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Official Title: A Parallel Phase 2 Study of Glesatinib, Sitravatinib or Mocetinostat in Combination With Nivolumab in Advanced or Metastatic Non-Small Cell Lung Cancer NCT Number: NCT02954991 Document Date: 11-February-2020
clinical research protocol
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| Glesatinib, Provisional USAN Name (MGCD265)          |                                               |
|------------------------------------------------------|-----------------------------------------------|
| Sitravatinib, Provisional USAN Name (MGCD516)        |                                               |
| DRUG:                                                | Mocetinostat (MGCD0103)                       |
| Nivolumab (OPDIVO®)                                  |                                               |
| STUDY NUMBER(S):                                     | MRTX-500                                      |
| A Parallel Phase 2 Study of Glesatinib, Sitravatinib |                                               |
| or Mocetinostat in Combination With Nivolumab        |                                               |
| PROTOCOL TITLE:                                      | in Advanced or Metastatic Non-Small Cell Lung |
| Cancer                                               |                                               |
| IND NUMBER:                                          | 130023                                        |
| Mirati Therapeutics, Inc.                            |                                               |
| SPONSOR:                                             | 9393 Towne Centre Drive, Suite 200            |
| San Diego, California, 92121, USA                    |                                               |
| ORIGINAL PROTOCOL                                    | 05 May 2016                                   |
| DATE:                                                |                                               |
| VERSION NUMBER:                                      | V6.0 (Amendment #5)                           |
| VERSION DATE:                                        | l February 2020                               |  
CONFIDENTIALITY STATEMENT
This document contains confidential information and/or trade secrets of Mirati Therapeutics, Inc.  As such, this document is protected from unauthorized disclosure or use by confidentiality agreement(s)
and/or is exempt from public disclosure pursuant to applicable FDA and foreign counterpart regulations.  
| DOCUMENT HISTORY   |                                                                                                                                                                                                                                                                                                                                                                                                                             |                    |
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| Document           | Version Date                                                                                                                                                                                                                                                                                                                                                                                                                | Summary of Changes |
| Original Protocol, | 05 May 2016                                                                                                                                                                                                                                                                                                                                                                                                                 | NA                 |
| Version 1.0        | At the request of US Food and Drug Administration during  IND review:  Revised definition of Dose Limiting Toxicity to include  any grade 4 non-hematologic toxicity and any toxicity  requiring treatment suspension for more than 2 weeks.   Added inclusion criterion that patients with tumors  positive for EGFR mutation or ALK fusion must have  received treatment with an applicable tyrosine kinase  inhibitor. |                    |
| Amendment #1,      | 31 May 2016                                                                                                                                                                                                                                                                                                                                                                                                                 |                    |
| Version 2.0        | Study Summary:  Added study arm allowing for enrollment of  patients who have experienced disease progression  after prior first line chemotherapy (checkpoint  inhibitor therapy [CIT] naïve). Patients will be  stratified by PD-L1 expression.   Revised statistical considerations to Predictive  Probability Design allowing for flexibility in the  number of evaluable patients for making study  decisions. Schedule of Assessments (Table 1):  Added clarification for CIT Naïve cohorts for PDL1 testing prior to enrollment.  Clarified footnote 12 to require collection of RR  interval to calculate QTcF.  Removed requirement for ECHO at Cycle 2 for  patients in the mocetinostat and sitravatinib arms.  Clarified footnote 13 for the timing of on-study  disease evaluations to be calculated based on the  calendar from the first day of dosing. Section 1 Introduction:  Updated clinical data section for consistency with  the most current version of the Investigator's  Brochure for glesatinib, sitravatinib and  mocetinostat and the nivolumab package insert. Section 1.9 Study Rationale:   Added rationale for including patients who are  checkpoint inhibitor therapy naïve.  Section 3 Study Design:  Added study arm allowing for enrollment of  patients who have experienced disease progression  after prior first line chemotherapy (checkpoint                                                                                                                                                                                                                                                                                                                                                                                                                             |                    |
| Amendment #2,      | 06 June 2017                                                                                                                                                                                                                                                                                                                                                                                                                |                    |
| Version 3.0        | Mirati Therapeutics, Inc.                                                                                                                                                                                                                                                                                                                                                                                                   |                    |  
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| Document   | Version Date   | Summary of Changes inhibitor therapy [CIT] naïve). Patients will be  stratified by PD-L1 expression.   Revised statistical considerations to Predictive  Probability Design allowing for flexibility in the  number of evaluable patients for making study  decisions.  Added definition of evaluable population.  Nivolumab will be administered as per the approved  labeling of 240 mg every 2 weeks (per Protocol  Administrative letter dated 26Sep16). Section 4.1 Inclusion criteria:  Inclusion criteria #2: updated to include patients who have not received prior treatment with a  checkpoint inhibitor in the CIT naïve arm.   Removed criteria #2b and included these patients in  exclusion criteria #2.  Added inclusion criteria #3 regarding PD-L1 assay  for CIT naïve patients.  Section 4.2 Exclusion criteria:   Revised exclusion #1 to note that patients are  eligible if brain metastases are adequately treated  and patients are neurologically stable (except for  residual signs or symptoms related to the CNS  treatment) for at least 2 weeks prior to enrollment  without the use of corticosteroids, or on a stable or  decreasing dose of ≤ 10 mg daily prednisone (or  equivalent).  Added exclusion #1a: Patients with carcinomatous  meningitis.  Added exclusion #2: Patients who test positive for  EGFR, ROS1, ALK mutations or ALK fusions or  any other mutations for which there are tyrosine  kinase inhibitors available or under development.  Revised exclusion #7 to include patients with a  history of chronic hepatitis C that is no longer  present. Section 5 Study Treatments:  Added reference to the Pharmacy Manual for details  on dose strengths, bottle size and number of units  per bottle supplied.  Section 5.4 Concomitant medications and Appendix 3:  Added sitravatinib arm patients to those who should  avoid medications that may prolong QT interval. Section 7.3.5 Sample collection for PD-L1 expression:   |
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| Glesatinib, Sitravatinib, or Mocetinostat with Nivolumab   | Page 4 of 147                                                                                                                |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       |                                                                                                                     |
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| Document                                                   | Version Date                                                                                                                 | Summary of Changes  Added language regarding tissue sample collection  for PD-L1 expression through the central laboratory  for the CIT naïve cohort.  Section 9.1.2 Statistics:  Revised statistical considerations to Predictive  Probability Design allowing for flexibility in the  number of evaluable patients for making study  decisions.  Added statistics regarding CIT naïve patients.  Section 9.3.2 Statistics:  Added definition of Phase 2 clinical activity  evaluable population.  Addressed clerical errors and made minor clarifications.  Added update on status of glesatinib, sitravatinib and  mocetinostat cohorts.  Updated anticipated number of patients in study.  Added update on preliminary results of sitravatinib plus  nivolumab segment of study in Section 1.5.3.2.2.  Added two sitravatinib PK sub-studies: o Appendix 5 - PK of three sitravatinib capsule  formulations o Appendix 6 - PK of sitravatinib administered with  food  Adjusted sitravatinib CIT-experienced cohort expansion  plan following discussion with the US FDA: combined CIT-experienced cohorts (prior clinical benefit and no  prior clinical benefit) for the purpose of enrollment  expansion, with the limit of 125 patients in the  combined population. |                                                                                                                     |
| Amendment #3, Version 4.0                                  | 15 June 2018                                                                                                                 |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      | Eliminated potential consideration of expansion of  enrollment into sitravatinib CIT-naïve cohorts beyond  Stage 2. |
|                                                           | Clarified schedule for triplicate ECGs.                                                                                      |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       |                                                                                                                     |
|                                                           | Clarified exclusion criterion concerning patients with  tumors having driver mutations.                                      |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       |                                                                                                                     |
|                                                           | Updated details concerning sitravatinib free-base  capsule content and storage.                                              |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       |                                                                                                                     |
|                                                           | Added guidance for sitravatinib or nivolumab dose  management: o Sitravatinib recommended Phase 2 starting dose:  120 mg QD. |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       |                                                                                                                     |
| Mirati Therapeutics, Inc.                                  |                                                                                                                              |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       |                                                                                                                     |  
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| Document                                                   | Version Date    | Summary of Changes o Following sitravatinib dose reduction and control of  adverse event, re-challenge at a higher sitravatinib  dose is permitted at the discretion of the  Investigator. o In the event of sitravatinib-related AE, dose  reduction with continuous treatment is preferred  over repeated dose interruption. o If sitravatinib or nivolumab treatment is interrupted,  administration of the other study drug may continue  at the discretion of the Investigator.   Updated nivolumab information and guidance to  OPDIVO US Prescribing Information dated April 2018.  Provided web site with current manufacturer updates for  consultation during conduct of the study. o Updated recommended dose of nivolumab to either  240 mg Q2W or 480 mg Q4W, infused over  approximately 30 minutes, per Product Information  changes and at the discretion of the Investigator. o Updated reprint of nivolumab AE management  guidelines per OPDIVO US Product Information  dated April 2018.  Added that disease assessments will be performed until  objective disease progression is documented or  subsequent anti-cancer therapy is begun.   Addressed clerical errors and made minor clarifications. Following FDA review of Amendment #3, Amendment # 4  is implemented to provide additional details in the update on  clinical experience in the sitravatinib segment of the study and to clarify the purpose of enrollment beyond Stage 2.  The two amendments together describe changes to the  protocol for Study MRTX-500. A document showing a  composite of the changes is available from the Sponsor.   Updated preliminary safety and clinical activity results  of ongoing studies of sitravatinib monotherapy and the  sitravatinib plus nivolumab segment of the current study in Section 1.5.3.2.  Clarified that the purpose of enrollment beyond Stage 2 is to further evaluate safety and efficacy in the treatment  setting (previous description of the purpose was to  narrow the 95% CI around the ORR point estimate). |    |
| Amendment #4,                                              | 16 August       |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         |    |
| Version 5.0                                                | 2018            |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        | Clarified timing of early triplicate ECGs for patients  participating in the PK sub-studies that includes a leadin period.    |  
MRTX-500 v6.0 - Phase 2 in NSCLC  
| Glesatinib, Sitravatinib, or Mocetinostat with Nivolumab    | Page 6 of 147                                          |                                                         |
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| Document                                                    | Version Date                                           | Summary of Changes                                      |
| Exempted patients enrolled in PK sub-studies from           |                                                        |                                                         |
| participation in flow cytometry and protein/cytokine        |                                                        |                                                         |
| biomarker studies to reduce blood sample collection.        |                                                        |                                                         |
| .                                                           | Increased the potential size of patient cohorts in the |                                                         |
| sitravatinib formulation sub-study from 8-10 patients to    |                                                        |                                                         |
| as many as 12 patients per cohort.                          |                                                        |                                                         |
| The rationale for this protocol amendment is to incorporate |                                                        |                                                         |
| study information that were provided via various protocol   |                                                        |                                                         |
| administrative letters during 2018, 2019 and 2020           |                                                        |                                                         |
| specifically in the following sections:                     |                                                        |                                                         |
| .                                                           | 24Oct2018 Administrative Letter to the Protocol        |                                                         |
| providing a modified process for PK sub-study as            |                                                        |                                                         |
| outlined within Appendix 5 based on the Food and Drug       |                                                        |                                                         |
| Administration's review and feedback for the study          |                                                        |                                                         |
| protocol amendment #4                                       |                                                        |                                                         |
| .                                                           | 28Jan2019 Administrative Letter to the Protocol        |                                                         |
| clarifying Inclusion Criterion #2 and Exclusion criterion   |                                                        |                                                         |
| #3 for the patients participating in the PK sub-studies as  |                                                        |                                                         |
| outlined within Appendix 5 and Appendix 6                   |                                                        |                                                         |
| .                                                           | 18Mar2019 Clarification / modifications regarding      |                                                         |
| Pharmacokinetic (PK) collection timepoints for the PK       |                                                        |                                                         |
| sub-studies described within Appendix 5 and Appendix        |                                                        |                                                         |
| 6                                                           |                                                        |                                                         |
| .                                                           | 10Apr2019 letter clarifying the protocol exclusion     |                                                         |
| Amendment #5,                                               | 11 February                                            | criterion #2 for patients participating for the PK sub¬ |
| 2020                                                        | study                                                  |                                                         |
| Version 6.0                                                 | .                                                      | 16May2019 Administrative Letter providing modified      |
| recommendations to section 5.1.4.2.5 : Management of        |                                                        |                                                         |
| Investigational Study Treatment in Event of Non-            |                                                        |                                                         |
| Hematological Toxicities                                    |                                                        |                                                         |
| .                                                           | 28Aug2019 Update to the sitravatinib Drug Formulation  |                                                         |
| Pharmacokinetic (PK) sub-study as described within          |                                                        |                                                         |
| Appendix 5                                                  |                                                        |                                                         |
| .                                                           | 18Oct2019 Administrative Letter to the Protocol        |                                                         |
| providing a revised meal requirement for patients           |                                                        |                                                         |
| participating in the sub-study to evaluate PK of            |                                                        |                                                         |
| sitravatinib administered with food ( Appendix 6 ) based    |                                                        |                                                         |
| on Food and Drug Administration's feedback.                 |                                                        |                                                         |
| .                                                           | 09Jan2020 Administrative Letter to the Protocol to     |                                                         |
| provide the starting dose of sitravatinib for Cohort-3 of   |                                                        |                                                         |
| the Pharmacokinetic drug formulation sub-study with         |                                                        |                                                         |
| sitravatinib malate capsules (roller compaction             |                                                        |                                                         |
| formulation) and the food effect sub-study cohort with      |                                                        |                                                         |
| sitravatinib malate capsules                                |                                                        |                                                         |  
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| Document                                                   | Version Date    | Summary of Changes  Provide more clarity with unacceptable toxicity on prior  checkpoint inhibitor treatment (CIT-experienced  patients only) within Exclusion Criterion #4  Provide clarification with active or prior  immunocompromising conditions within Exclusion  Criterion #6  Updates provided to sitravatinib formulation, packaging  and storage within section 5.1.2.1  Table 9: Sitravatinib Dose Reductions were updated  based on sitravatinib dose formulations utilized in the  study  Table 15: Investigational Study Treatment Dose  Modifications - Non-Hematological Drug-Related  Toxicities was updated to provide clarity  Global change: volume of water during sitravatinib  administration was updated to keep it consistent across  all sitravatinib dosings  Global editorial changes and fix formatting errors |
clinical research protocol
study summary

Title: A Parallel Phase 2 Study of Glesatinib, Sitravatinib or Mocetinostat in Combination With Nivolumab in Advanced or Metastatic Non-Small Cell Lung Cancer The use of tyrosine kinase inhibitors (TKIs) to treat cancer is well established based on robust clinical efficacy achieved with well-tolerated inhibitors directed toward oncogenic tyrosine kinases. In addition, selected TKIs have been shown to modulate the immunogenic status of tumors, improve tumor perfusion by reducing intratumoral pressure and modulate subsets of immune cells, increasing the frequency and function of effector immune elements, while decreasing the number and function of immune suppressor cells. Taken together, these effects on the tumor microenvironment (TME) may lead to improved efficacy when TKIs are combined with checkpoint inhibitors. The TAM (Tyro3, Axl and MERTK) receptor tyrosine kinases (RTKs) are expressed by select innate immune cell subpopulations including macrophages and dendritic cells. The TAM receptors cooperate to create and maintain an immunosuppressive TME. MERTK suppresses the M1 macrophage pro-inflammatory cytokine response involving IL-12, IL-6 and TNF and enhances M2 macrophage anti-inflammatory cytokine production involving IL-10, IL-4, TGFβ and hepatocyte growth factor (HGF). Given that antitumor host defense is usually mediated by cytotoxic T lymphocytes whose activation and stimulation is supported by Th1 type cytokines, the inhibition of Axl and MERTK are predicted to enhance an antitumor immune response. Furthermore, both Axl and MERTK are expressed by natural killer (NK) cells and negatively regulate NK cell activity in the TME as part of a feedback regulatory mechanism resulting in decreased NK cell anti-tumor activity and enhanced tumor progression and metastasis. Given the immunosuppressive function of TAM RTKs in the TME, inhibition of Axl and MERTK may complement PD-1/PD-L1 checkpoint inhibition to unleash the host anti-cancer immune response.  
| Cell Lung Cancer   |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       |
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| Rationale:         | Combining an immunotherapeutic PD-1/PD-L1 checkpoint inhibitor  with an agent that has both immune modulatory and antitumor  properties could enhance the antitumor efficacy observed with either  agent alone.  The use of tyrosine kinase inhibitors (TKIs) to treat cancer is well  established based on robust clinical efficacy achieved with  well-tolerated inhibitors directed toward oncogenic tyrosine kinases.  In addition, selected TKIs have been shown to modulate the  immunogenic status of tumors, improve tumor perfusion by reducing  intratumoral pressure and modulate subsets of immune cells, |  
The MET (Mesenchymal-Epithelial Transition) RTK is implicated in modification of tumor immune responses based on its role in mediating an immunosuppressive TME as well as its role in regulating antigen presenting cell (APC) function. MET is expressed by immature CD14-positive monocytes and can induce an immunosuppressive phenotype when its ligand, hepatocyte growth factor (HGF), is secreted by tumor stroma and mesenchymal stem cells (MSCs). Depletion of CD14-positive monocytes or neutralization of HGF secretion by MSCs reverses the suppression of T effector proliferation and triggers a shift back toward a Th1 activated T cell phenotype. MSCs are also implicated in expansion of immunosuppressive myeloid-derived suppressor cells (MDSCs), which are also dependent on the secretion of HGF. APCs (i.e., dendritic cells) also express MET and the activation of MET by HGF results in suppression of APC function including both antigen presenting capacity and antigen-dependent T cell responses.  
Therefore, inhibition of MET may enhance the antitumor response by restoring APC function and reducing or eliminating MDSCs within the TME. Glesatinib is an orally administered multi-targeted TKI that primarily targets the Axl and MET receptors. Additional RTK targets potentially include the MERTK, DDR2, and PDGFR and receptors. The TKI profile of glesatinib suggests the potential for synergistic anti-tumor effect when administered in combination with a checkpoint inhibitor. Inhibition of the VEGF receptor family and KIT may further enhance antitumor immunoreactivity by depletion of immunosuppressive cellular subset from the TME including regulatory T cells and MDSCs. T regulatory cells express VEGFR2 and the inhibition of VEGFR2 utilizing a specific VEGFR2 antibody antagonist or VEGFA neutralizing antibody (but not a VEGFR1 antagonist) inhibited Treg proliferation in vitro and in tumor-bearing mice and patient peripheral blood. MDSCs notably express both KIT and VEGFR1 and the inhibition of these RTKs using pharmacologic or genetic approaches resulted in the inhibition of MDSC viability in vitro and depletion of this cell population in mouse tumor models. Sitravatinib is an orally-available, potent small molecule inhibitor of a closely related spectrum of RTKs including MET, Axl, MERTK, VEGFR family, PDGFR family, KIT, FLT3, Trk family, RET, DDR2, and selected Eph family members. In addition to the immunostimulatory effects of Axl and MET inhibition, sitravatinib may further condition the TME in favor of antitumor activity by its immunomodulatory effects mediated through VEGFR and KIT inhibition. Histone deacetylases (HDACs) have been implicated in the epigenetic regulation of innate and adaptive immunity. Increasing evidence supports the proposal that spectrum-selective inhibitors of class I
HDACs can reverse immune evasion and elicit antitumor host response through immunostimulatory mechanisms. The immunomodulatory properties of class I HDAC inhibitors are reported to be mediated through multiple mechanisms including: 1) induction of programmed cell death ligand 1 (PD-L1) expression on the tumor cell surface, 2) induction of tumor associated antigens (TAAs) and MHC Class I and Class II molecules on tumor cells, 3) induction of immunogenic cell death via activation and cross-presentation of tumor antigens by antigen presenting cells (APCs), 4) enhanced function of T effector cells, and 5) decreased function of immunosuppressive cell subsets including Tregs and MDSCs. In addition, HDAC inhibitors are associated with anticancer effects through inhibiting cell cycle progression and inducing apoptosis in tumor cells. Mocetinostat is an orally administered spectrum-selective Class I/IV HDAC inhibitor specifically targeting HDACs 1, 2, 3 and 11. Given these pleiotropic immune activating effects of class I HDAC inhibitors, combination therapy of mocetinostat with checkpoint inhibition may result in increased efficacy compared to immunotherapy alone. Nivolumab is a human immunoglobulin G4 (IgG4) monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, releasing PD-1 pathway-mediated inhibition of the immune response, including the anti-tumor immune response. This study will evaluate the clinical activity of nivolumab in combination with 3 separate investigational agents, glesatinib, sitravatinib or mocetinostat. The study will begin with a lead-in dose escalation evaluation in small cohorts of patients administered one of the investigational study treatments in combination with nivolumab. Following identification of the dose level to be used in the Phase 2 evaluation for each investigational study treatment, full enrollment will proceed.  
| will proceed.  Patients with advanced or metastatic non-squamous NSCLC, who  have experienced disease progression on or after prior treatment with a checkpoint inhibitor therapy (CIT) (CIT- experienced) or patients  who have experienced disease progression after prior first line  platinum-based doublet chemotherapy (CIT- naive).   |
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| Number in      | As many as 280 patients.                                                                                                 |                                                            |
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| Trial: Primary | To evaluate the clinical activity of nivolumab in 3 combination                                                          |                                                            |
| Objective:     | regimens with the investigational agents glesatinib, sitravatinib, or mocetinostat, in patients with non-squamous NSCLC. |                                                            |
| Secondary      |                                                                                                                         | To evaluate the safety and tolerability of the combination |
| Objectives:    | regimens in the selected population.                                                                                     |                                                            |
|               | To evaluate secondary efficacy endpoints of the combination  regimens in the selected population.                        |                                                            |
|               | To evaluate the pharmacokinetics (PK) of the investigational  agents administered in combination with nivolumab.         |                                                            |  
To evaluate the PK of three sitravatinib capsule formulations. To evaluate the PK of sitravatinib administered with food.  
  
| Exploratory  Objectives:   |
|----------------------------|  
Primary Endpoints:
Objective Response Rate (ORR) as defined by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1).  
Secondary efficacy endpoints:  
|    | Safety characterized by type, incidence, severity, timing,  seriousness and relationship to study treatment of adverse events  and laboratory abnormalities.   |
|-----|----------------------------------------------------------------------------------------------------------------------------------------------------------------|  
o Duration of Response (DR);
o Clinical Benefit Rate (CBR);
o Progression-Free Survival (PFS);
o 1-Year Survival Rate; and o Overall Survival (OS).  
Blood plasma concentrations of the investigational agents.  
  
Exploratory Endpoints:  
| Sitravatinib: Enrollment is ongoing in all sitravatinib cohorts. A brief  summary of preliminary results available to date is presented in  Section 1.5.3.2.2.   |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
Glesatinib: Enrollment into glesatinib cohorts was discontinued in November 2017 as the result of Sponsor portfolio reprioritization. The decision was not based on patient safety in Study MRTX-500. Five patients were treated with nivolumab plus glesatinib in this study.  
| mocetinostat in combination with durvalumab, a PD-L1 inhibitor, are  pending. Plans for further investigation of mocetinostat in  combination with checkpoint inhibitor therapies are pending.   |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   |
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| Study Design:                                                                                                                                                                                    | Study MRTX-500 is an open-label, parallel Phase 2 evaluation of  nivolumab in combination with 3 investigational agents, glesatinib,  sitravatinib or mocetinostat, in patients with locally advanced,  unresectable or metastatic non-squamous NSCLC. Patients who have  experienced progression of disease on or after treatment with a  checkpoint inhibitor (CIT-experienced) as well as those who have  experienced disease progression after treatment with platinum-based  doublet chemotherapy (CIT- naïve) will be enrolled. The primary |  
| Study Segment Update June 2018   |
|----------------------------------|  
objective is to evaluate the clinical activity of the combination study treatments using ORR in accordance with RECIST 1.1. Secondary objectives include evaluation of safety, secondary efficacy endpoints, and PK for the investigational agents. The Schedule of Assessments to be performed in the study is presented in Table 1. Pharmacokinetic and blood biomarker sample collection and triplicate ECG assessment time points are presented in Table 2, Table 3, and Table 4. Specifics of two sitravatinib sub-studies are presented in appendices, including the PK evaluation of three sitravatinib capsule formulations (Appendix 5) and the PK of sitravatinib administered with food (Appendix 6).  
The treatment arms included in this study are the following:
1. Glesatinib plus nivolumab.  
2. Sitravatinib plus nivolumab. 3. Mocetinostat plus nivolumab.
To control bias in assignment of individual patients to treatment arms and to mitigate the risk of medication errors with the 3 investigational study treatments administered in specific regimens, study sites will be aligned with one specified treatment combination. Site alignment may change as patient cohorts are filled or patient recruitment factors shift at sites. The study will begin with a lead-in dose escalation evaluation of two dose levels of each investigational agent in combination with nivolumab in small cohorts of CIT-experienced patients. The dose escalation plan is described below under Study Treatments and in more detail in Section 3.1.  
Following completion of the lead-in dose escalation evaluation, enrollment into the Phase 2 will proceed. For CIT-experienced patients, each investigational study treatment arm (i.e., glesatinib, sitravatinib and mocetinostat) will be stratified by prior outcome of treatment with a checkpoint inhibitor:  
a. Clinical benefit (i.e., RECIST defined partial, complete response or stable disease for at least 12 weeks [-2 week window permitted for radiograph scheduling]) followed by radiographic progression of disease.
b. No prior clinical benefit (i.e., radiographic progression of disease
≤ 12 weeks after initiation of treatment [+2 week window permitted for radiograph scheduling]).  
For patients without prior checkpoint inhibitor therapy (CIT-naïve), each investigational study treatment arm (i.e., glesatinib, sitravatinib, and mocetinostat) will be stratified according to PD-L1 status: a. Having tumor with no/low PD-L1 expression.
clinical research protocol
b. having tumor with high

Tumor PD-L1 expression will be determined by the PD-L1 (28-8) companion diagnostics (CDx) assay completed through the central laboratory. No/low PD-L1 expression is defined as positivity < 5% of tumor cells; high PD-L1 expression is defined as positivity ≥ 5% of tumor cells. Tumor samples used to establish PD-L1 expression for eligibility must have been collected after the most recent systemic therapy. The main Phase 2 study will include 12 parallel evaluations of clinical activity of nivolumab combination regimens (depicted in the figure below). A Predictive Probability Design will be applied to each treatment arm, as described under Statistical Considerations. Patients enrolled in the lead-in dose escalation evaluation and receiving the dose of investigational study treatment selected for the Phase 2 study will be included in the analysis of the Phase 2 endpoints.  
  
Disease response and progression as documented by the Investigator in the Case Report Form (CRF) will be the basis for patient management  
and study expansion decision making. Unconfirmed objective  
responses recorded in the CRF may be used as the initial basis for expansion of study enrollment; however, follow-up evaluations on patients with unconfirmed responses must continue to support the decision to continue to the full number of patients to be included in the next stage. Disease assessments will be performed until objective disease progression is documented or subsequent anti-cancer therapy is begun. Central radiology review for disease response and progression may be added to the study during Stage 2. If this occurs, central  
review of all radiologic assessments performed in the study will be  
expected (including retrospective review of patients enrolled in Stage 1), and central radiology review for disease response will be the basis for the primary statistical analyses to estimate the objective response rate and its confidence interval, as well as the duration of response and PFS.  
| decision to continue to the full number of patients to be included in the  next stage. Disease assessments will be performed until objective  disease progression is documented or subsequent anti-cancer therapy is  begun. Central radiology review for disease response and progression  may be added to the study during Stage 2. If this occurs, central  review of all radiologic assessments performed in the study will be  expected (including retrospective review of patients enrolled in Stage  1), and central radiology review for disease response will be the basis  for the primary statistical analyses to estimate the objective response  rate and its confidence interval, as well as the duration of response and  PFS. Throughout the study, nivolumab will be administered in accordance  with approved labeling. Nivolumab is to be administered by  intravenous infusion, using either regimen included in the approved  label: 240 mg every 2 weeks (Q2W) or 480 mg every 4 weeks (Q4W).  Guidance for adverse event management and associated nivolumab  treatment modifications are provided in product labeling and replicated  in Section 5.2.   |
|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
The investigational agents will be administered in the following regimens:
1. Glesatinib tablets administered orally, twice daily (BID). 2. Sitravatinib capsules administered orally, once daily (QD). 3. Mocetinostat capsules administered orally, three times weekly
(TIW, e.g., Monday, Wednesday and Friday).  
The study will begin with a lead-in dose escalation evaluation of two dose levels of each investigational agent in combination with nivolumab in small cohorts of CIT-experienced patients. In addition, a dose de-escalation step may be undertaken as appropriate.  
| Dose Escalation Steps   |                     |        |        |        |
|-------------------------|---------------------|--------|--------|--------|
| Drug                    | Regimen             | 1      | 2      | -1     |
| Glesatinib Tablets      | Twice Daily         | 500 mg | 750 mg | 350 mg |
| Sitravatinib Capsules   | Once Daily          | 120 mg | 150 mg | 80 mg  |
| Mocetinostat            | Three Times  Weekly | 70 mg  | 90 mg  | 50 mg  |
| Capsules                |                     |        |        |        |
clinical research protocol
investigational study drug starting dose

Guidelines for adverse event management and associated treatment modifications of each agent are provided in Section 5.1. The dose escalation phase of the study will employ the modified toxicity probability interval (mTPI) method for dose escalation and reduction decision making.  
Statistical Considerations:
This Phase 2 study will use a Predictive Probability Design (Lee-2008) in each treatment arm and strata. In creating the statistical designs, the Type 1 error (α) is constrained to <0.05 and Power (1-β) is constrained to ≥0.90.
clinical research protocol
statistical design applied to cit-experienced

The ORR using nivolumab in the population with advanced nonsquamous NSCLC having prior disease progression on a checkpoint inhibitor or patients with non-squamous NSCLC without prior checkpoint inhibitor therapy with no/low PD-L1 expression is assumed to be 5% (p0); thus, this rate is considered uninteresting. The target ORR using the investigational agents in combination with nivolumab in this study is 30% (p1). Stage 1 of enrollment will include a minimum of 9 evaluable patients in each treatment strata. With exactly 9 evaluable patients at Stage 1, if at least 1 patient has an Objective Response, 8 additional evaluable patients will be enrolled in the treatment stratum, for a total sample size of 17 evaluable patients. If at least 3 Objective Responses are observed in a treatment stratum, further investigation may be warranted. If the true ORR is 5% (null hypothesis), the probability of early termination during the study is 0.63; the Type 1 error is equal to 0.0466 and the power is equal to 0.9045.
clinical research protocol
statistical design applied to cit-naive

The ORR using nivolumab in the population with non-squamous NSCLC having high PD-L1 expression is assumed to be 27% (p0); thus, this rate is considered uninteresting. The target ORR using the investigational agents in combination with nivolumab is 50% (p1).  
Stage 1 of enrollment will include approximately 17 evaluable patients. With exactly 17 evaluable patients at Stage 1, if at least 5 patients have Objective Responses, 27 additional evaluable patients will be enrolled, for a total sample size of 44 evaluable patients. If at least 18 Objective Responses are observed, further investigation may be warranted. If the true ORR is 27% (null hypothesis), the probability of early termination during the study is 0.50; the Type 1 error is equal to 0.0303 and the power is equal to 0.9018. The exact stopping rules for all cohorts will be calculated based on the Predictive Probability Design, once the exact number of patients evaluable at Stage 1 is known. The aim is to get a minimum of 9 evaluable patients at Stage 1 for CIT-experienced and CIT-naïve with no/low PD-L1 expression cohorts and a minimum of 17 evaluable patients at Stage 1 for CIT-naïve with high PD-L1 expression cohort.
clinical research protocol
expansion beyond stage 2

The original protocol provided that if results in any strata were of high interest for efficacy, enrollment might be expanded to as many as 100 patients total in each cohort to narrow the 95% Confidence Interval (CI) around the ORR point estimate. Protocol Amendment 3 (Version 4.0)
eliminates enrollment expansion beyond Stage 2 except in the sitravatinib segment of the study enrolling patients with CITexperience. For the sitravatinib segment of the study enrolling patients with CITexperience, expansion of enrollment beyond Stage 2 will be managed as one cohort that includes all patients, regardless of prior clinical benefit during treatment with CIT. Based on preliminary clinical activity results (described in Section 1.5.3.2.2), enrollment into the combined cohort will expand to as many as 125 patients total, to further evaluate safety and efficacy in this setting. Expansion of sitravatinib CIT-naïve cohorts beyond Stage 2 of enrollment is not anticipated.
clinical research protocol
table 1 schedule of assessments

The Schedule of Assessments provides an overview of the protocol visits and procedures. Refer to Section 7 for detailed information on each assessment. Additional, unplanned assessments should be performed as clinically indicated, including for the purpose of fully evaluating adverse events.  
| Screen/ Baseline                                                                         | Cycle 1    | Cycle 2 and 3           | ≥ Cycle 4   | End of Treatment15   |       |        |    |    |
|------------------------------------------------------------------------------------------|------------|-------------------------|-------------|----------------------|-------|--------|----|----|
| Assessments                                                                              | End of     |                         |             |                      |       |        |    |    |
| Treatment/  Withdrawal                                                                   | Post       |                         |             |                      |       |        |    |    |
| Treatment  Follow Up                                                                     |            |                         |             |                      |       |        |    |    |
| Within 28  days                                                                          | Day 1      | Day 15                  | Day 1       | Day 15               | Day 1 | Day 15 |    |    |
| (± 2 days)                                                                               | (± 2 days) | (± 2 days)              | (± 2 days)  | (± 2 days)           |       |        |    |    |
| Before  study  specific                                                                  |            |                         |             |                      |       |        |    |    |
| assessments                                                                              |            |                         |             |                      |       |        |    |    |
| Study Participation  Informed Consent1 Tumor Tissue Collection  for PD-L1 Expression and | X          |                         |             |                      |       |        |    |    |
| Tumor Gene Alterations2 Medical History, Disease  History, Prior Therapy                 | X          |                         |             |                      |       |        |    |    |
| ECOG Performance Status                                                                  | X          |                         |             |                      |       |        |    |    |
| Physical Exam3                                                                           | X          | X                       |             |                      |       |        |    |    |
| Abbreviated Physical  Exam3                                                              | X          | X                       | X           | X                    | X     | X      |    |    |
| Vital Signs4                                                                             | X          | X                       | X           | X                    | X     | X      | X  | X  |
| Pregnancy Test5                                                                          | X          | As clinically indicated |             |                      |       |        |    |    |
| Hematology6,7                                                                            | X          | X                       | X           | X                    | X     | X      | X  |    |  
| Table 1:                                     | Schedule of Assessments (Continued) Screen/ Baseline Cycle 1                                        | Cycle 2 and 3                                     | ≥ Cycle 4   | End of Treatment15   |       |        |    |
|----------------------------------------------|-----------------------------------------------------------------------------------------------------|---------------------------------------------------|-------------|----------------------|-------|--------|----|
| Assessments                                  | End of                                                                                              |                                                   |             |                      |       |        |    |
| Treatment/  Withdrawal                       | Post                                                                                                |                                                   |             |                      |       |        |    |
| Treatment  Follow Up                         |                                                                                                     |                                                   |             |                      |       |        |    |
| Within 28  days                              | Day 1                                                                                               | Day 15                                            | Day 1       | Day 15               | Day 1 | Day 15 |    |
| (± 2 days)                                   | (± 2 days)                                                                                          | (± 2 days)                                        | (± 2 days)  | (± 2 days)           |       |        |    |
| Coagulation6,7                               | X                                                                                                   | As clinically indicated                           |             |                      |       |        |    |
| Urinalysis6,7                                | X                                                                                                   | As clinically indicated                           |             |                      |       |        |    |
| Serum Chemistry6,7                           | X                                                                                                   | X                                                 | X           | X                    | X     | X      | X  |
| Thyroid Function Test 6,7                    | X                                                                                                   | X                                                 | X           | X                    | X     |        |    |
| Blood for  Pharmacokinetics8                 | See Table 2, Table 3, and Table 4 and sub-study appendix Table 22, Table 23, Table 24, and Table 25 |                                                   |             |                      |       |        |    |
| Biopsy of Tumor for                          | Cycle 2                                                                                             |                                                   |             |                      |       |        |    |
| Biomarker Studies                            | Pre-dose X                                                                                          | Only                                              | X           |                      |       |        |    |
| (Optional)9                                  | X                                                                                                   |                                                   |             |                      |       |        |    |
| Blood Samples - Flow  Cytometry10            | X                                                                                                   | See Table 2, Table 3, and Table 4                 | X           |                      |       |        |    |
| Blood Samples - Protein  10                  | See Table 2, Table 3, and Table 4                                                                   | X                                                 |             |                      |       |        |    |
| and Cytokine Biomarkers ctDNA blood sample11 | X                                                                                                   | Time of confirmation of disease response PR or CR | X           |                      |       |        |    |
| As clinically indicated except -             |                                                                                                     |                                                   |             |                      |       |        |    |
| Single 12-Lead ECG12                         | X                                                                                                   | Mocetinostat arm: Day 1 of each treatment cycle   | X           |                      |       |        |    |
| Triplicate 12-Lead ECG12                     | See Table 2, Table 3, and Table 4                                                                   |                                                   |             |                      |       |        |    |
clinical research protocol
table 1 schedule of assessments

| Screen/ Baseline                                                     | Cycle 1                                                                                                                                            | Cycle 2 and 3                                                  | ≥ Cycle 4   | End of Treatment15   |       |          |
|----------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------|-------------|----------------------|-------|----------|
| Assessments                                                          | End of                                                                                                                                             |                                                                |             |                      |       |          |
| Treatment/  Withdrawal                                               | Post                                                                                                                                               |                                                                |             |                      |       |          |
| Treatment  Follow Up                                                 |                                                                                                                                                    |                                                                |             |                      |       |          |
| Within 28  days                                                      | Day 1                                                                                                                                              | Day 15                                                         | Day 1       | Day 15               | Day 1 | Day 15   |
| (± 2 days)                                                           | (± 2 days)                                                                                                                                         | (± 2 days)                                                     | (± 2 days)  | (± 2 days)           |       |          |
| Echocardiogram (Mocetinostat and  Sitravatinib Treatment  Arms Only) | X                                                                                                                                                  |                                                                |             |                      |       |          |
| X                                                                    | Mocetinostat  arm only                                                                                                                             | X                                                              |             |                      |       |          |
| Mocetinostat                                                         | X                                                                                                                                                  |                                                                |             |                      |       |          |
| arm only                                                             |                                                                                                                                                    |                                                                |             |                      |       |          |
| X                                                                    |                                                                                                                                                    |                                                                |             |                      |       |          |
| Cycle 3 only                                                         |                                                                                                                                                    |                                                                |             |                      |       |          |
| Disease Evaluation13                                                 | X                                                                                                                                                  | Every 8 weeks (± 10 days) for ~1 year  and then every 16 weeks |             |                      |       |          |
| Investigational Agent  Dispensing and/or                             | X                                                                                                                                                  | X                                                              | X           |                      |       |          |
| Reconciliation Nivolumab Administration                              | X                                                                                                                                                  | X if Q2W                                                       | X           | X if Q2W             | X     | X if Q2W |
| Adverse Events14 and  Concomitant Medications                        | SAEs only                                                                                                                                          | Throughout                                                     |             |                      |       |          |
| Long Term Follow-up16                                                | X                                                                                                                                                  |                                                                |             |                      |       |          |
| 1                                                                    | Study Participation Informed Consent: May be performed more than 28 days prior to the first dose of study treatment and must be completed prior to |                                                                |             |                      |       |          |  
1 Study Participation Informed Consent: May be performed more than 28 days prior to the first dose of study treatment and must be completed prior to initiation of any study specific assessments.  
2 Tumor Testing for PD-L1 Expression and Tumor Gene Alterations: Encouraged for all patients. Archival tumor tissue allowed. For patients enrolled in CIT Naïve cohorts, the sample must have been collected following the completion of the most recent systemic treatment regimen and the central laboratory testing is to begin prior to study entry. Biopsy may precede informed consent if performed as Standard of Care (SOC) or to assess eligibility for a different clinical trial.  
3 Physical Examinations: A complete physical examination required at Screening and End of Treatment only. Height will be recorded at screening only.  
All other evaluations will be symptom-directed, abbreviated evaluations.  
4 Vital Signs: Weight, temperature, blood pressure, and pulse rate to be assessed prior to dosing as indicated.  
5 Pregnancy Test: If the patient is a woman of childbearing potential, negative serum or urine pregnancy test performed by the local laboratory at screening will be required. The informed consent process must include discussion of the risks associated with pregnancy and adequate contraception methods. Additional pregnancy testing may be necessary if required by local practices or regulations, or if potential pregnancy is suspected.  
6 Selected Day 1 Assessments: Repeat assessment not required if screening assessment performed within 7 days before the first dose.  
7 Safety Laboratory Assessments: Hematology, coagulation, chemistry, thyroid function and urinalysis evaluations (see Table 19) will be performed by local laboratories.  
8 Pharmacokinetic Samples: Blood samples to be collected following ECGs and assessment of vital signs as scheduled in Table 2, Table 3 and Table 4 and sub-study appendix Table 22, Table 23, Table 24, and Table 25. In addition, unscheduled PK blood samples should be drawn in association with two kinds of safety events: 1) as soon as possible after a Serious Adverse Event (SAE), and 2) at a clinic visit at least one week following a dose modification of the investigational agent.  
9 Tumor Biopsy for Biomarker Studies: Consent for serial sampling of tumor tissue (preferably the same lesion) is requested but is not mandatory for study entry. If tumor biopsy has been performed during screening, then that biopsy may be used for the baseline assessment. Markers of interest in tumor tissue include PD-L1 expression, CD8+ tumor infiltrating lymphocytes (TILs) including proliferating (Ki67+) CD8+ cells, natural killer cells
(NK-cells), T regulatory cells (Tregs), macrophages and myeloid derived suppressor cells (MDSCs). Gene expression analyses may also be performed.  
10 Blood Samples for Biomarker Studies: Blood samples for flow cytometry and protein/cytokine assays will be collected as outlined in Table 2, Table 3 and Table 4. Markers of interest in circulation include circulating PD-L1, Tregs, MDSCs, NK-cells, flow cytometry for T- and B-cell including CD4, CD8 and Ki67, monocytes and selected cytokines including CD8A, GZMB, IFNγ, CXCL9, CXCL10, CXCL11, and TBX21. Patients participating in the sitravatinib formulation and food effect sub-studies described in Appendix 5 and Appendix 6 are exempt from sample collection for biomarker studies, including flow cytometry and protein/cytokine assays.  
11 Blood samples for ctDNA analysis: Blood will be collected in two 10ml Streck brand Cell-Free DNA Blood Collection tubes allowing shipping and stability at ambient temperatures.  
12 12-Lead ECGs: Triplicate ECGs will accompany PK sampling as described in Table 2, Table 3 and Table 4. Only for the mocetinostat containing treatment arm, ECGs are to be performed on Day 1 of each cycle, either as a triplicate ECG accompanying PK or as a single ECG. In addition, ECGs are to be performed as clinically indicated. Assessments will include an evaluation of rhythm, heart rate, and PR, QRS, QT, and QTc intervals. RR
interval should be recorded during each ECG assessment in order to calculate QTcF.  
13 Disease Evaluations: To be performed at screening (28 day window allowed) and every 8 weeks from Cycle 1 Day 1 (± 10 days window for all other assessments except screening) until Week 49 (~1 year) and then every 16 weeks. All on-study disease evaluations should be based on a calendar beginning from the first day of dosing. At screening/baseline, assessments are to include CT with contrast of the chest, abdomen and pelvis, as well as brain Magnetic Resonance Imaging (MRI) with and without gadolinium or Computed Tomography Scan (CT) with contrast, a whole body bone scan and evaluation of any superficial lesions. Subsequent disease assessments should include all sites of disease identified at baseline or suspected to have developed; bone scans may be performed half as often (every 16 weeks) as other radiology evaluations and should be performed during assessment for confirmation of disease response. More detailed guidance on exceptional circumstances is provided in the protocol.  
14 Adverse Events: SAEs will be reported from the time of informed consent until at least 28 days after the last administration of investigational agent or nivolumab. Adverse events will be reported from the first day of study treatment until at least 28 days after last dose of study drug, and until resolution or stabilization of acute AEs and/or ongoing SAEs.  
15 End of Treatment: All patients will be followed for AEs for at least 28 days after the last dose of Study Treatment. Assessments that have been completed in the previous 4 weeks do not need to be repeated (8 or 16 weeks for tumor assessments in accordance with schedule).  
16 Long Term Follow-up: Survival status and subsequent therapies will be collected during long term follow-up every 2 months (±14 days) from the End of Treatment visit until death or lost to follow-up. Follow-up may be performed by telephone contact.
clinical research protocol
table 2 glesatinib schedule of

| Cycle 1  Day 15 (± 2 days)            | Cycle 2, 3, 5 Day 1 (± 2 days)                                                                                                                         | Cycle 2  Day 15  (± 2 days)   |                    |                         |    |    |    |
|---------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------|--------------------|-------------------------|----|----|----|
| Screen/ Baseline                      | Cycle 1 Day 1                                                                                                                                          |                               |                    |                         |    |    |    |
| Collection Time and Allowable  Window | Within 28  days                                                                                                                                        | Pre-dose (-0.5-0  hour)       | 30 min (± 10  min) | Pre-dose (-0.5-0  hour) |    |    |    |
| 3 hour                                | 6 hour                                                                                                                                                 | Pre-dose                      | Pre-dose           |                         |    |    |    |
| (2-4 hour)                            | (5-8 hour)                                                                                                                                             | (-0.5-0 hour)                 | (-0.5-0 hour)      |                         |    |    |    |
| PK Sample 1                           | X                                                                                                                                                      | X                             | X                  | X                       | X  | X  | X  |
| Flow Cytometry 2                      | X                                                                                                                                                      | X                             | X                  |                         |    |    |    |
| Protein and Cytokine Biomarkers 2     | X                                                                                                                                                      | X                             |                    |                         |    |    |    |
| Triplicate ECG 3                      | X                                                                                                                                                      | X                             | X                  | X                       | X  |    |    |
| 1                                     | Scheduled vital signs and triplicate ECGs precede PK sample collection in all cases. Glesatinib dosing and sampling should precede nivolumab infusion. |                               |                    |                         |    |    |    |  
1 Scheduled vital signs and triplicate ECGs precede PK sample collection in all cases. Glesatinib dosing and sampling should precede nivolumab infusion. 2 The Day 1 blood samples for biomarker studies may be drawn up to 2 hours before dosing. The screen/baseline sample should not be collected on the same day as the pre-dose Cycle 1 Day 1 sample.  
3 ECGs should be taken in triplicate, each reading at least 2 minutes apart. On Cycle 1 Day 1, two sets of triplicate ECGs should be done within 30 minutes prior to dosing (e.g., at 15 minute intervals) to firmly establish the baseline for the patient. In general, ECGs should be performed prior (within -30 to -5 minutes) to the respective PK blood collection.
clinical research protocol
table 3 sitravatinib schedule of

| Cycle 1  Day 15 (± 2 days)            | Cycle 2, 3, 5 Day 1 (± 2 days)                                                                                                                           | Cycle 2 Day 15 (± 2 days)   |              |               |               |               |          |          |
|---------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------|--------------|---------------|---------------|---------------|----------|----------|
| Screen/ Baseline                      | Cycle 1 Day 1                                                                                                                                            |                             |              |               |               |               |          |          |
| Collection Time and                   | Within 28  days                                                                                                                                          | Pre-dose                    | 30 min       | 4 hour        | 6 hour        | Pre-dose      | Pre-dose | Pre-dose |
| Allowable Window                      | (± 10 min)                                                                                                                                               | (3-5 hour)                  | (5.5-8 hour) | (-0.5-0 hour) | (-0.5-0 hour) | (-0.5-0 hour) |          |          |
| PK Sample 1, 4                        | X                                                                                                                                                        | X                           | X            | X             | X             | X             | X        |          |
| Flow Cytometry 2, 5                   | X                                                                                                                                                        | X                           | X            |               |               |               |          |          |
| Protein and Cytokine  Biomarkers 2, 5 | X                                                                                                                                                        | X                           |              |               |               |               |          |          |
| X                                     |                                                                                                                                                          |                             |              |               |               |               |          |          |
| Triplicate ECG 3, 6                   | (-1  hour)                                                                                                                                               | X (-0.5                     | X            | X             | X             | X             |          |          |
| hour)                                 |                                                                                                                                                          |                             |              |               |               |               |          |          |
| 1                                     | Scheduled vital signs and triplicate ECGs precede PK sample collection in all cases. Sitravatinib dosing and sampling should precede nivolumab infusion. |                             |              |               |               |               |          |          |  
1 Scheduled vital signs and triplicate ECGs precede PK sample collection in all cases. Sitravatinib dosing and sampling should precede nivolumab infusion. 2 The Day 1 blood samples for biomarker studies may be drawn up to 2 hours before dosing. The screen/baseline sample should not be collected on the same day as the pre-dose Cycle 1 Day 1 sample.  
3 ECGs should be taken in triplicate, each reading approximately 2 minutes apart. On Cycle 1 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. Examples of the schedule are presented below:
o Example for Cycle 1 Day 1 pre-dose ECGs/PK: ~-1.0 hr (Triplicate ECGs); ~-30 mins (Triplicate ECGs); ~-15 mins (Vitals/PK) o Example for all other pre-dose ECG/PK assessments: ~-30 mins (Triplicate ECGs); ~-15 mins (Vitals/PK).  
4 Sample schedules for sitravatinib formulation and food effect evaluations are presented in Appendix 5 and Appendix 6, Table 22, Table 23, Table 24, and Table 25.  
5 Patients participating in the sitravatinib formulation and food effect sub-studies described in Appendix 5 and Appendix 6 are exempt from sample collection for biomarker studies, including flow cytometry and protein/cytokine assays.  
6 Patients participating in the sitravatinib formulation and food effect sub-studies described in Appendix 5 and Appendix 6 will undergo evaluation by triplicate ECG on Lead-In Day 1 instead of Cycle 1 Day 1.
clinical research protocol
table 4 mocetinostat schedule of

| Baseline                               | Cycle 1 Day 1                                                                                                                                     | Cycle 1 Day 15 (± 2 days)   | Cycle 2, 3, 5     |                         |                        |                         |                        |    |
|----------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------|-------------------|-------------------------|------------------------|-------------------------|------------------------|----|
| Screen/                                | Day 1 (± 2 days)                                                                                                                                  |                             |                   |                         |                        |                         |                        |    |
| Collection Time  and Allowable  Window | Pre-dose (-0.5-0  hour)                                                                                                                           | 1 hour  (0.5-1.5 hour)      | 7 hour (6-8 hour) | Pre-dose (-0.5-0  hour) | 1 hour  (0.5-1.5 hour) | Pre-dose (-0.5-0  hour) | 1 hour  (0.5-1.5 hour) |    |
| Within 28  days                        | 3 hour (2-4 hour)                                                                                                                                 |                             |                   |                         |                        |                         |                        |    |
| PK Sample 1                            | X                                                                                                                                                 | X                           | X                 | X                       | X                      | X                       | X                      | X  |
| Flow Cytometry 2                       | X                                                                                                                                                 | X                           | X                 |                         |                        |                         |                        |    |
| Protein and  Cytokine                  | X                                                                                                                                                 | X                           |                   |                         |                        |                         |                        |    |
| Biomarkers 2 Triplicate ECG 3          | X                                                                                                                                                 | X                           | X                 | X                       | X                      |                         |                        |    |
| 1                                      | Scheduled vital signs and triplicate ECGs precede PK sample collection in all cases. On days mocetinostat and nivolumab are both administered and |                             |                   |                         |                        |                         |                        |    |  
1 Scheduled vital signs and triplicate ECGs precede PK sample collection in all cases. On days mocetinostat and nivolumab are both administered and scheduled for PK assessment, mocetinostat dosing and sampling should precede nivolumab infusion.  
2 The Day 1 blood samples for biomarker studies may be drawn up to 2 hours before dosing. The screen/baseline sample should not be collected on the same day as the pre-dose Cycle 1 Day 1 sample.  
3 ECGs should be taken in triplicate, with readings at least 2 minutes apart. On Cycle 1 Day 1, two sets of triplicate ECGs should be done within 30 minutes prior to dosing (e.g., at 15 minute intervals) to firmly establish the baseline. In general, ECGs should be performed prior (within -30 to -5 minutes) to the respective PK blood collection.
clinical research protocol
table of contents

| TABLE OF CONTENTS                                                                                                                   |                                                                                                                                                  |                                                                                                              |
|-------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------|
| CLINICAL RESEARCH PROTOCOL .......................................................................................................1 |                                                                                                                                                  |                                                                                                              |
| DOCUMENT HISTORY .                                                                                                                  |                                                                                                                                                  |                                                                                                              |
| STUDY SUMMARY                                                                                                                       |                                                                                                                                                  |                                                                                                              |
| TABLE OF TABLES                                                                                                                     |                                                                                                                                                  |                                                                                                              |
| TABLE OF FIGURES                                                                                                                    |                                                                                                                                                  |                                                                                                              |
| LIST OF ABBREVIATIONS                                                                                                               |                                                                                                                                                  |                                                                                                              |
| INTRODUCTION AND RATIONALE ....................................................................36                                   |                                                                                                                                                  |                                                                                                              |
| 1                                                                                                                                   | 1.1                                                                                                                                              | Disease and Therapeutic Strategy .........................................................................36 |
| 1.1.1                                                                                                                               | Non-Small Cell Lung Cancer............................................................36                                                         |                                                                                                              |
| 1.2                                                                                                                                 | Overall Rational for Proposed Combination Regimens..............................37                                                               |                                                                                                              |
| 1.3                                                                                                                                 | Checkpoint Pathway................................................................................................38                             |                                                                                                              |
| 1.4                                                                                                                                 | Glesatinib Background..............................................................................................38                            |                                                                                                              |
| Glesatinib Drug Substance................................................................39                                         |                                                                                                                                                  |                                                                                                              |
| 1.4.1                                                                                                                               |                                                                                                                                                  |                                                                                                              |
| 1.4.2                                                                                                                               | Non-Clinical Data ...............................................................................39                                              |                                                                                                              |
| 1.4.3                                                                                                                               | Clinical Experience.............................................................................40                                               |                                                                                                              |
| 1.5                                                                                                                                 | Sitravatinib Background....................................................................................41                                    |                                                                                                              |
| 1.5.1                                                                                                                               | Sitravatinib Drug Substance............................................................42                                                        |                                                                                                              |
| 1.5.2                                                                                                                               | Non-Clinical Data .................................................................................42                                            |                                                                                                              |
| Sitravatinib Clinical Experience .....................................................43                                            |                                                                                                                                                  |                                                                                                              |
| 1.5.3                                                                                                                               |                                                                                                                                                  |                                                                                                              |
| 1.6                                                                                                                                 | Mocetinostat Background ........................................................................................47                               |                                                                                                              |
| 1.6.1                                                                                                                               | Mocetinostat Drug Substance                                                                                                                      |                                                                                                              |
| Mocetinostat Non-Clinical Data ....................................................48                                               |                                                                                                                                                  |                                                                                                              |
| 1.6.2                                                                                                                               |                                                                                                                                                  |                                                                                                              |
| 1.6.3                                                                                                                               | Mocetinostat Clinical Data...............................................................................51                                      |                                                                                                              |
| 1.7                                                                                                                                 | Nivolumab ....................................................................................................................................52 |                                                                                                              |
| 1.7.1                                                                                                                               | Nivolumab Drug Substance .....................................................................52                                                 |                                                                                                              |
| 1.7.2                                                                                                                               | Nivolumab Non-Clinical Data ................................................................52                                                   |                                                                                                              |
| 1.7.3                                                                                                                               | Nivolumab Clinical Data .................................................................................53                                      |                                                                                                              |
| 1.8                                                                                                                                 | Expectations for Combination of Study Investigational Agents                                                                                     |                                                                                                              |
| and Nivolumab                                                                                                                       |                                                                                                                                                  |                                                                                                              |
| 1.8.1                                                                                                                               | Potential for Drug-Drug Interactions ............................................58                                                              |                                                                                                              |
| 1.8.2                                                                                                                               | Evaluation of Potential for Increased Toxicities with                                                                                            |                                                                                                              |
| Combination Use of Nivolumab and Study                                                                                              |                                                                                                                                                  |                                                                                                              |
| Investigational Agents .................................................................................58                          |                                                                                                                                                  |                                                                                                              |
| 1.9                                                                                                                                 | Study Rationale                                                                                                                                  |                                                                                                              |
| 2                                                                                                                                   | STUDY OBJECTIVES ...................................................................................................................62           |                                                                                                              |
| 2.1                                                                                                                                 | Objectives ........................................................................................................................62            |                                                                                                              |
| 2.1.1                                                                                                                               | Primary Objective ...................................................................................62                                          |                                                                                                              |
| 2.1.2                                                                                                                               | Secondary Objectives ...............................................................................62                                           |                                                                                                              |
| 2.1.3                                                                                                                               | Exploratory Objectives ........................................................................63                                                |                                                                                                              |
| 2.2                                                                                                                                 | Endpoints......................................................................................................................63                |                                                                                                              |
| Primary Endpoints ...................................................................................63                             |                                                                                                                                                  |                                                                                                              |
| 2.2.1                                                                                                                               |                                                                                                                                                  |                                                                                                              |
| 2.2.2                                                                                                                               | Secondary Endpoints................................................................................63                                            |                                                                                                              |  
| MRTX-500 v6.0 - Phase 2 in NSCLC                         | Confidential                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           |
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| 2.2.3                                                    | Exploratory Endpoints 63                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               |
| 3                                                        | STUDY DESIGN 64 3.1 Lead-In Dose Escalation Evaluation 65 3.1.1 Definition of Dose Limiting Toxicity 65 3.1.2 Enrollment and Dose Escalation Plan 66 3.1.3 Definition of Maximum Tolerated Dose 67 3.1.4 Selection of Phase 2 Dose for Investigational Study  Drugs 67 3.2 Phase 2 Study 67                                                                                                                                                                                                                                                                                                                            |
| 4                                                        | PATIENT SELECTION AND ENROLLMENT 73 4.1 Inclusion Criteria 73 4.2 Exclusion Criteria 74 4.3 Life Style Guidelines 77 4.4 Enrollment into Study 77                                                                                                                                                                                                                                                                                                                                                                                                                                                                      |
| 5                                                        | STUDY TREATMENTs 78 5.1 Investigational Agents 78 5.1.1 Glesatinib 78 5.1.2 Sitravatinib 80 5.1.3 Mocetinostat 85 5.1.4 Instructions Common to Investigational Study  Treatments 89 5.2 Nivolumab Study Drug 93 5.2.1 Formulation and Packaging 93 5.2.2 Preparation and Dispensing 93 5.2.3 Administration 94 5.2.4 Infusion Modification and Discontinuation 94 5.2.5 Nivolumab Adverse Event Management Guidelines 96 5.3 Medication Error 98 5.4 Concomitant Therapies 98 5.4.1 Concomitant Medication(s) 98 5.4.2 Concomitant Surgery or Radiation Therapy 100 5.4.3 Other Anticancer or Experimental Therapy 100 |
| 6                                                        | STUDY ASSESSMENTS 100 6.1 Screening 100 6.2 Study Period 101 6.3 End of Treatment Assessment 101 6.4 Long-Term Follow-up and End of Study Assessment 101 6.5 Patient Discontinuation/Withdrawal 101                                                                                                                                                                                                                                                                                                                                                                                                                    |
| 7                                                        | PROCEDURES 102 7.1 Efficacy 102 7.2 Safety Assessments 104 7.2.1 Adverse Events 104 7.2.2 Physical Examination and Vital Signs 104 7.2.3 Laboratory Safety Assessments 104 7.2.4 Electrocardiogram (ECG) 105Mirati Therapeutics, Inc.                                                                                                                                                                                                                                                                                                                                                                                  |  
| MRTX-500 v6.0 - Phase 2 in NSCLC                         | Confidential                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          |
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| Glesatinib, Sitravatinib, or Mocetinostat with Nivolumab | Page 29 of 147                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        |
| 7.2.5                                                    | Echocardiogram (ECHO) 105                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             |
| 7.3                                                      | Laboratory Studies 106 7.3.1 Pharmacokinetic Evaluation 106 7.3.2 Pharmacodynamic Evaluation in Tumor Tissue 106 7.3.3 Pharmacodynamic Evaluation in Blood 106 7.3.4 Circulating Tumor DNA 107 7.3.5 Sample Collection for PD-L1 Expression and Tumor Gene Alterations 107                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            |
| 7.4                                                      | Post-treatment Follow-up 107                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          |
| 8                                                        | ADVERSE EVENT REPORTING 108 8.1 Sponsor Medical Monitor Personnel 108 8.2 Adverse Events 108 8.2.1 Laboratory Abnormalities 109 8.2.2 Severity Assessment 109 8.2.3 Causality 109 8.3 Serious Adverse Events 110 8.3.1 Definition of a Serious Adverse Events 110 8.3.2 Exposure During Pregnancy 111 8.4 Reporting of SAEs and AEs 112 8.4.1 Reporting Period 112 8.4.2 Reporting Requirements 112                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   |
| 9                                                        | STATISTICS 113 9.1 Hypothesis and Sample Size 113 9.1.1 Lead-In Dose Escalation Evaluation 113 9.1.2 Phase 2 114 9.2 Data Handling 115 9.3 Analysis Populations 116 9.3.1 Modified Intent-to-Treat Population 116 9.3.2 Clinical Activity Evaluable Population 116 9.3.3 Safety Population 116 9.3.4 Molecular Marker Evaluable Population 116 9.3.5 Pharmacokinetic Evaluable Population 116 9.3.6 Pharmacodynamic Evaluable Population 116 9.4 Efficacy Endpoint Definitions and Analyses 117 9.4.1 Objective Response Rate 117 9.4.2 Clinical Benefit Rate 117 9.4.3 Duration of Response 117 9.4.4 Progression Free Survival 117 9.4.5 Overall Survival 118 9.5 Safety Data Presentations and Summaries 118 9.5.1 Adverse Events 118 9.5.2 Prior and Concomitant Medications 118 9.5.3 Clinical and Laboratory Assessments 118 9.5.4 Patient Demographics, Baseline Characteristics and  Disposition 119Mirati Therapeutics, Inc. |  
| MRTX-500 v6.0 - Phase 2 in NSCLC                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               | Confidential                                                                                                                                                                                                                                                                                                               |
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| 9.5.5                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          | Analysis of Study Treatment Dosing 119                                                                                                                                                                                                                                                                                     |
| 9.6                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            | Other Study Endpoints 119 9.6.1 Pharmacokinetic Analysis 119 9.6.2 Pharmacodynamic and Exploratory Analyses 120                                                                                                                                                                                                            |
| 9.7                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            | Interim Analysis 120                                                                                                                                                                                                                                                                                                       |
| 9.8                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            | Data Monitoring Committee 120                                                                                                                                                                                                                                                                                              |
| 10                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             | ETHICS AND RESPONSIBILITIES 120 10.1 Ethical Conduct of the Study 120 10.2 Obligations of Investigators 120 10.3 Institutional Review Board/Ethics Committee/Research Ethics  Board (IRB/EC) 121 10.4 Informed Consent Form 121 10.5 Confidentiality 121 10.6 Reporting of Serious Breaches of the Protocol or ICH GCP 122 |
| 11                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             | RECORDS MANAGEMENT 122 11.1 Source Documentation 122 11.2 Study Files and Records Retention 122                                                                                                                                                                                                                            |
| 12                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             | QUALITY CONTROL AND QUALITY ASSURANCE 123 12.1 Monitoring Procedures 123 12.2 Auditing and Inspection Procedures 123                                                                                                                                                                                                       |
| 13                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             | CHANGES IN STUDY CONDUCT 123 13.1 Protocol Amendments 123 13.2 Protocol Deviations 124                                                                                                                                                                                                                                     |
| 14                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             | END OF TRIAL 124 14.1 End of Trial in a European Union Member State 124 14.2 End of Trial in all other Participating Countries 124 14.3 Premature Termination 124                                                                                                                                                          |
| 15                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             | STUDY REPORT AND PUBLICATION POLICY 125                                                                                                                                                                                                                                                                                    |
| 16                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             | REFERENCES 125                                                                                                                                                                                                                                                                                                             |
| APPENDIX 1. ECOG PERFORMANCE STATUS 129 APPENDIX 2. DOSE-FINDING SPREADSHEET OF THE MODIFIED  TOXICITY PROBABILITY INTERVAL (MTPI) METHOD 130 APPENDIX 3. MEDICATIONS OR SUBSTANCES TO BE AVOIDED OR  USED WITH CAUTION DURING STUDY TREATMENT 131 APPENDIX 4. ABBREVIATED PRESENTATION OF RECIST VERSION  1.1 GUIDELINES 133 APPENDIX 5. SITRAVATINIB SUB-STUDY TO EVALUATE THE  PHARMACOKINETICS OF THREE FORMULATIONS 138 APPENDIX 6. SITRAVATINIB SUB-STUDY TO EVALUATE  PHARMACOKINETICS WHEN ADMINISTERED WITH  FOOD 144 |                                                                                                                                                                                                                                                                                                                            |  
| TABLE OF TABLES   |                                                                                                                                                                                                                              |
|-------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Table 1:          | Schedule of Assessments 19                                                                                                                                                                                                   |
| Table 2:          | Glesatinib Schedule of PK, Biomarker Samples and Triplicate ECG Assessments 24                                                                                                                                               |
| Table 3:          | Sitravatinib Schedule of PK, Biomarker Samples and Triplicate ECG Assessments 25                                                                                                                                             |
| Table 4:          | Mocetinostat Schedule of PK, Biomarker Samples and Triplicate ECG Assessments 26                                                                                                                                             |
| Table 5:          | Summary of Adverse Events for Study 516-001 as of 26 June 2018 - Most Frequent (≥10%) Treatment-Related, Treatment Emergent Adverse Events and ≥ Grade 3 Events in At Least Two Patients 44                                  |
| Table 6:          | Summary of Adverse Events for Study MRTX-500 as of 26 June 2018 - Most Frequent (≥10%) Treatment-Related (Sitravatinib and/or Nivolumab), Treatment Emergent Adverse Events and ≥ Grade 3 Events in At Least Two Patients 46 |
| Table 7:          | Investigational Study Drug Starting Dose Levels for Cohorts of Patients in the Lead-In Dose Evaluation 65                                                                                                                    |
| Table 8:          | Glesatinib Sequential Dose Reductions for Individual Patients 79                                                                                                                                                             |
| Table 9:          | Sitravatinib Free Base Formulation Sequential Dose Reductions for Individual Patients 82                                                                                                                                     |
| Table 10:         | Sitravatinib Dose Modification for Increased Blood Pressure 83                                                                                                                                                               |
| Table 11:         | Mocetinostat Sequential Dose Reductions for Individual Patients 86                                                                                                                                                           |
| Table 12:         | Definitions of Pericardial Events 87                                                                                                                                                                                         |
| Table 13:         | Pericardial Effusion and Patient Management Guidelines 88                                                                                                                                                                    |
| Table 14:         | Investigational Study Treatment Modification for Increased Hepatic Transaminase1 91                                                                                                                                          |
| Table 15:         | Investigational Study Treatment Dose Modifications - Non-Hematological Drug-Related Toxicities1, 2 92                                                                                                                        |
| Table 16:         | Recommended Dose Modifications for OPDIVO - Reprinted from OPDIVO US Prescribing Information 95                                                                                                                              |
| Table 17:         | Management of Nivolumab Immune-Related Adverse Events - Reprinted from OPDIVO US Prescribing Information 96                                                                                                                  |
| Table 18:         | Treatment Interruption for Major Surgery 100                                                                                                                                                                                 |
| Table 19:         | Laboratory Safety Parameters 105                                                                                                                                                                                             |
| Table 20:         | Estimates of 95% CI Using Clopper-Pearson After Enrollment of 125 Patients 115                                                                                                                                               |
| Table 21:         | Pharmacokinetic Parameters in Dog Following Oral Administration of Three Sitravatinib Capsule Formulations 139                                                                                                               |
| Table 22:         | PK Sample Collection and Triplicate ECG Schedule During Lead-In Period 142                                                                                                                                                   |
| Table 23:         | PK Sample Collection and Triplicate ECG Schedule Cycle 1 Day 15 (± 2 Days) 143                                                                                                                                               |  
| Table 24:   | PK Sample Collection and Triplicate ECG Schedule During Lead-In Period 146     |
|-------------|--------------------------------------------------------------------------------|
| Table 25:   | PK Sample Collection and Triplicate ECG Schedule Cycle 1 Day 15 (± 2 Days) 146 |
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table of figures

| Figure 1:   | Mocetinostat Modulates Expression of PD-L1 and Antigen Presentation Regulatory Genes in NCSLC Cell Lines 49   |
|-------------|---------------------------------------------------------------------------------------------------------------|
| Figure 2:   | Mocetinostat Modulates Key Immune Cell Populations In Vivo 50                                                 |
| Figure 3:   | Study Diagram 71                                                                                              |
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list of abbreviations

| LIST OF ABBREVIATIONS   |                                                                 |
|-------------------------|-----------------------------------------------------------------|
| ADR                     | Adverse Drug Reaction                                           |
| AE                      | Adverse Event                                                   |
| ALT                     | Alanine Aminotransferase                                        |
| APC                     | Antigen Presenting Cells                                        |
| AST                     | Aspartate Aminotransferase                                      |
| AUC                     | Area Under the Curve                                            |
| CFR                     | Code of Federal Regulations                                     |
| CDx                     | Companion Diagnostics                                           |
| CI                      | Confidence Interval                                             |
| CIT                     | Checkpoint Inhibitor Therapy                                    |
| Cmax                    | Maximum Plasma Concentration                                    |
| CR                      | Complete Response                                               |
| CRF                     | Case Report Form                                                |
| CRO                     | Contract Research Organization                                  |
| CT                      | Computed Tomography Scan                                        |
| CTA                     | Clinical Trial Application                                      |
| CTCAE                   | Common Terminology Criteria for Adverse Events                  |
| ctDNA                   | Circulating Tumor Deoxyribonucleic Acid                         |
| DLT                     | Dose Limiting Toxicity                                          |
| DR                      | Duration of Response                                            |
| EC                      | Ethics Committee                                                |
| ECG                     | Electrocardiogram                                               |
| ECOG                    | Eastern Cooperative Oncology Group                              |
| EIU                     | Exposure In-Utero                                               |
| FDA                     | Food and Drug Administration                                    |
| FFPE                    | Formalin-Fixed, Paraffin-Embedded                               |
| GCP                     | Good Clinical Practice                                          |
| GLP                     | Good Laboratory Practice                                        |
| HDAC                    | Histone Deacetylases                                            |
| HDPE                    | High-Density Polyethylene                                       |
| IB                      | Investigator's Brochure                                         |
| ICF                     | Informed Consent Form                                           |
| ICH                     | International Council on HarmonizationMirati Therapeutics, Inc. |  
| LIST OF ABBREVIATIONS (CONTINUED)   |                                              |
|-------------------------------------|----------------------------------------------|
| IND                                 | Investigational New Drug                     |
| INR                                 | International Normalized Ration              |
| irAE                                | Immune-related Adverse Event                 |
| IRB                                 | Institutional Review Board                   |
| ITT                                 | Intent-to-Treat                              |
| IUD                                 | Intrauterine Device                          |
| IV                                  | Intravenous                                  |
| MAb                                 | Monoclonal Antibody                          |
| MDSC                                | Myeloid-derived Suppressor Cell              |
| MDSCs                               | Myeloid-Derived Suppressor Cells             |
| MedDRA                              | Medical Dictionary for Regulatory Activities |
| mg                                  | Milligram                                    |
| MHC                                 | Major Histocompatibility Complex             |
| mITT                                | Modified Intent-to-Treat                     |
| mL                                  | Milliliter                                   |
| MRI                                 | Magnetic Resonance Imaging                   |
| MTD                                 | Maximum Tolerated Dose                       |
| mTPI                                | Modified Toxicity Probability Interval       |
| NCI                                 | National Cancer Institute                    |
| NE                                  | Not Evaluable                                |
| NK                                  | Natural Killer                               |
| NSCLC                               | Non-Small Cell Lung Cancer                   |
| ORR                                 | Objective Response Rate                      |
| OS                                  | Overall Survival                             |
| PD                                  | Objective Progression of Disease             |
| PD-1                                | Programmed Cell Death 1                      |
| PD-L1                               | Programmed Cell Death Ligand 1               |
| PFS                                 | Progression-Free Survival                    |
| PK                                  | Pharmacokinetics                             |
| PKAP                                | Pharmacokinetic Analysis Plan                |
| PPD                                 | Predictive Probability Design                |
| PR                                  | Partial Response                             |
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list of abbreviations (continued)

| PTT    | Partial Thromboplastin Time                  |
|--------|----------------------------------------------|
| Q2W    | Every 2 weeks                                |
| Q4W    | Every 4 weeks                                |
| RECIST | Response Evaluation Criteria in Solid Tumors |
| SAE    | Serious Adverse Event                        |
| SAP    | Statistical Analysis Plan                    |
| SD     | Stable Disease                               |
| SOC    | System Organ Class                           |
| TAA    | Tumor Associated Antigens                    |
| TIW    | Three Times Weekly                           |
| Treg   | T Regulatory Cells                           |
| ULN    | Upper Limit of Normal                        |
| WBC    | White Blood Cell                             |
| WOCBP  | Women of Child Bearing Potential             |
clinical research protocol
1 introduction and rationale 1.1

Lung cancer remains the leading cause of cancer-related death in the United States (US). Approximately 221,200 new cases of lung cancer are expected to be diagnosed in the US in 2015, and approximately 158,040 deaths will be attributed to lung cancer (Cancer Facts and Figures-2015). Non-small cell lung cancer (NSCLC) accounts for approximately 83% of lung cancer cases (Cancer Facts and Figures-2015), of which approximately half are classified as adenocarcinoma of the lung; squamous cell carcinoma accounts for approximately one-third of NSCLC cases and large cell carcinoma is less frequently diagnosed. In 1995, the use of cisplatin-based chemotherapy was reported to lead to modest improvement in survival in patients with advanced NSCLC as compared to best supportive care, with a 27% reduction in death as reported in a meta-analysis of 11 trials (NSCLC Collaborative Group-1995). Subsequently, other chemotherapeutic agents have been reported to be active in NSCLC, leading to a comparison of 4 platinum-based doublets in the first-line treatment setting, all of which demonstrated similar activity (Schiller-2002). The importance of histology in the selection of first-line treatment for NSCLC was later described in the development of bevacizumab and pemetrexed. In a Phase 3 clinical trial, treatment with bevacizumab, a monoclonal antibody directed against vascular endothelial growth factor (VEGF), demonstrated an improvement in survival when added to doublet chemotherapy, specifically in patients with non-squamous NSCLC (Sandler-2006). Similarly, treatment with pemetrexed, an antifolate chemotherapeutic agent, resulted in an improvement in survival when used as part of a chemotherapy doublet in patients with non-squamous NSCLC, but with a probable decrease in survival among patients with squamous cell NSCLC (Scagliotti-2008). Based on the results of these and other trials, platinum-based chemotherapy doublets, with or without bevacizumab in selected patients, remain a standard of care for most patients with advanced NSCLC in the first-line treatment setting. Effective options are limited however for patients with advanced NSCLC whose disease progresses after first-line treatment. Over the past few years there has been increasing interest in treating cancer with immunotherapy, in particular manipulating the anticancer host immune response with human monoclonal antibodies (MAbs). Nivolumab, a fully human IgG4, PD-1 receptor antagonist, was evaluated in a Phase 3 clinical trial of patients with squamous cell carcinoma of the lung with disease progression during or after first-line chemotherapy. This study demonstrated a significant improvement in survival compared with docetaxel, with a hazard ratio (HR) of 0.59 (95% CI: 0.44, 0.79, p<0.001) (Brahmer-2015). A similar Phase 3 trial of patients with non-squamous NSCLC that had progressed during or after platinum-based doublet chemotherapy demonstrated an improvement in survival with nivolumab over docetaxel
(HR 0.73, 96% [sic] CI 0.59, 0.89, p=0.002) (Borghaei-2015). OPDIVO® (nivolumab)
was approved by the FDA for the treatment of patients with metastatic NSCLC with progression on or after platinum-based chemotherapy. Nivolumab was approved in the US in March 2015 for squamous NSCLC and October 2015 for non-squamous NSCLC. Pembrolizumab is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2. In a large international Phase 1 clinical trial, pembrolizumab was given to 495 patients with advanced NSCLC to evaluate safety, side-effect profile, and antitumor activity (Garon-2015). Patients (some of whom had received previous therapy and some of whom had not) were treated with various doses and regimens of pembrolizumab. Pembrolizumab had an acceptable side-effect profile and showed anti-tumor activity. Among all patients, the objective response rate was 19.4%, and the median duration of response was 12.5 months. The median duration of progression-free survival was 3.7 months, and the median duration of overall survival was 12.0 months. Keytruda® (pembrolizumab) was approved by the FDA in October 2015 for the treatment of patients with metastatic squamous or non-squamous NSCLC with progression on or after platinum-based chemotherapy. Despite these advances, most patients with advanced NSCLC have incurable disease, and additional, effective treatment options are needed. More recently, a trial of pembrolizumab, demonstrated an advantage of pembrolizumab over standard chemotherapy in patients with untreated, advanced NSCLC characterized by ≥ 50% tumor PD-L1 expression. Improvement was reported across multiple efficacy endpoints including survival along with a favorable safety profile (Reck-2016), leading to the approval of pembrolizumab in the first-line treatment setting in this patient population in the US.
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1.2 overall rational for proposed

Immune checkpoint inhibitors targeting the PD-1/PD-L1 pathway have demonstrated clinical activity across a range of cancer types, including non-small cell lung cancer
(Brahmer-2015, Borghaei-2015, Garon-2015). While this therapy leads to durable clinical responses in a subset of patients, strategies to improve its clinical efficacy and overcome innate or acquired resistance to checkpoint inhibitor monotherapy are needed. Combination therapy with agents that target the molecular and cellular mechanisms of resistance to checkpoint inhibitor therapy is a rational approach to improving outcomes in patients. Resistance mechanisms have been described based on fundamental knowledge of the immune system as well as emerging clinical data. Expression of PD-L1 appears to correlate with response in multiple clinical studies (Herbst-2014, Tumeh-2014). In the tumor microenvironment, PD-L1 can be upregulated in tumor cells via oncogenic signaling or in response to immune stimulatory factors such as interferon gamma (IFN-γ).  
Therefore, the absence of PD-L1 expression may reflect a tumor cell population and microenvironment with a suppressed immune response. A potentially related state termed immunological ignorance was recently described and is characterized by a near complete absence of immune markers in the tumor. Tumors harboring a non-functional immune response or an excluded immune cell infiltrate represent additional cellular patterns found associated with resistance to checkpoint inhibition (Herbst-2014). Several immune cell types normally function to suppress immune responses, are often found in abundance in cancer and may underlie these recently described resistance mechanisms to checkpoint blockade (Vanneman-2012). Regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs) and M2-polarized macrophages, in particular, are immunosuppressive in nature as they counteract pro-inflammatory immune responses and lead to tolerance. Inhibition of the accumulation and/or function of these cell types therefore represents a rational combination strategy to reprogram the immunosuppressive tumor microenvironment and increase the effectiveness of PD-1/PD-L1 therapy. As described in further detail below, both glesatinib and sitravatinib target key receptor tyrosine kinases present on these immune cell types. Moreover, in addition to inhibiting some of the same immunosuppressive cell types noted above, mocetinostat enhances tumor antigen presentation, increases immunologic cell death and recruits pro-inflammatory cell types through modulation of gene expression in the tumor cell compartment. In summary, these therapies selectively inhibit key molecular and cellular pathways strongly implicated in checkpoint inhibitor resistance and therefore represent rational strategies to enhance or restore anti-tumor immunity when combined with nivolumab.
clinical research protocol
1.3 checkpoint pathway

The PD-1 receptor along with the ligands PD-L1 and PD-L2 constitutes an immune checkpoint pathway that inhibits T-cell activation when engaged (Mellman-2011, Topalian-2015). PD-1 is expressed on T-cells whereas PD-L1 and PD-L2 are expressed on some cancer cells and immune cell types. PD-L1 is the predominant ligand expressed in solid tumors and is upregulated by IFNg. PD-L1 normally functions to limit collateral damage in normal tissues where an immune response has been triggered. When PD-L1 is upregulated in tumors, this functions to block the immune response and avoid elimination by the host. PD-L1 expression in tumor, including in lung cancer, has been associated with poor survival motivating the development of PD-1 pathway inhibitors (Mu-2011).
clinical research protocol
1.4 glesatinib background

Glesatinib (MGCD265) is an orally administered multi-targeted receptor tyrosine kinase (RTK) inhibitor that primarily targets the Axl and MET receptors. Additional RTK
targets potentially include MERTK, DDR2, and PDGFR and  receptors. This subset of tyrosine kinases is involved in a number of processes implicated in human cancer including regulation of tumor growth and cell survival pathways, tumor invasion and metastatic progression, as well as tumor angiogenesis. Background information in addition to that presented below is available in the MGCD265 Investigator's Brochure.
clinical research protocol
1.4.1 glesatinib drug substance

The chemical structure of glesatinib (MGCD265) is as follows: MGCD265 Free Base
clinical research protocol
1.4.2 non-clinical data

Glesatinib demonstrated potent, concentration-dependent inhibition of the kinase activity of MET, Axl, MERTK, PDGFR family and DDR2 in biochemical assays and inhibited phosphorylation in cell-based assays. Glesatinib also inhibited MET-dependent cell viability and migration and endothelial tube formation and angiogenesis in cell-based experiments. In a variety of human tumor xenograft models, glesatinib demonstrated anti-tumor efficacy including robust tumor regression in models exhibiting genetic alterations of the MET RTK including MET mutations and gene amplification.  
The potential for glesatinib cardiovascular effects was tested in vitro and in vivo. The IC50 for potassium (hERG/Kv11.1) and sodium channel (hNav1.5) inhibition were not calculated but were estimated to be >30 M, a level that far exceeds exposures observed clinically. In a dog cardiovascular study, oral treatment with glesatinib did not affect hemodynamic functions (heart rate; systolic, mean and diastolic arterial pressure) or electrocardiogram parameters at dose levels up to 40 mg/kg. In in vitro membrane permeability studies, Glesatinib was highly permeable and did not show significant efflux (efflux ratio 0.7) suggesting that glesatinib is not a substrate of Pgp or BCRP (efflux transporters). Protein binding studies of glesatinib in mouse, rat, and human plasma demonstrated greater than 99.9% protein binding by an ultrafiltration assay; binding to dog plasma proteins was 99.8%. In addition, a serum shift experiment in a cell-based assay estimated glesatinib to be 98% bound to human plasma. Glesatinib is relatively stable when incubated in human liver microsomes, suggesting that it is not extensively metabolized by the cytochrome P-450 system. Reaction phenotyping shows that metabolism of glesatinib that does occur appears to be mediated by several CYP enzymes without a specific enzyme predominance. Additionally, in vitro studies in human liver microsomes and in primary cultures of fresh human hepatocytes indicate that glesatinib is neither a potent inhibitor nor a potent inducer of CYP enzymes at the clinically observed concentration levels.
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1.4.3 clinical experience 1.4.3.1 glesatinib

Following single dose administration of 750 mg BID SDD glesatinib tablets, MGCD265 was rapidly absorbed, with median Cmax occurring 6 hours after dosing. The mean elimination half-life was 30.9 hours. Drug accumulation was observed after multiple dose administration, whereby Cmax and AUC0-12 were 4.0- and 4.5-fold higher, respectively, than single dose administration. The mean peak to trough ratio at steady state was 1.12. At steady state, mean Cmax,ss, Cave,ss and AUC0-12,ss values were 432 ng/mL, 396 ng/mL and 4751 ng•h/mL, respectively.
clinical research protocol
1.4.3.2 glesatinib clinical safety

Single agent glesatinib has been evaluated using various oral formulations and regimens in Phase 1, 1/2, and 2 clinical trials in over 370 patients with advanced malignancies. As of 17 January 2017, in Study No. 265-101, a total of 165 patients have been treated with single agent glesatinib daily dosing. Dose escalation started at 24 mg/m2 administered once daily and progressed through multiple formulation changes. The maximum tolerated dose (MTD) with the non-aqueous suspension formulation was defined as 1050 mg BID, with diarrhea and fatigue being the most common dose-limiting adverse events. The SDD tablet formation was introduced with the expectation that the incidence and severity of diarrhea would be reduced as compared with the non-aqueous formulation that includes Miglyol® as an excipient. The dose escalation evaluation of the SDD formulation identified that the recommended dose when glesatinib is administered as a single agent is 750 mg BID; 1000 mg BID using the SDD formulation exceeded the maximum tolerated dose. The incidence, severity and speed of onset of diarrhea were less among patients receiving the SDD formulation as compared to the non-aqueous suspension formulation. Across the clinical trial program, the most commonly observed treatment-emergent adverse events (TEAEs) reported as related to glesatinib when administered alone were diarrhea (62%), nausea (39%), fatigue (31%), vomiting (26%), aspartate aminotransferase (AST) increase (25%), and alanine aminotransferase (ALT) increase (20%). Grade 3 TEAEs that were reported as related to treatment in more than one patient included diarrhea (8%), fatigue (5%), AST increase, ALT increase, lipase increase, nausea, and vomiting (2% each), and abdominal pain, anemia, blood alkaline phosphatase increase, blood phosphorus decrease, dehydration, hypertension, hypokalemia (1% each). Adverse events of grade 4 that were reported related to treatment included lipase increase in 3 patients (1%) and amylase increase and lymphocyte count decrease (< 1%). Events listed in the Investigator's Brochure as glesatinib Adverse Drug Reactions (ADRs) include diarrhea, nausea, vomiting, fatigue, asthenia, AST and ALT increase and dehydration.  
Based on reported clinical experience with glesatinib and similar agents, and non-clinical data with glesatinib, guidance to the Investigator is provided for selected adverse events in Section 5.1.1.4.
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1.5 sitravatinib background

Sitravatinib (MGCD516) is an orally-available, potent small molecule inhibitor of a closely related spectrum of receptor tyrosine kinases (RTKs) including MET, Axl, MERTK, VEGFR family, PDGFR family, KIT, FLT3, Trk family, RET, DDR2, and selected Eph family members. Receptor tyrosine kinases (RTKs) are key regulators of signaling pathways leading to cell growth, survival, and migration (Blume Jensen-2001). These kinases are found dysregulated in many cancers through overexpression, genetic alteration or co-expression with high affinity ligands (Blume Jensen-2001). Multiple sitravatinib RTK targets are genetically altered in a variety of cancer indications and act as oncogenic drivers promoting cancer development and progression. Background information in addition to that presented below is available in the Sitravatinib (MGCD516) Investigator's Brochure.
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1.5.1 sitravatinib drug substance

The chemical structure of sitravatinib (MGCD516) is as follows: MGCD516 Free Base  
  
Molecular Weight: 629.68 g/mol
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1.5.2 non-clinical data

Sitravatinib demonstrated potent, concentration-dependent inhibition of the kinase activity of MET, Axl, MERTK, VEGFR family, PDGFR family, KIT, FLT3, Trk family, RET, DDR2, and selected Eph family members in biochemical assays and inhibited phosphorylation and kinase dependent function in cell-based assays. Sitravatinib also inhibited oncogenic functions associated with target RTKs including MET-dependent cell viability and migration and endothelial tube formation and angiogenesis. Consistent with this anti-tumor and anti-angiogenic mechanism of action, sitravatinib demonstrated anti-tumor efficacy over a broad spectrum of human tumor xenograft models including robust cytoreductive anti-tumor activity in a subset of models exhibiting genetic alterations in RTK targets including MET, RET, FLT3 and others.  
In vitro results from the hERG assay demonstrate an IC50 of 0.6 μM on the potassium current, which far exceeds exposures observed clinically. There were no adverse effects on the cardiovascular system, including no effect on the QTc interval, when sitravatinib was administered to dogs at doses up to 4 mg/kg (mean 6 hr concentration of 0.072 μg/mL). Minor increases in vascular pressures were observed during the dog cardiovascular study; however these were mild and considered of limited biological consequence. Assessment of the neurological functional observation battery (FOB) and respiratory evaluations (tidal volume, respiration rate, and minute volume) in rats did not reveal any sitravatinib-related effects at doses up to 25 mg/kg. In a bidirectional permeability study with Caco-2 cell lines, sitravatinib is classified as a highly permeable compound, and not a substrate of P-gp and BCRP. Using an ultra-centrifugation technique sitravatinib was 98.6% bound to human plasma proteins.  
Sitravatinib was evaluated for cytochrome P-450-mediated metabolism using human liver microsomes and recombinant human enzymes. Results suggest that multiple enzymes, including CYP 1A2, 2A6, 2B6, 2C8, 2C9, 2D6, 2E1, and 3A4 are involved in the metabolism of sitravatinib with a low risk of one enzyme contributing to metabolism in a disproportionate manner. In vitro studies in human primary cultures of cryopreserved human hepatocytes and human liver microsomes indicate that sitravatinib is unlikely to inhibit or induce the tested enzymes at the systemic concentrations associated with 150 mg daily administration.
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1.5.3 sitravatinib clinical experience 1.5.3.1

After single dose administration, sitravatinib reaches peak concentration in a median time of 3 to 9 hours. Exposure parameters (maximum concentration [Cmax] and area under the curve [AUC]) are dose proportional with doses up to 150 mg. Mean elimination half-life varies between 35 and 53 hours after oral administration. Drug accumulation is observed after multiple dose administration and averaged 2.7-fold for Cmax and 3.1-fold for AUC0-24. Mean peak to through ratio at steady state is 1.8. Based on current data following administration of 150 mg once daily to patients, the steady state mean Cmax, Cave,ss and AUC0-24,ss values are 116 ng/mL, 95.1 ng/mL and, 2281 mg.h/mL, respectively.
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1.5.3.2 sitravatinib clinical trial experience

Study 516-001 is a multi-center Phase 1/1b clinical trial of sitravatinib as monotherapy in patients with advanced solid tumor diseases. The Phase 1 dose-escalation segment of the study evaluated sitravatinib dose levels between 10 mg and 200 mg administered QD. Dose-limiting toxicity (DLT) was reported in four patients who developed palmar-plantar erythrodysesthesia, neuropathy, mucositis, or fatigue. The maximum tolerated dose was identified as 150 mg QD and, based on long-term tolerability, the recommended Phase 2 dose is 120 mg QD. The sitravatinib exposure achieved using 120 mg QD is expected to be adequate to inhibit the target TAM and VEGF receptors necessary to achieve antitumor activity in combination with nivolumab. The Phase 1b segment is ongoing, evaluating the clinical activity of sitravatinib in patients having tumors with selected histological diagnoses and/or tumor gene alterations targeted by sitravatinib. As of 26 June 2018, preliminary safety data are available for 153 patients treated in Study 516-001. Treatment-related adverse events reported in ≥ 10% of patients and Grade 3 or higher AEs reported in at least two patients are listed in Table 5.
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table 5 summary of adverse

| Two Patients                        | N=153      |          |
|-------------------------------------|------------|----------|
| Adverse Event (Preferred Term)      | All Grades | Grade ≥3 |
| n (%)                               | n (%)      |          |
| Diarrhea                            | 74 (48)    | 16 (11)  |
| Fatigue                             | 65 (43)    | 9 (6)    |
| Hypertension                        | 56 (37)    | 29 (19)  |
| Nausea                              | 45 (29)    | 5 (3)    |
| Vomiting                            | 40 (26)    | 4 (3)    |
| Decreased appetite                  | 38 (25)    | 1 (1)    |
| Palmar-plantar erythrodysaesthesia  | 28 (18)    | 6 (4)    |
| Aspartate aminotransferase increase | 26 (17)    | 1 (1)    |
| Alanine aminotransferase increase   | 25 (16)    | 1 (1)    |
| Hypothyroidism                      | 22 (14)    | 0        |
| Weight decrease                     | 21 (14)    | 2 (1)    |
| Dysphonia                           | 18 (12)    | 0        |
| Stomatitis                          | 18 (12)    | 0        |
| Abdominal pain                      | 16 (11)    | 0        |
| Rash                                | 15 (10)    | 0        |
| Lipase increased                    | 13 (9)     | 6 (4)    |
| Mucosal inflammation                | 13 (9)     | 3 (2)    |
| Anaemia                             | 13 (9)     | 2 (1)    |
| Rash maculo-papular                 | 10 (7)     | 3 (2)    |
| Hypophosphataeamia                  | 9 (6)      | 5 (3)    |
| Amylase increased                   | 9 (6)      | 2 (1)    |
| Ejection fraction decreased         | 7 (5)      | 3 (2)    |
| Pulmonary embolism                  | 6 (4)      | 6 (4)    |
| Embolism                            | 4 (3)      | 2 (1)    |
| Left ventricular dysfunction        | 3 (2)      | 3 (2)    |
| Pancreatitis                        | 3 (2)      | 2 (1)    |  
Grade 4 AE events reported as related to treatment in 1 patient each (0.7%) included dehydration, febrile neutropenia and lipase increased. Grade 5 treatment-related adverse event of cardiac arrest was reported in one patient. Treatment-related SAEs were reported in 24 patients (16%) and included diarrhea, nausea and vomiting (3% each); fatigue (2%); pancreatitis, pulmonary embolism, and hypertension (1.3% each); cardiac arrest, ejection fraction decreased, embolism, febrile neutropenia, headache, hypotension, left ventricular dysfunction, lipase increased, odynophagia, oropharyngeal pain, palmarplantar erythrodysesthesia and tachycardia (0.7% each). Fifty patient deaths were reported in this study, with the primary cause of death being the disease under study (n=31), unknown (n=12), other (n=7), including sepsis (n=3), and hypoxic respiratory failure, respiratory failure, gastrointestinal bleed, or cardiac arrest (n=1 each).  
Efficacy results are awaited from the Phase 1b segment of Study 516-001.
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1.5.3.2.2 sitravatinib in combination with

The current study began with a lead-in safety evaluation of sitravatinib in combination with nivolumab administered by intravenous infusion, 240 mg Q2W. The starting dose for sitravatinib was 120 mg administered orally, once daily, in 28-day cycles. No protocol defined DLTs were reported in the first 6 evaluable patients treated at the sitravatinib starting dose 120 mg daily in combination with nivolumab administered by intravenous infusion, 240 mg Q2W. Based on the experience of patients enrolled into the 516-001 study and the patients enrolled in the MRTX-500 study, 120 mg daily was selected as the Phase 2 dose of sitravatinib in combination with nivolumab. As of 26 June 2018, preliminary safety data are available for 70 patients treated in the sitravatinib segment of Study MRTX-500. The data summarized below include the experience of patients enrolled in all sitravatinib patient strata in MRTX-500 (i.e., both CIT-experienced and CIT-naïve). Treatment-related AEs reported in ≥ 10% of patients and Grade 3 or higher AEs reported in at least two patients are listed in Table 6.
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table 6 summary of adverse

| N=70                                |            |          |
|-------------------------------------|------------|----------|
| Adverse Event (Preferred Term)      | All Grades | Grade ≥3 |
| n (%)                               | n (%)      |          |
| Diarrhea                            | 31 (44)    | 8 (11)   |
| Nausea                              | 28 (40)    | 0        |
| Fatigue                             | 27 (39)    | 2 (3)    |
| Decreased appetite                  | 18 (26)    | 0        |
| Vomiting                            | 18 (26)    | 1 (1)    |
| Dysphonia                           | 17 (24)    | 0        |
| Weight decrease                     | 16 (23)    | 1 (1)    |
| Hypertension                        | 16 (23)    | 9 (13)   |
| Alanine aminotransferase increase   | 12 (17)    | 0        |
| Aspartate aminotransferase increase | 10 (14)    | 0        |
| Stomatitis                          | 10 (14)    | 1 (1)    |
| Palmar-plantar erythrodysaesthesia  | 10 (14)    | 1 (1)    |
| Hypothyroidism                      | 10 (14)    | 0        |
| Mucosal Inflammation                | 8 (11)     | 3 (4)    |
| Lipase increase                     | 4 (6)      | 2 (3)    |
| Hyponatremia                        | 5 (7)      | 2 (3)    |  
Grade 4 events related to treatment were seen in 1 patient each (1.4%) included:
hypertensive crisis, gastric ulcer perforation, and hypomagnesaemia. Grade 5 treatmentrelated cardiac arrest was reported in one patient. The Investigator stated that the death was due to the patient's disease process; however, the treating physician felt that sitravatinib could not be ruled out because of the known cardiac effects. The Sponsor assessed the Cardiac Arrest as unlikely related to sitravatinib and not related to nivolumab because of the Investigator statement and the event occurred 4 days after initiating treatment with sitravatinib (steady state PK is reached in a mean time of 11 to 15 days). Treatment-related SAEs were reported in 13 patients (19%); diarrhea (3%), and fatigue, vomiting, hypertension, cardiac arrest, hypertensive crisis, syncope, confusional state, myocarditis, gastric ulcer perforation, hypoxia, deep vein thrombosis, pulmonary embolism, anaemia, dehydration, hyponatraemia, and pancreatitis in one patient each (1.4% each). Immune-related AEs (irAEs) of special interest reported were pneumonitis and myocarditis in one patient each and attributed to treatment with sitravatinib and nivolumab. The case of pneumonitis was reported as Grade 3 on Cycle 1 Day 15 and resulted in permanent discontinuation of study treatment; the event did not meet the criteria for SAE reporting. The case of myocarditis was reported as Grade 3 on Cycle 1 Day 15, resolved following study treatment interruption, but recurred upon rechallenge. The patient permanently discontinued study treatment and the event was reported as an SAE. The patient subsequently developed clinically significant pericardial effusion requiring treatment. Three deaths were reported in this study, disease under study, staphylococcal sepsis, and cardiac arrest (n=1 each). Nonclinical toxicology studies as well as clinical safety data from the Phase 1/1b and Phase 2 studies suggest that AEs associated with sitravatinib are similar to those observed with other small molecule inhibitors of the VEGFR pathway. Based on reported clinical experience with sitravatinib and similar agents, and nonclinical data with sitravatinib, guidance to the Investigator is provided for selected AEs in Section 5.1.2.4.  
Please refer to the latest Sitravatinib (MGCD516) Investigator's Brochure for more information.
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1.6 mocetinostat background

Mocetinostat (MGCD0103) is an oral, second generation benzamide inhibitor of HDAC 1, 2, 3 and 11 with broad spectrum antitumor activity in vitro and in vivo (Fournel-2008, Zhou-2008). Background information in addition to that presented below is available in the MGCD0103 Investigator's Brochure.
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1.6.1 mocetinostat drug substance

The chemical structure of mocetinostat (MGCD0103) is as follows:
MGCD0103 Free Base  
  
| Chemical Formula:   | C23H20N6O    |
|---------------------|--------------|
| Molecular Weight:   | 396.45 g/mol |