clinical research protocol
10 ethics and responsibilities 10.1

This study will be conducted in accordance with International Ethical Guidelines for Biomedical Research Involving Human Patients (Council for International Organizations of Medical Sciences 2002), Guidelines for Good Clinical Practice (GCP) (International Conference on Harmonization [ICH] 1996), ICH E6 (R2) and concepts that have their origin in the Declaration of Helsinki (World Medical Association 1996, 2008 & 2013). Specifically, this study is based on adequately performed laboratory and animal experimentation; the study will be conducted under a protocol reviewed and approved by an IRB/EC; the study will be conducted by scientifically and medically qualified persons; the benefits of the study are in proportion to the risks; the rights and welfare of the patients will be respected; the physicians conducting the study do not find the hazards to outweigh the potential benefits; and each patient will give his or her written informed consent before any protocol-driven tests or evaluations are performed.
clinical research protocol
10.2 obligations of investigators

The Investigator is responsible for complying with the protocol and all applicable regulations and guidelines governing clinical research. Additionally, he/she is responsible for ensuring that all participating staff members are adequately trained and competent to perform his/her assigned tasks. All Investigators must provide the sponsor with a current *curriculum vitae*. Only Investigators and designated Sub-Investigators are permitted to sign CRFs and examination findings (e.g., laboratory results or ECGs). The Investigator or designee is responsible for informing the patient of all available information relevant to his/her safety and obtaining signed, written consent from all participating patients. Additionally, the Investigator is responsible for monitoring patient safety and providing periodic and requested reports to the IRB/EC. The Investigator is responsible for the accuracy and completeness of all study records including CRFs, source documents, and the Site Trial Master File. The Investigator will allow the study monitor, Sponsor, auditor, regulatory agencies, and IRB/EC full access to the study and source documents.
clinical research protocol
10.3 institutional review board/ethics committee/research

Prior to the shipment of clinical supplies or initiation of the study, the clinical trial protocol along with the informed consent form (ICF), Investigator's Brochure, and any other written information or instructions for the patient must be submitted to the IRB/EC for written approval. The Investigator will provide the Sponsor with a copy of the IRB/EC's written approval, as well as the membership list or a compliance statement from the IRB/EC. The Investigator is responsible for notifying the IRB/EC of any Sponsor-approved amendments to the protocol or ICF, SAEs occurring in patients treated at the study site in accordance with local IRB/EC practice, and all expedited safety reports from SAEs occurring at other study sites participating in the drug development program.
clinical research protocol
10.4 informed consent form

The ICF must contain all elements required by the Food and Drug Administration (FDA) under 21 Code of Federal Regulations (CFR) Part 50 and the ICH GCP guidelines (ICH E6) in addition to any other elements required by applicable national, state, provincial, and local regulations, or institutional policies.  
All patients who choose to participate in the study must provide written consent after having had adequate time to consider whether they will participate in the study. The written consent must be obtained prior to any protocol-related procedures that are not part of the patient's normal medical care. The patient must be advised of his/her right to withdraw from the study at any time.  
Written documentation of consent must be recorded in the patient's source documents, study records and CRF indicating the date the consent was signed. The patient should receive a signed copy of the consent form according to GCP guidelines.
clinical research protocol
10.5 confidentiality

All information generated in this study is considered confidential, is patient to applicable privacy rules and regulations, and must not be disclosed to any person or entity not directly involved with the study unless prior written consent is gained from the Sponsor and otherwise except in accordance with applicable law or regulations. However, authorized regulatory officials, IRB/EC personnel, the Sponsor and its authorized representatives (as and to the extent authorized in the patient's ICF) are allowed access to the records. Identification of patients in CRFs shall be by study assigned patient numbers only. If required, the patient's full name may be made known to an authorized regulatory agency or other authorized official.
clinical research protocol
10.6 reporting of serious breaches

In the event of any prohibition or restriction (i.e., clinical hold) imposed by an applicable Regulatory Authority, or if the Investigator is aware of any new information which might influence the evaluation of the benefits and risks of the investigational product, the Sponsor must be informed immediately. In addition, the Investigator will inform the Sponsor immediately of any serious breaches of this protocol or of ICH GCP of which the Investigator becomes aware.
clinical research protocol
11 records management 11.1 source

Source documents include hospital or clinical patient charts, pertinent historical medical records, laboratory test reports, ECG tracings, pathology reports, radiographs, etc. All source documents must be legible. Data reported in CRFs and evidence of patient's informed consent must be documented in source documents.
clinical research protocol
11.2 study files and records

A CRF must be completed for each patient for whom informed consent for the study is obtained. The CRFs must be maintained by properly trained and delegated site representatives. The Principal Investigator has responsibility for ensuring the authenticity, accuracy, completeness and timeliness of all data collected in the CRF. CRFs must be signed by the Principal Investigator or by an authorized Sub-Investigator to attest that the information included is true. The study site will maintain a Site Trial Master File in accordance with GCPs. The Investigator shall retain all records for the longest of the following periods: (i) 15 years; (ii) the period of time that conforms to ICH GCP guidelines; (iii) the period of time required by applicable law or regulations, or (iv) the period of time specified in the Clinical Research Agreement.
clinical research protocol
12 quality control and quality

Sponsor appointed Site Monitor(s) must be allowed access to all study records, original source documents, and investigational products throughout the duration of the study. These personnel are responsible to assess compliance with the protocol, appropriate health authority regulations, ICH GCP guidelines, and Sponsor requirements. The study monitor is responsible for complying with the monitoring guidelines established by the Sponsor for the study, assessing the site's needs, and liaising with the assigned Sponsor staff. If the Investigator withdraws from the study and relinquishes his/her responsibility for the maintenance and retention of records, he/she must notify the Sponsor in writing so arrangements can be made to properly store the study materials.
clinical research protocol
12.2 auditing and inspection procedures

The Sponsor's Quality Assurance representatives, IRB/EC reviewers, or inspectors from regulatory agencies may perform an audit or inspection at any time during or after completion of the clinical study. All study-related documentation must be made available to the designated auditor. In addition, representatives of applicable regulatory health authorities may choose to inspect a study. A Sponsor representative will be available to assist in the preparation for such an inspection.
clinical research protocol
13 changes in study conduct

Changes to the study protocol, except those intended to reduce immediate risk to study patients, may be made only by the Sponsor. A protocol change intended to eliminate an apparent immediate hazard to patients may be implemented immediately, provided the IRB/EC is notified within 5 days. Any urgent safety measures taken by the Investigator to protect the study patients against any immediately life threatening hazard must be reported immediately to the Sponsor. Any permanent change to the protocol must be handled as a protocol amendment. The change and the justification will be documented in writing by the Sponsor, as an Administrative Letter or amended protocol. Protocol amendments will be provided with a separate document describing each change and rationale. The written Administrative Letter or amendment must be submitted to the IRB/EC and the Investigator must await approval before implementing the changes. The Sponsor will be responsible for submitting protocol amendments to the appropriate regulatory authorities for approval. If in the judgment of the IRB/EC, the Investigator, and/or the Sponsor, the amendment to the protocol substantially changes the study design and/or increases the potential risk to the patient and/or has an impact on the patient's involvement as a study participant, the currently approved written informed consent form will require similar modification. In such cases, informed consents (revised as appropriate to address protocol amendments) will be obtained for patients enrolled in the study before continued participation.
clinical research protocol
13.2 protocol deviations

Prospective permission to deviate from the eligibility criteria for this protocol will not be provided by the Sponsor. Study specified assessments should not be omitted and the study treatment regimen should not deviate from protocol specifications. Minor, occasional adjustments in the clinic visit schedule may be necessary for logistical reasons (e.g., due to weather conditions) but must not become routine or systematically alter the study schedule. The IRB/EC should be informed of any deviations that may affect a patient's treatment or informed consent, especially those increasing potential risks, which must receive prior written approval by the IRB/EC.
clinical research protocol
14 end of trial 14.1

End of Trial in a Member State of the European Union is defined as the time at which it is deemed that sufficient patients have been recruited and completed the study as stated in the regulatory application (i.e., Clinical Trial Application [CTA]) and ethics application in the Member State.
clinical research protocol
14.2 end of trial in

End of Trial in all other participating countries is defined as the time at which all patients enrolled in the study have completed the last study visit and data from those visits have been reviewed by the Investigator or designee.
clinical research protocol
14.3 premature termination

Premature termination of this study may occur at any time because of a regulatory authority decision, change in opinion of the IRB/EC, drug safety concerns, or at the discretion of the Sponsor. In addition, the Sponsor retains the right to discontinue development of glesatinib, sitravatinib or mocetinostat at any time. If termination becomes necessary, the Sponsor will inform the appropriate regulatory authorities of the termination and the reason. The Principal Investigator will inform the IRB/EC of the same. In terminating the study, the Sponsor and the Principal Investigator will assure that adequate consideration is given to the protection of the patients' interests.
clinical research protocol
15 study report and publication

The Sponsor is responsible for preparing and providing the appropriate regulatory authorities with clinical study reports according to the applicable regulatory requirements. The publication of study results will be governed by the applicable Clinical Research Agreement between the Sponsor and the Study Site and Investigator (as applicable).
clinical research protocol
16 references

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2015;373(17):1627-1639. doi:10.1056/NEJMoa1507643. Brahmer J, Reckamp K, Baas P, et al. Nivolumab versus docetaxel in advanced squamous-cell non-small cell lung cancer. N Engl J Med. 2015;373:123135.doi:10.1056/NEJMoa1504627. Camenisch TD, Koller BH, Earp HS, Matsushima GK. A novel receptor tyrosine kinase, Mer, inhibits TNF-alpha production and lipopolysaccharide-induced endotoxic shock. J Immunol. 1999;162(6):3498-3503. Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomised clinical trials. Non-small Cell Lung Cancer Collaborative Group. BMJ. 1995;311(7010):899-909. Chen P-M, Liu K-J, Hsu P-J, et al. Induction of immunomodulatory monocytes by human mesenchymal stem cell-derived hepatocyte growth factor through ERK1/2. J Leukoc Biol. 2014;96(2):295-303. doi:10.1189/jlb.3A0513-242R. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228-247. doi:10.1016/j.ejca.2008.10.026. Farsaci B, Higgins JP, Hodge JW. Consequence of dose scheduling of sunitinib on host immune response elements and vaccine combination therapy. Int J Cancer. 2012;130(8):1948-1959. doi:10.1002/ijc.26219. Fournel M, Bonfils C, Hou Y, et al. MGCD0103, a novel isotype-selective histone deacetylase inhibitor, has broad spectrum antitumor activity in vitro and in vivo. Mol Cancer Ther. 2008;7(4):759-768. doi:10.1158/1535-7163.MCT-07-2026.  
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doi:10.1038/icb.2011.94. Lemke G, Rothlin CV. Immunobiology of the TAM receptors. Nat Rev Immunol. 2008;8(5):327-336. doi:10.1038/nri2303. Mellman I, Coukos G, Dranoff G. Cancer immunotherapy comes of age. Nature. 2011;480(7378):480-489. doi:10.1038/nature10673.  
Mu CY, Huang JA, Chen Y, Chen C, Zhang XG. High expression of PD-L1 in lung cancer may contribute to poor prognosis and tumor cells immune escape through suppressing tumor infiltrating dendritic cells maturation. Med Oncol. 2011 Sep;28(3):682-8. Okunishi K, Dohi M, Nakagome K, et al. A novel role of hepatocyte growth factor as an immune regulator through suppressing dendritic cell function. J Immunol. 2005;175(7):4745-4753. OPDIVO (nivolumab) injection, for intravenous use [package insert]. Bristol-Myers Squibb Company, Princeton, NJ; 2018. https://packageinserts.bms.com/pi/pi_opdivo.pdf Ozao-Choy J, Ma G, Kao J, et al. The novel role of tyrosine kinase inhibitor in the reversal of immune suppression and modulation of tumor microenvironment for immunebased cancer therapies. Cancer Res. 2009;69(6):2514-2522. doi:10.1158/00085472.CAN-08-4709. Paolino M, Choidas A, Wallner S, et al. The E3 ligase Cbl-b and TAM receptors regulate cancer metastasis via natural killer cells. Nature. 2014;507(7493):508-512. doi:10.1038/nature12998. Reck M, Rodríguez-Abreu D, Robinson AG, et al. Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer. N Engl J Med. 2016;375(19):18231833. doi:10.1056/NEJMoa1606774. Sandler A, Gray R, Perry MC, et al. Paclitaxel-Carboplatin Alone or with Bevacizumab for Non-Small-Cell Lung Cancer. N Engl J Med. 2006;355(24):2542-2550. doi:10.1056/NEJMoa061884. Scagliotti GV, Parikh P, von Pawel J, et al. Phase III Study Comparing Cisplatin Plus Gemcitabine with Cisplatin Plus Pemetrexed in Chemotherapy-Naive Patients with Advanced-Stage Non-Small-Cell Lung Cancer. J Clin Oncol. 2008;26(21):3543-3551. doi:10.1200/JCO.2007.15.0375. Schiller JH, Harrington D, Belani CP, et al. Comparison of Four Chemotherapy Regimens for Advanced Non–Small-Cell Lung Cancer. New England Journal of Medicine. 2002;346(2):92-98. doi:10.1056/NEJMoa011954.  
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Tibrewal N, Wu Y, D'mello V, et al. Autophosphorylation docking site Tyr-867 in Mer receptor tyrosine kinase allows for dissociation of multiple signaling pathways for phagocytosis of apoptotic cells and down-modulation of lipopolysaccharide-inducible NF-kappaB transcriptional activation. J Biol Chem. 2008;283(6):3618-3627. doi:10.1074/jbc.M706906200. Topalian SL, Drake CG, Pardoll DM. Immune checkpoint blockade: a common denominator approach to cancer therapy. Cancer Cell. 2015;27(4):450-461. doi:10.1016/j.ccell.2015.03.001. Tumeh PC, Harview CL, Yearley JH, et al. PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature. 2014;515(7528):568-571. doi:10.1038/nature13954. Vanneman M, Dranoff G. Combining immunotherapy and targeted therapies in cancer treatment. Nat Rev Cancer. 2012;12(4):237-251. doi:10.1038/nrc3237. West AC, Christiansen AJ, Smyth MJ, Johnstone RW. The Combination of Histone Deacetylase Inhibitors with Immune-Stimulating Antibodies has Potent Anti-Cancer Effects. Oncoimmunology. 2012;1(3):377-379. doi:10.4161/onci.18804. Yen BL, Yen M-L, Hsu P-J, et al. Multipotent human mesenchymal stromal cells mediate expansion of myeloid-derived suppressor cells via hepatocyte growth factor/c-D201met and STAT3. Stem Cell Reports. 2013;1(2):139-151. doi:10.1016/j.stemcr.2013.06.006. Zhou N, Moradei O, Raeppel S, et al. Discovery of N-(2-aminophenyl)-4-[(4-pyridin-3ylpyrimidin-2-ylamino)methyl]benzamide (MGCD0103), an Orally Active Histone Deacetylase Inhibitor. J Med Chem. 2008;51(14):4072-4075. doi:10.1021/jm800251w.
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appendix 1. ecog performance status

| Grade   | ECOG                                                                                                                                                       |
|---------|------------------------------------------------------------------------------------------------------------------------------------------------------------|
| 0       | Fully active, able to carry on all pre-disease performance without restriction                                                                             |
| 1       | Restricted in physically strenuous activity but ambulatory and able to carry out work of a light  or sedentary nature, e.g., light house work, office work |
| 2       | Ambulatory and capable of all self care but unable to carry out any work activities. Up and  about more than 50% of waking hours                           |
| 3       | Capable of only limited self care, confined to bed or chair more than 50% of waking hours                                                                  |
| 4       | Completely disabled. Cannot carry on any self care. Totally confined to bed or chair                                                                       |
| 5       | Dead                                                                                                                                                       |  
| MRTX-500 v6.0 - Phase 2 in NSCLC                         | Confidential    |
|----------------------------------------------------------|-----------------|
| Glesatinib, Sitravatinib, or Mocetinostat with Nivolumab | Page 130 of 147 |  
Number of Dose Limiting Toxicities  
Appendix 2. DOSE-FINDING SPREADSHEET OF THE MODIFIED TOXICITY PROBABILITY INTERVAL (MTPI)  
METHOD  
Number of Patients Treated at Current Dose  
| METHOD   | Number of Patients Treated at Current Dose                                                                                                                                                          |    |    |    |    |    |    |    |    |    |    |    |    |    |    |    |    |    |    |    |    |    |    |    |    |    |    |    |    |    |
|----------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----|----|----|----|----|----|----|----|----|----|----|----|----|----|----|----|----|----|----|----|----|----|----|----|----|----|----|----|----|
| 1        | 2                                                                                                                                                                                                   | 3  | 4  | 5  | 6  | 7  | 8  | 9  | 10 | 11 | 12 | 13 | 14 | 15 | 16 | 17 | 18 | 19 | 20 | 21 | 22 | 23 | 24 | 25 | 26 | 27 | 28 | 29 | 30 |    |
| 0        | E                                                                                                                                                                                                   | E  | E  | E  | E  | E  | E  | E  | E  | E  | E  | E  | E  | E  | E  | E  | E  | E  | E  | E  | E  | E  | E  | E  | E  | E  | E  | E  | E  | E  |
| 1        | D                                                                                                                                                                                                   | S  | S  | S  | S  | S  | E  | E  | E  | E  | E  | E  | E  | E  | E  | E  | E  | E  | E  | E  | E  | E  | E  | E  | E  | E  | E  | E  | E  | E  |
| 2        | U                                                                                                                                                                                                   | D  | D  | S  | S  | S  | S  | S  | S  | S  | S  | S  | E  | E  | E  | E  | E  | E  | E  | E  | E  | E  | E  | E  | E  | E  | E  | E  | E  |    |
| 3        | U                                                                                                                                                                                                   | U  | U  | D  | S  | S  | S  | S  | S  | S  | S  | S  | S  | S  | S  | S  | S  | E  | E  | E  | E  | E  | E  | E  | E  | E  | E  | E  |    |    |
| 4        | U                                                                                                                                                                                                   | U  | U  | U  | U  | D  | S  | S  | S  | S  | S  | S  | S  | S  | S  | S  | S  | S  | S  | S  | S  | S  | E  | E  | E  | E  | E  |    |    |    |
| 5        | U                                                                                                                                                                                                   | U  | U  | U  | U  | U  | D  | S  | S  | S  | S  | S  | S  | S  | S  | S  | S  | S  | S  | S  | S  | S  | S  | S  | S  | S  |    |    |    |    |
| 6        | U                                                                                                                                                                                                   | U  | U  | U  | U  | U  | U  | U  | D  | S  | S  | S  | S  | S  | S  | S  | S  | S  | S  | S  | S  | S  | S  | S  | S  |    |    |    |    |    |
| 7        | U                                                                                                                                                                                                   | U  | U  | U  | U  | U  | U  | U  | U  | U  | S  | S  | S  | S  | S  | S  | S  | S  | S  | S  | S  | S  | S  | S  |    |    |    |    |    |    |
| 8        | U                                                                                                                                                                                                   | U  | U  | U  | U  | U  | U  | U  | U  | U  | U  | U  | S  | S  | S  | S  | S  | S  | S  | S  | S  | S  | S  |    |    |    |    |    |    |    |
| 9        | U                                                                                                                                                                                                   | U  | U  | U  | U  | U  | U  | U  | U  | U  | U  | U  | U  | U  | S  | S  | S  | S  | S  | S  | S  | S  |    |    |    |    |    |    |    |    |
| 10       | U                                                                                                                                                                                                   | U  | U  | U  | U  | U  | U  | U  | U  | U  | U  | U  | U  | U  | U  | U  | S  | S  | S  | S  | S  |    |    |    |    |    |    |    |    |    |
| 11       | U                                                                                                                                                                                                   | U  | U  | U  | U  | U  | U  | U  | U  | U  | U  | U  | U  | U  | U  | U  | U  | U  | S  | S  |    |    |    |    |    |    |    |    |    |    |
| 12       | U                                                                                                                                                                                                   | U  | U  | U  | U  | U  | U  | U  | U  | U  | U  | U  | U  | U  | U  | U  | U  | U  | U  |    |    |    |    |    |    |    |    |    |    |    |
| 13       | U                                                                                                                                                                                                   | U  | U  | U  | U  | U  | U  | U  | U  | U  | U  | U  | U  | U  | U  | U  | U  | U  |    |    |    |    |    |    |    |    |    |    |    |    |
| 14       | U                                                                                                                                                                                                   | U  | U  | U  | U  | U  | U  | U  | U  | U  | U  | U  | U  | U  | U  | U  | U  |    |    |    |    |    |    |    |    |    |    |    |    |    |
| 15       | E = Escalate to the next higher dose S = Stay at the current dose D = De-escalate to the next lower dose U = The current dose is unacceptably toxic MTD = 0.25 Sample Size = 30 ɛ1 = 0.05 ɛ2 = 0.05 | U  | U  | U  | U  | U  | U  | U  | U  | U  | U  | U  | U  | U  | U  | U  | U  |    |    |    |    |    |    |    |    |    |    |    |    |    |
| 16       | U                                                                                                                                                                                                   | U  | U  | U  | U  | U  | U  | U  | U  | U  | U  | U  | U  | U  | U  |    |    |    |    |    |    |    |    |    |    |    |    |    |    |    |
| 17       | U                                                                                                                                                                                                   | U  | U  | U  | U  | U  | U  | U  | U  | U  | U  | U  | U  | U  |    |    |    |    |    |    |    |    |    |    |    |    |    |    |    |    |
| 18       | U                                                                                                                                                                                                   | U  | U  | U  | U  | U  | U  | U  | U  | U  | U  | U  | U  |    |    |    |    |    |    |    |    |    |    |    |    |    |    |    |    |    |
| 19       | U                                                                                                                                                                                                   | U  | U  | U  | U  | U  | U  | U  | U  | U  | U  | U  |    |    |    |    |    |    |    |    |    |    |    |    |    |    |    |    |    |    |
| 20       | U                                                                                                                                                                                                   | U  | U  | U  | U  | U  | U  | U  | U  | U  | U  |    |    |    |    |    |    |    |    |    |    |    |    |    |    |    |    |    |    |    |
| 21       | U                                                                                                                                                                                                   | U  | U  | U  | U  | U  | U  | U  | U  | U  |    |    |    |    |    |    |    |    |    |    |    |    |    |    |    |    |    |    |    |    |
| 22       | U                                                                                                                                                                                                   | U  | U  | U  | U  | U  | U  | U  | U  |    |    |    |    |    |    |    |    |    |    |    |    |    |    |    |    |    |    |    |    |    |
| 23       | U                                                                                                                                                                                                   | U  | U  | U  | U  | U  | U  | U  |    |    |    |    |    |    |    |    |    |    |    |    |    |    |    |    |    |    |    |    |    |    |
| 24       | U                                                                                                                                                                                                   | U  | U  | U  | U  | U  | U  |    |    |    |    |    |    |    |    |    |    |    |    |    |    |    |    |    |    |    |    |    |    |    |
| 25       | U                                                                                                                                                                                                   | U  | U  | U  | U  | U  |    |    |    |    |    |    |    |    |    |    |    |    |    |    |    |    |    |    |    |    |    |    |    |    |
| 26       | U                                                                                                                                                                                                   | U  | U  | U  | U  |    |    |    |    |    |    |    |    |    |    |    |    |    |    |    |    |    |    |    |    |    |    |    |    |    |
| 27       | U                                                                                                                                                                                                   | U  | U  | U  |    |    |    |    |    |    |    |    |    |    |    |    |    |    |    |    |    |    |    |    |    |    |    |    |    |    |
| 28       | U                                                                                                                                                                                                   | U  | U  |    |    |    |    |    |    |    |    |    |    |    |    |    |    |    |    |    |    |    |    |    |    |    |    |    |    |    |
| 29       | U                                                                                                                                                                                                   | U  |    |    |    |    |    |    |    |    |    |    |    |    |    |    |    |    |    |    |    |    |    |    |    |    |    |    |    |    |
| 30       | U                                                                                                                                                                                                   |    |    |    |    |    |    |    |    |    |    |    |    |    |    |    |    |    |    |    |    |    |    |    |    |    |    |    |    |    |
clinical research protocol
appendix 3. medications or substances

Bold font indicates medications or substances that might be relatively commonly used.  
Italic font indicates medications for indications that are exclusionary for the current study or would likely result in discontinuation from study treatment with mocetinostat and sitravatinib for management of a concurrent illness.
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drugs that may prolong qt

| Drugs with a  Known Risk of  Torsades de  Pointes   | Amiodarone, anagrelide, arsenic trioxide, astemizole (off US  market), azithromycin, bepridil (off US market), chloroquine,  chlorpromazine, cisapride (off US market), citalopram,  clarithromycin, cocaine, disopyramide, dofetilide, domperidone  (not on US market), dronedarone, droperidol, erythromycin,  escitalopram, flecainide, halofantrine, haloperidol, ibutilide,  levomethadyl (off US market), mesoridazine (off US market),  methadone, moxifloxacin, ondansetron, pentamidine, pimozide,  probucol (off US market), procainamide, quinidine, sevoflurane,  sotalol, sparfloxacin (off US market), sulpiride (not on US  market), terfenadine (off US market), thioridazine, vandetanib.   |
|-----------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
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drugs to be avoided drugs

| Drugs with a  Conditional Risk  of Torsades de  Pointes   | Amantadine, amisulpride, amitriptyline, amoxapine, chloral  hydrate, ciprofloxacin, clomipramine, desipramine,  diphenhydramine, doxepin, fluconazole, fluoxetine,  furosemide, galantamine, hydrochlorothiazide, imipramine  (melipramine), indapamide, itraconazole, ivabradine,  ketoconazole, metronidazole, nelfinavir, nortriptyline,  paroxetine, posaconazole, protriptyline, quinine sulfate,  ritonavir, sertraline, solifenacin, telaprevir, trazodone,  trimethoprim-sulfa, trimipramine, voriconazole.   |
|-----------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
| SUBSTANCES DURING TREATMENT WITH MOCETINOSTAT Enzyme Inhibitor of  Disulfiram CYP 2E1 Inducers of  Ethanol, isoniazid, tobacco CYP 2E1 Strong Inhibitors  Boceprevir, clarithromycin, conivaptan, grapefruit juice,  of CYP 3A4 indinavir, itraconazole, ketoconazole, lopinavir/ritonavir,  mibefradil (withdrawn from US market), nefazodone, nelfinavir,  posaconazole, ritonavir, saquinavir, telaprevir, telithromycin,  voriconazole Strong Inducers  Carbamazepine, phenytoin, rifampin of CYP 3A4 Substrates of  Celecoxib, diclofenac, fluvastatin, glipizide, ibuprofen,  CYP 2C9 irbesartan, losartan, naproxen, phenytoin, piroxicam,  rosiglitazone, sulfamethoxazole, tamoxifen, tolbutamide,  torsemide   |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
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appendix 4. abbreviated presentation of

A modification to RECIST 1.1 has been made to account for the possibility of temporary changes resulting from the potentially beneficial treatment responses of tumor necrosis, cavitation or flare response.
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categorizing lesions at baseline measurable

Accurately measured in at least one dimension.  
When assessed by CT or MRI, longest diameter at least 10 mm or greater (slice thickness 5-8 mm), measured in the axial plane. If the slice thickness is greater than 5 mm (including any inter-slice gap), the longest diameter must be at least twice the slice thickness.  
Malignant lymph nodes with a short axis (defined as the largest measurement perpendicular to the longest diameter of the lesion) 15 mm or greater when assessed by CT or MRI.
The shortest axis is used as the diameter for malignant lymph nodes, longest axis for all other lesions.
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non-measurable disease

Lesions too small to be considered measurable (including nodes with short axis between 10 and 14.9 mm) or truly non-measurable disease such as pleural or pericardial effusions, ascites, inflammatory breast disease, leptomeningeal disease, lymphangitic involvement of skin or lung, and abdominal masses identified by physical exam that are not measurable by reproducible imaging techniques.  
Bone disease is non-measurable with the exception of soft tissue components that can be evaluated by CT or MRI and meet the definition of measurability at baseline.  
Previously irradiated lesions (or those patiented to other local treatment) are non-measurable unless it they have progressed since completion of treatment.
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normal lesions

Non-malignant simple cysts should not be recorded either as target or non-target disease. Cystic lesions thought to represent cystic metastases can be measurable lesions, if they meet the specific definition above.  
Lymph nodes with short axis <10 mm are considered normal and should not be followed as disease.
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tumor assessments

All sites of disease must be assessed at baseline. Baseline assessments should be done as close as possible prior to study start. All required scans must be done within the window of time specified in the Schedule of Assessments prior to treatment. If the baseline assessment is inadequate, subsequent statuses generally should be indeterminate. The determination of whether lesions are measurable is performed only at baseline. "Measurable" at baseline means eligible for selection as target lesions, and thus for quantitative assessment throughout the trial. Once selected as a target lesion, a lesion remains target throughout the trial.
clinical research protocol
target lesions

All measurable lesions up to a maximum of 2 lesions per organ, 5 lesions in total, representative of all involved organs, should be identified as target lesions at baseline. Target lesions should be selected on the basis of size (longest lesions) and suitability for accurate repeated measurements. Record the longest diameter for each lesion, except in the case of pathological lymph nodes for which the short axis should be recorded. The sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target lesions at baseline will be the basis for comparison to look for partial response at later assessments.  
If 2 target lesions coalesce the longest diameter measurement of the coalesced mass is used. If a large target lesion splits, the sum of the parts is used.  
Measurements for target lesions that become small should continue to be recorded. If a target lesion becomes too small to measure, 0 mm should be recorded if the lesion is considered to have disappeared; otherwise a default value of 5 mm should be recorded.  
When nodal lesions decrease to <10 mm (normal), the actual measurement should still be recorded.
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non-target lesions

All non-measurable disease is non-target. All measurable lesions not identified as target lesions are also included as non-target disease. Measurements are not required but rather qualitative evaluations of status will be recorded. Multiple non-target lesions in one organ may be recorded as a single item on the CRF (e.g., 'multiple liver metastases').
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objective response status at each

Disease sites must be assessed using the same technique as baseline, including consistent administration of contrast. If not, subsequent objective statuses may be indeterminate.
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target disease

Complete Response (CR): Complete disappearance of all target lesions with the exception of nodal disease. All target nodes must decrease to normal size (short axis < 10 mm). All target lesions must be assessed.  
Partial Response (PR): Greater than or equal to 30% decrease under baseline of the sum of diameters of all target measurable lesions. The short diameter is used in the sum for target nodes, while the longest diameter is used in the sum for all other target lesions. All target lesions must be assessed.  
Stable Disease (SD): Does not qualify for CR, PR or Progression. All target lesions must be assessed. Stable can follow PR only in the rare case that the sum increases by less than 20% from the nadir, but enough that a previously documented 30% decrease no longer holds.  
Progressive Disease (PD): 20% increase in the sum of diameters of target measurable lesions above the smallest sum observed (over baseline if no decrease in the sum is observed during therapy) with a minimum absolute increase of 5 mm.  
Indeterminate: Progression has not been documented, and o one or more target lesions have not been assessed, o or assessment methods used were inconsistent with those used at baseline and impaired assessment, o or one or more target lesions cannot be measured accurately (e.g., poorly visible unless due to being too small to measure),
o or one or more target lesions were excised or irradiated and have not reappeared or increased.
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non-target disease

CR: Disappearance of all non-target lesions and normalization of tumor marker levels. All lymph nodes must be 'normal' in size (<10 mm short axis).  
Non-CR/Non-PD: Persistence of any non-target lesions and/or tumor marker level above the normal limits.
PD: Unequivocal progression of preexisting lesions. Generally the overall tumor burden must increase sufficiently to merit discontinuation of therapy. In the presence SD or PR in target disease, progression due to unequivocal increase in non-target disease should be rare.  
Indeterminate: Progression has not been determined and one or more non-target sites were not assessed or assessment methods were inconsistent with those used at baseline.
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new lesions

The appearance of any new unequivocal malignant lesion indicates PD. If a new lesion is equivocal, for example due to its small size, continued assessment will clarify the etiology. If repeat assessments confirm the lesion, then progression should be recorded on the date of the initial assessment. A lesion identified in an area not previously scanned will be considered a new lesion.
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lesion changes that may be

Potential exists for individual tumor lesions to develop necrosis, to cavitate, have a flare response to treatment or become otherwise difficult to evaluate for a period of time as the result of beneficial study treatment impact. For example, tumor necrosis, cavitation or flare may result in increase in overall size of individual lesions or unclear tumor margins prior to recovery to smaller lesions, development of scar tissue, or complete resolution. The true tumor measurements of lesions should be recorded but the conclusion of progressive disease may be suspended until continued assessment clarifies the nature of the tumor change. If repeat assessments indicate progression of disease, then PD should be recorded on the date of the first assessment giving the impression of progression. If repeat assessments indicate that the change was a process of transition, then NE (not evaluable) should be recorded during the period of transition, and PR or CR may be recorded for subsequent evaluations. The CRF will collect information on the observations during the period of transition to support the assessment conclusions.
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supplemental investigations

If CR determination depends on a residual lesion that decreased in size but did not disappear completely, it is recommended the residual lesion be investigated with biopsy or fine needle aspirate. If no disease is identified, objective status is CR.  
| Best Objective Response Target  Non-Target  Lesions   | New Lesion    | Point in Time Response   | Best Response   |                                                                          |
|-------------------------------------------------------|---------------|--------------------------|-----------------|--------------------------------------------------------------------------|
| Lesions CR                                            | CR            | No                       | CR              | CR and PR require  confirmation at least                                 |
| CR                                                    | Non-CR/Non-PD | No                       | PR              | 4 weeks after first  observation                                         |
| PR                                                    | Non-PD        | No                       | PR              | SD requires an on-study  assessment after at least  6weeks on treatment. |
| Unconfirmed PR or CR are  reported as SD.             |               |                          |                 |                                                                          |
| SD                                                    | Non-PD        | No                       | SD              |                                                                          |
| PD                                                    | Any           | Yes or No                | PD              |                                                                          |
| Any                                                   | PD            | Yes or No                | PD              |                                                                          |
| Any                                                   | Any           | Yes                      | PD              |                                                                          |
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patientive progression

Patients requiring discontinuation of treatment due to worsening health status attributable to advancement of the malignancy under study but without objective evidence of disease progression should not be reported as PD on tumor assessment CRFs. This should be indicated on the end of treatment CRF as off treatment due to Global Deterioration of Health Status.
clinical research protocol
appendix 5. sitravatinib sub-study to

This sub-study within Study MRTX-500 will be conducted at selected study sites. It is an open-label evaluation of sitravatinib PK using three formulations of capsules. The sitravatinib formulations to be studied are free base hard gelatin capsules with 10%
polysorbate 80 (Tween® 80), the formulation used in the main study and reference product, and as many as two new malate formulations: malate capsules, and free base softgel capsules. Investigation of alternative formulations is for the purpose of optimizing product characteristics and manufacturing efficiency. This investigation is being performed within the context of Study MRTX-500 to enable evaluation in one of the patient populations of interest for future sitravatinib clinical trials and in patients whose steady-state PK may be evaluated, and long-term sparse PK samples may be collected. In preparation for this sub-study, a non-clinical PK study was conducted in dogs after administration of single and multiple doses of the three sitravatinib capsule formulations. Groups of 6 dogs (3 male and 3 female) were included in each evaluation. PK sampling was performed on Day 1 and at steady state on Day 7. The PK parameters Cmax, AUC0-24, and AUC0-∞ (for Day 1 only) were estimated (Table 21). The ratios of the geometric means were used to compare the free base Tween capsule (reference product) to the malate salt capsule and the free base softgel capsule. Preliminary data indicate that the malate salt capsule to reference product ratios were 2.52, 2.19, and 2.15 for Cmax, AUC024, and AUC0-∞, respectively, on Day 1 and, 1.85 and 1.65 for Cmax and AUC0-24, respectively, on Day 7. The free base softgel capsule to reference product ratios were 2.18, 2.29, and 2.26 for Cmax, AUC0-24, and AUC0-∞, respectively, on Day 1 and, 1.70 and 1.81 for Cmax and AUC0-24, respectively, on Day 7. Concentration time profiles for the formulations were comparable, with a median tmax of 4, 3 and 4 hrs and a mean half-life of 5.6, 4.9 and 5.1 hrs for the reference product, malate salt capsule and free base softgel capsule, respectively. The new formulations showed lower variability as compared to the reference product, expressed as lower geometric mean CV% values for all the PK parameters.  
| Administration of Three Sitravatinib Capsule Formulations Dose (mg) Cmax AUC0-24 AUC0-inf   |               |           |            |            |        |
|---------------------------------------------------------------------------------------------|---------------|-----------|------------|------------|--------|
| Day                                                                                         | (Formulation) | (ng/mL)   | (ng·hr/mL) | (ng·hr/mL) |        |
| Day 1                                                                                       | 20            | Geo. Mean | 57.61      | 451.22     | 470.64 |
| Malate Salt Capsule                                                                         | Geo. CV%      | 51.4      | 45.5       | 44.7       |        |
| N                                                                                           | 6             | 6         | 6          |            |        |
| 20                                                                                          | Geo. Mean     | 49.91     | 472.04     | 495.13     |        |
| Free Base Softgel Capsule                                                                   | Geo. CV%      | 21.3      | 18.6       | 21.0       |        |
| N                                                                                           | 6             | 6         | 6          |            |        |
| 20                                                                                          | Geo. Mean     | 22.85     | 205.82     | 219.28     |        |
| Free Base 10% Tween Capsule                                                                 | Geo. CV%      | 110.0     | 118.7      | 125.5      |        |
| N                                                                                           | 6             | 6         | 6          |            |        |
| Malate Salt to:                                                                             |               |           |            |            |        |
| Free Base 10% Tween                                                                         | Ratioa        | 2.52      | 2.19       | 2.15       |        |
| Free Base Softgel to: Free Base 10% Tween                                                   | Ratioa        | 2.18      | 2.29       | 2.26       |        |
| Day 7                                                                                       | 20            | Geo. Mean | 73.85      | 637.62     |        |
| Malate Salt Capsule                                                                         | Geo. CV%      | 44.8      | 41.2       |            |        |
| N                                                                                           | 6             | 6         |            |            |        |
| 20                                                                                          | Geo. Mean     | 67.98     | 698.55     |            |        |
| Free Base Softgel Capsule                                                                   | Geo. CV%      | 32.2      | 32.3       |            |        |
| N                                                                                           | 6             | 6         |            |            |        |
| 20                                                                                          | Geo. Mean     | 39.92     | 385.99     |            |        |
| Free Base 10% Tween Capsule                                                                 | Geo. CV%      | 115.1     | 130.2      |            |        |
| N                                                                                           | 6             | 6         |            |            |        |
| Malate Salt to:                                                                             |               |           |            |            |        |
| Free Base 10% Tween                                                                         | Ratioa        | 1.85      | 1.65       |            |        |
| Free Base Softgel to: Free Base 10% Tween                                                   | Ratioa        | 1.70      | 1.81       |            |        |
| a Ratio calculated based on Geo. Mean.                                                      |               |           |            |            |        |  
The exposure levels observed in the dog study were higher for both of the new formulations as compared to the reference product. For this reason, a dose escalation approach will be implemented in this sub-study for the new formulations. The starting dose for each was determined by applying the Day 1 and Day 7 (steady state) exposure ratios to the starting dose using the reference product in the main study (120 mg QD). If the exposure ratios observed in dogs reflect exposure in patients, administration of 50-70 mg of either new formulation would be expected to result in exposure comparable to the reference product (free base 10% Tween capsule) administered at 120 mg QD. The starting dose for the malate direct blend formulation will be 60 mg QD. This is considered conservative for two reasons, 1) the magnitude of exposure differences between oral formulations observed in dogs is most often attenuated when subsequently studied in humans, and 2) sitravatinib has been administered at 150 mg QD in a clinical trial (Study 516-001) and was tolerated. As described below, each new formulation may also be evaluated at a higher dose level. As described in Section 1.8.1 of this protocol, sitravatinib administered in combination with nivolumab is unlikely to result in a clinically relevant drug-drug interaction based on absorption, metabolism, elimination or protein binding. Nivolumab is a mAb and is intravenously administered, whereas sitravatinib is a small molecule therapeutic administered orally; no absorption interactions are expected. No studies on the metabolism of nivolumab have been reported in vitro or in humans. Like most therapeutic proteins, nivolumab is not expected to be metabolized by liver cytochrome P450 (CYP) or other drug metabolizing enzymes and is unlikely to have an effect on CYPs or other metabolizing enzymes in terms of inhibition or induction. This sub-study will include dedicated patient cohorts for the free base formulation, malate direct blend formulation and malate roller compaction formulation. Data evaluable for PK are needed from as many as 10 patients in each cohort; as many as 12 patients may be enrolled into each cohort to ensure sufficient PK data are evaluable. Patients eligible for this sub-study will meet applicable entry criteria in the main study.  
Specifically, patients will have locally advanced, unresectable or metastatic nonsquamous NSCLC and will have experienced progression of disease on or after at least one prior treatment in the advanced disease setting. Enrollment of the cohort of patients to receive the sitravatinib free base 10% Tween capsule formulation (reference product) may proceed upon approval of Protocol Amendment 4 (Version 5.0) by the IRB/EC. Enrollment into cohorts evaluating the new formulations is expected to begin in the fourth-quarter 2018. The sitravatinib malate salt capsule formulation is expected to be evaluated first, with evaluation of the free base softgel capsule undertaken if results using the malate salt are unfavorable. Reference sitravatinib exposure data using the sitravatinib free-base 10% Tween capsule formulation administered at 120 mg QD will be generated in one cohort of patients. Due to the observation in the dog study of increased exposure using the two new sitravatinib capsule formulations, two dose levels are planned for each of these formulations. The starting dose for both the malate salt capsule and free base softgel capsule formulation will be 60 mg QD, as described above. The PK data generated using the starting dose in patients will be used to extrapolate the dose of each capsule formulation needed to achieve exposure comparable to the reference product administered at 120 mg QD. The potential patient cohorts are listed below:  
1. Sitravatinib free base 10% Tween (free base) capsule formulation - 120 mg QD. 2. Sitravatinib malate direct blend salt capsule formulation - 60 mg QD. 3. Sitravatinib malate roller compaction capsule formulation - 100 mg QD.
This starting dose of 100 mg sitravatinib malate roller compaction capsule is extrapolated based on the safety and PK results in Cohort 2. The 60 mg QD sitravatinib malate exposure was compared to the 120 mg sitravatinib free base exposure and the 100 mg QD of sitravatinib malate is projected to achieve exposure comparable to the 120 mg QD sitravatinib free base. The following patient cohorts will no longer be explored and hence patient enrollment within these cohorts will not open at this time.  
4. Sitravatinib free base softgel capsule formulation - 60 mg QD.  
5. Sitravatinib free base softgel capsule formulation - dose to be extrapolated based on results in Cohort 4 to achieve exposure comparable to Cohort 1.
In the event that early results at a dose level are not within the exposure range expected, adaptations, including truncated enrollment into a cohort or addition of a limited number of cohorts may be undertaken after discussion between the Investigators participating in the sub-study and the Sponsor.
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sitravatinib administration and pk/ecg timepoints

The sub-study will begin with a 7-day lead-in period comprised of a single dose of the assigned sitravatinib formulation/dose followed by sample collection for PK analysis over a 168-hour period as defined in Table 22. At only the Lead-in Day 1 and C1D15 visits: following an overnight fast of at least 10 hours, patients enrolled in this sub-study will receive the assigned sitravatinib capsule formulation administered with ~240 mL (a cup) of water. Patients will continue to fast for at least 4 hours before the next meal. Water is allowed as desired except for one hour before and one hour after sitravatinib administration. All other doses of sitravatinib (with the exception of Lead-in Day 1 and C1D15) should be taken, at the assigned daily dose, in the modified fasted state, specifically, at least a 2hour fast before each dose and no food for a minimum of 1 hour after each dose. On days of PK sampling, patients should delay taking the daily sitravatinib dose until the pre-dose PK sample has been collected in the clinic.  
Several changes to the assessment schedule outlined in the main study will apply to patients enrolled in this sub-study.  
l Patients enrolled in this sub-study are exempt from sample collection for the  
purposes of flow cytometry and protein or cytokine biomarker studies.  
2 Triplicate ECGs will be performed on Day 1 of the lead-in period as described in Table 22 instead of later, on Cycle 1 Day 1, as described in Table 3.  
3 The PK sample collection schedule describe in Table 22 and Table 23 are to be followed up to Cycle 1 Day 15, after which the sparse sampling schedule described in Table 3 applies.
Please see the central lab manual for collection, processing, and shipping instructions of PK blood samples.  
Upon completion of the lead-in period, patients will begin Cycle 1 Day 1 (same visit as lead-in period Day 8) of study treatment as described in the main study, using the assigned sitravatinib formulation and dose in combination with nivolumab.  On Cycle 1 Day 15 (± 2 days), a steady-state PK profile will be evaluated with sample collection over a 24-hour period ( Table 23 ).  Treatment of patients beyond Cycle 1 Day 15 will continue using the assigned sitravatinib formulation and dose in combination with nivolumab.  
Individual patient escalation from the starting dose using a new capsule formulation to any subsequent higher dose may be considered, at the discretion of the Investigator, after PK data at the higher dose are available.  Patient assessment and management will be as described in the main study.
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table 22 pk sample collection

| PK Lead-In Period Following a Single Dose of Sitravatinib                                               | Day 8             |       |      |      |      |      |      |                                    |      |        |        |      |
|---------------------------------------------------------------------------------------------------------|-------------------|-------|------|------|------|------|------|------------------------------------|------|--------|--------|------|
| Day 1                                                                                                   | Day 2 Day 3 Day 4 | /C1D1 |      |      |      |      |      |                                    |      |        |        |      |
| Collection                                                                                              | Pre-              | 30    | 1    | 2    | 4    | 6    | 8    | 12                                 | 24   | 48     | 72     | 168  |
| Time and                                                                                                | dose              | min   | hour | hour | hour | hour | hour | hour                               | hour | hour 1 | hour 1 | hour |
| Allowable                                                                                               | (-30              | (± 10 | (±15 | (±15 | (±30 | (±30 | (±30 | (±2                                | (±2  | (±5    | (±7    | (±7  |
| Window                                                                                                  | min)              | min)  | min) | min) | min) | min) | min) | hours) hours) hours) hours) hours) |      |        |        |      |
| PK Sample                                                                                               | x                 | x     | x    | X    | x    | x    | X    | x                                  | x    | X      | x      | x    |
| Triplicate                                                                                              | X                 | x     |      |      |      |      |      |                                    |      |        |        |      |
| ECG 2                                                                                                   | twice             |       |      |      |      |      |      |                                    |      |        |        |      |
| Sample collections at 12 hours, 48 hours and 72 hours after dosing is optional. While sample collection |                   |       |      |      |      |      |      |                                    |      |        |        |      |  
at these timeframes are highly desirable to strengthen PK analysis, they are not mandatory in the event of logistical constraints.  
2 approximately -1.0 hr and again approximately -30 mins, followed by vital signs and PK sample approximately -15 min.
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table 23 pk sample collection

| Cycle 1 Day 15                                                                                       |      |      |      |      |      |        |        |        |    |
|------------------------------------------------------------------------------------------------------|------|------|------|------|------|--------|--------|--------|----|
| Collection                                                                                           | Pre- | 30   | 1    | 2    | 6    | 8      | 12     | 24     |    |
| 4 hour                                                                                               |      |      |      |      |      |        |        |        |    |
| Time and                                                                                             | dose | min  | hour | hour | hour | hour 1 | hour   |        |    |
| hour                                                                                                 |      |      |      |      |      |        |        |        |    |
| (±30                                                                                                 |      |      |      |      |      |        |        |        |    |
| Allowable                                                                                            | (-30 | (±15 | (±15 | (±30 | (±30 |        |        |        |    |
| (± 10                                                                                                | (±2  | (±2  |      |      |      |        |        |        |    |
| min)                                                                                                 |      |      |      |      |      |        |        |        |    |
| Window                                                                                               | min) | min) | min) | min) | min) | min)   | hours) | hours) |    |
| PK Sample                                                                                            | x    | x    | X    | x    | x    | X      | X      | x      | x  |
| Triplicate                                                                                           | x    |      |      |      |      |        |        |        |    |
| EG 2                                                                                                 |      |      |      |      |      |        |        |        |    |
| Sample collection at 12 hours after dosing is optional. While sample collection at this timeframe is |      |      |      |      |      |        |        |        |    |
| 1                                                                                                    |      |      |      |      |      |        |        |        |    |  
2 highly desirable to strengthen PK analysis, it is not mandatory in the event of logistical constraints.  
ECGs should be taken in triplicate, each reading approximately 2 minutes apart.  
The PK evaluable population will consist of all patients who received treatment with sitravatinib and had sufficient concentration-time data to permit calculation of PK
parameters for sitravatinib.  For patients who were noncompliant with respect to administration of sitravatinib, or for patients with incomplete data, a decision as to their inclusion in the analysis will be made on a case-by-case basis. After completion of the PK sub-study specific assessments and depending on the duration of treatment of individual patients and the long-term availability of various sitravatinib capsule formulations, patients may be transferred from the formulation assigned at the time of study entry to a more available formulation.  The need for any such transfers will be communicated to Investigators by the Sponsor in writing (to be retained with patient source documents).  
PK concentration and parameter data will be descriptively derived and displayed.  A
descriptive comparison will be conducted using AUCo-t, AUC(0-o), Cmax, Tmax, t1/2, and steady state PK exposure parameters.  Steady state exposure comparison will also be assessed and accounted for.  Descriptive statistics will be used to summarize patient characteristics, treatment administration and safety variables between the formulation cohorts.  Details of this analysis will be provided in the PKAP.
clinical research protocol
appendix 6. sitravatinib sub-study to

This sub-study within Study MRTX-500 will be conducted at selected study sites. It is an open-label evaluation of PK when sitravatinib capsules are administered orally in the fed state. The potential to administer sitravatinib in the fed or fasted state is being investigated to provide flexibility and convenience for future patients enrolling in sitravatinib clinical trials. Reference data in the fasted state will be generated in the substudy described in Appendix 5. Depending on timing of availability of drug product for different sitravatinib capsule formulations and results from the formulation PK sub-study, evaluation of sitravatinib PK in the fed state may be undertaken with one or more capsule formulation(s). Sitravatinib administered in combination with nivolumab is unlikely to result in a clinically relevant drug-drug interaction based on absorption, metabolism, elimination or protein binding. Nivolumab is a mAb and is intravenously administered, whereas sitravatinib is a small molecule therapeutic administered orally; no absorption interactions are expected. No studies on the metabolism of nivolumab have been reported in vitro or in humans. Like most therapeutic proteins, nivolumab is not expected to be metabolized by liver cytochrome P-450 (CYP) or other drug metabolizing enzymes and is unlikely to have an effect on CYPs or other metabolizing enzymes in terms of inhibition or induction. This sub-study will be conducted in as many as three dedicated patient cohorts. Data evaluable for PK are needed from at least 6 patients in each cohort; as many as 8-10 patients may be enrolled into each cohort to ensure 6 patients are evaluable for PK. The sitravatinib dose to be administered using either of the new capsule formulations will be determined in the PK sub-study described in Appendix 5. Patients eligible for the sub-study will meet applicable entry criteria in the main study.  
Specifically, patients will have locally advanced, unresectable or metastatic nonsquamous NSCLC and will have experienced progression of disease on or after at least one prior treatment in the advanced disease setting.  
The definition of the fed state for the purpose of this sub-study is consumption of a highfat (approximately 50% of total caloric content of the meal), high-calorie (800-1000 calories) meal at the time of sitravatinib dosing. For the purposes of this sub-study, a high-fat meal consists of approximately 150, 250, 500-600 calories from protein, carbohydrates and fat respectively. An example meal consists of two eggs fried with butter, two strips of bacon, two slices of toast with butter, four ounces of hash brown potatoes and eight ounces of whole milk. The nutritionist at the study site may recommend an alternative meal that follows the guidance for fat and calorie content.
clinical research protocol
sitravatinib administration and high-fat meal/pk/ecg

The sub-study will begin with a 7-day lead-in period comprised of a single dose of the assigned sitravatinib formulation followed by sample collection for PK analysis over a 168-hour period (Table 24). At only Lead-in Day 1 and C1D15 visits: Patients will be seen in clinic at the end of an overnight fast of at least 10 hours. The pre-dose PK sample will be obtained and then the patient will consume a high-fat, high-calorie meal (as described above). Patients should start the recommended meal 30 minutes prior to sitravatinib dosing. Patients should eat this meal in 30 minutes or less. Sitravatinib is to be administered 30 minutes after the start of the meal with ~240 mL of water. If the meal is not finished in 30 minutes, patients should not complete the meal post sitravatinib administration. No food should be consumed for at least 4 hours after the dose. Water can be allowed as desired except for 1 hour before and 1 hour after the drug administration. C1D1 to C1D14: Patients should consume their typical meal within 30 minutes prior to each dose of sitravatinib. Sitravatinib should be taken with ~240 mL of water. C1D16 and beyond: Sitravatinib should be taken in the modified fasted state, specifically, at least a 2-hour fast before each dose and no food for a minimum of 1 hour after each dose. On days of PK sampling, patients should delay taking the daily sitravatinib dose until the pre-dose PK sample has been collected in the clinic. Patients enrolled in this sub-study will receive sitravatinib administered orally at the daily dose of 120 mg QD for the reference product and, for the new capsule formulations, at the dose recommended after conduct of the PK sub-study described in Appendix 5. Several changes to the assessment schedule outlined in the main study will apply to patients enrolled in this sub-study.  
1 Patients enrolled in this sub-study are exempt from sample collection for the purposes of flow cytometry and protein or cytokine biomarker studies.  
2 Triplicate ECGs will be performed on Day 1 of the lead-in period as described in Table 22 instead of later, on Cycle 1 Day 1, as described in Table 3.  
3 The PK sample collection schedule describe in Table 22 and Table 23 are to be followed up to Cycle 1 Day 15, after which the sparse sampling schedule described in Table 3 applies.
PK blood samples will each collect 4 mL of blood. PK samples collected during this substudy will be analyzed by the central laboratory in convenient batches. See the Study Manual for instructions concerning sample transfer.  
Upon completion of the lead-in period, patients will begin Cycle 1 Day 1 (same visit as lead-in period Day 8) of study treatment using the assigned sitravatinib formulation and in combination with nivolumab (as described in the main study).  On Cycle 1 Day 15 (± 2 dys), rather than the single PK sample, a steady-state PK profile of sitravatinib administered with the described high-fat, high-calorie meal will be evaluated with sample collection over a 24-hour period (Table 25).  Patient assessment and management will be as described in the main study.
clinical research protocol
table 24 pk sample collection

| PK Lead-In Period Following a Single Dose of Sitravatinib                                                | Day 8                                                                                                   |      |      |      |      |      |               |               |        |      |      |    |
|----------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------|------|------|------|------|------|---------------|---------------|--------|------|------|----|
| Day 1                                                                                                    | Day 2 Day 3 Day 4                                                                                       | /    |      |      |      |      |               |               |        |      |      |    |
| C1D1                                                                                                     |                                                                                                         |      |      |      |      |      |               |               |        |      |      |    |
| 30                                                                                                       |                                                                                                         |      |      |      |      |      |               |               |        |      |      |    |
| Collection                                                                                               | Pre-                                                                                                    | 1    | 2    | 4    | 6    | 8    | 12            | 24            | 48     | 72   | 168  |    |
| min                                                                                                      |                                                                                                         |      |      |      |      |      |               |               |        |      |      |    |
| Time and                                                                                                 | dose                                                                                                    | hour | hour | hour | hour | hour | hour          | hour          | hour   | hour | hour |    |
| (±                                                                                                       |                                                                                                         |      |      |      |      |      |               |               |        |      |      |    |
| Allowable                                                                                                | (-30                                                                                                    | (±15 | (±15 | (±30 | (±30 | (±30 | (±2           | (±2           | (±5    | (±7  | (±7  |    |
| 10                                                                                                       |                                                                                                         |      |      |      |      |      |               |               |        |      |      |    |
| Window                                                                                                   | min)                                                                                                    | min) | min) | min) | min) | min) | hours) hours) | hours) hours) | hours) |      |      |    |
| min)                                                                                                     |                                                                                                         |      |      |      |      |      |               |               |        |      |      |    |
| PK Sample                                                                                                | X                                                                                                       | X    | X    | X    | X    | X    | X             | X             | X      | x    | x    | X  |
| X                                                                                                        |                                                                                                         |      |      |      |      |      |               |               |        |      |      |    |
| Triplicate ECG 2                                                                                         | x                                                                                                       |      |      |      |      |      |               |               |        |      |      |    |
| twice                                                                                                    |                                                                                                         |      |      |      |      |      |               |               |        |      |      |    |
| Sample collection at 12 hours after dosing is optional. While the sample collection at this timeframe is |                                                                                                         |      |      |      |      |      |               |               |        |      |      |    |
| l                                                                                                        | highly desirable to strengthen PK analysis, it is not mandatory in the event of logistical constraints. |      |      |      |      |      |               |               |        |      |      |    |  
2 ECGs should be taken in triplicate, each reading approximately 2 minutes apart.  On Lead-in Day 1 only, two sets of triplicate ECGs should be done within 1 hour prior to dosing (e.g., at 30-minute intervals prior to dosing) to firmly establish the baseline for the patient.  One set of triplicate ECGs is required at all other time points. In general, ECGs should be performed prior to the respective PK
blood collection.  An example of the schedule on Lead-in Day 1 would be triplicate ECG
approximately -1.0 hr and again approximately -30 mins, followed by vital signs and PK sample approximately -15 min.
clinical research protocol
table 25 pk sample collection

| Cycle 1 Day 15   |                                                                                                          |       |      |      |      |      |        |        |    |
|------------------|----------------------------------------------------------------------------------------------------------|-------|------|------|------|------|--------|--------|----|
| Collection       | Pre-                                                                                                     | 30    | 1    | 2    | 6    | 8    | 12     | 24     |    |
| 4 hour           |                                                                                                          |       |      |      |      |      |        |        |    |
| Time and         | dose                                                                                                     | min   | hour | hour | hour | hour | hour 1 | hour   |    |
| (±30             |                                                                                                          |       |      |      |      |      |        |        |    |
| Allowable        | (-30                                                                                                     | (± 10 | (±15 | (±15 | (±30 | (±30 | (±2    | (±2    |    |
| min)             |                                                                                                          |       |      |      |      |      |        |        |    |
| Window           | min)                                                                                                     | min)  | min) | min) | min) | min) | hours) | hours) |    |
| PK Sample        | x                                                                                                        | x     | x    | x    | x    | x    | X      | x      | x  |
| Triplicate ECG ² | X                                                                                                        |       |      |      |      |      |        |        |    |
| l                | Sample collection at 12 hours after dosing is optional. While the sample collection at this timeframe is |       |      |      |      |      |        |        |    |  
highly desirable to strengthen PK analysis, it is not mandatory in the event of logistical constraints.  
ECGs should be taken in triplicate, each reading approximately 2 minutes apart.  
2 The PK evaluable population will consist of all patients who received treatment with sitravatinib and had sufficient concentration-time data to permit calculation of PK parameters for sitravatinib. For patients who were noncompliant with respect to administration of sitravatinib or prescribed food regimen, or for patients with incomplete data, a decision as to their inclusion in the analysis will be made on a case-by-case basis. After completion of the food effect sub-study specific assessments and depending on the duration of treatment of individual patients and the long-term availability of various sitravatinib capsule formulations, patients may be transferred from the formulation assigned at the time of study entry to a different formulation to alleviate supply concerns. The need for any such transfers will be communicated to Investigators by the Sponsor in writing (to be retained with patient source documents). PK concentration and parameter data will be descriptively derived and displayed. A descriptive comparison will be conducted using AUC0-t, AUC(0-∞), Cmax, Tmax, t1/2, and steady state PK exposure parameters. The effect of food will be assessed based on the clinical relevance. Steady state exposure comparison will also be assessed and accounted for. Descriptive statistics will be used to summarize patient characteristics, treatment administration and safety variables between fed and fasted groups. Details of this analysis will be provided in the PKAP.