Clinical trial NCT04123704
Conditions: Breast Cancer Stage IV Triple Negative Breast Cancer Breast Neoplasms Breast Cancer Metastatic
Keywords: triple negative metastatic breast cancer sitravatinib
Sponsor: Xiang Zhang
Start date: 2021-09-22; Completion date: 2023-01-22
Enrollment: 3 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This study evaluates the efficacy of sitravatinib in patients with metastatic breast cancer. All study participants will receive sitravatinib, 100 mg daily, until their cancer worsens, or until they develop intolerable side effects.

Detailed description:

Arms: arm 1: Sitravatinib 100 mg daily
Interventions: intervention 1: Sitravatinib
Intervention descriptions: intervention 1: sitravatinib capsule

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
 
 
A Phase II Study of Sitravatinib in Metastatic, Pre-Treated, Triple Negative Breast Cancer 
 
Protocol Number 
H-43432 
 
Protocol Version Date  
July 29, 2022   
 
Coordinating Center  
Baylor College of Medicine 
 
 
 
 
Dan L. Duncan Comprehensive Cancer Center 
 
 
 
 
7200 Cambridge Street 
 
 
 
 
Houston, TX 77030 
 
Principal Investigator 
C. Kent Osborne, MD 
 
 
 
 
Baylor College of Medicine  
One Baylor Plaza, BCM305 
Houston, TX 77030 
(713) 798-1641 
kosborne@bcm.edu 
 
Statistician 
 
 
Susan Hilsenbeck, PhD  
Baylor College of Medicine  
One Baylor Plaza, BCM600 
Houston, TX 77030 
(713) 798-1627 
 
 
 
 
 
sgh@bcm.edu  
 
 
  
Supporter 
Mirati Therapeutics, Inc.  
 
 
 
 
 
Investigational New Drug (IND) Number: 146679 


A Phase II Study of Sitravatinib in Metastatic, Pre-Treated Triple Negative Breast Cancer  
Principal Investigator: C. Kent Osborne, MD 
Protocol number: H-43432 
 
 
 Protocol Version [07-29-2022] 
CONFIDENTIAL 
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This document is confidential 
 
Do not disclose or use except as authorized 
 
Table of Contents 
 
1. 
SCHEMA ............................................................................................................................................................. 4 
2. 
STUDY DESIGN/SUMMARY .......................................................................................................................... 5 
3. 
OBJECTIVES ..................................................................................................................................................... 5 
 
PRIMARY OBJECTIVE .................................................................................................................................... 5 
 
SECONDARY OBJECTIVES .............................................................................................................................. 5 
 
EXPLORATORY OBJECTIVES .......................................................................................................................... 5 
4. 
BACKGROUND ................................................................................................................................................. 6 
 
SCIENTIFIC BACKGROUND AND RATIONALE ................................................................................................. 6 
 
CORRELATIVE SCIENCE BACKGROUND ......................................................................................................... 8 
 
INVESTIGATIONAL AGENT ............................................................................................................................ 9 
5. 
PARTICIPANT SELECTION......................................................................................................................... 13 
 
INCLUSION CRITERIA .................................................................................................................................. 13 
 
EXCLUSION CRITERIA ................................................................................................................................. 14 
 
INCLUSION OF UNDERREPRESENTED POPULATIONS .................................................................................... 14 
6. 
REGISTRATION PROCEDURES ................................................................................................................. 15 
7. 
STUDY PROCEDURES .................................................................................................................................. 15 
 
SCREENING PHASE ...................................................................................................................................... 15 
 
TREATMENT PHASE .................................................................................................................................... 16 
 
FOLLOW-UP ................................................................................................................................................ 17 
 
LOST TO FOLLOW-UP .................................................................................................................................. 18 
8. 
STUDY CALENDAR ....................................................................................................................................... 19 
9. 
TOXICITY MANAGEMENT – DOSE MODIFICATIONS ........................................................................ 21 
 
SITRAVATINIB-RELATED ADVERSE EVENTS ............................................................................................... 21 
 
POTENTIAL DRUG INTERACTIONS ............................................................................................................... 25 
 
SPECIAL CONSIDERATIONS ......................................................................................................................... 28 
10. SITRAVATINIB DRUG FORMULATION/STORAGE .............................................................................. 29 
11. CORRELATIVE/SPECIAL STUDIES .......................................................................................................... 30 
 
BLOOD SAMPLES ........................................................................................................................................ 30 
 
TISSUE SAMPLES ......................................................................................................................................... 30 
 
TRANSLATIONAL RESEARCH PLANNED ANALYSIS...................................................................................... 30 
 
SPECIMEN BANKING ................................................................................................................................... 32 
12. MEASUREMENT OF EFFECT ..................................................................................................................... 33 
 
DEFINITIONS ............................................................................................................................................... 33 
 
GUIDELINES FOR EVALUATION OF DISEASE ................................................................................................ 34 
 
LESION DOCUMENTATION .......................................................................................................................... 36 
 
RESPONSE CRITERIA ................................................................................................................................... 37 
13. ADVERSE EVENT REPORTING REQUIREMENTS ................................................................................ 40 
 
GENERAL .................................................................................................................................................... 40 
 
DEFINITIONS ............................................................................................................................................... 41 
 
REPORTING PROCEDURES ........................................................................................................................... 42 
14. DATA AND SAFETY MONITORING .......................................................................................................... 43 


A Phase II Study of Sitravatinib in Metastatic, Pre-Treated Triple Negative Breast Cancer  
Principal Investigator: C. Kent Osborne, MD 
Protocol number: H-43432 
 
 
 Protocol Version [07-29-2022] 
CONFIDENTIAL 
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Do not disclose or use except as authorized 
 
 
DATA MANAGEMENT AND REPORTING ....................................................................................................... 43 
 
MEETINGS ................................................................................................................................................... 44 
15. REGULATORY CONSIDERATIONS ........................................................................................................... 45 
 
INFORMED CONSENT ................................................................................................................................... 45 
 
ETHICS AND GCP ........................................................................................................................................ 45 
 
COMPLIANCE WITH TRIAL REGISTRATION AND RESULTS POSTING REQUIREMENTS ................................... 45 
16. STATISTICAL CONSIDERATIONS ............................................................................................................ 46 
 
STUDY DESIGN ........................................................................................................................................... 46 
 
DECISION RULE(S) ...................................................................................................................................... 46 
 
SAMPLE SIZE AND ACCRUAL RATE ............................................................................................................. 47 
 
STRATIFICATION FACTORS .......................................................................................................................... 47 
 
ENDPOINTS AND ANALYSIS ......................................................................................................................... 47 
 
REPORTING AND EXCLUSIONS .................................................................................................................... 48 
17. REFERENCES .................................................................................................................................................. 49 
APPENDICES ............................................................................................................................................................ 51 
APPENDIX A:  ECOG PERFORMANCE STATUS SCALE .......................................................................................... 51 
 
 
 


A Phase II Study of Sitravatinib in Metastatic, Pre-Treated Triple Negative Breast Cancer  
Principal Investigator: C. Kent Osborne, MD 
Protocol number: H-43432 
 
 
 Protocol Version [07-29-2022] 
CONFIDENTIAL 
Page 4 of 51 
 
This document is confidential 
 
Do not disclose or use except as authorized 
 
1. SCHEMA 
 
Figure 1: Treatment schema and correlative endpoints that will determine a) whether CTC analysis can contribute to an 
assessment of PTPN12 status and response to treatment b) whether acute changes in ddPCR assessent of ctDNA can predict the 
outcome of subsequent response determined radiologically and c) conduct proteogenomic analysis of snap frozen OCT-
embedded tumor biopsies to analyze the TNBC kinome and purtubations induced by treatment with sitavatinib. 
 
 


A Phase II Study of Sitravatinib in Metastatic, Pre-Treated Triple Negative Breast Cancer  
Principal Investigator: C. Kent Osborne, MD 
Protocol number: H-43432 
 
 
 Protocol Version [07-29-2022] 
CONFIDENTIAL 
Page 5 of 51 
 
This document is confidential 
 
Do not disclose or use except as authorized 
 
2. STUDY DESIGN/SUMMARY 
This is a phase II, two cohort trial designed to evaluate the efficacy of sitravatinib in patients with 
metastatic triple-negative breast cancer (mTNBC) after treatment with at least one line of 
chemotherapy for advanced disease. The drug, sitravatinib at 100 mg, will be dosed daily at the 
initiation of the study and continued until progression or unacceptable toxicity.  
The study will employ a modified optimal Simon’s two stage design. Participants will be 
recruited into two cohorts: Protein Tyrosine Phosphatase, Non-Receptor Type 12 (PTPN12) low 
or PTPN12 high/normal cohorts simultaneously and independently. Seven participants will be 
enrolled to each arm during the first stage. After the first stage, depending on the observed 
number of responses, the study will proceed to the second stage utilizing an adaptation of the 
Jones and Holmgren approach [1]. The primary endpoint is progression-free survival status at 24 
weeks (PFS24) and the secondary endpoints will include: Time to Progression (TTP), Objective 
Response Rate (ORR), Clinical Benefit Rate (CBR), and grade 3 or higher adverse events. The 
maximum accrual needed is 25 participants. This study approach will have 90% power to detect 
PFS24 rate of 30% in the PTPN12low stratum, or 85% power to detect a PFS24 rate of 25% in 
the unselected population. 
3. OBJECTIVES  
 
Primary Objective 
To evaluate the efficacy of sitravatinib as measured by progression-free survival at 24 weeks 
(PFS24), as evaluated by RECIST version 1.1, in participants with mTNBC that have been 
treated with at least one line of chemotherapy.  
 
Secondary Objectives 
3.2.1 To evaluate Time to Progression (TTP), defined as the duration of time from initiation 
of treatment until progression according to RECIST 1.1 criteria  
3.2.2 To evaluate Objective Response Rate (ORR), defined as the proportion of participants 
who achieve a Complete Response (CR) or Partial Response (PR) to treatment per 
RECIST 1.1 criteria 
3.2.3 To evaluate the Clinical Benefit Rate (CBR), defined as the proportion of participants 
who achieve CR, PR, or stable disease (SD) per RECIST 1.1 criteria 
3.2.4 To evaluate the number of participants with grade 3 or higher adverse events as per the 
NCI Common Terminology Criteria for Adverse Events version 5.0 (CTCAEv5) 
 
Exploratory Objectives 
3.3.1 To examine the relationship between Circulating Tumor Cell (CTC) expression of 
PTPN12 and tumor tissue expression to determine if CTC analysis can contribute to an 
assessment of PTPN12 status and response to treatment 
3.3.2 To examine the relationship between acute changes in digital droplet PCR-based 
ctDNA mutant allele frequencies in the first month of treatment and subsequent 
radiological response evaluations  
3.3.3 To evaluate the effect of sitravatinib on the drug bead-based tumor kinome profiling 
and mass spectrometry-based phosphoproteomics through examination of protein 


A Phase II Study of Sitravatinib in Metastatic, Pre-Treated Triple Negative Breast Cancer  
Principal Investigator: C. Kent Osborne, MD 
Protocol number: H-43432 
 
 
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extracts from tumor biopsy material before and during treatment, performed on OCT-
embedded snap frozen tissue biopsy from patients with disease accessible by core 
needle biopsy 
3.3.4 To evaluate immune biomarkers to explore the effects of sitravatinib on the immune 
microenvironment and the influence of tumor infiltrating lymphocytes on response 
4. BACKGROUND 
 
Scientific Background and Rationale 
4.1.1 Triple-Negative Breast Cancer  
Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer diagnosed in 
more than 200,000 women each year across the world [2]. There are currently no targeted 
therapies available for this disease and after relapse prognosis is extremely poor, although 
recently a PD-L1 inhibitor atezolizumab with nab paclitaxel has been shown to prolong 
progression free survival as first line treatment [3]. After progression on first line treatment 
there is no consensus treatment and no other therapies that are definitively helpful, except 
treatment with a PARP inhibitor in the uncommon setting of a germline BRCA mutation [4]. 
4.1.2 Targeted Therapy in TNBC 
Inhibitors of oncogenic receptor tyrosine kinases (RTK) comprise a substantial fraction of the 
targeted therapies in various cancer types. The precise application of these inhibitors has been 
largely guided by RTK mutations, amplification, and chromosomal translocations in human 
cancers including HER2-amplified breast cancer. However, most cancers, like TNBC, do not 
harbor frequent mutations in RTKs that can account for aberrant receptor signaling, thus 
obfuscating the rational use of RTK inhibitors in these malignancies. Indeed, while TNBCs 
harbor multiple hyperactive RTKs, therapeutic targeting of single RTKs, for example 
epidermal growth factor receptor (EGFR), have been largely ineffective in TNBC patients [5]. 
Work from our collaborative team has discovered that rather than mutational activation of 
RTKs, TNBCs often lose feedback control of RTKs, thus locking these receptors in a 
chronically active or constitutive state. In particular, Dr. Westbrook and his colleagues have 
discovered that approximately 45-55% of TNBCs are driven by the concerted activity of 
Hepatocyte Growth Factor Receptor (HGFR) precursor, MET, and Platelet-Derived Growth 
Factor Receptor (PDGFR) [6, 7]. Importantly, in a pre-clinical trial of patient derived 
xenografts (PDX) from 14 independent TNBC patients, therapeutic targeting of MET and 
PDGFR elicits robust regressions in more than half of the models from chemorefractory 
patients [7]. These receptors share a common negative regulator called PTPN12. Baylor 
investigators have shown that PTPN12- deficient TNBCs may be responsive to combined RTK 
inhibition. Restoring PTPN12 protein levels restrains signaling from RTKs, including PDGFR 
and MET, and impairs TNBC cell survival. However, the repertoire of RTKs that are restrained 
by PTPN12 in human cells has not been systematically explored. By methodically identifying 
the suite of RTK substrates (MET, PDGFR, EGFR and others) inhibited by PTPN12, the team 
has rationalized a combination RTK-inhibitor therapy that induces potent tumor regression 
across heterogeneous models of TNBC. In contrast with single agents, combined inhibition of 
PDGFR and MET receptors have shown to induce apoptosis in TNBC cells in vitro and in vivo. 
This therapeutic strategy resulted in tumor regressions in chemo-refractory PDX TNBC 


A Phase II Study of Sitravatinib in Metastatic, Pre-Treated Triple Negative Breast Cancer  
Principal Investigator: C. Kent Osborne, MD 
Protocol number: H-43432 
 
 
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models. Notably, response was found to correlate with PTPN12 deficiency, suggesting that 
impaired receptor feedback may establish a combined addiction to these proto-oncogenic 
receptors. Taken together, this data provided the scientific rationale for combining RTK 
inhibitors in TNBC that lack receptor-activating mutations. Notably, this was the underlying 
premise of the CRIZENT clinical trial (NCT02074878), a phase I two-drug combination of 
crizotinib and sunitinib in different doses across three arms in metastatic TNBC. The trial 
stopped accrual and closed early due to intolerable toxicity of the two drug combination.  
4.1.3 Sitravatinib 
An alternative to combining several tyrosine kinase inhibitors is to use a single broad spectrum 
inhibitor that is effective against the relevant targets. Sitravatinib (MGCD516) is a spectrum-
selective RTK inhibitor that has so far been tested in 3 phase II trials and an ongoing phase III  
trial in combination with nivolumab (NCT03575598, NCT03606174, NCT02954991, 
NCT03680521, NCT03906071) with a favorable toxicity profile. Sitravatinib is a potent 
inhibitor of the TAM family (TYRO3, AXL, MERTK), Vascular Endothelial Growth Factor 
Receptor (VEGFR) family, Platelet Derived Growth Factor Receptor (PDGFR) family, KIT 
Proto-Oncogene Receptor Tyrosine Kinase (KIT), RET Receptor Tyrosine Kinase (RET), and 
MET with additional immunomodulatory effects including depletion of regulatory T cells  
(Treg) or suppressor T cells, Myeloid-Derived Suppressor Cells (MDSC) and enhancement of 
M1 tumor macrophage profile. 
A phase 1 trial of 32 patients established the 150 mg daily dosing as the maximum tolerated 
dose (MTD). However, an assessment of longer term tolerability for patients starting at the 120 
mg dose of sitravatinib, together with data from patients who were dose reduced from 150 mg 
to 120 mg suggests the 120 mg dose has better tolerability beyond the first cycle of treatment; 
therefore, 120 mg is considered the recommended phase 2 dose. However, that formulation 
subsequently changed to malate base with dosing of 100 mg daily, which is equivalent to 120 
mg of free base dosing. Notable grade 3 and higher toxicities included hypertension (20%), 
diarrhea (11.7%), fatigue (10%), vomiting and mucosal inflammation (3.3%), loss of appetite 
and nausea (1.7%). No grade 4 toxicities were reported.  
The rationale for this protocol is based on the activity of sitravatinib in PTPN12low TNBC 
models derived from patients with chemotherapy refractory disease. Sitravatinib effectively 
inhibits tumor growth and induces tumor regression in a similar pattern previously observed 
with the crizotinib and sunitinib combination (Figures 2 and 3). This study will therefore 
evaluate the efficacy and safety of sitravatinib in metastatic TNBC given this supportive 
preclinical data. 


A Phase II Study of Sitravatinib in Metastatic, Pre-Treated Triple Negative Breast Cancer  
Principal Investigator: C. Kent Osborne, MD 
Protocol number: H-43432 
 
 
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Correlative Science Background 
Orthogonal approaches have revealed that PTPN12 is recruited to inhibit several RTK receptors 
after ligand stimulation, thereby serving as a feedback mechanism to limit receptor signaling. 
Response to combination RTK inhibition is correlated with PTPN12 deficiency, suggesting that 
impaired receptor feedback may establish a combined addiction to these proto-oncogenic 
receptors. Cancer-associated mutation of PTPN12 or reduced PTPN12 protein levels diminish 
this feedback mechanism, leading to aberrant activity of these receptors. PTPN12 deficiency in 
TNBC is largely secondary to absent protein rather than mutation, and low PTPN12 levels have 
been reported in 62% of all TNBC. Inactivating PTPN12 mutations account for only 3% of 
PTPN12 deficiency.  
A highly specific PTPN12 monoclonal antibody has been developed at Baylor College of 
Medicine for PTPN12 analysis. An immunohistochemistry (IHC) assay will be used to detect the 
level of this protein in primary and metastatic breast cancer tissue.  This assay will be used to 
place patients into the two cohorts of the study. Additionally this antibody will be used to 
measure PTPN12 in CTCs by immunofluorescence to address whether CTC PTPN12 status will 
be a useful biomarker in future studies if the CTC status correlates well with tissue PTPN12 
status. RTK signaling in cancer cells contributes to shape the immune microenvironment by 
regulating tumor secretomes. In addition we will collaborate with the Clinical Proteomic Tumor 
Analysis Consortium to analyze any OCT-embedded frozen specimens that are generated in the 
Figure 2. Crizotinib + sunitinib confers tumor regression in PDXs 
from TNBC patients 
Figure 3. Sitravatinib inhibits the growth of PTPN12-deficient TNBC PDX 


A Phase II Study of Sitravatinib in Metastatic, Pre-Treated Triple Negative Breast Cancer  
Principal Investigator: C. Kent Osborne, MD 
Protocol number: H-43432 
 
 
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protocol. We will analyze them using mass-spectrometry-based proteomics and also conduct 
RNA sequencing and Whole Exome Sequencing for a full proteogenomic profile [8]. We have 
recently adapted these techniques to interrogate fresh frozen core biopsy material embedded in 
OCT [9]. 
Recent data indicate that sitravatinib may impair myeloid-derived suppressor cells (MDSCs) and 
other immunosuppressive compartments, thus raising the provocative hypothesis that Sitravatinib 
may have both tumor-autonomous and non-autonomous immunostimulatory effects. Prompted 
by this knowledge, we will assess important constituents of the tumor immune 
microenvironment using established assays, and correlate the results to PTPN12 status. 
Sitravatinib’s effects on the microenvironment will be examined by comparing pre- and post-
treatment biopsies. Although the results may be preliminary and limited by sample size, 
important insights may be derived to inform future clinical trials. Tumor-infiltrated lymphocytes 
will be determined by morphology following previously established guidelines [10]. IHC assays 
of the following molecules will be performed to quantitate major immune cell types/pathways 
(see Table 1). 
Table 1: Exploratory Immune Biomarkers 
Marker 
Cell type 
Function 
Reference (PMID) 
CD8 
CD8 T cells 
Anti-tumor cytotoxicity 
[11] 
FOXP3 
Regulatory T cells 
Inhibit CD8 T cell-mediated 
cytotoxicity 
[12] 
LOX-1 
Neutrophils (MDSCs) 
Immunosuppressive myeloid 
cells that may confer 
resistance to 
immunotherapies.  
 
[12] 
CD15 
Neutrophils (MDSCs) 
[12] 
S100A8/MRP8 
Neutrophils (MDSCs) 
[13] 
CD66b 
Granulocytes 
[14] 
CD68 
Tumor Associate Macrophages 
(TAMs) 
[14] 
CD163 
Tumor Associate Macrophages 
(TAMs) 
[14] 
CD20 
B cells 
Potential roles in regulating 
responses to check point 
blockade 
[14] 
Granzyme B 
Activated CD8 T cells 
T cell activation/ anti-tumor 
[14] 
PDCD1 (PD-1) 
T cells  
Check point molecules 
indicative of T cell functions 
and targeting agents 
available. 
[14] 
PD-L1 
Various cell types 
[3] 
Tim3 
T cells and Dendritic cells 
[15] 
LAG3 
T cells and Dendritic cells 
[16] 
Arg1 
Various cell types 
Important metabolic enzymes 
with known 
immunosuppressive functions 
[17] 
iNOS 
Various cell types 
[18] 
IDO1 
Various cell types  
[19] 
 
Investigational Agent 
Sitravatinib is an orally-available, potent small molecule inhibitor of a closely related spectrum 
of tyrosine kinases including MET, TAM (TYRO3, AXL, MERTK) family, VEGFR family, 
PDGFR family, KIT, FLT3, TRK family, RET, DDR2, and selected EPH family members. This 
subset of tyrosine kinases is involved in a number of processes implicated in human cancer 


A Phase II Study of Sitravatinib in Metastatic, Pre-Treated Triple Negative Breast Cancer  
Principal Investigator: C. Kent Osborne, MD 
Protocol number: H-43432 
 
 
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including regulation of tumor growth and cell survival pathways, tumor invasion and metastatic 
progression, as well as tumor angiogenesis. Anti-tumor activity of sitravatinib has been observed 
over several human tumor xenograft models exhibiting genetic alterations in receptor tyrosine 
kinase (RTK) targets, providing rationale for evaluating sitravatinib monotherapy in tumors 
driven by these pathways in the clinical setting. 
Additionally, based on its tyrosine kinase target profile, sitravatinib may modulate effects on the 
tumor microenvironment to overcome resistance to checkpoint inhibitors by effects on relevant 
immune cell populations. Inhibition of TAM RTKs (MERTK, TYRO3 and AXL) expressed by 
macrophages and dendritic cells may enhance the innate, M1 macrophage pro-inflammatory 
cytokine response and suppress M2 macrophage anti-inflammatory cytokine production, while 
inhibition of AXL and MERTK on natural killer (NK) cells may abrogate negative regulation of 
anti-tumor NK cell activity. Inhibition of the split kinase receptors may enhance anti-tumor 
immunoreactivity by depletion of regulatory T-cells (through VEGFR2) and myeloid-derived 
suppressor cells (MDSCs) (through KIT and VEGFR family members), resulting in the 
expansion and migration of anti-tumor cytotoxic T-cells, and their infiltration into tumor tissue. 
Inhibition of MET may inhibit expansion of MDSCs and restore antigen-presenting cell function. 
Together, these effects are predicted to complement and augment the activity observed with 
checkpoint inhibitor therapy (CIT). 
Nonclinical pharmacokinetic (PK) and toxicology studies support clinical evaluation of 
sitravatinib. It is metabolized to eight putative metabolites (M1-M8) in mouse, rat, dog, monkey 
and human hepatocytes and to 13 putative metabolites (M1-M7 and M9-M14) in vivo in dog and 
rat plasma samples, with studies using human liver microsomes and recombinant human P450 
enzymes suggesting that multiple enzymes (CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, 
CYP2D6, CYP2E1, and CYP3A4) are involved in the metabolism of sitravatinib. Toxicology 
studies with repeated dosing of sitravatinib for 7 days and 4 weeks demonstrated no target organs 
identified in the dog, despite overt decreases in body weight and food consumption, while 
VEGF-related target organs were identified in the rat, including the adrenal gland, Brunner’s 
glands in the duodenum, femur and sternum (bone and bone marrow), spleen, lymph nodes, 
thymus, ovary, kidney (glomerulopathy, tubule necrosis, increased basophilic tubules), pancreas, 
and tongue. All effects in rats, except those in the kidney and pancreas, either recovered or 
showed partial recovery. 
In clinical trials sitravatinib was administered as a single agent in the first-in-human Study 516-
001 and in combination with the PD-1 inhibitor nivolumab in patients with advanced or 
metastatic non-squamous non-small cell lung cancer (NSCLC) who have experienced disease 
progression either on or after prior treatment with a checkpoint inhibitor therapy (CIT-
experienced) or after treatment with a platinum-based doublet chemotherapy (CIT-naïve) in 
Study MRTX-500. Study 516-001 is a multi-center, Phase 1/1b clinical trial characterizing the 
safety, PK, metabolism, pharmacodynamic (PD) and clinical activity of sitravatinib in patients 
with advanced solid tumor malignancies. The primary objective of the Phase 1 was the 
determination of the maximum tolerated dose, while Phase 1b objectives included assessment of 
safety and clinical activity in patients with certain tumor types (e.g., renal cell carcinoma [RCC]) 
or with tumors characterized by certain genetic alterations; sitravatinib monotherapy was 
administered orally once daily, and based on the Phase 1 results, the starting dose in Phase 1b 
was 150 mg daily, which was subsequently changed to 120 mg during the trial. Study MRTX-
500 is a parallel Phase 2 study of glesatinib, sitravatinib or mocetinostat in combination with 


A Phase II Study of Sitravatinib in Metastatic, Pre-Treated Triple Negative Breast Cancer  
Principal Investigator: C. Kent Osborne, MD 
Protocol number: H-43432 
 
 
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nivolumab administered at a dose of 240 mg intravenously every two weeks, with sitravatinib 
120 mg administered once daily after the safety of this dose was confirmed in the lead-in portion 
of the study.  
Pharmacokinetic evaluation in Study 516-001 shows that after single dose administration, 
sitravatinib reaches peak concentration in a median time of approximately 3 to 9 hours, and Cmax 
and AUC are approximately dose proportional with single doses up to 200 mg. Median 
elimination half-life varies between 43 and 58 hours, and the steady state PK is reached in a 
mean time of 11 to 15 days. After multiple dose administration, drug accumulation ranged from 
1.6- to 4.2-fold for Cmax and 2.0- to 5.1-fold for AUC0-24. Steady-state Cmax to Cmin mean ratio 
was 1.50 to 1.88.  
As of 26 Jun 2021, a total of 1,106 subjects with advanced/metastatic solid malignancies have 
received at least one dose of sitravatinib in 8 clinical studies. Of these subjects, 220 have 
received treatment with sitravatinib as a single agent, approximately 565 have received 
sitravatinib in combination with the PD-1 inhibitor nivolumab, 300 have received sitravatinib in 
combination with the PD-1 inhibitor tislelizumab, 13 have received sitravatinib in combination 
with pembrolizumab and the antibody drug conjugage enfortumab vedotin-ejfv, and 10 have 
received sitravatinib in combination with nivolumab and ipilimumab. 
Among the 1,106 subjects with solid malignancies who were treated with sitravatinib, 1,012 
(92%) experienced at least one sitravatinib-related AE. Sitravatinib-related AEs reported in ≥ 5% 
of these subjects are presented in Table 2. Among the 1,106 subjects, sitravatinib-related Grade 3 
events were reported in 485 subjects (44%) overall. Sitravatinib-related Grade 3 events reported 
in ≥ 5% of subjects were hypertension (16%), diarrhea (7%), and fatigue (5%). Sitravatinib-
related Grade 4 AEs were reported in 26 subjects (2%). The only Grade 4 sitravatinib-related 
events occurring in more than 1 subject by Preferred Term were amylase increased, 
hyperuricemia, and cerebrovascular accident in 2 subjects each (0.2%), and lipase increased in 5 
subjects (0.5%). Sitravatinib-related Grade 5 AEs were reported in 12 subjects, including death 
in 6 subjects, cardiac arrest in 2 subjects, and cardiac failure, hepatic encephalopathy, ischemic 
stroke and respiratory failure in 1 subject each. 
Among the 1,106 subjects with solid malignancies, a total of 501 (45%) experienced at least one 
AE regardless of causality. No healthy subjects experienced an SAE. Among the 1,106 subjects 
with solid malignancies, sitravatinib-related SAEs were reported in 194 subjects (18%). Related 
SAEs reported in 5 or more subjects (≥ 5%) included diarrhea (3.0%), vomiting (1.2%), nausea 
and pulmonary embolism (1.0%), fatigue, hepatobiliary disorders, and hypertension (0.7%), and 
cardiac failure, pancreatitis, death, hepatic function abnormal, acute kidney injury, pneumonitis, 
deep vein thrombosis, and embolism (0.5% each). 
Among the 1,106 treated subjects with solid malignancies across all studies, the most common 
sitravatinib-related AEs leading to discontinuation of sitravatinib were diarrhea and nausea (19 
subjects each [0.8%]), fatigue (13 [1.2%]), vomiting and hypertension (7 subjects each [0.6%]), 
and lipase increased and pneumonitis (5 subjects each [0.5%]). 
For this study, the malate formulation of sitravatinib at 100 mg will be used, which is equivalent 
to 120 mg of free base sitravatinib. 
 
 


A Phase II Study of Sitravatinib in Metastatic, Pre-Treated Triple Negative Breast Cancer  
Principal Investigator: C. Kent Osborne, MD 
Protocol number: H-43432 
 
 
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Table 2: Sitravatinib-related Adverse Events Reported in ≥ 5% of Subjects with Solid Malignancies (all studies combined) 
Adverse Event  
Preferred Term, n (%)  
Subjects (N=1,106)  
Any Sitravatinib-Related AE  
1,012 (91.5)  
Diarrhoea  
526 (47.6)  
Fatigue  
362 (32.7)  
Hypertension  
348 (31.5)  
Decreased appetite 
309 (27.9) 
Nausea  
298 (26.9)  
Alanine aminotransferase increased  
281 (25.4)  
Aspartate aminotransferase increased  
275 (24.9) 
Palmar-Plantar Erythrodysaesthesia Syndrome  
252 (22.8)  
Vomiting  
214 (19.3)  
Dysphonia  
200 (18.1)  
Weight decreased  
197 (17.8)  
Hypothyroidism  
150 (13.6) 
Proteinuria  
144 (13.0) 
Stomatitis  
134 (12.1)  
Platelet count decreased 
90 (8.1) 
Dry mouth 
88 (8.0) 
Anaemia  
87 (7.9)  
Lipase increased  
87 (7.9)  
Rash  
79 (7.1)  
Abdominal pain 
77 (7.0) 
Dysgeusia  
76 (6.9)  
Constipation  
73 (6.6)  
Blood alkaline phosphatase increased  
60 (5.4)  
Blood thyroid stimulating hormone increased 
60 (5.4) 
Dizziness  
60 (5.4)  
Hypoalbuminaemia  
57 (5.2)  
 
 
 


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5. PARTICIPANT SELECTION 
 
Inclusion Criteria 
5.1.1 Women or men age 18 and older 
5.1.2 Metastatic or locally advanced inoperable breast cancer (beyond curative management) 
that is measureable according to RECIST 1.1 criteria.  
NOTE: Patients with bone-only disease are eligible if there is at least one lytic lesion that can be 
followed for response. 
5.1.3 Tumor is ER-negative and PR-negative per ASCO/CAP Guidelines of 2010 
5.1.4 Tumor is HER2neu-negative per ASCO/CAP Guidelines of 2018  
5.1.5 Patient has archival tissue from metastatic or locally advanced breast cancer for the 
analysis of PTPN12 status.   
NOTE: For patients who do not have archival tissue available, a research biopsy of the locally 
advanced or metastatic breast tumor is required. 
5.1.6 At least one prior line of chemotherapy with or without a PD-L1 or PD-1 antibody in 
the metastatic setting 
5.1.7 ECOG performance status ≤ 2 (Karnofsky ≥ 60%) 
5.1.8 Normal organ and hematologic function as defined below: 
o Absolute neutrophil count 
 
 
> 1000/mcL 
o Hemoglobin  
 
 
 
 
 
> 11 g/dL  
o Platelets 
 
 
 
 
 
> 100,000/mcL 
o Total bilirubin 
 
 
 
 
 
≤ 1.5 x normal institutional limits 
o AST (SGOT)/ALT (SGPT)  
 
≤ 2.5 x institutional ULN or ≤ 5.0 × 
ULN for patients with documented liver 
metastases. 
o Creatinine 
 
 
 
 
 
within normal institutional limits 
o Creatinine clearance  
 
 
 
> 30 mL/min  
o Normal LVEF function defined as normal LV wall motion and ejection 
fraction of ≥ 50% 
5.1.9 If patient has brain metastasis, documented treatment and stability for at least 30 days 
by scans and off steroids at the time of enrollment 
5.1.10 Women of child-bearing potential and actively menstruating must have a negative 
pregnancy test prior to starting study treatment 
5.1.11 If sexually active in a way that could lead to pregnancy, participant must agree to use a 
highly effective method of birth control starting at the time of informed consent and 
continuing throughout the study and for at least 3 months after the final dose of 
sitravatinib.  Highly effective methods of birth control include: 
o Intrauterine device 
o Condoms with spermicide 
o Bilateral tubal occlusion/ligation 


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o Vasectomy (for male participants) or vasectomized partner (for female 
participants) 
o Sexual abstinence when it is the preferred and usual lifestyle choice of the 
participant 
5.1.12 Ability to understand and the willingness to give informed consent  
 
Exclusion Criteria 
5.2.1 Uncontrolled hypertension, defined as systolic blood pressure > 150 and/or diastolic 
blood pressure > 100, on two or more occasions within 30 days prior to enrollment  
5.2.2 Imaging suggestive of lymphangitic carcinomatosis in the lung, or use of home O2  
5.2.3 Untreated brain metastases 
5.2.4 Women who are pregnant or nursing  
5.2.5 Concurrent metastatic disease of another tumor type 
5.2.6 Impairment of gastrointestinal (GI) function or GI disease that may significantly alter 
the absorption of sitravatinib 
5.2.7 History of stroke, pulmonary embolus (PE), or myocardial infarction (MI)  
5.2.8 Known proteinuria of ≥ 2 g urinary protein/24 h  
5.2.9 HIV-positive participants 
5.2.10 History of Hepatitis C or Hepatitis B infection  
5.2.11 History of congestive heart failure (CHF), and/or LVEF < 50%  
5.2.12 Concurrent use of medications that prolong QTc (listed in Section 9, Table 11) . These 
medications need to be discontinued at least 2 weeks prior to starting study treatment.  
5.2.13 Concurrent medical condition that, in the sole judgment of the principal investigator, 
would make the patient inappropriate for trial participation 
 
Inclusion of Underrepresented Populations 
Individuals of all races and ethnic groups are eligible for this trial. There is no bias towards age 
or race in the clinical trial outlined. This trial is open to the accrual of women and men.  
 
 
 


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6. REGISTRATION PROCEDURES 
All consented participants will be registered in the online collaborative research environment 
(OnCore), a Clinical Trials Management System available at Baylor College of Medicine Dan L. 
Duncan Cancer Center. Prior to study enrollment, the eligibility data must be reviewed and 
verified by a delegated member of the study team. After eligibility status is confirmed, the 
participant will be assigned a unique subject identification number. If the participant does not 
meet all eligibility criteria (i.e., is a screen failure), he/she will be given a status of Ineligible in 
OnCore, and the reason will be recorded appropriately. 
NOTE: OnCore is also being used for electronic data collection (i.e., completion of case report 
forms) for this study. 
7. STUDY PROCEDURES 
 
Screening Phase 
Participants who have a diagnosis of triple-negative metastatic or inoperable locally advanced 
breast cancer, post-progression on at least one line of chemotherapy in the metastatic setting, will 
be evaluated for eligibility to enroll in the trial. Those who meet eligibility criteria will be 
identified by the investigator and study staff, and will be asked to provide a signed informed 
consent form prior to any study-related activities. 
Participants who signed an informed consent form but are found ineligible for any reason will be 
considered screen failures. 
7.1.1 Collection of Demographics and Other Baseline Characteristics 
The data that will be collected on participant characteristics at screening includes: 
• Demographics (date of birth and initials, sex, race, ethnicity, source of patient referral) 
• Diagnosis and extent of cancer (including staging at study entry and histology/cytology) 
• Medical history (e.g., important medical, surgical, and allergic conditions from the 
patient’s medical history which could have an impact on the patient’s evaluation) / current 
medical conditions (e.g., all relevant current medical conditions present at the time of 
signing informed consent). 
• ER, PR and HER2 status 
• All prior antineoplastic therapies including surgical interventions and chemo-, biologic-, 
immunologic- and radiation-therapies provided as treatment for cancer prior to the 
administration of study drug. 
• All medications and significant non-drug therapies taken within 28 days before starting 
study treatment 
7.1.2 Pre-Study Screening Assessments 
The following assessments will be performed as part of screening within 28 days prior to 
starting study treatment: 
• Vital signs (including height and weight) 
• Physical examination and performance status (ECOG) 
• Laboratory evaluations (hematology, biochemistry, TSH, urine protein/creatinine ratio, 


A Phase II Study of Sitravatinib in Metastatic, Pre-Treated Triple Negative Breast Cancer  
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and pregnancy test for women of childbearing potential) 
• Echocardiogram (LVEF assessment) 
• Tumor assessments (radiographic imaging or clinical exam as appropriate) 
• Blood collection for CTC and ctDNA analysis 
• Collection of archival tissue from primary tumor and metastatic/locally advanced site (if 
available) 
• If archival tissue from metastatic/locally advanced site is unavailable, a biopsy is required 
(optional for participants who do have archival tissue available) 
 
Treatment Phase 
Once registered/enrolled, participants will start treatment with sitravatinib 100 mg once daily 
until disease progression (assessed by RECIST 1.1), unacceptable toxicity, death or 
discontinuation from treatment for any other reason. Each cycle is 28 days in length. Study 
assessments, and efficacy and safety monitoring will continue as outlined in the study calendar.  
All assessments must be performed prior to the administration of study treatment unless 
otherwise specified. The following windows apply: 
• On-study assessments for all cycles must be performed within +/- 3 days of Day 1, unless 
otherwise indicated. 
• Re-staging scans for tumor evaluations should continue on schedule if treatment is held or 
delayed. 
7.2.1 Study Treatment and Agent Administration 
For this study, the term “study treatment” refers to sitravatinib. All dosages prescribed and 
dispensed to the participant and all dose changes during the study must be documented. 
Participants will receive a 28-day supply at every monthly visit. Participants should take 2 
capsules of 50 mg once daily for the full 100 mg dose. An additional number may be dispensed 
at the discretion of the study site to provide for holidays or inclement weather. The number of 
bottles and capsules dispensed should be documented by research pharmacy staff using an IP 
Accountability Log. Sitravatinib capsules should be taken during the morning hours, and at 
least 1 hour before breakfast. Sitravatinib capsules should be taken with at least 200 mL (1 cup) 
of water. Dose should be skipped if missed or vomited.  
Compliance with study treatment will be assessed by study staff at each visit. Participants will 
be asked to bring their bottle(s) of sitravatinib, along with all unused capsules, to each visit. 
Compliance will be assessed by counting the number of remaining capsules, and using that to 
evaluate how many days the study treatment was taken as prescribed. Repeated pill counts 
indicating less than 75% adherence to study treatment may result in removal from the study, as 
judged by the treating physician and/or Principal Investigator. 
7.2.2 Discontinuation of Study Treatment 
Study treatment must be discontinued under the following circumstances: 
• 
Adverse event or laboratory abnormalities, that, in the opinion of the treating physician, 
would preclude further participation in the study 
• 
Study treatment delay ≥ 28 days 
• 
Progressive Disease 


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• 
Pregnancy 
• 
Lost to follow-up 
• 
Physician decision 
• 
Participant/guardian decision 
• 
Death 
• 
Study terminated by sponsor 
• 
Repeated protocol deviations or non-compliance where continued participation would 
jeopardize the participant’s safety or the integrity of the study, as judged by the Principal 
Investigator or treating physician. 
7.2.3 Withdrawal of Consent 
Participants may voluntarily withdraw consent to participate in the study for any reason at any 
time. Withdrawal of consent occurs only when a participant does not want to participate in the 
study any longer, and does not want any further visits or assessments or further study-related 
contact. All biological samples that have already been collected may be retained and analyzed 
at a later date (or as required by local regulations). 
If a participant withdraws consent, the investigator (or designee) must make every effort (e.g., 
telephone, e-mail, letter) to determine the primary reason for this decision and record this 
information. Study treatment must be discontinued and no further assessments conducted. 
Further attempts to contact the participant regarding the study related follow-up are not allowed 
unless safety findings require communication or follow-up. 
 
 Follow-up  
7.3.1 Survival Follow-up 
All participants will be followed for survival status once every 3 months after treatment 
discontinuation regardless of discontinuation reason (except if consent is withdrawn) until 
death, lost to follow-up, or withdrawal of consent for survival follow-up. Additional survival 
assessments may be performed outside of this schedule if a survival update is required for an 
interim assessment to meet safety or regulatory needs. Survival information can be obtained via 
phone and documented in source documents. 
7.3.2 Follow-up for Safety Evaluations 
All participants who discontinue study treatment, including those who refuse to return for an 
end of treatment visit, will be contacted for safety evaluations (i.e., assessment of adverse 
events and/or Serious Adverse Events, concomitant medications) between 30-45 days after the 
last dose of study treatment. Participants whose treatment is interrupted or permanently 
discontinued due to an adverse event, including abnormal laboratory value, must be followed 
until resolution or stabilization of the event, whichever comes first. 
If participants refuse to return for safety evaluation visits or are unable to do so, every effort 
should be made to contact them by telephone to determine their status. Attempts to contact the 
participant should be documented in source documents (e.g., dates of telephone calls, registered 
letters, etc.). 


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Lost to Follow-up 
For participants whose status is unclear because they fail to appear for study visits without 
stating an intention to withdraw consent, the investigator should show due diligence by 
contacting the patient, family or family physician as agreed in the informed consent and by 
documenting in the source documents steps taken to contact the participant (e.g., dates of 
telephone calls, registered letters, etc.). A participant should not be considered lost to follow-up 
until due diligence has been completed.  
 
 


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8. STUDY CALENDAR 
 
Test/Procedure 
Pre-
Study1 
C1D1 
C1D14 
Subsequent 
Cycles 
Day 1 
End of 
Treatment 
Safety 
Follow-
Up11 
Survival 
Follow-Up 
Informed Consent 
X 
 
 
 
 
 
 
Participant Demographics 
X 
 
 
 
 
 
 
CLINICAL EVALUATIONS 
History and Physical Exam 
X 
X 
X 
X 
X 
 
 
Height 
X 
 
 
 
 
 
 
Vital signs and weight 
X 
X 
X 
X 
X 
 
 
Performance Status 
X 
X 
X 
X 
X 
 
 
LABORATORY/RADIOLOGIC EVALUATIONS 
CBC/differential 
X 
 
X 
X 
X 
 
 
Comprehensive Metabolic Panel 
X 
 
X 
X 
X 
 
 
TSH 
X 
 
X 
X4 
(odd cycles) 
X 
 
 
Urine Protein/Creatinine Ratio 
X 
 
X 
X4 
(odd cycles) 
X 
 
 
Pregnancy test 
X2 
 
 
 
 
 
 
Tumor Assessments 
X 
 
 
X5 
X 
 
 
Echocardiogram 
X 
 
 
X6 
 
 
 
TREATMENT DISPENSATION 
Sitravatinib 
 
X 
 
X 
 
 
 
CORRELATIVE 
ctDNA collection 
X 
 
X 
X7 
X 
 
 
CTC collection 
X 
 
X 
X7 
X 
 
 
Tumor/Tissue Biopsy8 
X10 
 
X3 
 
X 
 
 
Archival tissue 
X9 
 
 
 
 
 
 
ADDITIONAL INFORMATION 
Concomitant Medications 
X 
 
X 
X 
X 
X 
 
Adverse Events/Toxicity 
Assessment 
 
 
 
X 
X 
X 
 
Compliance Assessment 
 
 
 
X 
X 
 
 
Assess vital status 
 
 
 
 
 
 
X12 


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NOTE: The schedule may be modified +/- 3 days due to scheduling delays or conflicts (e.g. holidays, inclement weather, 
vacations, etc.) 
1. All pre-study assessments, with the exception of the informed consent, must be performed within 28 days prior to 
starting study treatment, unless otherwise indicated. 
2. Urine or serum pregnancy test is acceptable; to be performed for women of child-bearing potential only 
3. May be performed any time between Cycle 1, Day 14 and Cycle 3, Day 14 
4. To be performed prior to dosing on C3D1, then prior to dosing on Day 1 of every odd-numbered cycle thereafter 
(e.g., C5D1, C7D1, etc.) 
5. Clinical and radiological tumor assessments will be performed by CT, PET or MRI scan at baseline and then every 
2 cycles (i.e., within 7 days prior to Cycles 3, 5, 7, and 9) until disease progression. The same testing modality 
should be used for each evaluation. Responses of CR or PR should be confirmed with a second assessment no 
earlier than 4 weeks, but no later than the next scheduled scan, per protocol. Brain MRI and bone scan should be 
performed if clinically indicated (e.g., participants with known history of bone or brain mets). Results must be 
reviewed for each scan prior to dosing at next cycle 
6. To be performed within 7 days prior to C4D1. Further echocardiograms may be performed as clinically indicated. 
7. To be collected on C2D1, C3D1, then on Day 1 of each odd-numbered cycle thereafter (e.g., C5D1, C7D1, etc.) 
8. Applies only to participants with accessible disease. For these participants, each biopsy is optional, but encouraged. 
9. Archival tissue must be from a metastatic or locally advanced disease site. If locally advanced, disease must not be 
amenable to curative management. 
10. Baseline biopsy required for participants in the event that archival tissue from a metastatic site is not available.  
Otherwise, this biopsy is optional, and will be offered only to participants with accessible disease. Archival tissue 
from the primary tumor should be requested, but is not mandatory for enrollment. 
11. To be completed 30-45 days after last dose of sitravatinib. 
12. To be completed every 3 months from EOT date, via phone call or review of clinic notes. 
 
 
 


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9. TOXICITY MANAGEMENT – DOSE MODIFICATIONS   
 
Sitravatinib-Related Adverse Events 
In general, non-hematologic AEs should be managed using standards of care. Dose interruption 
should be considered for sitravatinib-related toxicities ≥ grade 3 until resolution to ≤ grade 1 or 
baseline. In the event of symptomatic sitravatinib-related AEs, dose reduction to a level that can 
be administered continuously is preferred over continuing dosing until interruption becomes 
necessary.  
Symptomatic grade 2 non-hematologic sitravatinib-related AEs occurring any time on study, 
particularly early in treatment (e.g., Cycle 1, Day 15 or Cycle 2, Day 1), are recommended to be 
managed using dose reduction to the next lower dose level rather than treatment interruption. If 
the toxicity is adequately managed by routine supportive care (e.g., anti-emetics, anti-diarrheals, 
electrolyte supplementation), or if the event is grade 3 fatigue, or asymptomatic amylase or lipase 
elevation, treatment may be resumed at the same dose; otherwise, treatment may be resumed at 
one or more levels below the dose level where toxicity was observed (Table 3). Recurrence of the 
toxicity may be managed similarly. Similar dose interruptions and reductions should be considered 
for grade 3/4 hematologic toxicities that cannot be adequately managed with supportive care. If 
treatment is interrupted for ≥ 28 days, sitravatinib must be permanently discontinued.  
Based on reported experience with sitravatinib and similar agents, and non-clinical data with 
sitravatinib, guidance to the investigator is provided for selected AEs. 
 
Table 3: Dose Modifications for Non‑Hematologic Sitravatinib-Related Toxicities 
Toxicity Grade 
Interruption 
Reduction 
Grade 1  
Continue treatment unchanged. 
Grade 2, asymptomatic  
May be implemented based on investigator discretion. 
Grade 2, symptomatic  
May be implemented based on investigator discretion. 
Dose reduction by one dose level is recommended over treatment 
interruption. 
Grade 3 or 4 
Hold until ≤ Grade 1 or return to 
baseline. 
Resume at one or more 
dose levels below that 
which induced the 
toxicity.* 
* Participants may resume at the same dose in the following cases: 
• Grade 3 or 4 electrolyte abnormality that is not clinically complicated and resolves spontaneously or with 
conventional medical treatment within 72 hours; 
• Grade 3 amylase or lipase elevation that is not associated with symptoms or clinical manifestations of 
pancreatitis. 
 
 
 


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Table 4: Sitravatinib Dose Level Reduction Table 
Sitravatinib Dose Level 
Dose and Schedule 
Number of Capsules and Strength 
Starting Dose 
100 mg once daily 
2 x 50 mg capsules 
Dose Level 1 (DL1) 
70 mg once daily 
2 x 35 mg capsules 
Dose Level 2 (DL2) 
50 mg once daily 
1 x 50 mg capsule 
Dose Level 3 (DL3) 
35 mg once daily 
1 x 35 mg capsule 
 
9.1.1 Hypertension 
Hypertension up to grade 3/4 has been reported with sitravatinib. Participants taking sitravatinib 
should undergo regular blood pressure monitoring and receive treatment with standard anti-
hypertensive therapy if necessary. Dihydropyridine calcium channel blockers such as nifedipine, 
amlodipine, and nicardipine may be considered if anti-hypertensive therapy is required. In cases 
of clinically significant grade 3 increases in blood pressure (such as an increase of ≥ 30 mmHg 
in systolic BP to ≥ 180 mmHg or increase of ≥ 20 mmHg in diastolic BP to ≥ 110 mmHg, 
confirmed with repeated testing after at least 5 minutes), temporary suspension of sitravatinib 
dosing is recommended until blood pressure is controlled. Treatment with sitravatinib may 
resume at the same or a lower dose at the discretion of the investigator. If significant hypertension 
recurs, options include change in medical management, reduction of sitravatinib dose to DL2 or 
DL3, or discontinuation of study treatment, at the discretion of the investigator. In the event of 
grade 4 hypertension, sitravatinib should be permanently discontinued (see Table 5). 
Table 5: Dose Modifications for Hypertension 
Toxicity Grade 
Interruption 
Reduction* 
Grade 1 or 2 hypertension 
Investigator discretion 
Grade 3, hypertension without clinically significant 
increases in BP as defined below 
Investigator discretion. Consider anti-
hypertensives per above paragraph. 
Grade 3, hypertension with clinically significant 
increases in BP defined as either an increase of ≥ 30 
mmHg in systolic BP to ≥ 180 mmHg or increase of 
≥ 20 mmHg in diastolic BP to ≥ 110 mmHg, 
confirmed with repeated testing after at least 5 
minutes 
Hold until ≤ Grade 
2 or return to 
baseline 
Investigator 
discretion 
Grade 4 hypertension 
Discontinue 
sitravatinib 
Discontinue 
sitravatinib 
* For dose reductions from 100 mg, reduce to 70 mg (DL1); if further dose reduction required, reduce to 50 mg 
(DL2). 
9.1.2 Fatigue 
Fatigue, defined as physical and/or mental exhaustion, occurs in patients with advanced stage 
tumors and long-term survivors, with a prevalence of approximately 30%. It has been reported 
in higher proportions of patients receiving chemotherapy and radiotherapy, with a prevalence 
between 59% and 96% and between 65% and 100%, respectively [20]. Asthenia, defined as loss 
of strength and energy, or weakness, is an event term that is frequently used to characterize the 


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same condition but is used more frequently among investigators outside of the US. Fatigue is 
also listed among the most common AEs observed in patients being administered other kinase 
inhibitors of VEGFR. Given that fatigue has been reported as a suspected adverse reaction (SAR) 
more than once, and because there is some corroboration with preclinical data and other VEGFR 
inhibitors, fatigue has been assessed as an expected SAR of sitravatinib. 
9.1.3 Nausea and Vomiting 
The prevalence of nausea and vomiting in patients with advanced cancer is up to 70%, and 
these events result from several etiologies [21]. Nausea and vomiting are also listed among the 
most common AEs observed in patients being administered other kinase inhibitors of VEGFR. 
Given that nausea and vomiting have each been reported as SARs more than once, and 
corroboration with preclinical data and other VEGFR inhibitors exists, nausea and vomiting 
have been assessed as expected SARs of sitravatinib. 
9.1.4 Palmar-Plantar Erythrodysesthesia Syndrome 
Palmar plantar erythrodysesthesia syndrome (PPES) has been reported as a dose-limiting toxicity 
in the Phase 1 study of sitravatinib. Signs and symptoms of PPES include redness, swelling, pain, 
and less commonly blisters on the palms of the hands and/or the soles of the feet. Participants 
who develop PPES should be counseled on measures to mitigate the effects of PPES. Such 
measures include avoidance of exposure of hands and feet to hot water when washing dishes or 
bathing, or to other sources of heat, avoidance of activities that cause unnecessary force or 
friction (rubbing) on the hands or feet, avoiding contact with harsh chemicals such as cleaning 
products, use of tools or household items that result in pressure on the hands, such as garden 
tools, knives, and screwdrivers, and wearing of loose fitting, well-ventilated shoes and clothes. 
Treatment may include use of topical moisturizing agents, topical anesthetics, or topical anti-
inflammatory medications such as corticosteroid creams. In more severe cases, dose interruption 
and reduction may be warranted. 
9.1.5 Diarrhea 
Diarrhea has been reported with sitravatinib treatment as with other small molecule RTK 
inhibitors, though the mechanism remains unclear. Participants should be counseled that diarrhea 
is a possible side effect and advised to take loperamide or a similar medication as needed if 
diarrhea develops. Diarrhea due to sitravatinib typically improves within several days if 
sitravatinib treatment is interrupted; any participants developing dehydration or clinically 
significant electrolyte abnormalities should interrupt treatment, but treatment may be restarted 
once diarrhea is controlled. For diarrhea prophylaxis, loperamide 4 mg daily can be started, 
followed by 2 mg after each loose stool (maximum: 16 mg/day). 
9.1.6 Increased Transaminases 
Sitravatinib dose modifications for increased transaminases are outlined in Table 6. Increased 
transaminases have been observed in patients treated with sitravatinib. Most cases were 
asymptomatic elevations in ALT or AST, while some were associated with liver metastases or 
cholestasis. No cases of drug-induced liver injury meeting Hy’s Law have been identified. In the 
setting of sitravatinib monotherapy, grade 2 transaminase increases related to treatment should 
generally be managed with dose reduction in sitravatinib. For grade ≥ 3 increases, dose 


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interruption until return to baseline followed by dose reduction may be warranted. In cases of 
prolonged interruptions, sitravatinib should be discontinued.  
Special consideration should be given to the potential for immune-mediated hepatitis in cases of 
combination treatment with checkpoint inhibitors. Where immune-mediated hepatitis is 
suspected, management should be consistent with standard treatment for immune-mediated 
hepatitis in consideration of the severity, and treatment with sitravatinib should also be 
interrupted. 
 
Table 6: Dose Modifications for Increased Hepatic Transaminases 
Toxicity Grade 
Interruption 
Reduction 
Grade 1 (> ULN to 3.0 × ULN)  May be implemented based on investigator and 
participant discretion 
Grade 2 (> 3.0 to 5.0 × ULN)  
Not required 
Decrease by one dose level 
Grade 3/4 (> 5.0 × ULN)  
 
Hold until Grade ≤ 1 
or return to baseline 
 
If resolution occurs within 29 
days, decrease by one dose 
level.  
If no resolution within 29 days, 
discontinue sitravatinib.  
9.1.7 Increased Amylase and Lipase 
Increased amylase and lipase have been observed in subjects treated with sitravatinib. Although 
the mechanism has not been fully elucidated, inhibition of VEGF may lead to acinar cell 
apoptosis resulting in the release of autodigestive enzymes (Sevin-2012). Accordingly, increases 
in amylase and lipase, and pancreatitis have been reported with other inhibitors of the VEGF 
pathway. Most sitravatinib-related treatment-emergent events of increased amylase and lipase 
were asymptomatic while some were associated with signs and/or symptoms of pancreatitis. 
Treatment with sitravatinib may continue without dose modification (e.g., interruption or 
reduction) in cases of asymptomatic amylase and/or lipase increases in the absence of other 
clinical evidence of pancreatitis (e.g., symptoms, electrolyte abnormalities, radiographic 
changes) at the investigator’s discretion. Sitravatinib should be interrupted for any grade 
pancreatitis and the participant managed according to standard-of-care. After resolution of 
pancreatitis, sitravatinib resumption is at the discretion of the investigator; if pancreatitis is 
assessed as sitravatinib-related and treatment is resumed, a dose reduction is recommended. 
9.1.8 Decrease in LVEF 
Decreased left ventricular ejection fraction (LVEF) has been in observed in < 10% of patients 
treated with sitravatinib. In cases where LVEF < 50%, then the dose of sitravatinib should be 
interrupted and/or reduced. Permanent discontinuation should be considered for participants 
requiring acute hospitalization for treatment of congestive heart failure (CHF). 
9.1.9 Hypothyroidism 
Abnormalities in thyroid function have been described with small molecule RTK inhibitors; most 
commonly, hypothyroidism, sometimes preceded by a brief period of hyperthyroidism, have 
been reported. TSH should be monitored during treatment with sitravatinib. Participants 


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diagnosed with hypothyroidism should be treated with thyroid replacement and may continue 
treatment with sitravatinib. When sitravatinib is used in combination with checkpoint inhibitors, 
thyroid dysfunction, including thyroiditis and hypothyroidism, may be immune-mediated. 
9.1.10 Proteinuria 
Proteinuria has been observed with sitravatinib treatment and described with other inhibitors of 
the VEGFR pathway. Urinalysis for urine protein should be performed prior to treatment and as 
clinically warranted during treatment with sitravatinib. Participants who develop ≥ 2+ proteinuria 
should undergo 24-hour urine collection for assessment of urine protein; treatment with 
sitravatinib should be discontinued in the presence of  ≥ 2g protein/24 hours and may restart 
when protein levels decrease to less than 2g/24 hours. Participants who develop nephrotic 
syndrome should be withdrawn from treatment with sitravatinib. 
9.1.11 Thrombotic Events  
Arterial and venous thrombotic events have been observed with sitravatinib and described with 
other inhibitors of the VEGFR pathway. The majority of thrombotic events observed with 
sitravatinib have been venous thrombotic events. The occurrence of thrombotic events with 
sitravatinib is being monitored for further characterization. Precautions should be taken in 
participants with recent, clinically significant thrombotic events, and treatment should be 
discontinued in subjects who develop clinically significant thromboembolic complications. 
9.1.12 Hemorrhagic Events  
The risk of hemorrhagic events with sitravatinib has not been fully characterized; however, such 
events have been reported with inhibitors of VEGFR. Patients with active hemoptysis or 
gastrointestinal bleeding should not take sitravatinib, and interruption of treatment is 
recommended for participants developing clinically significant bleeding. 
9.1.13 Other Sitravatinib-Related Events 
Other sitravatinib-related events include decreased appetite, dysphonia, fatigue, nausea, 
stomatitis, and vomiting. Management should be consistent with standard-of-care and 
sitravatinib dose modification as described in Tables 3 and 4. 
 
Potential Drug Interactions  
9.2.1 Cytochrome P-450 Substrates 
In vitro experiments indicate that sitravatinib is a potential inducer of CYPs 2B6 and 3A4, as 
well as a potential inhibitor of CYPs 2C8, 2D6, and 3A4, though neither time dependent nor 
metabolism dependent inhibition has been observed. Medications that are sensitive substrates for 
CYPs 2C8, 2D6 or 3A4 with a narrow therapeutic index should be used with caution during 
treatment with sitravatinib.  
In vitro experiments in microsomes and recombinant human P450 enzymes suggest that 
sitravatinib is metabolized by several cytochromes including CYPs 3A4, 2B6, and 2D6, with no 
single CYP enzyme contributing to > 25% of the total metabolism of sitravatinib. Therefore, the 
risk of drug-drug interactions with inhibitors or inducers of CYP enzymes is low. See Tables 7 


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and 8 for potential drug interactions and medications to be used with caution during treatment 
with sitravatinib. 
 
Table 7: Clinical Inhibitors for P450-Mediated Metabolisms (to be used with caution/closely monitored during 
treatment with sitravatinib) bold indicates medications that are commonly used 
Strong 
CYP3A4 
Inhibitors 
Boceprevir, clarithromycin, cobicistat, 
conivaptan, danoprevir/ritonavir, diltiazem, elvitegravir/ritonavir,  
grapefruit 
juice, idelalisib, indinavir/ritonavir, itraconazole, ketoconazole,  
lopinavir/ritonavir, nefazodone, nelfinavir,paritaprevir/ritonavir/ombitasvir 
plus dasabuvir, posaconazole, ritonavir, saquinavir/ritonavir, telaprevir,  
tipranavir/ritonavir, troleandomycin, voriconazole 
Moderate 
CYP3A4 
Inhibitors 
Aprepitant, cimetidine, ciprofloxacin, clotrimazole, crizotinib, 
cyclosporine, dronedarone, erythromycin, fluconazole, 
fluvoxamine, imatinib, tofisopam, verapamil 
  
Table 8: Sensitive Substrates with Narrow Therapeutic Index for the Indicated CYP Enzymes (to be used with 
caution/closely monitored during treatment with sitravatinib) bold indicates medications that are commonly used 
Enzyme 
CYP2B6 
Bupropion 
CYP2C8 
Repaglinide 
CYP2D6 
Atomoxetine,desipramine, dextromethorphan, eliglustat, nebivolol, 
nortriptyline, perphenazine, tolterodine, venlafaxine 
CYP3A 
Alfentanil, avanafil, budesonide, buspirone, conivaptan, darifenacin, darunavir, 
dasatinib, dronedarone, ebastine, eletriptan, 
eplerenone, everolimus, felodipine, ibrutinib, indinavir, 
lomitapide, lovastatin, lurasidone, maraviroc, midazolam, naloxegol, 
nisoldipine, quetiapine, saquinavir, sildenafil, simvastatin, sirolimus, 
tacrolimus, ticagrelor, tipranavir, tolvaptan, triazolam, vardenafil 
9.2.2 Transporter Substrates and Inhibitors  
Sitravatinib is a strong inhibitor of BCRP and P-gp transporters based on in vitro studies. 
Medications that are sensitive substrates or substrates with narrow therapeutic index for BCRP 
or P-gp transporters should be used with caution during treatment with sitravatinib (see Table 9).  
Sitravatinib is a substrate of P-gp in vitro. Inhibitors of P-gp may increase sitravatinib exposure, 
while inducers of P-gp may decrease sitravatinib exposure. Caution should therefore be used 
when administering sitravatinib to participants taking medications that inhibit or induce P-gp (see 
Table 10). 
 
 
 
 


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Table 9: Sensitive Substrates and Substrates with Narrow Therapeutic Index for P-gp and BCRP Transporters (to be 
used with caution/closely monitored during treatment with sitravatinib) 
Enzyme 
 
P-gp 
Aliskiren, ambrisentan, colchicine, dabigatran etexilate, digoxin, 
everolimus, fexofenadine, imatinib, lapatinib, maraviroc, nilotinib, 
posaconazole, ranolazine, saxagliptin, sirolimus, sitagliptin, talinolol, 
tolvaptan, topotecan 
BCRP 
Methotrexate, mitoxantrone, imatinib, irinotecan, lapatinib, rosuvastatin, 
sulfasalazine, topotecan 
 
Table 10: P-gp Inhibitors and Inducers (to be used with caution/closely monitored during treatment with sitravatinib) 
P-gp Inhibitors 
Clarithromycin, itraconazole, propafenone, quinidine, ranolazine, 
ritonavir, verapamil 
P-gp Inducers 
Rifampin 
9.2.3 Medications that Prolong QTc  
The risk of QTc prolongation in patients receiving treatment with sitravatinib has not been 
characterized. Use of medications known to prolong QTc and pose risk of Torsades de Pointes is 
to be avoided during treatment with sitravatinib (see Table 11).  
Table 11: Elevated Risk of Torsades de Pointes with Concurrent Use During Sitravatinib Treatment (avoid during 
treatment with sitravatinib) 
Anesthetics 
Propofol, sevoflurane 
Antiarrhythmics 
Amiodarone, disopyramide, dofetilide, dronedarone, 
flecainide, hydroquinidine (dihydroquinidine)*, ibutilide, 
nifekalant*, procainamide, quinidine, sotalol 
Antibiotics, antihistamines 
Astemizole†, azithromycin, ciprofloxacin, clarithromycin, 
erythromycin, gatifloxacin†, grepafloxacin†, levofloxacin, 
moxifloxacin, roxithromycin*, sparfloxacin†, terfenadine† 
Anticoagulants, calcium 
channel blockers, 
vasodilators 
Anagrelide, bepridil, cilostazol, papaverine HCl (intra-
coronary), terodiline* 
Antifungals, antimalarials, 
antimicrobials 
Chloroquine, fluconazole, halofantrine*, 
hydroxychloroquine, meglumine antimoniate*, 
pentamidine 
Cancer treatment agents 
Aclarubicin*, arsenic trioxide, oxaliplatin, vandetanib 
GI 
Cisapride†, domperidone*, ondansetron 
Psychiatric 
Chlorpromazine, chlorprothixene*, citalopram, donepezil, 
droperidol, escitalopram, haloperidol, levomepromazine 
(methotrimeprazine)*, levosulpiride*, mesoridazine†, 
pimozide, sulpiride*, sultopride*, thioridazine 
Other 
Cesium chloride, cocaine, ibogaine*, levomethadyl 
acetate†, methadone, probucol†, terlipressin* 
 * Only on non-US market     † Removed from US market 


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Special Considerations 
• For toxicities considered by the treating investigator unlikely to develop into serious or life–
threatening events (e.g., alopecia, altered taste etc.), treatment may be continued at the same 
dose without reduction or interruption. 
• The treating investigator may reduce a participant’s dose for a toxicity of any grade/duration 
where s/he believes it to be in the best interest of the participant. 
• Any consideration to modification of the above dose modification guidelines should be 
discussed with the Principal Investigator for approval or disapproval in advance. 


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10. SITRAVATINIB DRUG FORMULATION/STORAGE 
Sitravatinib is an investigational agent and will be supplied free-of-charge by Mirati 
Therapeutics, Inc.  
The malate capsule product consists of a blend of MGCD516 malate drug substance, 
microcrystalline cellulose, mannitol, croscarmellose sodium, colloidal silicon dioxide, and 
magnesium stearate. The blend is filled into hard gelatin capsules. The malate formulation is 
provided in dose strengths of 35 mg and 50 mg.  
Sitravatinib capsules will be provided by Mirati as the malate drug product packaged in 30-
count, high-density polyethylene, white opaque, round 60cc bottles. A tamper-resistant heat 
induction seal and a child-resistant closure are used for all dose strengths.  
Bottles of sitravatinib are to be stored in refrigerated conditions (at 2-8°C, 36-46°F) at the 
pharmacy in accordance with the label. After dispensing to the participant, sitravatinib bottles are 
stored at ambient room temperature. 
Each bottle is labelled with contents, product lot number, required storage conditions, and 
required regional specific information. Additional information regarding required storage 
conditions is provided in the study pharmacy manual. 
The storage area should be secure with limited access. Only qualified personnel who are familiar 
with procedures that minimize undue exposure to them and to the environment should undertake 
the preparation, handling, and safe disposal of small molecule therapeutic agents. 
 
 
 


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11. CORRELATIVE/SPECIAL STUDIES  
 Blood Samples 
In order to address the exploratory objectives described in Sections 3.3.1 and 3.3.2, all 
participants will have two 10 mL Streck tubes of blood and two 10 mL Rarecyte tubes of blood 
collected at the following timepoints for ctDNA and CTC analysis respectively: 
- 
Prior to beginning study treatment (may be collected at any time after the participant signs 
the informed consent, prior to the first dose of sitravatinib)  
- 
Cycle 1, Day 14 
- 
Cycle 2, Day 1 
- 
Cycle 3, Day 1 
- 
Day 1 of every odd-numbered cycle thereafter (e.g., C5D1, C7D1, etc.) 
- 
End of Treatment 
 Tissue Samples 
In order to address the exploratory objectives described in Sections 3.3.3 and 3.3.4, and to 
determine PTPN12 status, tissue samples will be collected from participants as outlined below. 
Archival tissue from the primary tumor (if available) will be requested for all participants, but is 
not mandatory for enrollment. 
Archival tissue from a metastatic or locally advanced site will be requested for all participants. If 
this is not available, a baseline biopsy of the metastatic or locally advanced site is required. 
Participants for whom archival tissue from a metastatic site is available will be offered an 
optional baseline biopsy (only if lesion is readily accessible, e.g., skin, regional superficial lymph 
nodes, peripheral liver lesions). 
At least 3 core biopsy specimens should be collected, if feasible. If obtained, the first core will be 
fixed in formalin and used for PTPN12 IHC testing, the second core OCT-embedded and flash 
frozen on dry ice, and the third core placed in culture media and used for patient derived 
xenograft (PDX). If collection of additional cores is feasible, these should be OCT-embedded 
and flash frozen on dry ice. Participants with recurrent breast masses or chest wall/skin 
involvement where a core needle biopsy (or punch biopsy as a second preference) is feasible will 
be asked to undergo an additional research biopsy while on study treatment (between Cycle 1, 
Day 14 and Cycle 3, Day 14) and another upon progression of disease at the EOT visit. The on-
treatment and EOT biopsies are optional, but highly encouraged for participants with accessible 
disease.   
 Translational Research Planned Analysis 
11.3.1 Analysis of Blood Samples  
 CTC Analysis  
We will track CTC number and expression of PTPN12 by immunofluorescence and 
compare, in an exploratory analysis, the relationships with PTPN12 tumor tissue expression 
and response to sitravatinib. After the depletion of red blood cell and enrichment of 
nucleated cells from 8mL of blood, CTCs and WBCs are spread onto microscope slides. 
Using automated fluorescence imaging, CTCs that are positive for EpCAM, cytokeratin, and 


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DAPI, but negative for the WBC marker CD45 are identified. The additional channels will 
be used for PTPN12 immunofluorescence. Positive and negative controls will be provided 
by appropriate cell lines. By monitoring PTPN12 expression in CTC we can explore the 
heterogeneity in PTPN12 expression and whether it is influenced by sitravatinib treatment. 
 ctDNA Analysis  
Digital PCR affords the ability to determine ultrasensitive measurements of mutated and 
wild type copies of DNA over tens of thousands of individual droplets based on emission of 
HEX and FAM-labeled primer probes. An automated water-emulsion droplet generator 
(QX200DG, BioRad) creates tens of thousands of individual droplets that partition analyte 
molecules and detection probes into separate PCR reactions. A typical starting sample of 20 
µL should yield up to 20,000 droplets. The QX200 can process and analyze up to 96 
samples per run, yielding and counting approximately 1.5 million droplets per 96-well plate. 
Such microfluidics-based sample partitioning and statistical analyses of up to millions of 
droplets provide absolute quantification of target DNA molecules for probe-based detection 
at high sensitivity without the need for standard curves. Completed droplet reactions are 
streamed single file through a specialized reader for fluorescence analysis using a multi-
pixel photon counter. Positive droplets exhibit increased fluorescence of target (mutant) 
probes compared to negative droplets (wild type), and the fraction of PCR-positive droplets 
are quantitated according to Poisson distribution. Thus, the fractional abundance of the 
mutant allele can be calculated by the ratio of the number of mutant-FAM probe copies per 
droplet over the total DNA concentration of the reaction.  
For ddPCR we must know the mutations we want to detect apriori, as unlike next generation 
sequencing panels, the method is specific to confirming the presence or absence of a 
mutation at specific locus. Qualifying mutations for the longitudinal ctDNA analysis by 
ddPCR will be selected from the sequenced surgical tissue samples with mutations 
prioritized by likely clonal/driver status. For each mutant allele, a custom ddPCR probe set 
(BioRad) will be designed and used for serial ctDNA monitoring across blood collection 
timepoints in the study. Digital droplet construction will be performed on the BioRad 
AutoDG QX200 (automatic droplet generator) ddPCR system with assays utilizing TaqMan 
hydrolysis chemistry with custom and/or commercially available primer-probe sets 
(BioRad). The partitioned PCR droplet assays will be subjected to amplification using a 
C1000 Touch™ thermal cycler (BioRad) and fluorometrically assessed on the QX200 droplet 
reader. The fraction of positive droplets will be fitted to a Poisson distribution using 
available QuantaSoft Pro software (BioRad) to calculate the number of mutant and wild-
type (WT) copies of DNA in the sample. We have previously confirmed that high sensitivity 
and specificity can be achieved on this platform using commercially available ctDNA 
reference standards prepared in synthetic plasma (Horizon Discovery). We will be utilizing 
this assay platform in collaboration with Dr. George Miles to monitor ctDNA abundance 
isolated from blood plasma at sampled timepoints outlined in the schema.   
11.3.2 Analysis of Tissue Samples 
 PTPN12 IHC Assay  
We will deploy the PTPN12 IHC on all formalin-fixed tissue accrued from the participants 
during the execution of the trial to identify changes in expression from primary to metastatic 


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disease, as a role of PTPN12 loss during metastatic progression has not been evaluated. If 
the PTPN12 status of the primary and metastatic samples are closely matched, analysis of 
the primary sample can be used for eligibility in future studies. For participants with 
accessible disease, pre-treatment, during treatment, and progression biopsies will be 
requested to profile the kinome in response to treatment using the drug bead technology. 
Upon completion of these studies we will understand whether primary tumor or CTC 
PTPN12 status, as opposed to a metastatic biopsy, can be used to determine eligibility in 
future studies. 
 Proteogenomic Analysis of Tumor Biopsies (DNA, RNA and Proteomics)  
This protocol aims to evaluate the kinome and phosphoproteome of metastatic TNBC. The 
analysis pipeline includes quantitative tandem mass tag (TMT)-based proteomics and 
phosphoproteomics, kinase inhibitor profiling (KiP)-based kinomics, tumor/normal exome 
sequencing, and RNA sequencing [9]. For participants with accessible disease, pre-
treatment, on-treatment, and progression biopsies will be requested for proteogenomic 
profiling. We aim to examine signaling perturbations in response to treatment as well as the 
influence of tumor PTPN12 status on the kinome. In the event of clinical trial success, we 
will build a kinome profile of responding versus non-responding tumors.   
 Generation and Analysis of Patient Derived Xenografts (PDX) 
When possible, we will collect viable cells from tumor biopsies and engraft them into 
immunocompromised mice. When a PDX is successful, proteogenomic analysis will be 
conducted parallel to the tissue analysis outlined in Section 11.3.2.2 to validate the PDX as a 
facsimile for the tumor from which it was derived. The PDX will also be treated with 
sitravatinib and the results compared with the patient matched response. Later PDX studies 
will examine sitravatinib combinations including with a taxane. 
 Exploratory Immune Biomarkers 
These are described in Table 1 (Section 4.2). 
 Specimen Banking 
All collected biospecimens will be banked indefinitely at the Coordinating Center’s Breast 
Center Tissue Bank, located at the following address: 
 
Breast Center Tissue Bank 
Baylor College of Medicine 
One Baylor Plaza RM 330C 
Houston, TX 77030 
 
Study participants will be asked to indicate their preferences for the future use of tissue at the 
time informed consent is obtained.     
 


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12.  MEASUREMENT OF EFFECT 
For the purposes of this study, participants are to be re-evaluated for response per the study 
calendar. Response and progression will be evaluated using the international criteria proposed by 
the Response Evaluation Criteria in Solid Tumors guideline, version 1.1 (RECIST 1.1) [22]. 
Changes in the largest diameter (unidimensional measurement) of the tumor lesions and the 
shortest diameter in the case of malignant lymph nodes are used in the RECIST criteria. 
 Definitions 
12.1.1 Evaluable for Toxicity 
All participants will be evaluable for toxicity from the time of their first treatment with 
sitravatinib. 
12.1.2 Evaluable for Objective Response 
Only those participants who have measurable disease present at baseline, have received at least 
one cycle of study treatment, and have had their disease re-evaluated, will be considered 
evaluable for response. These participants will have their response classified according to the 
definitions outlined in Section 12.4. (Note: Participants who exhibit objective disease 
progression prior to the end of Cycle 1 will also be considered evaluable.) 
12.1.3 Evaluable Non-Target Disease Response 
Participants who have lesions present at baseline that are evaluable but do not meet the 
definitions of measurable disease, have received at least one cycle of study treatment, and have 
had their disease re-evaluated will be considered evaluable for non-target disease response. The 
response assessment is based on the presence, absence, or unequivocal progression of the 
lesions.  
12.1.4 Measurable Disease 
A non-nodal lesion is considered measurable if its longest diameter can be accurately measured 
as ≥ 20 mm with chest x-ray, or as ≥ 10 mm with CT scan, CT component of a PET/CT, or 
MRI.  
A superficial non-nodal lesion is measurable if its longest diameter is ≥ 10 mm in diameter as 
assessed using calipers (e.g. skin nodules) or imaging. In the case of skin lesions, 
documentation by color photography, including a ruler to estimate the size of the lesion, is 
recommended. 
A malignant lymph node is considered measurable if its short axis is ≥ 15 mm when assessed 
by CT scan (CT scan slice thickness recommended to be no greater than 5 mm). At baseline 
and in follow-up, only the short axis will be measured and followed. 
NOTE: Tumor lesions in a previously irradiated area are only considered measurable disease in 
the event that there is evidence of post-radiation progression. 
12.1.5 Non-Measurable Disease 
All other lesions (or sites of disease), including small lesions (longest diameter < 10 mm or 
pathological lymph nodes ≥ 10 to < 15 mm, are considered non-measurable disease. Bone 


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lesions, leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis 
cutis/pulmonitis, inflammatory breast disease, and abdominal masses (not followed by CT or 
MRI), are considered non-measurable. 
NOTE: Cystic lesions that meet the criteria for radiographically defined simple cysts should not 
be considered as malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts. Cystic lesions thought to represent cystic metastases can be considered 
as measurable lesions, if they meet the definition of measurability described above. However, if 
non-cystic lesions are present in the same participant, these are preferred for selection as target 
lesions. In addition, lymph nodes that have a short axis < 10 mm are considered non-
pathological (i.e., normal) and should not be recorded or followed. 
 Guidelines for Evaluation of Disease 
12.2.1 Measurement Methods  
The same assessment method/technique must be used to characterize each identified and 
reported lesion at baseline and during follow-up; all measurements should be recorded in 
metric notation (i.e., decimal fractions of centimeters) using a ruler or calipers.  
Imaging-based evaluation is preferred to evaluation by clinical examination unless the lesion(s) 
being followed cannot be imaged but are assessable by clinical exam. 
12.2.2 Modalities for Measurable Disease  
 Conventional CT and MRI  
This guideline has defined measurability of lesions on CT scan based on the assumption that 
CT slice thickness is 5 mm or less. If CT scans have slice thickness greater than 5 mm, the 
minimum size for a measurable lesion should be twice the slice thickness. CT is preferred; 
MRI is also acceptable in certain situations (e.g., for body scans). 
Diagnostic quality CT is expected (with oral and IV contrast); any deviations from this must 
be approved by the Principal Investigator/designee in advance. (See note below regarding 
contrast allergy). 
Use of MRI remains a complex issue. MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which 
greatly impact image quality, lesion conspicuity, and measurement. Furthermore, the 
availability of MRI is variable globally. As with CT, if an MRI is performed, the technical 
specifications of the scanning sequences used should be optimized for the evaluation of the 
type and site of disease. Furthermore, as with CT, the modality used at follow-up should be 
the same as was used at baseline and the lesions should be measured/assessed on the same 
pulse sequence. It is beyond the scope of the RECIST guidelines to prescribe specific MRI 
pulse sequence parameters for all scanners, body parts, and diseases. Ideally, the same type 
of scanner should be used and the image acquisition protocol should be followed as closely 
as possible to prior scans. Body scans should be performed with breath-hold scanning 
techniques, if possible. 
NOTE: If it is known prior to enrollment that a participant is unable to undergo CT scans 
with IV contrast due to allergy or renal insufficiency, the decision as to whether a non-
contrast CT or MRI (with or without IV contrast) should be used to evaluate the participant 


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at baseline and follow-up should be guided by the anatomic location(s) of the disease. For 
participants who develop contraindications to contrast after the baseline contrast CT is done, 
the decision as to whether non-contrast CT or MRI (enhanced or non-enhanced) should be 
performed should also be based on the anatomic location of the disease and should be 
optimized to allow for comparison to the prior studies if possible. Each case should be 
discussed with the radiologist and Principal Investigator/designee to determine if 
substitution of these other approaches is possible and, if not, the participant may be 
considered not evaluable from that point forward.  
 Chest X-ray  
Lesions on chest x-ray are acceptable as measurable lesions when they are clearly defined 
and surrounded by aerated lung; however, CT scans are preferable. 
 Clinical Exam  
For superficial non-nodal lesions, physical examination is acceptable, but imaging is 
preferable, if both can be done. Clinical lesions will only be considered measurable when 
they are superficial (e.g., skin nodules and palpable lymph nodes) and ≥ 10 mm diameter as 
assessed using calipers (e.g., skin nodules). In the case of skin lesions, documentation by 
color photography, including a ruler to estimate the size of the lesion, is recommended. 
 Ultrasound  
Ultrasound is not useful in assessment of lesion size and should not be used as a method of 
measurement. Ultrasound examinations cannot be reproduced in their entirety for 
independent review at a later date and, because they are operator dependent, it cannot be 
guaranteed that the same technique and measurements will be taken from one assessment to 
the next. If new lesions are identified by ultrasound in the course of the study, confirmation 
by CT or MRI is advised. If there is concern about radiation exposure at CT, MRI may be 
used instead of CT in selected instances. 
 PET-CT  
If the site can document that the CT performed as part of a PET-CT is of identical diagnostic 
quality to a diagnostic CT (with IV and oral contrast), then the CT portion of the PET-CT 
can be used for RECIST measurements and can be used interchangeably with conventional 
CT in accurately measuring cancer lesions over time with approval from the Principal 
Investigator/designee.  
 FDG-PET  
FDG-PET scanning is allowed to complement CT scanning in assessment of progressive 
disease (PD) and particularly possible new disease. A positive FDG-PET scanned lesion is 
defined as one which is FDG avid with an uptake greater than twice that of the surrounding 
tissue on the attenuation corrected image; otherwise, an FDG-PET scanned lesion is 
considered negative. New lesions on the basis of FDG-PET imaging can be identified 
according to the following algorithm:  
• Negative FDG-PET at baseline, positive FDG-PET at follow-up: PD based on a new 
lesion. 
• No FDG-PET at baseline, positive FDG-PET at follow-up: If the positive FDG-PET at 


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follow-up corresponds to a new site of disease confirmed by CT, this is PD. If the 
positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, 
additional follow-up CT scans are needed to determine if there is truly progression 
occurring at that site (if so, the date of PD will be the date of the initial abnormal FDG-
PET scan). If the positive FDG-PET at follow-up corresponds to a pre-existing site of 
disease on CT that is not progressing on the basis of the anatomic images, this is not 
PD. 
• FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy in 
cases where a residual radiographic abnormality is thought to represent fibrosis or 
scarring. The use of FDG-PET in this circumstance should be prospectively described in 
the protocol and supported by disease-specific medical literature for the indication. 
However, it must be acknowledged that both approaches may lead to false positive CR 
due to limitations of FDG-PET and biopsy resolution/sensitivity. 
12.2.3 Additional Considerations 
• Tumor markers alone cannot be used to assess response. If markers are initially above the 
upper normal limit, they must normalize for a participant to be considered in complete 
clinical response.  
• The cytological confirmation of the neoplastic origin of any effusion that appears or 
worsens during treatment when the measurable tumor has met criteria for response or 
stable disease is mandatory to differentiate between response or stable disease (an effusion 
may be a side effect of the treatment) and progressive disease. 
• Cytologic and histologic techniques can be used to differentiate between PR and CR in rare 
cases (e.g., residual lesions in tumor types such as germ cell tumors, where known residual 
benign tumors can remain). 
 Lesion Documentation 
12.3.1 Target Lesions 
 Measurable Lesions 
Up to a maximum of 5 lesions, representative of all involved organs, should be identified as 
“Target Lesions” and recorded and measured at baseline. These lesions can be non-nodal or 
nodal (as defined), where no more than 2 lesions are from the same organ and no more than 
2 malignant nodal lesions are selected.  
NOTE: If fewer than 5 target lesions and target lymph nodes are identified, there is no reason 
to perform additional studies beyond those specified in the protocol to discover new lesions.  
Target lesions and target lymph nodes should be selected on the basis of their size, be 
representative of all involved sites of disease, but in addition should be those that lend 
themselves to reproducible repeated measurements. It may be the case that, on occasion, the 
largest lesion (or malignant lymph node) does not lend itself to reproducible measurements 
in which circumstance the next largest lesion (or malignant lymph node) which can be 
measured reproducibly should be selected.  
 Baseline Sum of Diameters (BSD) 


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A sum of the longest diameter for all target lesions plus the sum of the short axis of all the 
target lymph nodes will be calculated and reported as the baseline sum of dimensions 
(BSD). The BSD will be used as reference to further characterize any objective tumor 
response in the measurable dimension of the disease.  
 Post-Baseline Sum of the Diameters (PBSD) 
A sum of the longest diameter for all target lesions plus the sum of the short axis of all the 
target lymph nodes will be calculated and reported as the post-baseline sum of dimensions 
(PBSD). If the radiologist is able to provide an actual measurement for the target lesion (or 
target lymph node), that should be recorded, even if it is below 0.5 cm. If the target lesion 
(or target lymph node) is believed to be present and is faintly seen but too small to measure, 
a default value of 0.5 cm should be assigned. If it is the opinion of the radiologist that the 
target lesion or target lymph node has likely disappeared, the measurement should be 
recorded as 0 cm. 
 Mimimum Sum of Diameters (MSD) 
The minimum sum of the diameters (MSD) is the minimum of the BSD and the PBSD. 
12.3.2 Non-Target Lesions & Non-Target Lymph Nodes 
Non-measurable sites of disease including any measurable lesions over and above the 5 target 
lesions should be identified as non-target lesions or non-target lymph nodes and should also be 
recorded at baseline. Measurements of these lesions are not required, but the presence, absence, 
or in rare cases unequivocal progression of each should be noted throughout follow-up.  
 Response Criteria 
12.4.1 Overview 
All target lesions, as well as non-target lesions must be measured at the evaluation time points 
specified in the study calendar. Specifically, a change in objective status to either a PR or CR 
cannot be done without re-measuring target lesions and target lymph nodes.  
NOTE: Non-target lesions and non-target lymph nodes should be evaluated at each assessment, 
especially in the case of first response or confirmation of response. In selected circumstances, 
certain non-target organs may be evaluated less frequently. For example, bone scans may need 
to be repeated only when complete response is identified in target disease or when progression 
in bone is suspected. 
12.4.2 Evaluation of Target Lesions 
 Complete Response (CR) 
Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-
target) must have reduction in short axis to < 10 mm. 
 Partial Response (PR) 
At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the 
baseline sum diameters. 


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 Progressive Disease (PD) 
At least a 20% increase in the sum of the diameters of target lesions, taking as reference the 
smallest sum on study (this includes the baseline sum if that is the smallest on study). In 
addition to the relative increase of 20%, the sum must also demonstrate an absolute increase 
of at least 5 mm. 
NOTE: The appearance of one or more new lesions is also considered progression. 
 Stable Disease (SD) 
Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, 
taking as reference the smallest sum diameters while on study. 
12.4.3 Evaluation of Non-Target Lesions & Non-Target Lymph Nodes 
 Complete Response (CR) 
Disappearance of all non-target lesions and normalization of tumor marker level. All lymph 
nodes must be non-pathological in size (< 10 mm short axis). 
NOTE: If tumor markers are initially above the upper normal limit, they must normalize for a 
subject to be considered in complete clinical response. 
 Non-CR/Non-PD 
Persistence of one or more non-target lesion(s) and/or maintenance of tumor marker level 
above the normal limits. 
 Progressive Disease (PD) 
Appearance of one or more new lesions and/or unequivocal progression of existing non-
target lesions. Unequivocal progression should not normally trump target lesion status. It 
must be representative of overall disease status change, not a single lesion increase. 
NOTE: To achieve unequivocal progression on the basis of non-target disease, there must be 
an overall level of substantial worsening in non-target disease such that, even in presence of 
CR, PR or SD in target disease, the overall tumor burden has increased sufficiently to merit 
discontinuation of therapy. A modest increase in the size of one or more non-target lesions is 
usually not sufficient to qualify for unequivocal progression status. The designation of 
overall progression solely on the basis of change in non-target disease in the face of CR, PR 
or SD of target disease is therefore expected to be rare. In order for a PD to be assigned on 
the basis of non-target lesions, the increase in the extent of the disease must be substantial 
even in cases where there is no measurable disease at baseline. If there is unequivocal 
progression of non-target lesion(s), then at least one of the non-target lesions must be 
assigned a status of “Worsened.” Where possible, similar rules to those described above for 
target lesions for assigning PD following a CR for the non-target lesion response in the 
presence of non-target lesions nodal lesions should be applied. 
12.4.4 Symptomatic Deterioration 
Participants with global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time, and not either related to study 
treatment or other medical conditions, should be reported as PD due to “symptomatic 
deterioration.” Every effort should be made to document the objective progression even after 


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discontinuation of treatment due to symptomatic deterioration. A participant is classified as 
having PD due to symptomatic deterioration if any of the following occur that are not either 
related to study treatment or other medical conditions: 
• Weight loss > 10% of body weight 
• Worsening of tumor-related symptoms 
• Decline in performance status of > 1 level on ECOG scale 
12.4.5 Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of study treatment until 
disease progression/recurrence (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started). The participant's best response assignment 
will depend on the achievement of both measurement and confirmation criteria. 
For participants with measurable disease at baseline:  
 
Target Lesions 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Non-CR/ Non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all evaluated 
No 
PR 
SD 
Non-PD or not all evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
Non-evaluable 
PD 
Any 
Yes or No 
PD 
Any 
PD* 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
*In exceptional circumstances, unequivocal progression in non-target lesions may be accepted 
as disease progression. 
 
For participants with non-measurable/evaluable disease only at baseline:  
 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/Non-PD 
No 
Non-CR/Non-PD 
UNK/Not All Evaluated 
No 
Indeterminate 
Unequivocal progression 
Yes or No 
PD 
Any 
Yes 
PD 
 
In some circumstances, it may be difficult to distinguish residual disease from normal tissue. 
When the evaluation of complete response depends on this determination, it is recommended 
that the residual lesion be investigated (fine needle aspirate/biopsy) to confirm the complete 
response status. 
12.4.6 Progression-Free Survival 
Progression-free survival (PFS) is defined as the time from the initiation of the study treatment 
until the date of objective disease progression or death (by any cause in the absence of 


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progression). 
12.4.7 Response Review 
There is no independent or central review of the radiology assessments planned for this trial. It 
is the responsibility of each participating site’s Principal Investigator to ensure that tumor 
assessments are reported per the RECIST 1.1 criteria outlined above. The Principal Investigator 
(or designee) may choose to review select cases. 
12.4.8 Confirmatory Measurement/Duration of Response 
 Confirmation of Response    
To be assigned a status of PR or CR, changes in tumor measurements must be confirmed by 
repeat assessments performed no less than 4 weeks after the criteria for response are first 
met.  
 Duration of Overall Response   
The duration of overall response is measured from the time measurement criteria are met for 
CR or PR (whichever is first recorded) until the first date that recurrent or progressive 
disease is objectively documented (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started). 
The duration of overall CR is measured from the time measurement criteria are first met for 
CR until the first date that progressive disease is objectively documented. 
 
 Duration of Stable Disease 
The duration of SD is measured from the start of the treatment until the criteria for 
progression are met, taking as reference the smallest measurements recorded since the 
treatment started, including the baseline measurements.  
13. ADVERSE EVENT REPORTING REQUIREMENTS 
 General 
Adverse event collection and reporting is a routine part of every clinical trial. This study will use 
the descriptions and grading scales found in the NCI Common Terminology Criteria for Adverse 
Events version (CTCAE v5.0) that is available at 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
Information on all adverse events, whether reported by the participant, directly observed, or 
detected by physical examination, laboratory test or other means, will be collected, recorded, 
followed and reported as described in the following sections.  
Adverse events experienced by participants will be collected and reported from initiation of 
study medication, throughout the study, and within 30 days of the last dose of study medication. 
Participants who experience an ongoing adverse event related to a study procedure and/or study 
medication beyond 30 days will continue to be contacted by a member of the study team until the 
event is resolved, stabilized, or determined to be irreversible by the participating investigator.  
Participants should be instructed to report any serious post-study event(s) that might reasonably 
be related to participation in this study. The investigator should notify the IRB and any other 


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applicable regulatory agency of any unanticipated death or adverse event occurring after a 
participant has discontinued or terminated study participation that may reasonably be related to 
the study.  
 Definitions 
13.2.1 Adverse Event (AE) 
An adverse event is any undesirable sign, symptom or medical condition or experience that 
develops or worsens in severity after starting the first dose of study treatment or any procedure 
specified in the protocol, even if the event is not considered to be related to the study.  
Abnormal laboratory values or diagnostic test results constitute adverse events only if they 
induce clinical signs or symptoms or require treatment or further diagnostic tests.  
 Suspected Adverse Reaction 
Suspected adverse reactions are the subset of all adverse events for which there is a 
“reasonable possibility” (i.e., there is evidence to suggest a causal relationship between the 
drug and the adverse event) that the drug caused the event.  
13.2.2 Serious Adverse Event (SAE) 
A serious adverse event is an undesirable sign, symptom, or medical condition which: 
• is fatal;  
• is life-threatening (immediate risk of death); 
• requires or prolongs inpatient hospitalization for ≥ 24 hours; 
• results in persistent or significant disability/incapacity to conduct normal life functions; 
• constitutes a congenital anomaly or birth defect; or 
• Important Medical Events (IME) that may not result in death, be life threatening, or require 
hospitalization may be considered serious when, based upon medical judgment, they may 
jeopardize the patient or subject and may require medical or surgical intervention to 
prevent one of the outcomes listed in this definition. 
Events not considered to be serious adverse events are hospitalizations for: 
• routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition, or for elective procedures 
• elective or pre-planned treatment for a pre-existing condition that did not worsen, or that is 
required per protocol 
• emergency outpatient treatment for an event not fulfilling the serious criteria outlined 
above and not resulting in inpatient admission 
• respite care 
• Death due to disease progression unless attributable to the study treatment 
Events listed above may be reported to a participating site’s local IRB, if required per local 
regulations. 
13.2.3 Expectedness  
Expected: Expected adverse events are those that have been previously identified as resulting 
from administration of the agent. For the purposes of this study, AEs are considered “expected” 


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if they are included in the Reference Safety Information section of the most current version of 
the sitravatinib Investigator’s Brochure. 
Unexpected: An adverse event is considered unexpected when it is not included, or varies in 
nature, intensity or frequency, from information provided in the Reference Safety Information 
section of the most current version of the sitravatinib Investigator’s Brochure. 
13.2.4 Attribution  
Attribution is the relationship between an adverse event and the study treatment. Attribution will 
be assigned as follows: 
• Unrelated: The adverse event is clearly unrelated to the study treatment. 
• Unlikely: The adverse event is unlikely to be related to the study treatment. 
• Possibly: The adverse event is possibly related to the study treatment. 
• Probably: The adverse event is probably related to the study treatment. 
• Definite: The adverse event is clearly related to the study treatment. 
 Reporting Procedures 
13.3.1 General 
All adverse events will be recorded on study-specific case report forms (CRFs).  
13.3.2 Serious Adverse Events 
All serious adverse events, regardless of causality to study drug, will be reported to the 
Principal Investigator and/or the Study Coordinator. Information pertaining to the SAE should 
be compiled on the Form FDA 3500A – MedWatch Mandatory Reporting (available on the 
FDA website). The Principal Investigator or designee should review the information in this 
report, along with any supporting documentation, and make a determination of causality. The 
Principal Investigator or designee should also review any follow-up information as it becomes 
available to determine if the causality assessment has changed. 
13.3.3 Suspected, Unexpected Serious Adverse Reactions (SUSARs) 
The Principal Investigator or designee must report any suspected adverse reaction to study 
treatment that is both serious and unexpected to the FDA via an IND safety report no later than 
15 calendar days after determining that the information qualifies for reporting. Any unexpected 
fatal, or life-threatening, suspected adverse reactions must be reported to the FDA no later than 
7 calendar days after initial receipt of the information.  
13.3.4 Institutional Review Board (IRB) 
Adverse events requiring modifications to the protocol and/or informed consent will be 
reported to the IRB. These modifications will be provided to the IRB with the report of the 
adverse event.  
13.3.5 Food and Drug Administration (FDA) 
The Dan L. Duncan Cancer Center at Baylor College of Medicine (DLDCC-BCM) has been 
designated as the Coordinating Center to manage the Investigational New Drug Application 


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(IND) associated with this protocol. The Coordinating Center and/or CRO will cross-reference 
this submission to Mirati Therapeutics’ parent IND at the time of submission. Additionally, the 
Coordinating Center will submit a copy of these documents to Mirati Therapeutics at the time 
of submission to FDA. 
The Coordinating Center will be responsible for all communication with the FDA in accordance 
with 21 CFR Part 312, which includes but is not limited to the 7- and 15-Day Safety Reports, as 
well as an Annual Progress Report. Additionally, the Coordinating Center will submit a copy of 
these reports to Mirati Therapeutics at the time of submission to FDA. 
13.3.6 Mirati Therapeutics, Inc. 
Mirati Therapeutics’ procedure for SUSAR exchange is outlined below. All exchange of 
processed data will be by Form FDA 3500A – MedWatch. The narratives must contain 
assessments of expectedness and causality for all SAEs. Non-SUSAR SAEs are not routinely 
exchanged. 
 From Coordinating Center to Mirati Therapeutics 
The Coordinating Center will forward Suspected Unexpected Serious Adverse Reactions 
(SUSARs) occurring on study with sitravatinib as follows:  
• Reports of fatal or life threatening Serious Adverse Drug Reactions will be forwarded 
within three (3) calendar days of receipt date.  
• Reports of Serious Adverse Drug Reactions (other than fatal or life threatening) will be 
forwarded within eight (8) calendar days of receipt date.  
 From Mirati Therapeutics to Coordinating Center 
Mirati will forward SUSARs occurring with sitravatinib to the Coordinating Center as 
follows:  
• Reports of fatal or life threatening Serious Adverse Drug Reactions will be sent within 
four (4) calendar days of receipt date. 
• Reports of Serious Adverse Drug Reactions (other than fatal or life threatening) will be 
sent within ten (10) calendar days of receipt date.  
Baylor College of Medicine Contact:  
C. Kent Osborne, MD 
Baylor College of Medicine 
Email:  kosborne@bcm.edu  
Fax: (713) 798-8884  
   Phone (for fax issues): (713) 798-1641 
14.  DATA AND SAFETY MONITORING 
 Data Management and Reporting 
All participants who received any amount of study drug will be included in the safety analysis.  
Participants will be monitored at each clinic visit and at any other contact throughout the study 
for the occurrence of AEs and SAEs. The investigator and/or site staff will inquire about the 
occurrence of AEs/SAEs at every clinic visit or contact during the study. Adverse events will be 
graded according to the NCI Common Terminology Criteria v. 5.0 (CTCAEv5). All AEs/SAEs 
that occur during active treatment will be recorded in source documents and on CRFs, regardless 
Mirati Therapeutics Contact:  
Mirati Therapeutics, Inc.  
Email: wilsafety@ppdi.com  
Fax: 1-888-488-9697 
Phone (for fax issues): 1-800-201-8725 


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of grade or relationship to study treatment. Non-serious adverse events that occur during the 30-
day follow-up period will only be recorded on the CRFs if the investigator believes there to be a 
possible relationship to study treatment. Serious adverse events occurring during the 30-day 
follow-up period should be recorded on the CRFs, regardless of suspected relationship to study 
treatment. 
Safety analyses will include summaries of adverse event rates (both frequency and incidence 
tables), baseline laboratory parameters and changes from baseline, frequency of CTC toxicity 
grades for both laboratory and non-laboratory data. The investigators and others responsible for 
patient care at individual sites should institute any supplementary investigations of major adverse 
events based on their clinical judgment of the likely causative factors. 
 Meetings 
We will utilize the Data and Safety Monitoring Plan of the Dan L. Duncan Cancer Center at 
Baylor College of Medicine (DLDCC-BCM). Additionally, the Principal Investigator will review 
all adverse events as they occur to evaluate causality and severity. This will ensure that any 
unanticipated risks or changes to the risk/benefit ratio are identified and reported in a timely 
manner. 
The external Data and Safety Monitoring Board (DSMB) at DLDCC-BCM will review the study 
annually, at a minimum. The DSMB consists of five members not affiliated with BCM or the 
DLDCC, who have prior experience and expertise in the conduct of clinical trials. The DSMB 
will review and monitor study progress, toxicity, safety and other data from this study.  
Information that raises any questions about participant safety or protocol performance will be 
addressed by the Principal Investigator, statistician and study team. Should any major concerns 
arise, the DSMB will offer recommendations regarding whether or not to suspend the study. 
Information to be provided to the DSMB includes, but is not limited to, the following: participant 
accrual, participant demographics, response data, and toxicity data. Additional information may 
be provided to the DSMB upon request. Additional information regarding DSMB policies and 
procedures is located in the DLDCC External DSMB Charter. 
 
 


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15. REGULATORY CONSIDERATIONS 
 Informed Consent 
The investigator (or designee) will explain to each participant the nature of the study, its purpose, 
the procedures involved, the expected duration, the potential risks and benefits involved and any 
discomfort it may entail. Each participant will be informed that participation in the study is 
voluntary, that s/he may withdraw from the study at any time, and that withdrawal of consent 
will not affect his/her subsequent medical treatment or relationship with the treating physician(s) 
or institution. The informed consent will be given by means of a standard written statement, 
written in non-technical language, which will be IRB-approved. The participant should read and 
consider the statement before signing and dating it, and will be given a copy of the document. No 
participant will enter the study or have study-specific procedures done before his/her informed 
consent has been obtained. 
In accordance with the Health Information Portability and Accountability Act (HIPAA), the 
written informed consent document (or a separate document to be given in conjunction with the 
consent document) will include a subject authorization to release medical information to the 
study sponsor and supporting agencies and/or allow these bodies, a regulatory authority, or 
Institutional Review Board access to subjects’ medical information that includes all hospital 
records relevant to the study, including particpants’ medical history. 
 Ethics and GCP 
This study will be carried out in compliance with the protocol and Good Clinical Practice, as 
described in: 
ICH Harmonized Tripartite Guidelines for Good Clinical Practice 1996. 
US 21 Code of Federal Regulations dealing with clinical studies (including parts 50 and 56 
concerning informed consent and IRB regulations). 
Declaration of Helsinki, concerning medical research in humans (Recommendations Guiding 
Physicians in Biomedical Research Involving Human Subjects, Helsinki 1964, amended Tokyo 
1975, Venice 1983, Hong Kong 1989, Somerset West 1996). 
The investigator agrees to adhere to the instructions and procedures described in it and thereby to 
adhere to the principles of Good Clinical Practice that it conforms to. 
 Compliance with Trial Registration and Results Posting Requirements 
Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and the 
Food and Drug Administration Amendments Act (FDAAA), the Principal Investigator is solely 
responsible for determining whether the trial and its results are subject to the requirements for 
submission to the Clinical Trials Data Bank, http://www.clinicaltrials.gov. Information posted 
will allow participants to identify potentially appropriate trials for their disease conditions and 
pursue participation by calling a central contact number for further information on appropriate 
trial locations and study site contact information. 
 
 


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16. STATISTICAL CONSIDERATIONS 
 Study Design 
This phase 2 biomarker-stratified study employs a modified optimal Simon two stage design. 
The decision rule, based on an adaptation of the approach of Jones and Holgren[1], is detailed 
below.  
The primary endpoint is PFS24, where the success is defined as being alive and progression-free 
at 24 weeks after initiation of study treatment.  
 Decision Rule(s) 
The general flow and decision points are illustrated in Figure 4. 
 
In Stage 1, the study will separately enroll seven PFS24 evaluable participants each in the 
PTPN12high/normal and PTPN12low cohorts. If there are no PFS24 events in the 
PTPN12high/normal cohort, enrollment to that stratum will close. If there is at least one PFS24 
event observed in the PTPN12high/normal cohort, then, in Stage 2, the previously accrued 
PTPN12low and PTPN12high/normal cases will be combined into a single cohort, and the study 
will enroll additional cases, regardless of biomarker status, up to a total of 25 participants. At the 
end of the trial, three or more PFS24 events will be required to deem the therapy a success.  
If there is no PFS24 event in the PTPN12high/normal cohort during Stage 1, the PTPN12low 
cohort will continue to accrue to 7 participants. If there are no PFS24 events in the PTPN12low 
cohort, enrollment to that stratum will close, and the trial will close. If there is at least one PFS24 
event, then, in Stage 2, the study will accrue up to a total of 15 PFS24-evaluable PTPN12low 
participants. At the end of the trial, two or more PFS24 events will be required to deem the 
therapy a success, with PTPN12low status as a biomarker of benefit. Extensive simulations 
 
Figure 4. Adapted Phase 2 Design.  
High
nh=7
Low
nl=7
X1h >
rh=1?
X1l > 
rl=1?
Low
Nl=15
Unselected
Nt=25
Xt >
Rt=3
Unselected
Success 
(p1t=0.25)
Unselected
Failure 
(p0t=0.03)
Xl >
Rl=2
Low
Success 
(p1l=0.3)
Low
Failure 
(p0l=0.03)
Yes
No
Yes
No
Yes
No
Yes
STOP
No
Adapt after 
Stage 1
Adapted from Jones & Holmgren


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indicate that operating characteristics of the proposed design perform as expected and are 
independent of the frequency of PTPN12low status. 
  Sample Size and Accrual Rate 
Up to twenty-five PFS24-evaluable participants will be required. This study will have 90% 
power (alpha=0.075 one-tailed) to detect a PFS24 rate of 30% in the PTPN12low cohort 
compared to an unacceptable rate of 3%, and 85% power to detect 25% vs 3% in the unselected 
group. The study is expected to complete accrual within 2 years of study initiation.  
 Stratification Factors 
Participants will be enrolled into two cohorts based on Protein Tyrosine Phosphatase, Non-
Receptor Type 12 (PTPN12) status, which will be determined via analysis of tissue from a 
metastatic site: PTPN12low or PTPN12high/normal.  
 Endpoints and Analysis 
16.5.1 Primary Endpoint and Analysis 
Progression-free survival status at 24 weeks will be used in trial decision-making as described 
above. At the end of the trial, PFS24 events will be summarized descriptively with counts, rates 
and 95% confidence intervals, with appropriate adjustment for the group sequential nature of 
the study design [23]. 
16.5.2 Secondary Endpoints and Analysis 
Time to progression (TTP), objective response rate (ORR), and clinical benefit rate (CBR) will 
be summarized descriptively using appropriate statistics such as counts, rates, and Kaplan-
Meier estimates for time to events and 95% confidence intervals. 
The assessment of safety will be based on the frequency of adverse events, grade, attribution, and 
on the number of laboratory values that fall outside of pre-determined ranges. In particular, the 
number of participants experiencing grade 3 or higher adverse events will be summarized. Data 
will be summarized descriptively with counts, rates and 95% confidence intervals, as appropriate. 
16.5.3 Exploratory Endpoints and Analysis 
CTCs, CTC PTPN12 expression and ctDNA will be assessed longitudinally and will be 
correlated with baseline PTPN12 expression, to determine whether baseline CTCs can be used 
to assess PTPN12 status, to determine whether CTCs and ctDNA are predictive of response 
and/or PFS24. As appropriate, general linear mixed models will be used to model CTC and/or 
ctDNA trajectories. Exploratorally, phosphoproteomics will be examined before and after 
treatment to identify differentially expressed phosphoproteins due to treatment and baseline 
levels or changes in the phosphoproteome that might be predictive of clinical benefit. Tumor 
kinome profiling will be examined to identify differential kinase activity. Similarly, immune 
biomarkers will be examined to identify baseline differences or differential changes that might 
indicate the effect of immunocomponents on response. Data will be summarized descriptively 
with means and/or medians and 95% confidence intervals. False discovery methods will be 
employed to avoid multiple comparison issues with these higher dimensional data. 


A Phase II Study of Sitravatinib in Metastatic, Pre-Treated Triple Negative Breast Cancer  
Principal Investigator: C. Kent Osborne, MD 
Protocol number: H-43432 
 
 
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 Reporting and Exclusions 
All PFS-evaluable participants will be included in analyses of the primary and secondary outcomes 
in their assigned group (modified-ITT population). All participants who receive any study 
treatment will be considered evaluable for the safety analysis (safety population). 
All registered participants will be accounted for. Participants withdrawn or considered ineligible 
before starting study treatment will be replaced. Participants withdrawn prior to completing the 
first cycle of study treatment or determined to be ineligible, will be considered inevaluable for 
PFS24 and will be replaced.  
 
 
 


A Phase II Study of Sitravatinib in Metastatic, Pre-Treated Triple Negative Breast Cancer  
Principal Investigator: C. Kent Osborne, MD 
Protocol number: H-43432 
 
 
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17. REFERENCES 
1. 
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human breast cancer and predict poor clinical outcome. Breast Cancer Res Treat, 2014. 
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Tsujikawa, T., et al., Quantitative Multiplex Immunohistochemistry Reveals Myeloid-
Inflamed Tumor-Immune Complexity Associated with Poor Prognosis. Cell Rep, 2017. 
19(1): p. 203-217. 
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de Mingo Pulido, A., et al., TIM-3 Regulates CD103(+) Dendritic Cell Function and 
Response to Chemotherapy in Breast Cancer. Cancer Cell, 2018. 33(1): p. 60-74 e6. 
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de Boniface, J., et al., Expression patterns of the immunomodulatory enzyme arginase 1 
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A Phase II Study of Sitravatinib in Metastatic, Pre-Treated Triple Negative Breast Cancer  
Principal Investigator: C. Kent Osborne, MD 
Protocol number: H-43432 
 
 
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Do not disclose or use except as authorized 
 
18. 
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A Phase II Study of Sitravatinib in Metastatic, Pre-Treated Triple Negative Breast Cancer  
Principal Investigator: C. Kent Osborne, MD 
Protocol number: H-43432 
 
 
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Do not disclose or use except as authorized 
 
APPENDICES  
 
APPENDIX A:  ECOG Performance Status Scale 
 
Score 
Definition 
Karnofsky Equivalent 
0 
Asymptomatic 
100 
1 
Symptomatic, fully ambulatory 
80 – 90 
2 
Symptomatic, in bed less than 50% of day 
60 – 70 
3 
Symptomatic, in bed more than 50% of day,  
but not bedridden 
40 – 50 
4 
Bedridden 
20 – 30