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for patients with non-measurable disease

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).  
NCI
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.
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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.
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11.1.7 response review

Response will be reviewed at each participating institution using the RECIST guidelines provided in Section 11.
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12. study oversight and data

Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7.0 (Adverse Events: List and Reporting Requirements).
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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.
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12.2 data reporting

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 email at ctsucontact@westat.com.
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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. Onsite 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.
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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. 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-informaticsresources/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 ).
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12.4 collaborative agreements language

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.  
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 nonCooperative 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.
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13. statistical considerations 13.1 study

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. NCI 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.
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alternative analysis for the number

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.
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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.  
| Ethnic Categories                          |                    |        |      |    |    |
|--------------------------------------------|--------------------|--------|------|----|----|
| Racial 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  |  
| Ethnic Categories                                          |                        |        |      |    |    |
|------------------------------------------------------------|------------------------|--------|------|----|----|
| Racial 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 |        |      |    |    |
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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.
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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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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.
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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 nextgeneration 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 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 antiEGFR 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-METamplified 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
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appendix a performance status criteria

| ECOG Performance Status Scale                                                                                                                                                              | Karnofsky Performance Scale                                   |                                                                           |                                                                        |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------|---------------------------------------------------------------------------|------------------------------------------------------------------------|
| Grade                                                                                                                                                                                      | Descriptions                                                  | Percent                                                                   | Description                                                            |
| 100                                                                                                                                                                                        | Normal, no complaints, no evidence  of disease.               |                                                                           |                                                                        |
| Normal activity. Fully active, able                                                                                                                                                        |                                                               |                                                                           |                                                                        |
| 0                                                                                                                                                                                          | to carry on all pre-disease  performance without restriction. | 90                                                                        | Able to carry on normal activity;  minor signs or symptoms of disease. |
| 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.          |                                                                        |
| 1                                                                                                                                                                                          | 70                                                            | Cares for self, unable to carry on  normal activity or to do active work. |                                                                        |
| 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.                             | Requires occasional assistance, but                           |                                                                           |                                                                        |
| 60                                                                                                                                                                                         | is able to care for most of his/her  needs.                   |                                                                           |                                                                        |
| 2                                                                                                                                                                                          | 50                                                            | Requires considerable assistance and  frequent medical care.              |                                                                        |
| 40                                                                                                                                                                                         | Disabled, requires special care and  assistance.              |                                                                           |                                                                        |
| In bed >50% of the time. Capable  of only limited self-care, confined  to bed or chair more than 50% of  waking hours.                                                                     |                                                               |                                                                           |                                                                        |
| 3                                                                                                                                                                                          | 30                                                            | Severely disabled, hospitalization  indicated. Death not imminent.        |                                                                        |
| 100% bedridden. Completely  disabled. Cannot carry on any  self-care. Totally confined to bed  or chair.                                                                                   | 20                                                            | Very sick, hospitalization indicated.  Death not imminent.                |                                                                        |
| 4                                                                                                                                                                                          | 10                                                            | Moribund, fatal processes  progressing rapidly.                           |                                                                        |
| 5                                                                                                                                                                                          | Dead.                                                         | 0                                                                         | Dead.                                                                  |
appendix b patient drug diary
subject id number cycle #

- 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          | #            | Time          | Day   | Date   | #   | Time   |
|--------------|---------------|--------------|---------------|-------|--------|-----|--------|
| (mm/dd/yyyy) | (00:00 am/pm) | (mm/dd/yyyy) | (00:00 am/pm) |       |        |     |        |
| Tablets      | Tablets       |              |               |       |        |     |        |
| 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:                                          |                      |           |
appendix b patient drug diary
appendix c patient drug information

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.
appendix b patient drug diary
these are the things that

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 NADPHindependent 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
appendix b patient drug diary
to the patient take this

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.
appendix b patient drug diary
these are the things that

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 **_____________________________**  
| ➢ 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.   | list of drugs to avoid, or contact your study doctor.   |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------|
| ➢ Your study doctor's name is _____________________________ and can be contacted at _________________________________.                                                                                   |                                                         |  
NCI
appendix b patient drug diary
appendix d new york heart

| 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 GUARDANT360 BLOOD COLLECTION AND SHIPPING
APPENDIX E
INSTRUCTIONS
appendix b patient drug diary
appendix f guidance regarding potential

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.
appendix b patient drug diary
drugs with a known risk

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                                                                                                                                                      |                                                     |