema; Non-cardiac chest pain; Pain 
HEPATOBILIARY DISORDERS - Hepatic pain; Hepatobiliary disorders - Other (hepatic encephalopathy); 
Hepatobiliary disorders - Other (hepatomegaly); Hepatobiliary disorders - Other (cholestasis); Hepatobiliary 
disorders - Other (hepatic lesion) 
INFECTIONS AND INFESTATIONS - Abdominal infection; Conjunctivitis; Fungemia; Lung infection; Sepsis; 
Upper respiratory infection; Urinary tract infection 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Injury, poisoning and procedural 
complications - Other (craniocerebral injury) 
INVESTIGATIONS - GGT increased; Lymphocyte count decreased; Neutrophil count decreased; Platelet count 
decreased 
METABOLISM AND NUTRITION DISORDERS - Dehydration; Hyperglycemia; Hyperkalemia; 
Hypertriglyceridemia; Hypoglycemia; Hypokalemia; Hyponatremia; Tumor lysis syndrome 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Back pain; Flank pain; Myalgia 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - Neoplasms 
benign, malignant and unspecified (incl cysts and polyps) - Other (malignant neoplasm progression) 
NERVOUS SYSTEM DISORDERS - Dizziness; Dysgeusia; Headache; Spinal cord compression 
PSYCHIATRIC DISORDERS - Confusion 
RENAL AND URINARY DISORDERS - Acute kidney injury; Chronic kidney disease; Renal and urinary 
disorders - Other (urine albumin/creatinine ratio increased) 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Genital edema 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Bronchopulmonary hemorrhage; 
Dyspnea; Hypoxia; Pleural effusion; Pneumonitis 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Photosensitivity; Pruritus; Rash maculo-papular 
VASCULAR DISORDERS - Hematoma; Hypertension; Hypotension; Thromboembolic event 
 
Note: Savolitinib (AZD6094) in combination with other agents could cause an exacerbation of any adverse event 
currently known to be caused by the other agent, or the combination may result in events never previously 
associated with either agent. 
 
7.2 
Adverse Event Characteristics  
 
• CTCAE term (AE description) and grade:  The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
5.0 will be utilized for AE reporting.  All appropriate treatment areas should have access 
to a copy of the CTCAE version 5.0.  A copy of the CTCAE version 5.0 can be 
downloaded from the CTEP web site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 
• For expedited reporting purposes only:   
- 
AEs for the agent that are bold and italicized in the CAEPR should be reported 
through CTEP-AERS only if the grade is above the grade provided in the SPEER. 
 
• Attribution of the AE: 


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32 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 
- 
Unlikely – The AE is doubtfully related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 
 
7.3 
Expedited Adverse Event Reporting 
 
7.3.1 Expedited AE reporting for this study must use CTEP-AERS (CTEP Adverse Event 
Reporting System), accessed via the CTEP Web site (https://eapps-
ctep.nci.nih.gov/ctepaers).  The reporting procedures to be followed are presented in the 
“NCI Guidelines for Investigators: Adverse Event Reporting Requirements for DCTD 
(CTEP and CIP) and DCP INDs and IDEs” which can be downloaded from the CTEP 
Web site 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.ht
m).  These requirements are briefly outlined in the tables below (Section 7.3.3). 
 
In the rare occurrence when Internet connectivity is lost, a 24-hour notification is to be 
made to CTEP by telephone at 301-897-7497.  Once Internet connectivity is restored, the 
24-hour notification phoned in must be entered electronically into CTEP-AERS by the 
original submitter at the site. 
 
7.3.2 Distribution of Adverse Event Reports 
 
CTEP-AERS is programmed for automatic electronic distribution of reports to the 
following individuals:  Principal Investigator and Adverse Event Coordinator(s) (if 
applicable) of the Corresponding Organization or Lead Organization, the local treating 
physician, and the Reporter and Submitter.  CTEP-AERS provides a copy feature for 
other e-mail recipients.  
 
7.3.3 Expedited Reporting Guidelines 
 
Use the NCI protocol number and the protocol-specific patient ID assigned during trial 
registration on all reports. 
 
Note:  A death on study requires both routine and expedited reporting, regardless of 
causality.  Attribution to treatment or other cause must be provided. 
 
Death due to progressive disease should be reported as Grade 5 “Disease Progression” 
in the system organ class (SOC) “General disorders and administration site 
conditions.” .  Evidence that the death was a manifestation of underlying disease (e.g., 
radiological changes suggesting tumor growth or progression: clinical deterioration 
associated with a disease process) should be submitted.  
 
Phase 1 and Early Phase 2 Studies:  Expedited Reporting Requirements for Adverse 
Events that Occur on Studies under an IND/IDE within 30 Days of the Last Administration 


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33 
of the Investigational Agent/Intervention 1, 2 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, whether or not 
they are considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
An adverse event is considered serious if it results in ANY of the following outcomes:   
1) 
Death 
2) 
A life-threatening adverse event  
3) 
An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 
hours  
4) 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions  
5) 
A congenital anomaly/birth defect.  
6) 
Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization 
may be considered serious when, based upon medical judgment, they may jeopardize the patient or 
subject and may require medical or surgical intervention to prevent one of the outcomes listed in this 
definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI via electronic 
submission within the timeframes detailed in the table below. 
Hospitalization 
Grade 1 and Grade 2 Timeframes 
Grade 3-5 
Timeframes 
Resulting in 
Hospitalization  
≥ 24 hrs 
10 Calendar Days 
24-Hour 5 Calendar 
Days 
Not resulting in 
Hospitalization  
≥ 24 hrs 
Not required 
NOTE:  Protocol specific exceptions to expedited reporting of serious adverse events are found in the Specific 
Protocol Exceptions to Expedited Reporting (SPEER) portion of the CAEPR. 
Expedited AE reporting timelines are defined as: 
o 
“24-Hour; 5 Calendar Days” - The AE must initially be submitted electronically within 24 hours of learning 
of the AE, followed by a complete expedited report within 5 calendar days of the initial 24-hour report. 
o 
“10 Calendar Days” - A complete expedited report on the AE must be submitted electronically within 10 
calendar days of learning of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as follows:  
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
• 
All Grade 3, 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
• 
Grade 2 AEs resulting in hospitalization or prolongation of hospitalization 
2For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive half-lives, 
rounded UP to the nearest whole day, after the agent/intervention was last administered.  Footnote “1” above 
applies after this reporting period. 
Effective Date:  May 5, 2011 
 
 
7.4 
Routine Adverse Event Reporting 
 
All Adverse Events must be reported in routine study data submissions.  AEs reported 
expeditiously through CTEP-AERS must also be reported in routine study data 
submissions. 
 


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34 
Adverse event data collection and reporting, which are required as part of every clinical trial, are 
done to ensure the safety of patients enrolled in the studies as well as those who will enroll in 
future studies using similar agents.  AEs are reported in a routine manner at scheduled times 
during the trial using Medidata Rave.  For this trial the Adverse Event CRF is used for routine 
AE reporting in Rave. 
 
7.5 
Pregnancy 
 
Although not an adverse event in and of itself, pregnancy as well as its outcome must be 
documented via CTEP-AERS.  In addition, the Pregnancy Information Form included within 
the NCI Guidelines for Adverse Event Reporting Requirements must be completed and 
submitted to CTEP.  Any pregnancy occurring in a patient or patient’s partner from the time of 
consent to 90 days after the last dose of study drug must be reported and then followed for 
outcome.  Newborn infants should be followed until 30 days old.  Please see the “NCI 
Guidelines for Investigators: Adverse Event Reporting Requirements for DCTD (CTEP and CIP) 
and DCP INDs and IDEs” (at http://ctep.cancer.gov/protocolDevelopment/adverse_effects.htm) 
for more details on how to report pregnancy and its outcome to CTEP.  
 
7.6 
Secondary Malignancy 
 
A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., 
treatment with investigational agent/intervention, radiation or chemotherapy). A secondary 
malignancy is not considered a metastasis of the initial neoplasm. 
 
CTEP requires all secondary malignancies that occur following treatment with an agent under an 
NCI IND/IDE be reported expeditiously via CTEP-AERS.  Three options are available to 
describe the event:  
 
• Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic leukemia 
[AML])  
• Myelodysplastic syndrome (MDS)  
• Treatment-related secondary malignancy  
 
Any malignancy possibly related to cancer treatment (including AML/MDS) should also be 
reported via the routine reporting mechanisms outlined in each protocol.  
 
7.7 
Second Malignancy 
 
A second malignancy is one unrelated to the treatment of a prior malignancy (and is NOT a 
metastasis from the initial malignancy).  Second malignancies require ONLY routine AE 
reporting unless otherwise specified. 
 
 
8. PHARMACEUTICAL INFORMATION 
 


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35 
A list of the adverse events and potential risks associated with the investigational agent 
administered in this study can be found in Section 7.1. 
 
8.1 
Savolitinib (NSC #785348) 
 
Chemical Name: 1-[(S)-1-(imidazo[1,2-a]pyridin-6-yl)ethyl]-6-(1-methyl-1H-pyrazol-4-yl)- 
1H-[1,2,3]-triazolo[4,5-b]pyrazine 
 
Other Names: volitinib, HMPL-504 
 
Classification:  oral c-Met kinase inhibitor 
 
CAS Registry Number: 1313725-88-0 
 
Molecular Formula: C17H15N9  
 
M.W.: 345.36 
 
Approximate Solubility: Savolitinib (AZD6094) has solubility of 64.07 to 21.56 mg/mL at pH 
1.2,  1.3 mg/mL to 0.92 mg/mL at pH 4.5 and 0.06 to 0.04 mg/mL at pH 6.8. Additional 
solubility in bio-relevant media was measured at 
0.11 mg/mL in fasted-state simulated intestinal fluid and 0.94 to 0.65 mg/mL in fed-state 
simulated intestinal fluid. 
 
Mode of Action: Savolitinib ((AZD6094) is an oral, potent and selective c-Met kinase inhibitor. 
The MET (mesenchymal epithelial transition) pathway is one of the most dysregulated 
pathways associated with a wide range of human malignancies. The MET receptor is 
normally phosphorylated by hepatocyte growth factor (HGF) which leads to downstream 
signaling of two major pathways, RAS/RAF/MEK/ERK and AKT/PI3K/mTOR.  Both 
downstream pathways contribute to cell proliferation and survival and when dysregulated, 
support tumor expansion and progression. 
 
Description: Savolitinib ((AZD6094) is off-white to yellow crystalline powder 
 
How Supplied: Astra Zeneca supplies and CTEP, NCI, DCTD distributes savolitinib ((AZD6094) 
as  coated tablets. Bottles are secured with a child-resistant closure; induction-sealed 
membranes provide tamper evidence. Savolitinib (AZD6094) tablets are supplied in 24-
count HDPE bottles containing desiccant in the following strengths and descriptions:  
• 200 mg yellow, plain, oval (7.25 x 14.5 mm) 
 
Savolitinib (AZD6094) tablets consist of drug substance, microcrystalline cellulose, 
mannitol, hydroxypropyl cellulose, and magnesium stearate. The film coating consists of 
hydroxypropyl methylcellulose, titanium dioxide, polyethylene glycol 400, black iron 
oxide, yellow iron oxide and red iron oxide. 
 
Storage: Store the savolitinib (AZD6094) tablets at controlled room temperature (20°C-25°C).   
Short excursions at clinical study sites are permitted as follows: Brief excursions are 
permitted between 15°C and 30°C.   


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36 
If a storage temperature excursion is identified, promptly return savolitinib (AZD6094) to 
controlled room temperature and quarantine the supplies.  Provide a detailed report of the 
excursion (including documentation of temperature monitoring and duration of the 
excursion) to PMBAfterHours@mail.nih.gov for determination of suitability. 
 
Stability: Stability studies are ongoing. The manufacturer does not have stability information to 
support repackaging tablets. Dispense in the original container. 
 
Route and Method of Administration: Oral. Take savolitinib ((AZD6094)) tablets with food. 
Swallow whole with water.    
 
Potential Drug Interactions: According to in vitro studies, savolitinib (AZD6094) is primarily 
metabolized by CYP 3A4/5 and 1A2 and some NADPH-independent non-CYP enzymes. 
Avoid administration of strong CYP 3A4/5 and 1A2 inducers and inhibitors within 2 weeks 
of starting and during savolitinib (AZD6094) study treatment. Savolitinib (AZD6094) is not 
a P-glycoprotein (P-gp) substrate.  
 
In vitro, savolitinib (AZD6094) and its metabolites weakly and reversibly inhibited 
CYP450 1A2, 2C8, 2C9, 2D6 and 3A4/5 isoforms and UGT1A1 . A drug interaction with 
substrates of CYP2C8/9 and/or CYP3A4/5 or UGT1A1 may occur when savolitinib 
(AZD6094) is dosed at the maximum tolerated dose. Use caution in patients who are 
taking concomitant medications whose clearance is exclusively dependent on CYP2C8, 
CYP2C9, CYP3A4/5 or UGT1A1 because exposure of the concomitant medication may 
be increased. Since there is limited clinical experience with this agent, patients on 
concomitant drugs with narrow therapeutic ranges, such as warfarin, should be monitored 
closely. 
 
Studies indicate that savolitinib (AZD6094) has little induction potential for major CYP 
isoforms. 
 
In vitro studies demonstrate that savolitinib (AZD6094) and its major metabolite inhibit a 
number of drug transporters to varying degrees. The manufacturer cautions that when 
administered at clinically relevant doses, savolitinib (AZD6094) has the potential to 
inhibit P-gp, BCRP (breast cancer resistance protein), OATP1B1, MATE1 and 
MATE2K. Therefore, co-administration of substrates that are dependent on these drug 
transporter systems should be used with caution. The potential for drug-drug interaction 
is considered unlikely when co-administering substrates of OATP1B3, OAT1, OAT3 or 
OCT2.     
 
Patient Care Implications: Advise women study participants of child-bearing potential to use 
effective contraception from the time of screening until 4 weeks after discontinuing study 
treatment.  Refer to the protocol for specific guidance.  
 
Advise male study participants to use a condom with female partners of child-bearing 
potential during the study and for 4 weeks after discontinuing study treatment.   If the female 
partner of a male study participant is not using effective contraception, men must use a 


NCI Protocol #: 10181 
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37 
condom during the study and for 6 months after discontinuing study treatment. Also advise 
men to avoid fathering a child and refraining from sperm donation from study start to 6 
months after discontinuing study treatment.  Refer to the protocol for specific guidance.     
 
Advise patients to avoid prolonged sun exposure and use protective clothing, hats and 
SPF 30+ sunscreen during study treatment and for 4 weeks after the last dose. Consult the 
protocol document for any dose modification necessary if sunburn occurs. 
 
8.1.1 Agent Ordering and Agent Accountability 
 
8.1.1.1 
NCI-supplied agents may be requested by eligible participating Investigators (or their 
authorized designee) at each participating institution.  The CTEP-assigned protocol 
number must be used for ordering all CTEP-supplied investigational agents.  The 
eligible participating investigators at each participating institution must be registered 
with CTEP, DCTD through an annual submission of FDA Form 1572 (Statement of 
Investigator), NCI Biosketch, Agent Shipment Form, and Financial Disclosure Form 
(FDF).  If there are several participating investigators at one institution, CTEP-
supplied investigational agents for the study should be ordered under the name of one 
lead participating investigator at that institution. 
 
 
In general, sites may order initial agent supplies when a subject is being screened for 
 
enrollment onto the study.” 
 
Active CTEP-registered investigators and investigator-designated shipping designees 
and ordering designees can submit agent requests through the PMB Online Agent 
Order Processing (OAOP) application.  Access to OAOP requires the establishment 
of a CTEP Identity and Access Management (IAM) account and the maintenance of 
an “active” account status and a “current” password.  For questions about drug orders, 
transfers, returns, or accountability, call or email PMB any time.  Refer to the PMB’s 
website for specific policies and guidelines related to agent management.   
 
8.1.1.2 
Agent Inventory Records – The investigator, or a responsible party designated by the 
investigator, must maintain a careful record of the receipt, dispensing and final 
disposition of all agents received from the PMB using the appropriate NCI 
Investigational Agent (Drug) Accountability Record (DARF) available on the CTEP 
forms page.  Store and maintain separate NCI Investigational Agent Accountability 
Records for each agent, strength, formulation and ordering investigator on this 
protocol. 
 
8.1.2 Investigator Brochure Availability 
The current versions of the IBs for the agents will be accessible to site investigators and 
research staff through the PMB OAOP application.  Access to OAOP requires the 
establishment of a CTEP IAM account and the maintenance of an “active” account 
status, a “current” password, and active person registration status.  Questions about IB 
access may be directed to the PMB IB Coordinator via email. 
 


NCI Protocol #: 10181 
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38 
8.1.3 Useful Links and Contacts 
• CTEP Forms, Templates, Documents:  http://ctep.cancer.gov/forms/ 
• NCI CTEP Investigator Registration:  RCRHelpDesk@nih.gov 
• PMB policies and guidelines: 
http://ctep.cancer.gov/branches/pmb/agent_management.htm  
• PMB Online Agent Order Processing (OAOP) application: 
https://ctepcore.nci.nih.gov/OAOP/ 
• CTEP Identity and Access Management (IAM) account: 
https://ctepcore.nci.nih.gov/iam/  
• CTEP IAM account help:  ctepreghelp@ctep.nci.nih.gov  
• IB Coordinator:  IBCoordinator@mail.nih.gov  
• PMB email:  PMBAfterHours@mail.nih.gov 
• PMB phone and hours of service: (240) 276-6575 Monday through Friday 
between 8:30 am and 4:30 pm (ET) 
 
9. BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 
 
9.1 
Summary Table for Specimen Collection 
 
Time Point 
Specimen and Quantity 
Send Specimens to: 
Screening 
 
• 20 mL blood in cfDNA Streck tubes 
 
Guardant Health 
Baseline (prior to start of study drug) 
 
• 6 mL blood in pink or lavender top ETDA 
tube 
 
• 30 mL blood in lavender top EDTA tubes 
processed for plasma  
 
• Archival tissue1 (primary and/or metastatic) 
Submit 1 FFPE block, or  
− From the same block (cut sequentially), 
section forty (40) 5-micron sections: 
▪ 1 H&E stained slide 
▪ Thirty-eight (38) on positively charged 
SuperFrost or any positively charged 
slides 
▪ Two (2) on Dako Flex or any silanized 
slides 
ETCTN Biorepository   
 
Cycle 1 Day 15 


NCI Protocol #: 10181 
Version Date: December 3, 2020 
 
39 
Time Point 
Specimen and Quantity 
Send Specimens to: 
 
• 30 mL blood in lavender top EDTA tubes 
processed for plasma 
 
ETCTN Biorepository   
 
Each Restaging - prior to the start of study drug on Day 1 of Cycle 3 and every 2 cycles thereafter   
(Cycle 5, 7, 9, etc) 
 
• 30 mL blood in lavender top EDTA tubes 
processed for plasma 
 
ETCTN Biorepository   
 
At Study Drug Discontinuation 
 
• 30 mL blood in lavender top EDTA tubes 
processed for plasma 
 
ETCTN Biorepository   
 
1For archival tissue, a copy of the corresponding anatomic pathology report must be sent with the 
tissue and uploaded to Rave. 
 
9.2 
Specimen Procurement Kits and Scheduling  
 
9.2.1 Specimen Shipping Kits for cfDNA Streck Blood 
 
Guardant360 kit is provided for whole blood collection in cfDNA Streck tubes at the 
Screening time point. The kit contains tubes, a requisition form, blood draw and shipping 
instructions, shipping box with materials and a FedEx shipping label.  
 
An initial supply of Guardant360 kits will be shipped to the participating site after the 
Study Initiation Meeting (SIM) is scheduled with the Study Chair/Lead Principal 
Investigator.  (Participating sites must contact Duke Cancer Institute LAO by emailing 
ETCTN-LAO-NC010@dm.duke.edu to schedule a SIM.)  Kits can be re-ordered by 
emailing a request to clientservices@guardanthealth.com.  In the email request, please 
include the study number 10181 and the participating site’s CTEP ID.  Kits are shipped 
overnight within 2 business days from the date the email request is received. 
 
9.2.2 Specimen Shipping Kits for Frozen Specimens 
 
Kits for the shipment of specimens to the ETCTN Biorepository can be ordered online 
via the Kit Management system: 
(https://ricapps.nationwidechildrens.org/KitManagement).  
 
Users at the clinical sites will need to set up an account in the Kit Management system 
and select a specific clinical trial protocol to request a kit. Please note that protocol may 
include more than one type of kit. Each user may order two kit types per protocol per day 
(daily max = 6 kits).  Kits are shipped ground, so please allow 5-7 days for receipt. A 
complete list of kit contents for each kit type is located on the Kit Management system 
website. 


NCI Protocol #: 10181 
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40 
 
Note: Kits or supplies are only provided for specimens shipped to the Biorepository. 
Institutional supplies must be used for all other specimen collection and processing.  
 
9.2.3 Blood Collection and Processing Supplies 
 
Blood collection and processing supplies for the plasma samples are provided by each 
participating site (i.e. not supplied by study). 
 
9.2.4 Scheduling of Specimen Collections 
 
Frozen plasma can be collected on any day, but must be stored frozen and shipped 
overnight to the ETCTN Biorepository on Monday through Thursday.  In the event that 
frozen specimens cannot be shipped immediately, they must be maintained in a -80°C 
freezer. 
 
Frozen whole blood specimens can be collected on any day, but must be stored frozen 
and shipped overnight to the ETCTN Biorepository on Monday through Thursday.  In the 
event that frozen specimens cannot be shipped immediately, they must be maintained in a 
-80°C freezer. 
 
Fresh blood specimens may be collected and shipped ambient overnight to Guardant 
Health on Monday through Friday.  Guardant Health can receive shipments on Saturday.  
 
9.3 
Specimen Collection  
 
9.3.1 Archival Formalin-Fixed Paraffin-Embedded (FFPE) Tumor Specimen  
 
If previously-collected FFPE tissue will be submitted, then the following criteria must 
be met: 
• Tissue must have been collected within 6 months prior to registration  
• Formalin-fixed paraffin-embedded tumor tissue block(s) must be submitted.  The 
optimal block is at least 70% tumor.  Specimen size requirement is as follows: 
o Surface area:  25 mm2 is optimal.  Minimum is 5 mm2. 
o Volume:  1 mm3 optimal.  Minimum volume is 0.2 mm3, however the success 
of DNA extraction decreases at suboptimal tissue volume. 
 
Submission of a block is preferred. If an existing block cannot be submitted, then the 
following are requested, for each available archival (primary and/or metastatic) 
paraffin tumor block: 
1. Face the block (i.e. cut 1-2 microns of the top section) and discard the cut tissue.  
2. Cut one (1) H&E stained slide 
3. Cut two (2) 5-micron sections and place on Dako Flex or any silanized slides. 
4. Cut thirty-eight (38) 5-micron sections and place on positively charged 
SuperFrost or any positively charged slides.  
 


NCI Protocol #: 10181 
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41 
Note: all slides must be sequentially numbered and prepared from the same block.  
 
In the event there is limited archival tissue to send all the requested slides, please use 
the following instructions, which is based on the priority of tissue analysis. 
• If available archived tissue yields less than 40 slides, the following is requested: 
1. Cut one (1) H&E stained slide 
2. Cut two (2) 5-micron sections and place on Dako Flex or any silanized 
slides. 
3. Cut the remaining into 5-micron sections and place on positively charged 
SuperFrost or any positively charged slides. 
 
See Section 9.4.2 for labeling instructions. 
 
9.3.2 Collection of Blood in cfDNA Streck Tube 
 
1. At Screening, label two 10ml Streck tubes (cell-free DNA BCT) per instructions 
provided in the Guardant360 kit (see Appendix E). 
2. Fill the tubes completely. 
3. Mix tubes by gentle inversion 8-10 times. 
4. Do not refrigerate or freeze blood samples.  
5. Store blood samples at room temperature and ship within 24 hours of collection.   
6. Complete the requisition form provided in the kit.  Keep a copy of the completed 
requisition form for study records.  Ensure all fields of the requisition form are 
complete and clearly written as processing of samples may be delayed if information 
is missing or illegible on requisition.  
 
9.3.3 Collection of Blood in EDTA Tubes for Plasma Processing 
 
1. Label EDTA tubes (BD Vacutainer, Catalog no. 366643 or K2EDTA equivalent) 
according to the instructions in Section 9.4.1. 
2. Collect 30 mL blood in EDTA tube(s) and gently invert tube to mix. 
3. Process plasma by centrifuging for 15 minutes at 2,500 x g at 4°C. 
4. Using a sterile transfer pipette, remove plasma into two separate clean 15 mL 
polypropylene tubes.  
5. Repeat centrifugation for 15 minutes at 2,500 x g at 4°C. 
6. Using a clean sterile transfer pipette, remove plasma, taking care to avoid contact 
with the buffy coat (white, yellowish or grayish layer between the plasma and red 
blood cells) by keeping the pipet above the buffy coat layer and leaving a small 
amount (about 0.5 cm) of plasma in the tube.  
7. Aliquot plasma into 10 labeled cryovials in approximately equal volumes.  
8. Tightly secure the cap of the vials before storage.  
9. Store plasma cryovials upright in a specimen box or rack in an -70°C to -90°C or 
colder freezer prior to shipping to the Biorepository. Do not allow specimens to thaw 
after freezing. 
 
NOTE:  EDTA tubes for plasma must be processed and frozen within 2 hours of 


NCI Protocol #: 10181 
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42 
collection time. 
 
9.3.4 Collection of Whole Blood in EDTA Tubes 
 
1. Label EDTA tube (BD Vacutainer, Catalog no. 367899 or K2EDTA equivalent) 
according to the instructions in Section 9.4.1. 
2. Collect 6 mL blood in EDTA tube(s) and gently invert tube to mix. 
3. Store tube upright in a specimen box or rack in an -70°C to -90°C or colder freezer 
prior to shipping to the Biorepository. Do not allow specimens to thaw after freezing. 
 
9.4 
Specimen Tracking System Instructions 
 
All biospecimens collected for this trial must be submitted using the ETCTN Rave 
Specimen Tracking System (STS) unless otherwise noted.  The system is accessed 
through special Rave user roles: “CRA Specimen Tracking” for data entry at the treating 
institutions and “Biorepository” for users receiving the specimens for processing and 
storage at reference labs and the Biorepository.  Please refer to the Medidata Account 
Activation and Study Invitation Acceptance link on the CTSU website under the 
Rave/DQP tab. 
 
Important:  Failure to complete required fields in STS may result in a delay in 
sample processing.  Any case reimbursements associated with sample submissions will 
not be credited if samples requiring STS submission are not logged into STS. 
 
Additionally, please note that the STS software creates pop-up windows when reports are 
generated, so you will need to enable pop-ups within your web browser while using the 
software.   
 
For questions regarding the Specimen Tracking System, please contact the Theradex 
Help Desk at CTMSSupport@theradex.com. 
 
A shipping manifest must be included with all sample submissions. 
 
9.4.1 Specimen Labeling 
 
9.4.1.1 
Blood Specimen Labels 
 
Include the following on blood specimens (including whole blood and frozen, processed 
blood products – like plasma): 
• Patient Study ID 
• Universal Patient ID (UPID) 
• Specimen ID (automatically generated by Rave) 
• Time point 


NCI Protocol #: 10181 
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43 
• Specimen type (e.g. blood, serum) 
• Collection date 
9.4.1.2 
Tissue Specimen Labels 
Include the following on all tissue specimens or containers (e.g. formalin jar).  
• Patient Study ID 
• Universal Patient ID (UPID) 
• Specimen ID (automatically generated by Rave) 
• Time point 
• Specimen type (e.g., FFPE Block) 
• Tissue type (P for primary, M for metastatic or N for normal) 
• Collection date 
• Surgical pathology ID (SPID) number   
• Block number from the corresponding pathology report (archival only) 
• Sequentially number slides (archival only) to indicate the cut order 
9.4.1.3 
Example of Specimen Label 
The following image is an example of a tissue specimen label printed on a standard Avery label 
that is 1” high and 2.625” wide. 
 
  
 
The QR code in the above example is for the Specimen ID shown on the second line.   
NOTE:  The QR code label is currently under development at Theradex as of 31-Aug-2018; 
therefore, labels generated by the STS for this study may not include a QR code. 
 
The second line item from the end includes four data points joined together: 
1. Tissue only: Primary (P), Metastatic (M), Normal (N) tissue indicated at the 
beginning of the specimen ID; this field is blank if not relevant (e.g., for blood) 
2. Block ID or blank if not relevant 
3. SPID (Surgical Pathology ID) or blank if none 
4. The last alpha-numeric code is protocol specific and is only included if the protocol 
requires an additional special code classification 
 
The last line on the example label is for the handwritten date and optional time. 


NCI Protocol #: 10181 
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44 
 
9.4.2 Overview of Process at Treating Site 
 
9.4.2.1 OPEN Registration 
 
All registrations will be performed using the Oncology Patient Enrollment Network (OPEN) 
system. OPEN communicates automatically with the Interactive Web Response System (IWRS) 
which handles identifier assignments, any study randomization and any prescribed slot 
assignments. If specimen analysis is required to determine eligibility, the protocol will be setup 
with multi-step registration. 
 
Registration with eligibility specimen analysis:  
1. Site enters first step data into OPEN. 
2. IWRS receives data from OPEN, generates the Patient Study ID and the Universal 
Patient ID, both of which are sent back to OPEN. 
3. IWRS sends first step registration data, including the IDs and a TAC of “NOT REG” 
directly to Rave. 
4. The specimen tracking system in Rave is utilized for the specimen that contributes to 
eligibility determination. 
5. Site enters second and any subsequent step data into OPEN including results of 
specimen analysis. 
6. IWRS receives all data from OPEN, then sends it onto Rave with either the treatment 
TAC or a TAC of “SCRN FAIL”. 
7. In addition to the specimen tracking forms completed to determine eligibility, data 
entry for screen failure patients should include Histology and Disease, all forms in the 
Baseline folder, any lab forms connected to eligibility determination, and Off 
Treatment/Off Study. 
 
Any data entry errors made during enrollment should be corrected in Rave. 
 
9.4.2.2 
Rave Specimen Tracking Process Steps 
 
Step 1:  Complete the Histology and Disease form (but do not upload reports until a 
specimen label can be applied to them) and the Baseline forms regarding Prior 
Therapies. Enter the initial clinical specimen data:  
• Specimen Tracking Enrollment CRF:  Enter Time Point, Specimen Category, 
Specimen Type, Block number, Tissue type, Surgical Path ID, number of labels 
needed (include extra labels to apply to reports to be uploaded). CRF generates 
unique Specimen ID.  
 
Step 2:  Print labels using report in EDC and collect specimen. 
• Label specimen containers and write collection date and for blood samples 
include collection time on each label. 
• After collection, store labeled specimens as described in Section 9.3. 
• Apply an extra specimen label to each report before scanning. Return to the 
Histology and Disease form to upload any initial Pathology, Radiology, 


NCI Protocol #: 10181 
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45 
Molecular Reports (up to 4), Surgical reports and Pathology Verification form 
(when applicable). Return to Specimen Tracking Enrollment CRF to upload any 
molecular report (one per specimen) and/or specimen specific pathology or 
related report (one per specimen).   Uploaded reports should have PHI data like 
name, mailing address, medical record number or SSN redacted. Do not redact 
SPID, block number or relevant dates.  
 
Step 3:  Complete specimen data entry. 
• Specimen Transmittal Form: Enter Collection date and time and other required 
specimen details. 
 
Step 4:  When ready to ship, enter shipment information. 
• Shipping Status CRF:  Enter tracking number, your contact information, 
recipient, number of containers and ship date once for the 1st specimen in a 
shipment. 
• Copy Shipping CRF:  Select additional specimens to add to an existing shipment 
referenced by the tracking number. 
 
Step 5:  Print shipping list report and prepare to ship.  
• Print two copies of the shipping list, one to provide in the box, the other for your 
own records. 
• Print pathology or other required reports to include in the box. Be sure the printed 
copy includes the specimen label. 
 
Step 6:  Send email notification.  
• For only one of the specimens in the shipment, click “Send Email Alert” 
checkbox on the Shipping Status CRF to email recipient. 
 
Step 7:  Ship the specimen(s). 
 
9.5 
Shipping Specimens from Clinical Site to the ETCTN Biorepository  
For all archival tissue, the corresponding anatomical clinical pathology report is required 
both in the package and uploaded in the ETCTN specimen tracking system. If this is not 
available at the time of shipment, then it must be uploaded to the ETCTN specimen tracking 
system, or the specimen will not be processed. The pathology report must state the disease 
diagnosis made by the reviewing pathologist. 
9.5.1 Specimen Shipping Instructions 
Archival tissue and frozen specimens may be shipped to the ETCTN Biorepository on 
Monday through Thursday.  Archival tissue is shipped at room temperature. 
 
Fresh blood may be shipped to Guardant on Monday through Friday.   Please select 
“Saturday Delivery” when shipping fresh blood on a Friday.  


NCI Protocol #: 10181 
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46 
9.5.1.1 
Shipping Frozen Specimens to the ETCTN Biorepository 
1. Before packaging specimens, verify that each specimen is labeled according to the 
instructions above and that lids of all primary receptacles containing liquid are tightly 
sealed.  
2. Place the specimens in zip-lock bags. Use a separate zip-lock bag for each specimen 
type and time point.  
3. Place the zip-lock bags in a biohazard envelope containing absorbent material. Expel 
as much air as possible and seal securely.  
4. Put the secondary envelope into a Tyvek envelope. Expel as much air as possible and 
seal securely.  
5. Place frozen specimens in an insulated box with dry ice.  Layer the bottom of the 
compartment with dry ice until it is approximately one-third full.  Place the frozen 
specimens on top of the dry ice.  Cover the specimens with the dry ice until the 
compartment is almost completely full. When packaging specimens, ensure that you 
leave enough room completely cover the specimens in dry ice.    
6. Do not tape the insulated container shut. 
7. Insert a copy of the required forms into a plastic bag and place in the shipping box. 
8. Close the shipping box and tape it shut with durable sealing tape.  Do not completely 
seal the container. 
9. Complete a FedEx air bill and attach to top of shipping container. 
10. Complete a dry ice label. 
11. Attach the dry ice label and an Exempt Human Specimen sticker to the side of the 
shipping container. 
 
Ship specimens via overnight courier to the address below. FedEx Priority Overnight is 
strongly recommended to prevent delays in package receipt. 
9.5.2 ETCTN Biorepository Shipping Address 
 
Ship to the address below. Ship formalin-fixed and fresh blood specimens the same day 
of specimen collection. Do not ship specimens the day before a holiday. 
 
ETCTN Biorepository 
The Research Institute at Nationwide Children's Hospital 
700 Children's Drive, WA1340 
Columbus, Ohio 43205 
PH: (614) 722-2865 
FAX: (614) 722-2897 
Email: BPCBank@nationwidechildrens.org 
 
FedEx Priority Overnight service is very strongly preferred.   
 
NOTE:  The ETCTN Biorepository FedEx Account will not be provided to submitting 
institutions. 
 


NCI Protocol #: 10181 
Version Date: December 3, 2020 
 
47 
9.5.3 Contact Information for Assistance 
 
For all queries, please use the contact information below: 
 
ETCTN Biorepository  
Toll-free Phone:  (800) 347-2486 
E-mail:  BPCBank@nationwidechildrens.org 
 
9.6 
Shipping of Specimens to Other Laboratories  
 
9.6.1 Shipping Blood in cfDNA Streck tubes to Guardant at Screening 
 
No patient identifiers are to be included on the tubes and requisition form sent to 
Guardant Health.  
 
Ensure all fields of the requisition form are complete and clearly written as processing of 
samples may be delayed if information is missing or illegible on requisition.  
 
Within 24 hours of blood collection, Streck blood tubes and completed requisition form 
must be shipped to Guardant Health at room temperature by overnight courier service 
delivery Monday through Friday (no holidays) to the following address: 
 
Guardant Health 
2686 Middlefield Road, Ste E 
Redwood City, CA 97063 
 
Once blood sample kit is received by Guardant Health, results are expected within 14 
business days. 
 
For each patient who has a Guardant360 test completed for this study, the Lead Principal 
Investigator will provide the patient’s treating physician with the Guardant360 test results 
via email. 
 
9.7 
Integral/Integrated Laboratory Studies 
 
Biomarker Name 
AND Lab PI and Site 
Assay 
 
Use (Integral, Integrated, 
or Exploratory) AND 
Purpose  
Tissue/Body Fluid 
Tested and Timing 
of Sample 
Collection 
Mandatory (M) 
/ Optional (O) 
Collection 
Protocol 
Section 
ctDNA analysis of MET 
gene amplification 
Guardant Health 
Guardant360 
 
Integral 
Detect MET gene 
amplification in ctDNA 
Blood in cfDNA 
Streck 
Screening 
M 
9.7.1 
>70-gene panel including 
KRAS, NRAS, EGFR, 
MET, etc. (cell free tumor 
DNA) 
Guardant Health 
Guardant360 
 
Integrated 
Characterize genetic 
alterations to treatment 
outcome 
Blood in cfDNA 
Streck 
Screening 
M 
9.7.2 


NCI Protocol #: 10181 
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48 
Biomarker Name 
AND Lab PI and Site 
Assay 
 
Use (Integral, Integrated, 
or Exploratory) AND 
Purpose  
Tissue/Body Fluid 
Tested and Timing 
of Sample 
Collection 
Mandatory (M) 
/ Optional (O) 
Collection 
Protocol 
Section 
ctDNA analysis of MET 
amplification 
Williams, Mickey / 
Molecular 
Characterization 
Laboratory (MoCha) at 
NCI Frederick 
Next 
Generation 
Sequencing 
 
Exploratory  
Detect MET gene 
amplification in ctDNA 
Blood 
Baseline, C1D15, 
each restaging, and 
at study drug 
discontinuation 
M 
9.8.1 
Panel including KRAS, 
NRAS, EGFR, MET, etc. 
(ctDNA) 
Williams, Mickey / 
Molecular 
Characterization 
Laboratory (MoCha) at 
NCI Frederick 
Next 
Generation 
Sequencing 
 
Exploratory 
Characterize genetic 
contributions to treatment 
outcome and analyze 
genetic changes over time 
on treatment 
Blood 
Baseline, C1D15, 
each restaging, and 
at study drug 
discontinuation 
M 
9.8.1 
Soluble protein analytes 
including c-MET, HGF, 
EGF, AXL, etc. 
Nixon, Andrew / Duke 
University Medical Center 
Multiplex 
ELISA 
 
Exploratory 
Characterize the 
relationship between 
soluble protein analyte 
expression and response to 
treatment 
Blood 
Baseline, C1D15, 
each restaging, and 
at study drug 
discontinuation  
M 
9.8.2 
Pharmacogenomics 
Nixon, Andrew / Duke 
University Medical Center 
Sequencing 
Exploratory 
Assess variants in genes 
anticipated to be involved in 
the pharmacokinetics or 
pharmacodynamics of 
savolitinib 
Blood 
Baseline 
M 
9.8.5 
Whole exome sequencing 
Williams, Mickey / 
Molecular 
Characterization 
Laboratory (MoCha) at 
NCI Frederick 
WES 
 
Exploratory  
Characterize genetic 
contributions to treatment 
outcome 
Tumor  
Archival 
O 
9.8.4 
c-MET expression and 
amplification 
Nixon, Andrew / Duke 
University Medical Center 
IHC and 
FISH 
 
Exploratory 
Characterize c-MET 
expression and 
amplification in tumor tissue 
Tumor 
Archival  
O 
9.8.3 
MET gene amplification 
Nixon, Andrew / Duke 
University Medical Center 
Next 
Generation 
Sequencing 
 
Exploratory 
Characterize genomic 
alterations including MET 
gene amplification in tumor 
tissue 
Tumor 
Archival  
O 
9.8.3 
 
9.7.1 
 MET gene amplification in blood (Integral) 
 


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49 
The hypothesis of this study is that MET amplification detected in the blood of patients with 
metastatic CRC will predict response to anti-MET therapy (savolitinib).  Because MET 
amplification is typically acquired after exposure to anti-EGFR therapy, primary tissue is 
unlikely to identify patients with MET amplification.  Blood-based profiling is a safe and non-
invasive methodology to detect acquired MET amplification.  
 
Guardant Health (Redwood City, CA) will perform the assay.  The analyte is circulating tumor-
derived cell-free DNA (cfDNA). The technical platform is Guardant360, a 73-gene hybridization 
capture, Illumina NGS-based panel offered by Guardant Health in their CLIA-certified 
(#05D2070300), CAP-accredited laboratory (Lanman et al., 2015). All assay components and 
reagents will be sourced through Guardant Health, and all testing performed to CLIA/CAP 
standards. 
 
The specimens will be collected in Streck cfDNA BCT, from which plasma will be isolated and 
stored at -80°C until use. Samples will be processed according to Guardant Health’s CLIA 
workflow.  
 
Specimens will be collected from patients who are most likely to have MET amplification 
detected in blood.  To maximize the probability of detecting MET amplification, this study will 
screen patients with KRAS and NRAS wild-type metastatic CRC who have received prior anti-
EGFR therapy.  
 
Guardant360’s clinical utility is demonstrated by its ability to: 1) accurately predict clinical 
response to approved targeted therapy; 2) expand access to targeted therapy to patients for whom 
tissue is unavailable or insufficient; 3) decrease the time to treatment, and 4) decrease harm to 
patients caused by invasive biopsy.   
 
Four outcome studies of advanced NSCLC cohorts show, in aggregate, that EGFR-directed 
targeted therapy response rates for Guardant360-selected patients are 85% (C-P Exact 55-98%) 
in the first-line (e.g. erlotinib) and 91% (C-P Exact 57-99%) in the second and greater (e.g. 
osimertinib), which are equivalent to those cited in these drugs’ FDA approvals. 
 
Table 1. Clinical studies of NSCLC patient drug response rate to Guardant360-directed therapy 
and corresponding FDA approvals. 
Study 
Key Findings 
Indication 
Lee et al. 2016 (NEXT-
NSCLC) In review 
•   n=72 tissue QNS NSCLC 
•   n=17 with therapeutic target identified 
•   n=15 (all EGFR and ALK) treated with 13 PR (87% RR by RECIST
NSCLC 
Villaflor et al. 2016 
Oncotarget 
•   n=68 advanced NSCLC with 54% tissue QNS rate 
•   n=10 EGFR mutations treated, 8 PR (80% RR by clinical CT 
assessment) 
•   PFS=11.5 months (equivalent to reported literature survival) 
NSCLC 
Thompson et al. 2016 
Clinical Cancer 
Research 
•   n=102 NSCLC with 51% tissue QNS rate (interim analysis) 
•   On-label therapy options in 31%, off-label in 55% 
•   n=3 available for outcome, all 3 with objective response (EGFR and
ALK) 
NSCLC 


NCI Protocol #: 10181 
Version Date: December 3, 2020 
 
50 
Clopper-Pearson Exact 95% confidence intervals reported in brackets.  
* http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/021743s018lbl.pdf  
# http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/208065s000lbl.pdf  
 
Data collected will include qualitative (presence/absence) and quantitative mutation (variant 
allele fraction) and amplification (CNV) detection. 
 
Amplification: Gene amplification results in increased copies of the gene present in the cfDNA. 
As the absolute number of copies in circulation is dependent on both tumor fraction and the 
magnitude of the tumor amplification, amplifications are reported on a semi-quantitative scale: 
Positive (+) amplification magnitude is in the lower 50th percentile of samples with 
amplifications; Strongly Positive (++) amplification magnitude is in the 50th to 90th percentile; 
Very Strongly Positive (+++) amplification magnitude is in the top 10th percentile. Copy number 
data will be available for all profiled blood samples. 
 
For this study, any patient with MET amplification detected in blood (MET copy number ≥ 2.2) 
will be eligible for treatment with savolitinib.   
 
Keep a copy of the completed requisition form for study records.   
 
9.7.1.1 
Specimen Receipt and Processing at Guardant 
 
Plasma processed from blood collected in cfDNA Streck tubes will be used for this 
assay. 
 
9.7.1.2 
Site(s) Performing Correlative Study 
 
Guardant Health (Redwood City, CA) is conducting the assay.   
 
9.7.2 > 70 gene circulating tumor DNA (ctDNA) panel (Integrated) 
 
See Section 9.7.1 for information regarding the 73-gene panel Guardant360 assay. 
Mutations of interest include but are not limited to, mutations in KRAS, NRAS and EGFR. 
Amplifications of interest include, but are not limited to, EGFR and ERBBR2. The allele 
frequency and copy number of these mutations and amplifications will be measured to evaluate 
the effect of their presence on response to treatment.  
 
Rozenblum et al. 2016 
J Thor Oncol (In Press)
•   n=19 tissue QNS ctDNA genotyping rescues 
•   n=6 (32%) with therapeutic target identified 
•   n=5 treated with 3 PR (EGFR, MET), 2 SD (RET, ERBB2) by 
RECIST 
NSCLC 
 
Genomic Target 
G360 Response Rate 
Published Response Rate 
EGFR ex19 deletion, L858R 
11/13, 85% [55-98%] 
65% [54-75%] (erlotinib)* 
EGFR T790M 
10/11, 91% [57-99%] 
59% [54-64%] (osimertinib)# 


NCI Protocol #: 10181 
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51 
9.7.2.1 
Specimen Receipt and Processing at Guardant 
 
Plasma processed from blood collected in cfDNA Streck tubes will be used for this 
assay.  
 
9.7.2.2 
Site(s) Performing Correlative Study 
 
Guardant Health (Redwood City, CA) is conducting the assay.   
 
9.8 
Exploratory/Ancillary Correlative Studies 
 
9.8.1 Circulating tumor DNA (ctDNA) panel  
 
The ctDNA assay platform that will be used in this protocol is still being evaluated by the 
Molecular Characterization (MoCha) Laboratory.  Exploratory mutations of interest include, but 
are not limited to BRCA2, BRAF, PIK3CA, AKT, PTEN, and MAP2K1. Amplifications of interest 
include, but not limited to, MYC and FGFR1. The allele frequency and copy number of these 
mutations and amplifications will be followed until progression (or end of study treatment). 
 
9.8.1.1 
Specimen Receipt and Processing at the ETCTN Biorepository 
 
Frozen plasma processed from K2EDTA tubes will be used for this assay.  Upon 
receipt, frozen plasma aliquots will be accessioned, barcoded and banked in a -80°C 
freezer until distribution for testing. 
 
9.8.1.2 
Site(s) Performing Correlative Study 
 
The analysis will be performed at the Molecular Characterization Laboratory 
(MoCha) at NCI Frederick. 
 
9.8.2 Circulating protein studies 
 
Plasma samples will be analyzed by multiplex ELISA assays for plasma-based biomarkers 
utilizing the Aushon Cirascan Imaging System. The Aushon Cirascan Imaging System is used 
specifically for the imaging and analysis of chemiluminescent protein arrays in a 96-well plate. 
The protein arrays are created by spotting up to 16 different capture antibodies per well in each 
well of the 96-well plate. The advantage of this system is that multiple target proteins of interest 
can be analyzed at the same time reducing the amount of sample required for analysis. In brief, a 
small volume of sample and/or standard is added to each well of the 96-well plate resulting in the 
capture of the target proteins by the arrayed antibodies. Biotinylated antibodies are then added 
that specifically bind the captured target proteins. Streptavidin conjugated to HRP (horseradish 
peroxidase) is then added followed by a chemiluminescent substrate. Imaging of the plate is 
performed using Aushon Cirascan Imaging System. Protein concentrations in the samples are 
quantified by comparing the intensity of the spots in the unknown wells to standard curves. 
 


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52 
Multiple soluble protein analytes, including (but not limited to) HGF, c-MET, EGF, HBEGF, 
TGF-α, EGFR, VEGFA-D, HER2, HER3, GAS6, and AXL will be analyzed. Additional 
biomarkers may also be explored using multiplex array technology. The results will help to 
characterize the relationship between soluble protein analyte expression and response to 
treatment. This analysis will also explore the association between soluble protein c-MET 
expression and gene amplification in tumor tissue. 
 
9.8.2.1 
Specimen Receipt and Processing at the ETCTN Biorepository 
 
Plasma processed from K2EDTA) tubes will be used for this assay.  Upon receipt, 
plasma will be accessioned, barcoded and banked in a -80°C freezer until distribution 
for testing. 
 
9.8.2.2 
Site(s) Performing Correlative Study  
 
The analysis will be performed at the Duke Phase I Biomarker Laboratory. 
 
9.8.3 c-MET protein expression and MET gene amplification in tissue 
 
Archival tumor tissue will be analyzed by IHC and FISH to assess c-MET protein expression and 
MET gene amplification in tumor tissue. The results will help to explore the association between 
c-MET protein expression and amplification, the association between soluble c-MET expression 
in whole blood and c-MET protein expression in tumor tissue, as well as the association between 
MET gene amplification in cfDNA and amplification in tumor tissue. 
 
We estimate that 90% of patients enrolled in the study should have archival tumor tissue 
available. Results from 12 tumors of 12 patients are sufficient to provide useful information on 
correlation of c-MET protein expression and MET gene amplification in tissue and blood.  
 
Archival tumor tissue will be analyzed by Next Generation Sequencing (NGS) to characterize 
genomic alterations, including MET gene amplification, in tumor tissue. These results will help 
to explore the contribution of these alterations to treatment outcome and prognosis. 
 
9.8.3.1 
Specimen Receipt and Processing at the ETCTN Biorepository 
 
Archival formalin-fixed, paraffin-embedded (FFPE) tissue will be used for this assay.  
 
9.8.3.2 
Site(s) Performing Correlative Study  
 
The analysis will be performed at the Duke Phase I Biomarker Laboratory. 
 
9.8.4 Whole exome sequencing 
 
Whole exome sequencing may be performed in archived tumor tissue to characterize the 
genomic alterations in anti-EGFR antibody refractory patient population and compare the 
genomic landscape of the tumor tissue to that of the ctDNA from the same patient. This analysis 


NCI Protocol #: 10181 
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53 
will provide novel and clinically relevant insight into tumor heterogeneity and therapeutic 
resistance.  
 
It is optional for the patient to be notified of information (if actionable) that results from the 
whole exome sequencing analysis of their archived tissue. 
 
9.8.4.1 
Specimen Receipt and Processing at the ETCTN Biorepository 
 
Archival formalin-fixed, paraffin-embedded (FFPE) tissue will be used for this assay. 
For all tumor specimens, the first section will be stained with H&E for pathology 
quality control review to assess tumor content; unstained slides will be 
macrodissected, if needed, and scraped for DNA and RNA co-extraction. DNA will 
be banked in a stock vial and RNA will be divided into 5 aliquots; all nucleic acids 
will be stored in a -80°C freezer until distribution for testing. 
 
9.8.4.2 
Site(s) Performing Correlative Study  
 
The analysis will be performed at the Molecular Characterization Laboratory 
(MoCha) at NCI Frederick. 
  
9.8.5 Pharmacogenomics 
 
A one-time, blood sample collected at Baseline will be used for assessment of variants in genes 
anticipated to be involved in the pharmacokinetics or pharmacodynamics of savolitinib.  
 
9.8.5.1 
Specimen Receipt and Processing at the ETCTN Biorepository 
 
DNA will be extracted from whole blood collected in EDTA tubes at Baseline. DNA 
will be stored in a -80°C freezer until distribution for testing.  
 
9.8.5.2 
 Site Performing Correlative Studies 
 
The analysis will be performed at the Duke Phase I Biomarker Laboratory. 
 
10. STUDY CALENDAR 
 
Baseline evaluations are to be conducted within 1 weeks prior to start of protocol therapy for the 
exception of scans.  Scans must be done <4 weeks prior to the start of therapy.  In the event that 
the patient’s condition is deteriorating, laboratory evaluations should be repeated within 48 hours 
prior to initiation of the next cycle of therapy. 
 


NCI Protocol #: 10181 
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54 
 
Pre- 
Study 
Cycle 1 
Cycle 2 and 
all 
subsequent 
cycles 
Cycle 3 and 
every 2 cycles 
thereafter   
(Cycle 5, 7, 9, 
etc.) 
End of 
Treatment 
Observation 
Prior to 
dosing on 
Day 1  
(Baseline) 
Prior to 
dosing on 
Day 15  
(±3 days) 
Prior to 
dosing on 
Day 1  
(±3 days) 
Prior to      
dosing on      
Day 1  
(±3 days) 
At disease 
progression/ 
drug 
discontinuation 
30-days 
after last 
dose  
(±3 days) 
Every 12 
weeks (as 
clinically 
indicated) 
Informed Consent 
X 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
Concurrent Medications 
X 
X-------------------------------------------------------------------------------------------X 
 
Physical Exam 
X 
X 
X 
X 
 
X 
X 
 
Vital Signs 
X 
X 
X 
X 
 
X 
X 
 
Height 
X 
 
 
 
 
 
 
 
Weight 
X 
X 
X 
X 
 
X 
X 
 
Performance Status 
X 
X 
X 
X 
 
X 
X 
 
B-HCG a  (women of 
childbearing potential only) 
X 
 
 
 
X 
X 
 
 
CBC w/diff, plts 
X 
X 
X 
X 
 
X 
X 
 
Serum Chemistry b 
X 
X 
X 
X 
 
X 
X 
 
Serum lactate dehydrogenase 
(LDH) 
X 
X 
X 
X 
 
X 
X 
 
Serum amylase 
X 
X 
X 
X 
 
X 
X 
 
Urine dipstick i 
X 
X 
X 
X 
 
X 
X 
 
EKG c 
X 
X 
X 
X 
 
X 
 
 
Adverse Event Evaluation 
 
X---------------------------------------------------------------------------------------------X 
 
Savolitinib A 
 
X--------------------------------------------------X 
 
 
 
Tumor Assessments d 
X 
 
 
 
X 
 
 
X e 
CEA (blood tumor marker) 
X 
 
 
X 
 
 
 
X e 
Whole blood in cfDNA 
Streck tubes (MET 
Amplification f ) 
X 
 
 
 
 
 
 
 
EDTA blood for Cell free 
tumor DNA g   and 
Circulating protein (plasma) 
 
X 
X 
 
X 
X 
 
 
6 mL EDTA whole blood  
 
X 
 
 
 
 
 
 
Archival Tumor Tissue h  
(FFPE) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
A: 
Savolitinib:  Dose as assigned and administration is once daily.  Refer to Sections 5 and 6 for dose delay and modification schema.  See 
Appendix B for patient drug diary card. 
a. 
A pregnancy test on urine or blood sample will be performed for pre-menopausal women of childbearing potential, at baseline (must be 
≤7 days prior to Cycle 1 Day 1), at every restaging (ie. every 2 cycles starting with Cycle 3), and at treatment discontinuation. Tests will 
be performed by the institutional laboratory. If results are positive the patient is ineligible/must be discontinued from the study. In the 
event of a suspected pregnancy during the study, the test should be repeated and if positive, the patient will be discontinued from study 
treatment immediately. 


NCI Protocol #: 10181 
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55 
 
Pre- 
Study 
Cycle 1 
Cycle 2 and 
all 
subsequent 
cycles 
Cycle 3 and 
every 2 cycles 
thereafter   
(Cycle 5, 7, 9, 
etc.) 
End of 
Treatment 
Observation 
Prior to 
dosing on 
Day 1  
(Baseline) 
Prior to 
dosing on 
Day 15  
(±3 days) 
Prior to 
dosing on 
Day 1  
(±3 days) 
Prior to      
dosing on      
Day 1  
(±3 days) 
At disease 
progression/ 
drug 
discontinuation 
30-days 
after last 
dose  
(±3 days) 
Every 12 
weeks (as 
clinically 
indicated) 
b. 
Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, phosphorus, potassium, total 
protein, SGOT [AST], SGPT [ALT], sodium. 
c. 
QTc evaluation will be done on triplicate 12 lead ECGs during the screening period, and every week in the first cycle and every cycle 
thereafter, and at the end of treatment as indicated in the study plan.  A 28-day follow-up assessment will be required if an on-treatment 
assessment was abnormal at the time of discontinuation of study therapy, to confirm reversibility of the abnormality. 
d. 
CT or MRI of the chest, abdomen, and pelvis to assess sites of measurable disease as per RECIST 1.1. Unless clinically indicated, the 
same method for tumor assessment should be employed at every restaging. At baseline must be ≤28 days prior to Cycle 1 Day 1; every 
restaging (may occur ≤14 days prior to Day 1 of the new cycle); and as clinically indicated. 
e. 
Subjects discontinued from study treatment with no documented disease progression and no subsequent anti-cancer treatment should be 
followed every 12 weeks or as clinically indicated with tumor assessments and CEA until disease progression or receipt of subsequent 
anti-cancer treatment is documented. No additional tumor assessment and CEA required for subjects discontinued from study treatment 
due to disease progression. Note: If subject is not able to return to the consenting institution, subject health records such as medical 
oncology physician notes, laboratory results, and/or radiology reports with tumor assessments from another institution is permissible for 
tumor assessment of disease progression or documentation of subsequent anti-cancer treatment. 
f. 
Blood collected in cfDNA Streck tubes at pre-study (ie. screening) to determine presence of MET amplification. Once blood tubes are 
received by lab, there is approximately a 14-day turnaround time for results.  Refer to Section 9 for details of collection and shipping 
instructions. 
g. 
Blood collected in EDTA lavender top tubes at baseline (prior to first dose), Cycle 1 Day 15, every restaging, and at study drug 
discontinuation.  Refer to Section 9 for details of collection, processing, and storage/shipping instructions.   
h. 
If available, formalin-fixed paraffin embedded tissue collected from pre-study biopsy and/or surgical procedure.  Refer to Section 9 for 
collection, processing, and storage/shipping instructions.    
i. 
If 3+ or greater proteinuria is identified by dipstick assessment, a 24-hour urine collection for formal quantification of the level of protein 
excretion should be performed.  
 
 
11. MEASUREMENT OF EFFECT 
 
11.1 
Antitumor Effect – Solid Tumors 
 
Response and progression will be evaluated in this study using the new international criteria 
proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline 
(version 1.1) [Eur J Ca 45:228-247, 2009].  Changes in the largest diameter (unidimensional 
measurement) of the tumor lesions and the shortest diameter in the case of malignant lymph 
nodes are used in the RECIST criteria. 
 
11.1.1 Definitions 
 
Evaluable for toxicity.  All patients will be evaluable for toxicity from the time of their 
first treatment with savolitinib. 
 
Evaluable for PFS. Patients who have received any protocol therapy regardless of 
duration.  
 
Evaluable for objective response.  Only those patients who have measurable disease 
present at baseline, have received at least one dose of treatment, and have had their 
disease re-evaluated will be considered evaluable for response.  These patients will have 


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56 
their response classified according to the definitions stated below.  (Note:  Patients who 
exhibit objective disease progression prior to the end of cycle 1 will also be considered 
evaluable.) 
 
Evaluable Non-Target Disease Response.  Patients who have lesions present at baseline 
that are evaluable but do not meet the definitions of measurable disease, have received at 
least one dose of treatment, and have had their disease re-evaluated will be considered 
evaluable for non-target disease.  The response assessment is based on the presence, 
absence, or unequivocal progression of the lesions.  
 
11.1.2 Disease Parameters 
 
Measurable disease.  Measurable lesions are defined as those that can be accurately 
measured in at least one dimension (longest diameter to be recorded) as ≥20 mm (≥2 cm) 
by chest x-ray or as ≥10 mm (≥1 cm) with CT scan, MRI, or calipers by clinical exam.  
All tumor measurements must be recorded in millimeters (or decimal fractions of 
centimeters). 
 
Note:  Tumor lesions that are situated in a previously irradiated area are considered 
measurable only if there is evidence of progression of those tumor lesions since the 
radiation and prior to the start of study treatment.  
 
Malignant lymph nodes.  To be considered pathologically enlarged and measurable, a 
lymph node must be ≥15 mm (≥1.5 cm) in short axis when assessed by CT scan (CT scan 
slice thickness recommended to be no greater than 5 mm [0.5 cm]).  At baseline and in 
follow-up, only the short axis will be measured and followed. 
 
Non-measurable disease.  All other lesions (or sites of disease), including small lesions 
(longest diameter <10 mm [<1 cm] or pathological lymph nodes with ≥10 to <15 mm [≥1 
to <1.5 cm] short axis), are considered non-measurable disease.  Bone lesions, 
leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis 
cutis/pulmonitis, inflammatory breast disease, and abdominal masses (not followed by 
CT or MRI), are considered as non-measurable. 
 
Note:  Cystic lesions that meet the criteria for radiographically defined simple cysts 
should not be considered as malignant lesions (neither measurable nor non-measurable) 
since they are, by definition, simple cysts. 
 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if non-
cystic lesions are present in the same patient, these are preferred for selection as target 
lesions. 
 
Target lesions.  All measurable lesions up to a maximum of 2 lesions per organ and 5 
lesions in total, representative of all involved organs, should be identified as target 
lesions and recorded and measured at baseline.  Target lesions should be selected on the 


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57 
basis of their size (lesions with the longest diameter), be representative of all involved 
organs, but in addition should be those that lend themselves to reproducible repeated 
measurements.  It may be the case that, on occasion, the largest lesion does not lend itself 
to reproducible measurement in which circumstance the next largest lesion which can be 
measured reproducibly should be selected.  A sum of the diameters (longest for non-
nodal lesions, short axis for nodal lesions) for all target lesions will be calculated and 
reported as the baseline sum diameters.  If lymph nodes are to be included in the sum, 
then only the short axis is added into the sum.  The baseline sum diameters will be used 
as reference to further characterize any objective tumor regression in the measurable 
dimension of the disease. 
 
Non-target lesions.  All other lesions (or sites of disease) including any measurable 
lesions over and above the 5 target lesions should be identified as non-target lesions and 
should also be recorded at baseline.  Measurements of these lesions are not required, but 
the presence, absence, or in rare cases unequivocal progression of each should be noted 
throughout follow-up.  
 
11.1.3 Methods for Evaluation of Measurable Disease 
 
All measurements should be taken and recorded in metric notation using a ruler or 
calipers.  All baseline evaluations should be performed as closely as possible to the 
beginning of treatment and never more than 4 weeks before the beginning of the 
treatment. 
 
The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up. Imaging-based 
evaluation is preferred to evaluation by clinical examination unless the lesion(s) being 
followed cannot be imaged but are assessable by clinical exam. 
 
Clinical lesions   
Clinical lesions will only be considered measurable when they are superficial (e.g., skin 
nodules and palpable lymph nodes) and ≥10 mm (≥1 cm) diameter as assessed using 
calipers (e.g., skin nodules).  In the case of skin lesions, documentation by color 
photography, including a ruler to estimate the size of the lesion, is recommended.  
 
Chest x-ray   
Lesions on chest x-ray are acceptable as measurable lesions when they are clearly defined 
and surrounded by aerated lung.  However, CT is preferable.  
 
Conventional CT and MRI   
This guideline has defined measurability of lesions on CT scan based on the assumption 
that CT slice thickness is 5 mm (0.5 cm) or less.  If CT scans have slice thickness greater 
than 5 mm (0.5 cm), the minimum size for a measurable lesion should be twice the slice 
thickness.  MRI is also acceptable in certain situations (e.g. for body scans).   
 


NCI Protocol #: 10181 
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58 
Use of MRI remains a complex issue.  MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which 
greatly impact image quality, lesion conspicuity, and measurement.  Furthermore, the 
availability of MRI is variable globally.  As with CT, if an MRI is performed, the 
technical specifications of the scanning sequences used should be optimized for the 
evaluation of the type and site of disease.  Furthermore, as with CT, the modality used at 
follow-up should be the same as was used at baseline and the lesions should be 
measured/assessed on the same pulse sequence.  It is beyond the scope of the RECIST 
guidelines to prescribe specific MRI pulse sequence parameters for all scanners, body 
parts, and diseases.  Ideally, the same type of scanner should be used and the image 
acquisition protocol should be followed as closely as possible to prior scans.  Body scans 
should be performed with breath-hold scanning techniques, if possible. 
 
PET-CT   
At present, the low dose or attenuation correction CT portion of a combined PET-CT is 
not always of optimal diagnostic CT quality for use with RECIST measurements.  
However, if the site can document that the CT performed as part of a PET-CT is of 
identical diagnostic quality to a diagnostic CT (with IV and oral contrast), then the CT 
portion of the PET-CT can be used for RECIST measurements and can be used 
interchangeably with conventional CT in accurately measuring cancer lesions over time.  
Note, however, that the PET portion of the CT introduces additional data which may bias 
an investigator if it is not routinely or serially performed.   
 
Ultrasound   
Ultrasound is not useful in assessment of lesion size and should not be used as a method 
of measurement.  Ultrasound examinations cannot be reproduced in their entirety for 
independent review at a later date and, because they are operator dependent, it cannot be 
guaranteed that the same technique and measurements will be taken from one assessment 
to the next.  If new lesions are identified by ultrasound in the course of the study, 
confirmation by CT or MRI is advised.  If there is concern about radiation exposure at 
CT, MRI may be used instead of CT in selected instances. 
 
Endoscopy, Laparoscopy   
The utilization of these techniques for objective tumor evaluation is not advised.  
However, such techniques may be useful to confirm complete pathological response 
when biopsies are obtained or to determine relapse in trials where recurrence following 
complete response (CR) or surgical resection is an endpoint. 
 
Tumor markers   
Tumor markers alone cannot be used to assess response.  If markers are initially above 
the upper normal limit, they must normalize for a patient to be considered in complete 
clinical response.  Specific guidelines for both CA-125 response (in recurrent ovarian 
cancer) and PSA response (in recurrent prostate cancer) have been published [JNCI 
96:487-488, 2004; J Clin Oncol 17, 3461-3467, 1999; J Clin Oncol 26:1148-1159, 2008].  
In addition, the Gynecologic Cancer Intergroup has developed CA-125 progression 


NCI Protocol #: 10181 
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59 
criteria which are to be integrated with objective tumor assessment for use in first-line 
trials in ovarian cancer [JNCI 92:1534-1535, 2000]. 
 
Cytology, Histology   
These techniques can be used to differentiate between partial responses (PR) and 
complete responses (CR) in rare cases (e.g., residual lesions in tumor types, such as germ 
cell tumors, where known residual benign tumors can remain). 
 
The cytological confirmation of the neoplastic origin of any effusion that appears or 
worsens during treatment when the measurable tumor has met criteria for response or 
stable disease is mandatory to differentiate between response or stable disease (an 
effusion may be a side effect of the treatment) and progressive disease. 
 
FDG-PET   
While FDG-PET response assessments need additional study, it is sometimes reasonable 
to incorporate the use of FDG-PET scanning to complement CT scanning in assessment 
of progression (particularly possible 'new' disease).  New lesions on the basis of FDG-
PET imaging can be identified according to the following algorithm:  
a. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of 
PD based on a new lesion. 
b. No FDG-PET at baseline and a positive FDG-PET at follow-up:  If the positive FDG-
PET at follow-up corresponds to a new site of disease confirmed by CT, this is PD.  If 
the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, 
additional follow-up CT  scans are needed to determine if there is truly progression 
occurring at that site (if so, the date of PD will be the date of the initial abnormal 
FDG-PET scan).  If the positive FDG-PET at follow-up corresponds to a pre-existing 
site of disease on CT that is not progressing on the basis of the anatomic images, this 
is not PD. 
c. FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy 
in cases where a residual radiographic abnormality is thought to represent fibrosis or 
scarring.  The use of FDG-PET in this circumstance should be prospectively 
described in the protocol and supported by disease-specific medical literature for the 
indication.  However, it must be acknowledged that both approaches may lead to false 
positive CR due to limitations of FDG-PET and biopsy resolution/sensitivity. 
 
Note:  A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake 
greater than twice that of the surrounding tissue on the attenuation corrected image. 
 
11.1.4 Response Criteria 
 
11.1.4.1 
Evaluation of Target Lesions 
 
Complete Response (CR):  Disappearance of all target lesions.  Any pathological 
lymph nodes (whether target or non-target) must have reduction in short axis to <10 
mm (<1 cm). 
 


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60 
Partial Response (PR):  At least a 30% decrease in the sum of the diameters of target 
lesions, taking as reference the baseline sum diameters. 
 
Progressive Disease (PD):  At least a 20% increase in the sum of the diameters of 
target lesions, taking as reference the smallest sum on study (this includes the 
baseline sum if that is the smallest on study).  In addition to the relative increase of 
20%, the sum must also demonstrate an absolute increase of at least 5 mm (0.5 cm).  
(Note:  the appearance of one or more new lesions is also considered progressions). 
 
Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum diameters while on 
study. 
 
11.1.4.2 
Evaluation of Non-Target Lesions 
 
Complete Response (CR):  Disappearance of all non-target lesions and normalization 
of tumor marker level.  All lymph nodes must be non-pathological in size (<10 mm 
[<1 cm] short axis). 
 
Note:  If tumor markers are initially above the upper normal limit, they must 
normalize for a patient to be considered in complete clinical response. 
 
Non-CR/Non-PD:  Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal limits. 
 
Progressive Disease (PD):  Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target lesions.  Unequivocal progression 
should not normally trump target lesion status.  It must be representative of overall 
disease status change, not a single lesion increase. 
 
Although a clear progression of “non-target” lesions only is exceptional, the opinion 
of the treating physician should prevail in such circumstances, and the progression 
status should be confirmed at a later time by the review panel (or Principal 
Investigator). 
 
11.1.4.3 
Evaluation of Best Overall Response 
 
The best overall response is the best response recorded from the start of the treatment 
until disease progression/recurrence (taking as reference for progressive disease the 
smallest measurements recorded since the treatment started).  The patient's best 
response assignment will depend on the achievement of both measurement and 
confirmation criteria. 
 
For Patients with Measurable Disease (i.e., Target Disease) 
 


NCI Protocol #: 10181 
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61 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response when 
Confirmation is Required* 
CR 
CR 
No 
CR 
≥4 wks. Confirmation is 
required for this protocol. 
CR 
Non-CR/Non-
PD 
No 
PR 
≥4 wks. Confirmation is 
required for this protocol. 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-
PD/not 
evaluated 
No 
PR 
SD 
Non-CR/Non-
PD/not 
evaluated 
No 
SD 
Documented at least once ≥4 
wks. from baseline 
PD 
Any 
Yes or No 
PD 
no prior SD, PR or CR 
Any 
PD*** 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
***  In exceptional circumstances, unequivocal progression in non-target lesions may be 
accepted as disease progression. 
 
Note:  Patients with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be 
reported as “symptomatic deterioration.”  Every effort should be made to document the 
objective progression even after discontinuation of treatment. 
 
For Patients with Non-Measurable Disease (i.e., Non-Target Disease) 
 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
 
‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is 
increasingly used as an endpoint for assessment of efficacy in some trials so to assign this 
category when no lesions can be measured is not advised 
 
11.1.5 Duration of Response 
 
Duration of overall response:  The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first 
date that recurrent or progressive disease is objectively documented (taking as reference 
for progressive disease the smallest measurements recorded since the treatment started). 
 


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62 
The duration of overall CR is measured from the time measurement criteria are first met 
for CR until the first date that progressive disease is objectively documented. 
 
 
Duration of stable disease:  Stable disease is measured from the start of the treatment 
until the criteria for progression are met, taking as reference the smallest measurements 
recorded since the treatment started, including the baseline measurements.  
 
11.1.6 Progression-Free Survival 
 
Progression-Free Survival (PFS) is defined as the duration of time from start of treatment 
to time of clinical or radiographic progression or death, whichever occurs first. 
 
11.1.7 Response Review 
 
Response will be reviewed at each participating institution using the RECIST guidelines 
provided in Section 11. 
 
12. STUDY OVERSIGHT AND DATA REPORTING / REGULATORY 
REQUIREMENTS 
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7.0 
(Adverse Events: List and Reporting Requirements). 
 
12.1 
Study Oversight 
 
This protocol is monitored at several levels, as described in this section.  The Protocol Principal 
Investigator is responsible for monitoring the conduct and progress of the clinical trial, including 
the ongoing review of accrual, patient-specific clinical and laboratory data, and routine and 
serious adverse events; reporting of expedited adverse events; and accumulation of reported 
adverse events from other trials testing the same drug(s).  The Protocol Principal Investigator and 
statistician have access to the data at all times through the CTMS web-based reporting portal.   
 
For this Phase 2 study, the Protocol Principal Investigator will have, at a minimum, quarterly 
conference calls with the Study Investigators and the CTEP Medical Officer(s) to review accrual, 
progress, and pharmacovigilance.   
 
All Study Investigators at participating sites who register/enroll patients on a given protocol are 
responsible for timely submission of data via Medidata Rave and timely reporting of adverse 
events for that particular study.  This includes timely review of data collected on the electronic 
CRFs submitted via Medidata Rave. 
 
All studies are also reviewed in accordance with the enrolling institution’s data safety monitoring 
plan. 
 
12.2 
Data Reporting 
 


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63 
Data collection for this study will be done exclusively through Medidata Rave.  Access to the 
trial in Rave is granted through the iMedidata application to all persons with the appropriate 
roles assigned in the Regulatory Support System (RSS).  To access Rave via iMedidata, the site 
user must have an active CTEP IAM account (check at https://ctepcore.nci.nih.gov/iam/.) and the 
appropriate Rave role (Rave CRA, Read-Only, CRA (Lab Admin, SLA or Site Investigator) on 
either the LPO or participating organization roster at the enrolling site. To the hold RAVE CRA 
role or CRA Lab Admin role, the user must hold a minimum of an AP registration type. To hold 
the RAVE Site Investigator role, the individual must be registered as an NPIVR or IVR. 
Associates can hold read-only roles in RAVE. 
 
Upon initial site registration approval for the study in RSS, all persons with Rave roles assigned 
on the appropriate roster will be sent a study invitation e-mail from iMedidata.  To accept the 
invitation, site users must log into the Select Login (https://login.imedidata.com/selectlogin) 
using their CTEP-IAM user name and password, and click on the “accept” link in the upper 
right-corner of the iMedidata page.  Please note, site users will not be able to access the study in 
Rave until all required Medidata and study specific trainings are completed.  Trainings will be in 
the form of electronic learnings (eLearnings), and can be accessed by clicking on the link in the 
upper right pane of the iMedidata screen.   
 
Users that have not previously activated their iMedidata/Rave account at the time of initial site 
registration approval for the study in RSS will also receive a separate invitation from iMedidata 
to activate their account. Account activation instructions are located on the CTSU website, Rave 
tab under the Rave resource materials (Medidata Account Activation and Study Invitation 
Acceptance).  Additional information on iMedidata/Rave is available on the CTSU members’ 
website under the Rave tab or by contacting the CTSU Help Desk at 1-888-823-5923 or by e-
mail at ctsucontact@westat.com. 
 
12.2.1 Method 
 
This study will be monitored by the Clinical Trials Monitoring Service (CTMS).  Data 
will be submitted to CTMS at least once every two weeks via Medidata Rave (or other 
modality if approved by CTEP).  Information on CTMS reporting is available at:  
http://www.theradex.com/clinicalTechnologies/?National-Cancer-Institute-NCI-11.  On-
site audits will be conducted on an 18-36 month basis as part of routine cancer center site 
visits. More frequent audits may be conducted if warranted by accrual or due to concerns 
regarding data quality or timely submission.  For CTMS monitored studies, after users 
have activated their accounts, please contact the Theradex Help Desk at (609) 799-7580 
or by email at CTMSSupport@theradex.com for additional support with Rave and 
completion of CRFs. 
 
12.2.2 Responsibility for Data Submission 
 
For ETCTN trials, it is the responsibility of the PI(s) at the site to ensure that all 
investigators at the ETCTN Sites understand the procedures for data submission for each 
ETCTN protocol and that protocol specified data are submitted accurately and in a timely 
manner to the CTMS via the electronic data capture system, Medidata Rave.   


NCI Protocol #: 10181 
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64 
 
Data are to be submitted via Medidata Rave to CTMS on a real-time basis, but no less 
than once every 2 weeks.  The timeliness of data submissions and timeliness in resolving 
data queries will be tracked by CTMS.  Metrics for timeliness will be followed and 
assessed on a quarterly basis.  For the purpose of Institutional Performance Monitoring, 
data will be considered delinquent if it is greater than 4 weeks past due. 
 
Data from Medidata Rave and CTEP-AERS is reviewed by the CTMS on an ongoing 
basis as data is received.  Queries will be issued by CTMS directly within Rave.  The 
queries will appear on the Task Summary Tab within Rave for the CRA at the ETCTN to 
resolve.  Monthly web-based reports are posted for review by the Drug Monitors in the 
IDB, CTEP.  Onsite audits will be conducted by the CTMS to ensure compliance with 
regulatory requirements, GCP, and NCI policies and procedures with the overarching 
goal of ensuring the integrity of data generated from NCI-sponsored clinical trials, as 
described in the ETCTN Program Guidelines, which may be found on the CTEP 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.htm
) and CTSU websites. 
 
An End of Study CRF is to be completed by the PI, and is to include a summary of study 
endpoints not otherwise captured in the database, such as (for phase 1 trials) the 
recommended phase 2 dose (RP2D) and a description of any dose-limiting toxicities 
(DLTs).  CTMS will utilize a core set of eCRFs that are Cancer Data Standards Registry 
and Repository (caDSR) compliant (http://cbiit.nci.nih.gov/ncip/biomedical-informatics-
resources/interoperability-and-semantics/metadata-and-models).  Customized eCRFs will 
be included when appropriate to meet unique study requirements.  The PI is encouraged 
to review the eCRFs, working closely with CTMS to ensure prospectively that all 
required items are appropriately captured in the eCRFs prior to study activation.  CTMS 
will prepare the eCRFs with built-in edit checks to the extent possible to promote data 
integrity. 
 
CDUS data submissions for ETCTN trials activated after March 1, 2014, will be carried 
out by the CTMS contractor, Theradex.  CDUS submissions are performed by Theradex 
on a monthly basis.  The trial’s lead institution is responsible for timely submission to 
CTMS via Rave, as above. 
 
Further information on data submission procedures can be found in the ETCTN Program 
Guidelines 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.htm
). 
 
12.3 
CTEP Multicenter Guidelines 
 
N/A 
 
12.4 
Collaborative Agreements Language 
 


NCI Protocol #: 10181 
Version Date: December 3, 2020 
 
65 
The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the NCI 
under a Collaborative Agreement (CRADA, CTA, CSA) between the Pharmaceutical 
Company(ies) (hereinafter referred to as “Collaborator(s)”) and the NCI Division of Cancer 
Treatment and Diagnosis.  Therefore, the following obligations/guidelines, in addition to the 
provisions in the “Intellectual Property Option to Collaborator”  
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm) contained within the 
terms of award, apply to the use of the Agent(s) in this study: 
 
1. Agent(s) may not be used for any purpose outside the scope of this protocol, nor can 
Agent(s) be transferred or licensed to any party not participating in the clinical study.  
Collaborator(s) data for Agent(s) are confidential and proprietary to Collaborator(s) and shall 
be maintained as such by the investigators.  The protocol documents for studies utilizing 
Agents contain confidential information and should not be shared or distributed without the 
permission of the NCI.  If a copy of this protocol is requested by a patient or patient’s family 
member participating on the study, the individual should sign a confidentiality agreement.  A 
suitable model agreement can be downloaded from: http://ctep.cancer.gov. 
 
2. For a clinical protocol where there is an investigational Agent used in combination with 
(an)other Agent(s), each the subject of different Collaborative Agreements, the access to and 
use of data by each Collaborator shall be as follows (data pertaining to such combination use 
shall hereinafter be referred to as "Multi-Party Data”): 
 
a. NCI will provide all Collaborators with prior written notice regarding the existence and 
nature of any agreements governing their collaboration with NCI, the design of the 
proposed combination protocol, and the existence of any obligations that would tend to 
restrict NCI's participation in the proposed combination protocol. 
 
b. Each Collaborator shall agree to permit use of the Multi-Party Data from the clinical trial 
by any other Collaborator solely to the extent necessary to allow said other Collaborator 
to develop, obtain regulatory approval or commercialize its own Agent. 
 
c. Any Collaborator having the right to use the Multi-Party Data from these trials must 
agree in writing prior to the commencement of the trials that it will use the Multi-Party 
Data solely for development, regulatory approval, and commercialization of its own 
Agent. 
 
3. Clinical Trial Data and Results and Raw Data developed under a Collaborative Agreement 
will be made available to Collaborator(s), the NCI, and the FDA, as appropriate and unless 
additional disclosure is required by law or court order as described in the IP Option to 
Collaborator (http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm).  
Additionally, all Clinical Data and Results and Raw Data will be collected, used and 
disclosed consistent with all applicable federal statutes and regulations for the protection of 
human subjects, including, if applicable, the Standards for Privacy of Individually 
Identifiable Health Information set forth in 45 C.F.R. Part 164. 
 


NCI Protocol #: 10181 
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66 
4. When a Collaborator wishes to initiate a data request, the request should first be sent to the 
NCI, who will then notify the appropriate investigators (Group Chair for Cooperative Group 
studies, or PI for other studies) of Collaborator's wish to contact them. 
 
5. Any data provided to Collaborator(s) for Phase 3 studies must be in accordance with the 
guidelines and policies of the responsible Data Monitoring Committee (DMC), if there is a 
DMC for this clinical trial. 
 
6. Any manuscripts reporting the results of this clinical trial must be provided to CTEP by the 
Group office for Cooperative Group studies or by the principal investigator for non-
Cooperative Group studies for immediate delivery to Collaborator(s) for advisory review and 
comment prior to submission for publication.  Collaborator(s) will have 30 days from the 
date of receipt for review.  Collaborator shall have the right to request that publication be 
delayed for up to an additional 30 days in order to ensure that Collaborator’s confidential and 
proprietary data, in addition to Collaborator(s)’s intellectual property rights, are protected.  
Copies of abstracts must be provided to CTEP for forwarding to Collaborator(s) for courtesy 
review as soon as possible and preferably at least three (3) days prior to submission, but in 
any case, prior to presentation at the meeting or publication in the proceedings.  Press 
releases and other media presentations must also be forwarded to CTEP prior to release.  
Copies of any manuscript, abstract and/or press release/ media presentation should be sent to: 
 
Email:  ncicteppubs@mail.nih.gov 
 
The Regulatory Affairs Branch will then distribute them to Collaborator(s).  No publication, 
manuscript or other form of public disclosure shall contain any of Collaborator’s confidential/ 
proprietary information. 
 
12.5 
Genomic Data Sharing Plan 
 
N/A 
 
 
13. STATISTICAL CONSIDERATIONS 
 
13.1 
Study Design/Endpoints 
 
This is an open-label phase II study to determine the clinical activity of savolitinib in patients 
with MET amplified metastatic CRC. Only patients with metastatic CRC who have received 
prior anti-EGFR monoclonal antibody therapy (cetuximab or panitumumab) are eligible. Patients 
will be considered evaluable for response as defined in Section 11.1.1.   
The primary endpoint is objective overall response (ORR) defined as a complete response (CR) 
or partial response (PR) by RECIST 1.1 criteria at any time during treatment. The ORR will be 
estimated when response data are available for 15 evaluable patients. 


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67 
The null hypothesis that the ORR is 0.10 (p=0.10) versus the alternative that the ORR is 0.25 
(p=0.25) will be tested using the exact test of a binomial proportion. With 15 patients studied the 
power and significance level to test this difference are 0.764 and 0.184 (1-sided), respectively, at 
critical value 3.0. The null hypothesis will be rejected if 3 or more of 15 responses are observed. 
In this case, savolitinib will merit further investigation as a treatment for MET amplified 
metastatic CRC.  
Enrollment to the study will end when 15 evaluable patients are accrued or 150 patients are 
prospectively screened, whichever time point is reached first.  
If 14 evaluable patients are studied the power and significance level to test this hypothesis are 
0.72 and 0.16 (1-sided), respectively, at critical value 3.0. The null hypothesis will be rejected if 
3 or more of 14 responses are observed. 
Alternative Analysis for the Number of Evaluable Patients, N≤14 
If fewer than 14 evaluable patients are studied the power and significance level to test this 
hypothesis is less than 0.70 for 1-sided α ≤ 0.2. Therefore, if fewer than 14 evaluable patients are 
enrolled the exact 80% lower confidence bound (LCB) for ORR will be estimated. If the exact 
80% LCB for ORR is ≥ 0.1, savolitinib will merit further investigation as a treatment for MET 
amplified metastatic CRC. The exact 80% LCB for ORR ≥ 0.1 is 3 patients respond for 13, 12, 
11, 10, or 9 evaluable patients, or 2 patients respond for 8, 7, 6 or 5 evaluable patients. If fewer 
than 5 evaluable patients are enrolled the study design will be re-evaluated. 
13.2 
Sample Size/Accrual Rate 
 
A maximum of 150 patients will be prospectively screened for MET amplification using a cf 
DNA assay (Guardant360TM). In our experience (see Section 2.3), approximately 15% of patients 
with anti-EGFR refractory metastatic CRC have detectable MET amplification in cfDNA. 
Approximately 10% of all screened patients will meet study eligibility.  Based on these 
assumptions, 15 patients  will be enrolled and treated with savolitinib.  Assuming 12 patients are 
screened per month, screening is expected to be completed in approximately 12.5 months.        
 
PLANNED ENROLLMENT REPORT 
Racial Categories 
Ethnic Categories 
Total 
Not Hispanic or Latino 
Hispanic or Latino 
 
Female 
Male 
Female 
Male 
 
American Indian/ Alaska 
Native 
1 
1 
0 
0 
2 
Asian 
0 
0 
0 
0 
0 
Native Hawaiian or 
Other Pacific Islander 
0 
0 
0 
0 
0 


NCI Protocol #: 10181 
Version Date: December 3, 2020 
 
68 
Racial Categories 
Ethnic Categories 
Total 
Not Hispanic or Latino 
Hispanic or Latino 
 
Female 
Male 
Female 
Male 
 
Black or African 
American 
2 
3 
1 
1 
7 
White 
1 
2 
1 
1 
5 
More Than One Race 
0 
0 
0 
1 
1 
Total 
4 
6 
2 
3 
15 
PHS 398 / PHS 2590 (Rev. 08/12 Approved Through 8/31/2015)  
OMB No. 0925-0001/0002 
 
13.3 
Stratification Factors 
 
No stratification factors are specified for this trial. 
 
13.4 
Analysis of Secondary Endpoints 
 
Secondary endpoints include duration of response (11.1.5) and PFS (11.1.6). If the numbers of 
events permit these endpoints will be estimated using the Kaplan-Meier method. 
 
Adverse events will be described by grade, frequency, and attribution according to CTCAE 5.0.  
 
As secondary analyses: 1) ORR will be estimated within each RAS subgroup (mutant; wildtype). 
Based on the normal approximation, with 7 patients studied in each subgroup, ORR can be 
estimated to within at most +/- 0.24 with 80% confidence. Exact confidence limits will be wider 
with maximum length of 0.552.  2) PFS will be measured in patients who have received any 
protocol therapy. 
 
In addition, potential associations between tissue and blood based biomarkers and clinical 
outcomes will be explored.  
 
Due to the small sample size all secondary analyses will be considered descriptive. 
 
13.5 
Reporting and Exclusions 
 
13.5.1 Evaluation of Toxicity 
 
All patients will be evaluable for toxicity from the time of their first treatment with 
Savolitinib. 
 


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69 
13.5.2 Evaluation of Response 
 
All patients considered evaluable for response as defined in Section 11.1.1 must be 
assessed for response to treatment. Each patient will be assigned one of the following 
categories:  1) complete response, 2) partial response, 3) stable disease, 4) progressive 
disease, 5) early death from malignant disease, 6) early death from toxicity, 7) early death 
because of other cause, or 9) unknown (not assessable, insufficient data).  [Note:  By 
arbitrary convention, category 9 usually designates the “unknown” status of any type of 
data in a clinical database.] 
 
All patients considered evaluable for response as defined in Section 11.1.1 should be 
included in the main analysis of the response rate.  Patients in response categories 4-9 
should be considered to have a treatment failure (disease progression).  Thus, an incorrect 
treatment schedule or drug administration does not result in exclusion from the analysis 
of the response rate.  Precise definitions for categories 4-9 will be protocol specific.  
 
All conclusions should be based on all eligible patients.  Subanalyses may then be 
performed on the basis of a subset of patients, excluding those for whom major protocol 
deviations have been identified (e.g., early death due to other reasons, early 
discontinuation of treatment, major protocol violations, etc.).  However, these 
subanalyses may not serve as the basis for drawing conclusions concerning treatment 
efficacy, and the reasons for excluding patients from the analysis should be clearly 
reported.  The 95% confidence intervals should also be provided.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


NCI Protocol #: 10181 
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70 
 
REFERENCES 
 
1. Jemal, A., et al., Cancer statistics, 2010. CA: A Cancer Journal for Clinicians, 2010. 60(5): 
p. 277-300.  
2. Douillard, J.Y., et al., Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal 
cancer. N Engl J Med, 2013. 369(11): p. 1023-34.  
3. Gavine, P.R., et al., Volitinib, a potent and highly selective c-Met inhibitor, effectively blocks 
c-Met signaling and growth in c-MET amplified gastric cancer patient-derived tumor 
xenograft models. Mol Oncol, 2015. 9(1): p. 323-33.  
4. Yang, J.-J., et al., Preliminary results of a phase Ib trial of savolitinib combined with 
gefitinib in EGFR-mutant lung cancer. J Clin Oncol, 2016. 34(suppl; abstr e20559).  
5. Gan, H.K., et al., cMet: Results in papillary renal cell carcinoma of a phase I study of 
AZD6094/volitinib leading to a phase 2 clinical trial with AZD6094/volitinib in patients with 
advanced papillary renal cell cancer (PRCC). J Clin Oncol, 2015. 33(suppl 7; abstr 487). 
6. Choueiri, T.K., et al., Biomarker-Based Phase II Trial of Savolitinib in Patients With 
Advanced Papillary Renal Cell Cancer. J Clin Oncol, 2017. 35(26): p. 2993-3001. 
7. Palma, N.A., et al., Frequency of MET amplification determined by comprehensive next-
generation sequencing (NGS) in multiple solid tumors and implications for use of MET 
inhibitors. J Clin Oncol, 2013. 31(suppl; abstr 11068).  
8. Jardim, D.L., et al., Analysis of 1,115 patients tested for MET amplification and therapy 
response in the MD Anderson Phase I Clinic. Clin Cancer Res, 2014. 20(24): p. 6336-45.  
9. Gatalica, Z., et al., Integrating molecular profiling into cancer treatment decision making: 
Experience with over 35,000 cases. J Clin Oncol, 2013. 31(suppl; abstr 11001).  
10. Engelman, J.A., et al., MET amplification leads to gefitinib resistance in lung cancer by 
activating ERBB3 signaling. Science, 2007. 316(5827): p. 1039-43.  
11. Turke, A.B., et al., Preexistence and clonal selection of MET amplification in EGFR mutant 
NSCLC. Cancer cell, 2010. 17(1): p. 77-88.  
12. Bardelli, A., et al., Amplification of the MET receptor to drive resistance to anti-EGFR 
therapies in colorectal cancer. J Clin Oncol, 2013. 31(suppl; abstr 11005).  
13. Morelli, M.P., et al., Frequency of concurrent gene mutations and copy number alterations in 
circulating cell-free DNA (cfDNA) from refractory metastatic CRC patients. J Clin Oncol, 
2014. 32(5s suppl; abstr 11117).  
14. Bardelli, A., et al., Amplification of the MET receptor drives resistance to anti-EGFR 
therapies in colorectal cancer. Cancer Discov, 2013. 3(6): p. 658-73.  
15. Boccaccio, C., et al., MET-mediated resistance to EGFR inhibitors: an old liaison rooted in 
colorectal cancer stem cells. Cancer Res, 2014. 74(14): p. 3647-51. 
16. Kim, S.T., et al., Prospective blinded study of somatic mutation detection in cell-free DNA 
utilizing a targeted 54-gene next generation sequencing panel in metastatic solid tumor 
patients. Oncotarget, 2015.  
17. Janku, F., et al., BRAF Mutation Testing in Cell-Free DNA from the Plasma of Patients with 
Advanced Cancers Using a Rapid, Automated Molecular Diagnostics System. Mol Cancer 
Ther, 2016.  
18. Sacher, A.G., et al., Prospective Validation of Rapid Plasma Genotyping for the Detection of 
EGFR and KRAS Mutations in Advanced Lung Cancer. JAMA Oncol, 2016.  
19. Lanman, R.B., et al., Analytical and Clinical Validation of a Digital Sequencing Panel for 


NCI Protocol #: 10181 
Version Date: December 3, 2020 
 
71 
Quantitative, Highly Accurate Evaluation of Cell-Free Circulating Tumor DNA. PLoS One, 
2015. 10(10): p. e0140712. 
20. Strickler, J.H., et al., Cell free DNA (cfDNA) to monitor clonal evolution in patients (pts) 
with KRAS wild-type (WT) metastatic colorectal cancer (mCRC): Preliminary results of a 
phase I/II clinical trial of the anti-MET multi-kinase inhibitor cabozantinib (C) plus the anti-
EGFR monoclonal antibody panitumumab (P). Mol Cancer Ther, 2015. 14(12 Suppl 2: 
Abstract nr A52).  
21. Camidge, D.R., et al., Efficacy and safety of crizotinib in patients with advanced c-MET-
amplified non-small cell lung cancer (NSCLC). J Clin Oncol, 2014. 32(5s suppl; abstr 8001).  
22. Strickler, J.H., et al., Phase 1, open-label, dose-escalation, and expansion study of ABT-700, 
an anti-C-met antibody, in patients (pts) with advanced solid tumors. J Clin Oncol, 2014. 
32(5s suppl; abstr 2507).  
23. Angevin, E., et al., A first-in-human (FIH) phase I study of SAR125844, a novel selective 
MET kinase inhibitor, in patients (pts) with advanced solid tumors: Dose escalation results. J 
Clin Oncol, 2014. 32(5s suppl; abstr 2506).  
24. Hong, D.S., et al., First-in-human study of AMG 337, a highly selective oral inhibitor of 
MET, in adult patients (pts) with advanced solid tumors. J Clin Oncol, 2014. 32(5s suppl; 
abstr 2508).  
25. Gavine, P.R., et al., Volitinib, a potent and highly selective c-Met inhibitor, effectively blocks 
c-Met signaling and growth in c-MET amplified gastric cancer patient-derived tumor 
xenograft models. Mol Oncol, 2015. 9(1): p. 323-33. 
26. Schuller, A.G., et al., The MET Inhibitor AZD6094 (Savolitinib, HMPL-504) Induces 
Regression in Papillary Renal Cell Carcinoma Patient-Derived Xenograft Models. Clin 
Cancer Res, 2015. 21(12): p. 2811-9. 
27. Luraghi, P., et al., MET signaling in colon cancer stem-like cells blunts the therapeutic 
response to EGFR inhibitors. Cancer Res, 2014. 74(6): p. 1857-69. 
28. Jia, J., et al., Cell-free DNA profiling to discover mechanisms of exceptional response to 
cabozantinib plus panitumumab in a patient with treatment refractory metastatic colorectal 
cancer. Front Oncol, 2018. 8:305. doi:10.3389/fonc.2018.00305 
 
 


NCI Protocol #: 10181 
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72 
APPENDIX A 
PERFORMANCE STATUS CRITERIA 
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
1 
Symptoms, but ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
2 
In bed <50% of the time.  
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities.  Up and about 
more than 50% of waking hours. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 
 
 
 


NCI Protocol #: 10181 
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73 
APPENDIX B 
PATIENT DRUG DIARY CARD 
 
Savolitinib (AZD6094) – Patient Drug Diary Card 
 
Subject ID Number: ___________ Cycle #: _____  ( ___/___/_____ to ___/___/_____ ) 
 
• You will be taking ____ 200 mg tablets per day.   
• If you miss (accidentally skip or forget to take) a dose, do not make it up and continue  
with your next scheduled dose. 
• If you vomit after taking a dose, do not make it up and continue with your next  
scheduled dose. 
• Take savolitinib (AZD6094) with food and swallow tablets whole with water.   
• Try to take savolitinib (AZD6094) at the same time each day. 
• Avoid ingesting grapefruit juice, grapefruit and Seville oranges while talking savolitinib 
(AZD6094).   
• Return unused drug and/or empty bottles at the next study visit. 
 
Day 
Date 
(mm/dd/yyyy) 
# 
Tablets 
Time 
(00:00 am/pm) 
Day 
Date 
(mm/dd/yyyy) 
# 
Tablets 
Time 
(00:00 am/pm) 
1 
 
 
 
 
15 
 
 
 
 
2 
 
 
 
 
16 
 
 
 
 
3 
 
 
 
 
17 
 
 
 
 
4 
 
 
 
 
18 
 
 
 
 
5 
 
 
 
 
19 
 
 
 
 
6 
 
 
 
 
20 
 
 
 
 
7 
 
 
 
 
21 
 
 
 
 
8 
 
 
 
 
22 
 
 
 
 
9 
 
 
 
 
23 
 
 
 
 
10 
 
 
 
 
24 
 
 
 
 
11 
 
 
 
 
25 
 
 
 
 
12 
 
 
 
 
26 
 
 
 
 
13 
 
 
 
 
27 
 
 
 
 
14 
 
 
 
 
28 
 
 
 
 
 
To Be Completed By Study Staff Only: 
Date Returned (mm/dd/yyyy) 
 
# Tablets Returned 
 
Study Staff Initials 
 
Discrepancy (circle) 
Yes or No 
If discrepancy, explain:  


NCI Protocol #: 10181 
Version Date: December 3, 2020 
 
74 
 
APPENDIX C 
PATIENT DRUG INFORMATION HANDOUT AND WALLET 
CARD 
 
Information for Patients, Their Caregivers and Non-Study Healthcare Team on Possible 
Interactions with Other Drugs and Herbal Supplements 
 
The patient ____________________________ is enrolled on a clinical trial using the 
experimental study drug, savolitinib (AZD6094). This clinical trial is sponsored by the National 
Cancer Institute.  This form is addressed to the patient, but includes important information for 
others who care for this patient.  
 
These are the things that you as a healthcare provider need to know: 
  
savolitinib (AZD6094) interacts with certain specific enzymes in the liver and certain transport 
proteins that help move drugs in and out of cells. 
 
• The enzymes in question are CYP 3A4, 3A5, 1A2, 2C8, 2C9, and 2D6. savolitinib 
(AZD6094) is primarily metabolized by CYP 3A4/5 and 1A2 and some NADPH-
independent non-CYP enzymes and may be affected by other drugs that strongly inhibit 
or induce CYP3A4/5 and CYP1A2.  Savolitinib (AZD6094) inhibits CYP 3A4, 3A5, 
1A2, 2C8, 2C9, 2D6 and UGT1A1 and may affect other drugs that are substrates of these 
enzymes.   
• Savolitinib (AZD6094) inhibits P-gp, BCRP, OATP1B1, MATE1 and MATE2K 
transporters and this may affect transport of other drugs that is dependent on any of these 
transport proteins. 
• Since there is limited clinical experience with this agent, patients on concomitant drugs 
with narrow therapeutic ranges, such as warfarin, should be monitored closely. 
 
 
 
 
 
 
 
 
 
 
  
September 2017 
 
To the patient: Take this paper with you to your medical appointments and keep the 
attached information card in your wallet.   
 
Savolitinib (AZD6094) may interact with other drugs which can cause side effects. For this 
reason, it is very important to tell your study doctors of any medicines you are taking before you 
enroll onto this clinical trial.  It is also very important to tell your doctors if you stop taking any 
regular medicines, or if you start taking a new medicine while you take part in this study.  When 
you talk about your current medications with your doctors, include medicine you buy without a 
prescription (over-the-counter remedy), or any herbal supplements such as St. John’s Wort.  It is 
helpful to bring your medication bottles or an updated medication list with you. 
 
Many health care providers can write prescriptions.  You must tell all of your health care 
providers (doctors, physician assistants, nurse practitioners, pharmacists) you are taking part in a 
clinical trial.  
 


NCI Protocol #: 10181 
Version Date: December 3, 2020 
 
75 
 
These are the things that you and they need to know:  
 
Savolitinib (AZD6094) must be used very carefully with other medicines that need certain liver 
enzymes and transport proteins to be effective or to be cleared from your system.  Before you 
enroll onto the clinical trial, your study doctor will work with your regular health care providers 
to review any medicines and herbal supplements that are considered “strong inducers/inhibitors 
of CYP 3A4, 3A5 and 1A2.” Savolitinib (AZD6094) inhibits enzymes CYP 3A4, 3A5, 1A2, 
2C8, 2C9, 2D6 and transport proteins P-glycoprotein (P-gp), BCRP (breast cancer resistance 
protein), OATP1B1, MATE1 and MATE2K. These characteristics may change how other 
medicine works in your body. 
 
• The heart’s electrical activity may be affected by savolitinib (AZD6094). The study 
doctor may be concerned about QTc prolongation and any other medicine that is 
associated with greater risk for having QTc prolongation.   
• Please be very careful!  Over-the-counter drugs (including herbal supplements) may 
contain ingredients that could interact with your study drug.  Speak to your doctors or 
pharmacist to determine if there could be any side effects.  
• Avoid ingesting grapefruit juice, grapefruit and Seville oranges while taking savolitinib 
(AZD6094). 
• You may need to be monitored more frequently if you are taking any drugs that have 
narrow therapeutic ranges. 
• Your regular health care provider should check a frequently updated medical reference or 
call your study doctor before prescribing any new medicine or discontinuing any 
medicine.  Your study doctor’s name is _________________________ and he or she can 
be contacted at _____________. 
 
September 2017 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
STUDY DRUG INFORMATION WALLET CARD   
You are enrolled on a clinical trial using the experimental study drug 
savolitinib (AZD6094).  This clinical trial is sponsored by the NCI.  
savolitinib (AZD6094) may interact with drugs that are processed by 
your liver, or use certain transport proteins in your body.  Because of 
this, it is very important to: 
➢ Tell your doctors if you stop taking any medicines or if you start 
taking any new medicines. 
➢ Tell all of your health care providers (doctors, physician assistants, 
nurse practitioners, or pharmacists) that you are taking part in a 
clinical trial. 
➢ Check with your doctor or pharmacist whenever you need to use an 
over-the-counter medicine or herbal supplement. 
➢ Avoid ingesting grapefruit, grapefruit juice and Seville oranges. 
➢ You may need to be monitored more frequently if you are taking 
any drugs that have narrow therapeutic ranges, such as warfarin. 
 
 
 
 
➢ savolitinib (AZD6094) interacts with CYP 1A2, 3A4/5, 2C8, 2C9, 
2D6 and transport proteins, P-gp, BCRP, OATP1B1, MATE1 and 
MATE2K, and must be used very carefully with other medicines 
that interact with these enzymes and proteins.  
➢ Before you enroll onto the clinical trial, your study doctor will 
work with your regular health care providers to review any 
medicines and herbal supplements that are considered “strong 
inducers/inhibitors of CYP 3A4/5, 1A2.” savolitinib (AZD6094) 
inhibits CYP 3A4/5, 1A2, 2C8, 2C9, 2D6 and transporters, P-gp, 
BCRP, OATP1B1, MATE1 and MATE2K. It may change how 
other medicine works in your body.  
➢ Before prescribing new medicines, your regular health care 
providers should go to a frequently-updated medical reference for a 
list of drugs to avoid, or contact your study doctor.   
➢ Your study doctor’s name is _____________________________ 
and can be contacted at _________________________________.  


NCI Protocol #: 10181 
Version Date: December 3, 2020 
 
76 
APPENDIX D 
NEW YORK HEART ASSOCIATION FUNCTIONAL 
CLASSIFICATION  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Class 
Patient Symptoms 
I 
No limitation of physical activity. Ordinary physical activity does not cause undue 
fatigue, palpitation, dyspnea (shortness of breath). 
II 
Slight limitation of physical activity. Comfortable at rest. Ordinary physical activity 
results in fatigue, palpitation, dyspnea (shortness of breath). 
III 
Marked limitation of physical activity. Comfortable at rest. Less than ordinary 
activity causes fatigue, palpitation, or dyspnea. 
IV 
Unable to carry on any physical activity without discomfort. Symptoms of heart 
failure at rest. If any physical activity is undertaken, discomfort increases. 


NCI Protocol #: 10181 
Version Date: December 3, 2020 
 
77 
APPENDIX E 
GUARDANT360 BLOOD COLLECTION AND SHIPPING 
INSTRUCTIONS  
 
 


NCI Protocol #: 10181 
Version Date: December 3, 2020 
 
78 
APPENDIX F 
GUIDANCE REGARDING POTENTIAL INTERACTIONS WITH 
CONCOMITANT MEDICATIONS KNOWN TO PROLONG QT INTERVAL 
 
Drugs that prolong QT interval 
The drugs listed in this section are taken from information provided by the Arizona Center for 
Education and Research on Therapeutics website: https://www.crediblemeds.org. The website 
categorizes drugs based on the risk of inducing Torsades de Pointes (TdP). During screening the 
drugs that patients are currently prescribed should be checked opposite the ArizonaCert website 
above. 
 
Drugs with a known risk of Torsades de Pointes 
The following drugs prolong the QT interval and are clearly associated with a known risk of 
TdP, even when taken as recommended. These drugs must have been discontinued prior to the 
start of administration of study treatment in accordance with guidance provided in the table 
below and should not be co-administered with savolitinib and for a period of one week after 
discontinuing study treatment. The list of drugs may not be exhaustive and is subject to change 
as new information becomes available. As such investigators are recommended to search the 
website to provide the most up to date information. 
 
Drugs with a known risk of TdP 
Drug name 
Withdrawal period prior 
to study treatment start 
Anagrelide, ciprofloxacin, clarithromycin, cocaine, droperidol, 
erythromycin, levofloxacin, ondansetron, papaverine hydrochloride, 
procainamide, sulpiride, sultopride, terfenadine, terlipressin 
2 days 
Cilostazol, Cisapride, disopyramide, dofetilide, domperidone, flecainide, 
gatifloxacin, grepafloxacin, ibutilide, moxifloxacin, oxaliplatin, propofol, 
quinidine, roxithromycin, sevoflurane, sotalol, sparfloxacin, thioridazine 
7 days 
Azithromycin bepridil, citalopram, chlorpromazine, dronedarone, 
escitalopram, fluconazole, halofantrine, haloperidol, levomepromazine, 
levosulpiride, mesoridazine 
14 days 
Donepezil, terodiline 
3 weeks 
Levomethadyl, methadone, pimozide 
4 weeks 
Arsenic trioxide*, Ibogaine 
6 weeks 
Pentamidine 
8 weeks 
Astemizole, Probucol, vandetanib 
4 months 
Amiodarone, chloroquine 
1 year 
* Estimated value as pharmacokinetics of arsenic trioxide has not been studied 
 
 

ICF_001.pdf: 
 
 
 
A Phase 2 Study of Savolitinib in Subjects with MET Amplified Metastatic 
Colorectal Cancer 
 
 
Trial: NCT03592641 
 
 
Pre-Screening Consent Form 
December 3, 2020 
 
& 
 
Main Consent Form 
December 3, 2020 


Screening Consent FormStudy Title for Study Participants: Testing the effects 
of savolitinib in metastatic colorectal cancer with MET gene changes. 
 
Official Study Title for Internet Search on http://www.ClinicalTrials.gov: 
Protocol 10181, A Phase 2 Study of Savolitinib in Subjects with MET Amplified 
Metastatic Colorectal Cancer (NCT# 03592641)   
 
Overview and Key Information 
 
What am I being asked to do? 
We are asking you to take part in a research study.  We do research studies to try to answer 
questions about how to prevent, diagnose, and treat diseases like cancer. 
 
We are asking you to take part in this study because you have metastatic colorectal cancer that 
has spread to other parts of your body, and your cancer has a change in the gene called MET.   
 
Taking part in this study is your choice. 
You can choose to take part or you can choose not to take part in this study.  You also can 
change your mind at any time.  Whatever choice you make, you will not lose access to your 
medical care or give up any legal rights or benefits. 
 
This document has important information to help you make your choice. Take time to read it.  
Talk to your doctor, family, or friends about the risks and benefits of taking part in the study.  
It’s important that you have as much information as you need and that all your questions are 
answered.  See the “Where can I get more information?” section for resources for more clinical 
trials and general cancer information. 
 
Why is this screening study being done? 
The purpose of the screening study is to test your blood to see if you may be eligible for the main 
study testing savolitinib.  That study is being done to learn if savolitinib can shrink tumors in 
patients with metastatic colorectal cancer with the MET gene change (amplification). In order to 
participate in the main study, we will need to show that your blood has a MET gene 
amplification. The Guardant 360TM test used to determine eligibility for the main study is not 
FDA approved for this purpose. 
 
There will be about 150 people taking part in the screening study. 
 
What is the usual approach to my metastatic colorectal cancer? 
You are being asked to take part in this screening study because you have metastatic colon 
cancer.  People who are not in a study are usually treated with either surgery, radiation, or with 
drugs, such as regorafenib or TAS-102 if you have not received either of them.  Both regorafenib 


Protocol Version Date 12/03/2020 
 
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Page 2 of 6 
 
and TAS-102 are FDA approved treatment for metastatic colorectal cancer. Sometimes, 
combinations of surgery, radiation and/or drugs are used and your study doctor can explain 
which may be best for you. These treatments can reduce symptoms and may stop the tumor from 
growing for several months or more. 
 
What are my choices if I decide not to take part in this study? 
• You may choose to have the usual approach described above. 
• You may choose to take part in a different research study, if one is available. 
• You may choose not to be treated for cancer. 
• You may choose to only get comfort care to help relieve your symptoms and not get 
treated for your cancer.   
 
What will happen if I decide to take part in this study? 
If you decide to take part in this screening study, you will have a blood draw. 
 
You will be part of the screening study for only the time required to perform the Guardant 360TM 
blood test for MET gene amplification. Your blood will be collected in the clinic and sent to a lab 
company to be tested called Guardant Health.  The blood tubes and paperwork sent to Guardant 
Health for your blood test will not include any of your personal information.  The results will be 
available in about two weeks and the Lead Study Principal Investigator will send the results to 
your study doctor who will discuss them with you at that time. 
 
If your blood has the MET gene amplification, he or she will discuss the clinical study in more 
detail and present you the main study informed consent as a separate document.  
 
What are the risks and benefits of taking part in this study? 
There are both risks and benefits to taking part in this study.  It is important for you to think 
carefully about these as you make your decision.     
 
Risks 
We want to make sure you know about a few key risks right now.  We give you more 
information in the “What risks can I expect from taking part in this study?” section. 
 
If you choose to take part in this screening study, there is a risk that: 
• 
Taking a blood sample may cause some discomfort. There may be slight pain, a small 
amount of bleeding, discoloration or bruising at the site where the needle is inserted. You 
may become dizzy or faint. Very rarely, irritation of a vein caused by a small blood clot or 
infection of the vein can develop. Care will be taken to avoid this. 
• 
You may be asked sensitive or private questions which you normally do not discuss 
 
Guardant 360TM assay is being used to determine eligibility for this trial and is not approved by 
the U.S. Food and Drug Administration for this indication. 
 


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Page 3 of 6 
 
There may be some risks that the study doctors do not yet know about.   
 
Benefits 
This screening study will help determine whether you could be eligible for the main study.  
 
If I decide to take part in this study, can I stop later? 
Yes. You can decide to stop at any time.  If you decide to stop for any reason, it is important to 
let the study doctor know as soon as possible so testing on your sample can be stopped.  
 
Your study doctor will tell you about new information or changes in the study that may affect 
your health or your willingness to continue in the study. 
 
Are there other reasons why I might stop being in the study? 
Yes.  The study doctor may take you off the screening study if: 
 
• Your health changes and the study is no longer in your best interest. 
• New information becomes available and the study is no longer in your best interest. 
• You do not follow the study rules. 
• The study is stopped by the Institutional Review Board (IRB), or U.S. Food and Drug 
Administration (FDA), or study sponsor (National Cancer Institute or NCI).  The study 
sponsor is the organization who oversees the study.   
 
It is important that you understand the information in the informed consent before making 
your decision. Please read, or have someone read to you, the rest of this document. If there is 
anything you don’t understand, be sure to ask your study doctor or nurse. 
 
What is the purpose of this study? 
The purpose of this screening study is to test for the presence of MET gene amplification. 
 
There will be about 150 people taking part in this screening study. 
 
What are the study groups? 
The screening study does not have any study groups. 
 
More details will be provided to you in the main study consent if your blood has the specific 
gene change called MET gene amplification.   
 
What exams, tests, and procedures are involved in this study?  
You will be asked to provide a blood sample (about 4 teaspoons) for this screening study.   
To have your blood tested for the MET gene amplification, your gender, cancer diagnosis, and 
blood collection date and time will be included on a form and shipped with your blood sample to 
Guardant Health.  Guardant Health will not receive any of your personal information.  Guardant 
Health is the lab company that will be testing the blood sample collected from you.  In addition 


Protocol Version Date 12/03/2020 
 
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Page 4 of 6 
 
to checking for the MET gene amplification, the blood test provides other information about gene 
changes that may be useful to you and your study doctor.   
 
The Lead Study Principal Investigator will send your study doctor a copy of the Guardant 360TM 
blood test results to include in your medical record.   
 
What risks can I expect from taking part in this study? 
General Risks 
You may have the following discomforts: 
 
• Spend more time in the hospital or doctor’s office. 
• Be asked sensitive or private questions about things you normally do not discuss. 
• May not be able to take part in future studies.  
 
Gene Testing Risks 
As part of this study, we are also studying a gene test. Because this gene test is still being studied, 
there is a risk that the test results may be wrong. If the test results are wrong, you may be included 
in this study even though it may not offer the best treatment option for you. Or, you may not be 
included in this study even though it may offer a good treatment option for you. 
 
What are my responsibilities in this study? 
If you choose to take part in this study you will need to: 
 
• Keep your study appointments. 
• Tell your doctor about: 
o all medications and supplements you are taking 
o any side effects  
o any doctors’ visits or hospital stays outside of this study  
o if you have been or are currently in another research study. 
 
What are the costs of taking part in this screening study? 
You and/or your health plan/insurance company will not need to pay for the cost of doing the 
Guardant 360TM blood test.  
 
You will not be paid for taking part in this study.  The research may lead to new tests, drugs, or 
other products for sale. 
 
What happens if I am injured because I took part in this screening study? 
If you are injured as a result of taking part in this study and need medical treatment, please talk 
with your study doctor right away. The study sponsors will not pay for medical treatment for 
injury. Your insurance company may not be willing to pay for study-related injury. Ask them if 
they will pay.  If you have no insurance, then you would need to pay for these medical costs. 
 


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Page 5 of 6 
 
If you feel this injury was caused by medical error on the part of the study doctors or others 
involved in the study, you have legal right to seek payment, even though you are in a study.  
Agreeing to take part in this study does not mean you give up these rights. 
 
Who will see my medical information? 
Your privacy is very important to us. The study doctors will make every effort to protect it. The 
study doctors have a privacy permit to help protect your records if there is a court case.  
However, some of your medical information may be given out if required by law. If this should 
happen, the study doctors will do their best to make sure that any information that goes out to 
others will not identify who you are.  
 
Some of your health information, such as the results of the Guardant360 test from this screening 
study will be kept in a central database for research. Your name or contact information will not 
be put in the database. The Lead Study Principal Investigator will have access to the database.  A 
copy of the Guardant360 blood test results will be shared by the Lead Study Prinicipal 
Investigator with your study doctor.  If the information from this study is published or presented 
at scientific meetings, your name and other personal information will not be used. 
 
There are organizations that may look at your study records. Your health information in the 
research database also may be shared with these organizations.  They must keep your 
information private, unless required by law to give it to another group.   
 
Some of these organizations are: 
• The study sponsor and any company supporting the screening study now or in the future. 
• The IRB, which is a group of people who review the research with the goal of 
• protecting the people who take part in the study. 
• The FDA and the groups it works with to review research.   
• The NCI and the groups it works with to review research. 
 
There are laws that protect your genetic information.  However, there is a risk that someone 
could get access to your genetic information and identify you by name.  In some cases, 
employers could use your genetic information to decide whether to hire or fire you.  The study 
doctors believe the risk of this happening is very small.  However, the risk may increase in the 
future as people find new ways of tracing information.  For more information about the laws that 
protect you, ask your study doctor. 
 
Where can I get more information? 
You may visit the NCI Web site at http://cancer.gov/ for more information about studies or 
general information about cancer. You may also call the NCI Cancer Information Service to get 
the same information at: 1-800-4-CANCER (1-800-422-6237). 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law.  This Web site will not include information that can identify you. At most, the Web 
site will include a summary of the results. You can search this Web site at any time. 


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Page 6 of 6 
 
 
My Signature Agreeing to Take Part in the Screening Study 
I have read this consent form or had it read to me. I have discussed it with the study doctor and 
my questions 
have been answered. I will be given a signed copy of this form. I agree to take part in the 
screening study 
 
Participant’s signature________________________________ 
 
Date of signature_____________________________________ 
 
Signature of person(s) conducting the informed consent 
discussion___________________________________ 
 
Date of signature_____________________________________ 
 


 
 
Research Study Informed Consent Document 
 
Study Title for Study Participants: Testing the effects of savolitinib in metastatic 
colorectal cancer with MET gene changes. 
 
Official Study Title for Internet Search on http://www.ClinicalTrials.gov: 
Protocol 10181, A Phase 2 Study of Savolitinib in Subjects with MET Amplified 
Metastatic Colorectal Cancer (NCT# 03592641)  
 
Overview and Key Information 
 
What am I being asked to do? 
We are asking you to take part in a research study.  We do research studies to try to answer 
questions about how to prevent, diagnose, and treat diseases like cancer. 
 
We are asking you to take part in this study because you have metastatic colorectal cancer that 
has spread to other parts of your body, and your cancer has a change in the gene called MET.   
 
Taking part in this study is your choice. 
You can choose to take part or you can choose not to take part in this study.  You also can 
change your mind at any time.  Whatever choice you make, you will not lose access to your 
medical care or give up any legal rights or benefits. 
 
This document has important information to help you make your choice. Take time to read it.  
Talk to your doctor, family, or friends about the risks and benefits of taking part in the study.  
It’s important that you have as much information as you need and that all your questions are 
answered.  See the “Where can I get more information?” section for resources for more clinical 
trials and general cancer information. 
 
Why is this study being done? 
This study is being done to answer the following question:  
 
Can we lower the chance of your colorectal cancer growing or spreading by using a new drug? 
 
We are doing this study because we want to find out if this approach is better or worse than the 
usual approach for your metastatic colorectal cancer.  The usual approach is defined as care most 
people get for metastatic colorectal cancer who have tried all treatments that are approved by the 
U.S. Food Drug Administration (FDA). 
 
 


 
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10181 
 
 
 
 
What is the usual approach to my metastatic colorectal cancer? 
You are being asked to take part in this study because you have metastatic colon cancer.  People 
who are not in a study are usually treated with either surgery, radiation, or with drugs, such as 
regorafenib or TAS-102 if you have not received either of them.  Both regorafenib and TAS-102 
are FDA approved treatment for metastatic colorectal cancer. Sometimes, combinations of 
surgery, radiation and/or drugs are used and your study doctor can explain which may be best for 
you. These treatments can reduce symptoms and may stop the tumor from growing for several 
months or more. 
  
What are my choices if I decide not to take part in this study? 
• You may choose to have the usual approach described above. 
• You may choose to take part in a different research study, if one is available. 
• You may choose not to be treated for cancer. 
• You may choose to only get comfort care to help relieve your symptoms and not get 
treated for your cancer.   
 
What will happen if I decide to take part in this study? 
If you decide to take part in this study, you will get the study drug, savolitinib, until your disease 
gest worse or the side effects become too severe. 
 
If you finish the study drug for any reason other than disease progression, your doctor will ask you 
to return to the clinic for routine evaluations until your cancer gets worse or you start a new anti-
cancer therapy.  These follow up visits will continue until 2 years after the last patient of this study 
starts the study drug. 
 
What are the risks and benefits of taking part in this study? 
There are both risks and benefits to taking part in this study.  It is important for you to think 
carefully about these as you make your decision.     
 
Risks 
We want to make sure you know about a few key risks right now.  We give you more 
information in the “What risks can I expect from taking part in this study?” section. 
 
If you choose to take part in this study, there is a risk that the the study drug may not be as good 
as the usual approach for your cancer at shrinking or stabilizing your cancer.   
 
There is also a risk that you could have side effects from the study drug.  These side effects may 
be worse and may be different than you would get with the usual approach for your cancer.   
 
Some of the most common side effects that the study doctors know about are: 
 


 
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10181 
 
 
 
 
• Nausea, vomiting 
• Tiredness 
• Anemia which may require blood transfusion  
• Constipation, diarrhea 
• Swelling of arms, legs 
• Fever 
• Liver damage which may cause yellowing of the eyes and skin 
• Loss of appetite 
 
There may be some risks that the study doctors do not yet know about.   
 
Benefits 
This study drug has shrunk (decreased the size of the tumor) or stabilized (no change in the size 
of the tumor) in a limited number of people with other types of cancer that carry a specific gene 
change called MET gene amplification.  It is unlikely that it will work in everyone with your type 
of cancer or help you live longer.  This study may help the study doctors learn things that may 
help other people in the future. 
 
If I decide to take part in this study, can I stop later? 
Yes, you can decide to stop taking part in the study at any time.  
 
If you decide to stop, let your study doctor know as soon as possible.  It’s important that you stop 
safely.  If you stop, you can decide if you want to keep letting the study doctor know how you 
are doing. 
 
Your study doctor will tell you about new information or changes in the study that may affect 
your health or your willingness to continue in the study. 
 
Are there other reasons why I might stop being in the study? 
Yes.  The study doctor may take you off the study if: 
 
• Your health changes and the study is no longer in your best interest. 
• New information becomes available and the study is no longer in your best interest. 
• You do not follow the study rules. 
• For women: You become pregnant while on the study. 
• The study is stopped by the Institutional Review Board (IRB), or U.S. Food and Drug 
Administration (FDA), or study sponsor (National Cancer Institute or NCI).  The study 
sponsor is the organization who oversees the study.   
 


 
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10181 
 
 
 
 
It is important that you understand the information in the informed consent before making 
your decision. Please read, or have someone read to you, the rest of this document. If there is 
anything you don’t understand, be sure to ask your study doctor or nurse. 
 
What is the purpose of this study? 
The purpose of this study is to test any good and bad effects of the study drug called savolitinib.  
Savolitinib could shrink your cancer, but it could also cause side effects, which are described in 
the risks section below.  The study doctors hope to learn if the study drug will shrink the cancer 
by at least one quarter compared to its present size.  Savolitinib has not been approved by the 
U.S. Food and Drug Administration (FDA) in the treatment of any cancer. It has not been tested 
in colorectal cancer, but has shrunk tumors in patients with stomach, lung, and ovarian cancers. 
 
There will be about 15 people taking part in this study. 
 
Another purpose of this study is for researchers to learn if the results of the MET gene test (used 
to determine your eligibility for this study) can help to predict which future patients may benefit 
from the study drug.  
 
What are the study groups? 
This study has a screening step. The purpose of this step is to test your blood to find out if it has 
a gene change called MET gene amplification. If it does and you meet all the study requirements, 
then you can choose to take part in the study testing savolitinib. If we find that your blood does 
not show the MET gene change, then your doctor will discuss other options for your care. This 
blood screening test is not approved by the FDA in your disease 
 
The following picture also shows what will happen if you take part in the study.  Read the 
illustration from left to right.  The following illustration also shows when the study drugs are 
given.  Read the illustration from left to right. 
 
 
 
In this study, you will get the study drug, savolitinib, as tablets you take by mouth once per day 
of each cycle.  Each cycle is 28 days.  You will repeat each cycle until your cancer gets worse or 
have difficulty tolerating the study drug.  See study calendar for more information. 
 


 
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What exams, tests, and procedures are involved in this study?  
Before you begin the study, your doctor will review the results of your exams, tests, and 
procedures.  This helps your doctor decide if it is safe for you to take part in the study.  If you 
join the study, you will have more exams, tests, and procedures to closely monitor your safety 
and health.  Most of these are included in the usual care you would get even if you were not in a 
study.  
 
Some exams, tests, and procedures are a necessary part of the research study, but would not be 
included in usual care.  Listed below are procedures that will be done for research purposes only.  
 
Before you begin the study 
 
Prior to starting the study drug, you will have a blood sample (about 4 teaspoons) taken to look 
at additional gene changes and protein markers that might predict response to treatment. 
 
Finding these changes would not affect your treatment in this study. However, they could affect 
your health in other ways. It is possible that tests on blood samples will identify information 
about you that was previously unknown, such as disease status or risk. There are no plans to 
provide this information to you or your treating physician unless the information indicates that 
you may be at risk for a disease known at the time of testing to potentially cause premature death 
if untreated. In that case, the lead investigator for this study will notify your treating physician, 
so that your treating physician can speak with you directly. No information will be provided in a 
voice mail, email, or otherwise prior to contacting you. Please notify us of any change in your 
contact information.  
 
During the study 
You will have research-related blood samples taken on Day 1 prior to starting study drug and 
Day 15 of the first 28-day cycle of the study drug. Samples will also be taken on day 1 of every 
other cycle beginning with cycle 3, (cycles, 3, 5, 7, and so on), and when you finish the study 
drug.  These sample are needed to look at factors in the blood that might show a response to the 
study drug. 
A patient study calendar is attached at the end of this document.  It shows how often these 
research samples will be done. 
 
What risks can I expect from taking part in this study? 
General Risks 
If you choose to take part in this study, there is a risk that the savolitinib (AZD6094) may not be 
as good as the usual approach for your cancer or condition at shrinking or stabilizing your 
cancer.   
 
You also may have the following discomforts: 


 
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• Spend more time in the hospital or doctor’s office. 
• Be asked sensitive or private questions about things you normally do not discuss. 
• May not be able to take part in future studies.  
 
The savolitinib (AZD6094) used in this study could be very harmful to an unborn or newborn 
baby.  There may be some risks that doctors do not yet know about.  It is very important that you 
check with your study doctor about what types of birth control or pregnancy prevention to use 
during the study and for 6 months after you have completed the study. 
 
Gene Testing Risks 
As part of this study, we are also studying a gene test. Because this gene test is still being studied, 
there is a risk that the test results may be wrong. If the test results are wrong, you may be included 
in this study even though it may not offer the best treatment option for you. Or, you may not be 
included in this study even though it may offer a good treatment option for you. 
 
Blood Drawing Risks 
Taking a blood sample may cause some discomfort. There may be slight pain, a small amount of 
bleeding, discoloration or bruising at the site where the needle is inserted. You may become dizzy 
or faint. Very rarely, irritation of a vein caused by a small blood clot or infection of the vein can 
develop. Care will be taken to avoid this. 
 
Side Effect Risks 
The savolitinib (AZD6094) used in this study may affect how different parts of your body work 
such as your liver, kidneys, heart, and blood.  The study doctor will test your blood and let you 
know if changes occur that may affect your health. 
 
There is also a risk that you could have side effects from the study drug(s)/study approach. 
 
Here are important things to know about side effects: 
 
1. The study doctors do not know who will or will not have side effects. 
2. Some side effects may go away soon, some may last a long time, and some may never go 
away. 
3. Some side effects may make it hard for you to have children. 
4. Some side effects may be mild.  Other side effects may be very serious and even result in 
death. 
 
You can ask your study doctor questions about side effects at any time.  Here are important ways 
to make side effects less of a problem: 
 


 
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• If you notice or feel anything different, tell your study doctor.  He or she can check to see 
if it is a side effect. 
• Your study doctor will work with you to treat your side effects. 
• Your study doctor may adjust the study drugs to try to reduce side effects. 
 
Drug Risks 
The tables below show the most common and most serious side effects doctors know about.  
Keep in mind that there might be other side effects doctors do not yet know about.  If important 
new side effects are found, the study doctor will discuss these with you. 
 
Possible Side Effects of Savolitinib (AZD6094)  
(Table Version Date: April 2, 2020) 
 
COMMON, SOME MAY BE SERIOUS   
In 100 people receiving savolitinib (AZD6094), more than 20 and up to 100 may have: 
• 
Nausea, vomiting 
• 
Swelling of arms, legs 
• 
Tiredness 
 
 
OCCASIONAL, SOME MAY BE SERIOUS   
In 100 people receiving savolitinib (AZD6094), from 4 to 20 may have: 
• 
Anemia which may require blood transfusion  
• 
Constipation, diarrhea 
• 
Swelling of arms, legs 
• 
Fever 
• 
Liver damage which may cause yellowing of the eyes and skin 
• 
Loss of appetite 
• 
Cough 
 
 
RARE, AND SERIOUS   
In 100 people receiving savolitinib (AZD6094), 3 or fewer may have:  
• 
Allergic reaction which may cause rash, low blood pressure, wheezing, shortness of breath, 
swelling of the face or throat 
• 
Change in heart rhythm  
• 
Severe skin rash with blisters and peeling which can involve mouth and other parts of the 
body 
 
Note: Deaths have occurred to participants in prior savolitinib studies. In 100 people receiving 
savolitinib, 1 or fewer may have died from effects possibly related to this study drug.   
 
Additional Drug Risks 


 
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The study drug could interact with other drugs and certain foods.  Your study doctor will give 
you a drug information handout and wallet card that lists these possible interactions.  Share this 
information with your family members, caregivers, other health care providers, and pharmacists. 
 
Rarely, there are problems getting enough supplies of the study drug.  If that happens, your 
doctor will talk with you about your options. 
 
During savolitinib therapy and for 4 weeks after the last dose you should avoid prolonged exposure 
to the sun, wear protective clothing and a hat, and seek shade from the sun as far as possible; you 
should also use a sunscreen with SPF 30+. Exposure to sunbeds and tanning booths should also be 
avoided. 
 
REMINDER: Report with no delay the symptoms listed in the table above. Some of the symptoms 
can indicate a very serious side effect that could require a change to the dose or the schedule of 
the savolitinib 
 
What are my responsibilities in this study? 
If you choose to take part in this study you will need to: 
 
• Keep your study appointments. 
• Tell your doctor about: 
o all medications and supplements you are taking 
o any side effects  
o any doctors’ visits or hospital stays outside of this study  
o if you have been or are currently in another research study. 
• Write down in your study drug diary when you take the study drug at home.   
 
For women: Do not get pregnant or breastfeed while taking part in this study.  For men: Do not 
father a baby while taking part in this study.  You should refrain from donating sperm from the 
start of dosing until 6 months after discontinuing study drug.  For all:  Tell your study doctor right 
away if you think that you or your partner have become pregnant during the study or within 6 
months after your last dose of study drug. 
 
What are the costs of taking part in this study? 
You and/or your insurance plan will need to pay for the costs of medical care you get as part of 
the study, just as you would if you were getting the usual care for your metastatic colorectal 
cancer.  This includes: 
 
• the costs of tests, exams, procedures, and drugs that you get during the study to monitor 
your safety, and prevent and treat side effects.   
• your insurance co-pays and deductibles. 
 


 
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Talk to your insurance provider and make sure that you understand what your insurance pays for 
and what it doesn’t pay for if you take part in this clinical trial.  Also, find out if you need 
approval from your plan before you can take part in the study.  
 
Ask your doctor or nurse for help finding the right person to talk to if you are unsure which costs 
will be billed to you or your insurance provider.  
 
You and/or your insurance provider will not have to pay for exams, tests, and procedures done 
for research purposes only or that are covered by the study.  These include:   
 
• Research blood collections prior to starting study drug, at Cycle 1 Day 15, on day 1 of 
every other cycle beginning with cycle 3, (cycles, 3, 5, 7, and so on), and when you finish 
the study drug 
 
You or your insurance provider will not have to pay for the savolitinib while you take part in this 
study.  
 
You will not be paid for taking part in this study.  The research may lead to new tests, drugs, or 
other products for sale.  If it does, you will not get any payment.   
 
What happens if I am injured because I took part in this study? 
If you are injured as a result of taking part in this study and need medical treatment, please talk 
with your study doctor right away about your treatment options.  The study sponsors will not pay 
for medical treatment for injury.  Your insurance company may not be willing to pay for a study-
related injury.  Ask them if they will pay.  If you do not have insurance, then you would need to 
pay for these medical costs. 
 
If you feel this injury was caused by medical error on the part of the study doctors or others 
involved in the study, you have the legal right to seek payment, even though you are in a study.  
Agreeing to take part in this study does not mean you give up these rights. 
 
Who will see my medical information? 
Your privacy is very important to us.  The study doctors will make every effort to protect it.  The 
study doctors have a privacy permit to help protect your records if there is a court case.  
However, some of your medical information may be given out if required by law.  If this should 
happen, the study doctors will do their best to make sure that any information that goes out to 
others will not identify who you are.  
 
Some of your health information, such as your response to cancer treatment, results of study 
tests, and medicines you took, will be kept by the study sponsor in a central research database.  
However, your name and contact information will not be put in the database.  If information 
from this study is published or presented at scientific meetings, your name and other personal 
information will not be used.  


 
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There are organizations that may look at your study records.  Your health information in the 
research database also may be shared with these organizations.  They must keep your 
information private, unless required by law to give it to another group.   
 
Some of these organizations are: 
 
• The study sponsor. 
• The IRB, which is a group of people who review the research with the goal of protecting 
the people who take part in the study. 
• The FDA and the groups it works with to review research.   
• The NCI and the groups it works with to review research. 
• Monitors and auditors. 
• Institutions/companies and associated laboratories affiliated with the study sponsor. 
 
There are laws that protect your genetic information.  However, there is a risk that someone 
could get access to your genetic information and identify you by name.  In some cases, 
employers could use your genetic information to decide whether to hire or fire you.  The study 
doctors believe the risk of this happening is very small.  However, the risk may increase in the 
future as people find new ways of tracing information.  For more information about the laws that 
protect you, ask your study doctor. 
 
Where can I get more information? 
You may visit the NCI Web site at http://cancer.gov/ for more information about studies or 
general information about cancer. You may also call the NCI Cancer Information Service to get 
the same information at: 1-800-4-CANCER (1-800-422-6237). 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law. This Web site will not include information that can identify you. At most, the Web 
site will include a summary of the results. You can search this Web site at any time. 
 
You can talk to the study doctor about any questions or concerns you have about this study or to 
report side effects or injuries. Contact the study doctor (insert name of study doctor[s]) at (insert 
telephone number). 
 
For questions about your rights while in this study, call the (insert name of organization or 
center) Institutional Review Board at (insert telephone number).  
 
Optional studies that you can choose to take part in 
This part of the consent form is about optional studies that you can choose to take part in.  They 
are separate from the main study described above.  These optional studies will not benefit your 
health.  The researchers leading these optional studies hope the results will help other people 


 
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with cancer in the future.  The results will not be added to your medical records and you or your 
study doctor will not know the results. 
 
Taking part in these optional studies is your choice.  You can still take part in the main study 
even if you say “no” to any or all of these studies.  There is no penalty for saying “no.” You and 
your insurance company will not be billed for these optional studies.  If you sign up for, but 
cannot complete any of these studies for any reason, you can still take part in the main study. 
 
Circle your choice of “yes” or “no” for each of the following studies. 
 
Optional sample collections for known laboratory studies and/or storage for 
possible future studies 
Researchers are trying to learn more about cancer and other health problems using blood and 
tissue samples from people who take part in clinical trials.  By studying these samples, 
researchers hope to find new ways to prevent, detect, treat, or cure diseases. 
 
Some of these studies may be about how genes affect health and disease.  Other studies may look 
at how genes affect a person’s response to treatment.  Genes carry information about traits that 
are found in you and your family.  Examples of traits are the color of your eyes, having curly or 
straight hair, and certain health conditions that are passed down in families.  Some of the studies 
may lead to new products, such as drugs or tests for diseases. 
 
Known future studies 
If you choose to take part in this optional study, researchers will collect tissue for research as 
indicated below:   
 
If available, a small piece of tumor tissue from your previous surgery and/or biopsy (archival 
tissue sample) will be obtained for research tests to look for some specific gene changes or 
markers in the cancer cell that might predict response to treatment. 
 
Unknown future studies 
If you choose to take part in this optional study, any leftover tissue after known studies are 
completed will be collected and stored.  Storing samples for future studies is called 
“biobanking.”  The biobank is being run by ETCTN Biorepository and is supported by the NCI.  
Also, any health-related information, such as your response to cancer treatment, results of study 
tests, and medicines you took, will be stored for future use.   
 
We don’t know what research may be done in the future using your tissue samples.  This means 
that: 
 
• You will not be asked if you agree to take part in the future research studies.   
• You and your study doctor will not be told when or what type of research will be done. 


 
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• Future research studies may include sequencing of all or part of your DNA called 
genomic sequencing.  All your genetic information makes up your genome.  Genomic 
sequencing is a test that records all or part of the pieces of DNA that are in your genes, 
piece by piece.  This is usually done to look for changes in your genome that may cause 
health problems.   
• You will not get reports or other information about any research that is done using your 
samples.  
 
What is involved in this optional sample collection? 
If you agree to take part, here is what will happen next: 
 
1. Your sample will be stored in the biobank.  There is no limit on the length of time we will 
keep your samples and research information.  The samples will be kept until they are 
used for research or destroyed. 
2. Researchers can only get samples from the biobank after their research has been 
approved by experts.  Researchers will not be given your name or contact information.   
3. Some of your genetic and health information may be placed in central databases for 
researchers to use.  The databases will not include your name or contact information.   
 
What are the risks in this optional sample collection? 
• Your medical and genetic information is unique to you.  There is a risk that someone 
outside of the research study could get access to your study records or trace information 
in a database back to you.  They could use that information in a way that could harm you.  
Researchers believe the chance that someone could access and misuse your information is 
very small.  However, the risk may increase in the future as people find new ways of 
tracing information.  
• In some cases, this information could be used to make it harder for you to get or keep a 
job and get or keep health insurance. There are laws against the misuse of genetic 
information, but they may not give full protection. For more information about the laws 
that protect you, ask your study doctor or visit:  https://www.genome.gov/10002328/  
 
How will information about me be kept private? 
Your privacy is very important to the study researchers and biobank.  They will make every 
effort to protect it.  Here are just a few of the steps they will take: 
 
1. They will remove identifiers, such as your initials, from your sample and information.   
They will replace them with a code number.  There will be a master list linking the code 
numbers to names, but they will keep it separate from the samples and information. 
2. Researchers who study your sample and information will not know who you are.   They 
also must agree that they will not try to find out who you are. 
3. Your personal information will not be given to anyone unless it is required by law.  


 
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4. If research results are published, your name and other personal information will not be 
used. 
 
What are the benefits to taking part in this optional sample collection? 
You will not benefit from taking part.  
 
The researchers, using the samples from you and others, might make discoveries that could help 
people in the future. 
 
Are there any costs or payments to this optional sample collection? 
There are no costs to you or your insurance.  You will not be paid for taking part in this study.  
The research may lead to new tests, drugs, or other products for sale.  If it does, you will not get 
any payment. 
 
What if I change my mind about this optional sample collection? 
If you decide you no longer want your samples to be used, you can call the study doctor, (insert 
name of study doctor for main trial), at (insert telephone number of study doctor for main trial), 
who will let the biobank know.  Then, any sample that remains in the biobank will be destroyed 
or returned to your study doctor.  This will not apply to any samples or related health information 
that have already been given to or used by researchers. 
 
What if I have questions about this optional sample collection? 
If you have questions about the use of your samples for research, contact the study doctor, (insert 
name of study doctor for main trial), at (insert telephone number of study doctor for main trial). 
 
Please circle your answer below to show if you would or would not like to take part in each 
optional study: 
 
Samples for known future studies: 
I agree that my samples and related health information may be used for the laboratory study 
described above. 
 
 
YES 
 
NO 
 
Samples for unknown future studies: 
I agree that my samples and related health information may be kept in a biobank for use in future 
health research. 
 
 
YES 
 
NO 
 
Contact for Future Research 


 
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I agree that my study doctor, or someone on the study team, may contact me or my doctor to see 
if I wish to participate in other research in the future. 
 
 
YES 
 
NO 
 
This is the end of the section about optional studies. 
 
My signature agreeing to take part in the study 
I have read this consent form or had it read to me.  I have discussed it with the study doctor and 
my questions have been answered.  I will be given a signed and dated copy of this form.  I agree 
to take part in the main study.  I also agree to take part in any optional studies where I circled 
“yes”. 
 
Participant’s signature ______________________________________________________ 
 
 
Date of signature ____________________________________________________________ 
 
 
Signature of person(s) conducting the informed consent discussion __________________ 
 
Date of signature _____________________________________________________________ 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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Patient Study Calendar  
 
Patient Activity 
Before the Study 
Pre-Study/Screening 
You will need to have the following tests and procedures to find 
out if you can be in the study: 
Routine: 
• Medical history  
• Physical exam 
- vital signs, weight, height, performance status 
• Review of current medications and supplements  
• Echocardiogram (EKG) to test your heart  
• Tumor measurements by x-ray, CT, MRI, or PET  
• Blood test  
- blood count, chemistry, and liver function 
- tumor marker called CEA 
• Urine test 
• Pregnancy test (if you are a woman who is able to become 
pregnant) 
Research-related: 
• OPTIONAL:  Archived tumor collection from a previous 
surgery or biopsy 
 
During the Study 
Cycle 1 Day 1 
 
 
Routine (prior to starting study drug): 
• Physical exam  
- vital signs, weight, performance status 
• Review of current medications and supplements 
• Blood test  
- blood count, chemistry, and liver function 
• Urine test  
Research-related (prior to starting study drug): 


 
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Patient Activity 
• Blood collection for pharmacogenomics, cell-free tumor 
DNA and circulating proteins (about 4 teaspoons) 
**Start taking savolitinib by mouth once daily** 
Cycle 1 Day 15 
 
Routine: 
• Physical exam  
- vital signs, weight, performance status 
• Review of current medications and supplements 
• Blood test  
- blood count, chemistry, and liver function 
• Urine test  
• Review of side effects 
Research-related: 
• Blood collection for cell-free tumor DNA and circulating 
proteins (about 3 teaspoons) 
Cycle 2 and all cycles 
following (ie., Cycle 3, 4, 
5, 6, etc) 
Routine: 
• Physical exam  
- vital signs, weight, performance status 
• Review of current medications and supplements 
• Blood test  
- blood count, chemistry, and liver function 
- tumor marker called CEA 
• Urine test  
• Review of side effects 
On day 1 of every other 
cycle beginning with 
cycle 3, (cycles, 3, 5, 7, 
and so on) 
Routine: 
• Echocardiogram (EKG) to test your heart  
• Tumor measurements by x-ray, CT, MRI, or PET  
Research-related: 
• Blood collection for cell-free tumor DNA and circulating 
proteins (about 3 teaspoons) 
End of Study Drug 
Routine: 
• Physical exam 
- vital signs, weight, performance status 


 
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Patient Activity 
• Echocardiogram (EKG) to test your heart  
• Blood test  
- blood count, chemistry, and liver function 
• Urine test 
• Review of side effects 
Research-related (prior to starting study drug): 
• Blood collection for cell-free tumor DNA and circulating 
proteins (about 3 teaspoons) 
Off Study 
Follow-Up  
 
 
 
Routine: 
• Physical exam 
- vital signs, weight, performance status 
• Echocardiogram (EKG) to test your heart  
• Blood test  
- blood count, chemistry, and liver function 
• Urine test 
• Review of side effects