Conditions: Thymic Carcinoma Non-small Cell Lung Cancer Refractory Thoracic Tumors Small-Cell Lung Cancer
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 88
Healthy volunteers: no

Brief summary:
This is a two-agent, open-label, non-randomized, Phase 1/2 dose escalation and dose expansion study of combinatorial oral vorolanib plus infusional nivolumab in patients with Non-Small Cell Lung Cancer naïve to checkpoint inhibitor therapy, Non-Small Cell Lung Cancer who have progressed on checkpoint inhibitor therapy, Small Cell Lung Cancer ( who have progressed on platinum-based chemotherapy, and thymic carcinoma.

Detailed description:
Primary Objectives:

* Phase I: To assess the safety and tolerability of nivolumab and vorolanib in combination in patients with refractory non small cell lung cancer naïve to checkpoint inhibitor therapy, non small cell lung cancer progressed on prior checkpoint inhibitor therapy considered primary refractory, non small cell lung cancer progressed on prior checkpoint inhibitor therapy considered acquired resistance, small cell lung cancer progressed on platinum-based chemotherapy, and thymic carcinoma.
* Phase II: To evaluate the efficacy as measured by response to the combination nivolumab and vorolanib in patients with refractory non small cell lung cancer naïve to checkpoint inhibitor therapy, non small cell lung cancer progressed on prior checkpoint inhibitor therapy considered primary refractory, non small cell lung cancer progressed on prior checkpoint inhibitor therapy considered acquired resistance, small cell lung cancer progressed on platinum-based chemotherapy, and thymic carcinoma as compared to historical controls.

Secondary Objectives:

* Phase I: To assess antitumor activity as measured by response rate for this novel combination.
* Phase II: To assess, safety, progression free survival and overall survival

Exploratory Objectives:

• To assess the effects of combinatorial treatment on specific pharmacodynamic and pharmacogenetic biomarkers including PD-L1 expression and tumor mutation burden.

Arms:
arm 1: Participants receive vorolanib PO QD on days 1-56 and nivolumab IV over 30 minutes every two weeks (i.e. on Days 1, 15, 29, and 43 of each 56-day cycle) for the first two treatment cycles. After which, the treatment schedule can change to every four weeks (i.e., on Days 1 and 29 of each 56-day cycle) if the patient is not exhibiting disease progression. arm 2: Participants receive vorolanib PO QD on days 1-56 and nivolumab IV over 30 minutes every two weeks (i.e. on Days 1, 15, 29, and 43 of each 56-day cycle) for the first two treatment cycles. After which, the treatment schedule can change to every four weeks (i.e., on Days 1 and 29 of each 56-day cycle) if the patient is not exhibiting disease progression. arm 3: Participants receive vorolanib PO QD on days 1-56 and nivolumab IV over 30 minutes every two weeks (i.e. on Days 1, 15, 29, and 43 of each 56-day cycle) for the first two treatment cycles. After which, the treatment schedule can change to every four weeks (i.e., on Days 1 and 29 of each 56-day cycle) if the patient is not exhibiting disease progression. arm 4: Participants receive vorolanib PO QD on days 1-56 and nivolumab IV over 30 minutes every two weeks (i.e. on Days 1, 15, 29, and 43 of each 56-day cycle) for the first two treatment cycles. After which, the treatment schedule can change to every four weeks (i.e., on Days 1 and 29 of each 56-day cycle) if the patient is not exhibiting disease progression. arm 5: Participants receive vorolanib PO QD on days 1-56 and nivolumab IV over 30 minutes every two weeks (i.e. on Days 1, 15, 29, and 43 of each 56-day cycle) for the first two treatment cycles. After which, the treatment schedule can change to every four weeks (i.e., on Days 1 and 29 of each 56-day cycle) if the patient is not exhibiting disease progression. arm 6: Participants receive vorolanib PO QD on days 1-56 and nivolumab IV over 30 minutes every two weeks (i.e. on Days 1, 15, 29, and 43 of each 56-day cycle) for the first two treatment cycles. After which, the treatment schedule can change to every four weeks (i.e., on Days 1 and 29 of each 56-day cycle) if the patient is not exhibiting disease progression.

Interventions: intervention 1: Vorolanib intervention 2: Nivolumab
Intervention descriptions: intervention 1: Given by mouth intervention 2: Given by IV

Protocol document:
Prot_SAP_001.pdf: 
Phase 1/2 Study to Evaluate the Safety and Preliminary Activity of 
Nivolumab in Combination with Vorolanib  
in Patients with Refractory Thoracic Tumors
VICC THO 1802 
CA209-982 
NCT03583086
Protocol Chair/Sponsor-Investigator: Katy Beckermann, PhD, MD 
Statistician: Yu Shyr 
Coordinating Center: Vanderbilt University Medical Center 
28 March 2024 


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1. SYNOPSIS .......................................................................................................... 6 
2. BACKGROUND AND RATIONALE .................................................................. 11 
2.1. Introduction ....................................................................................................................... 11 
2.2 Targeting Angiogenesis ..................................................................................................... 12 
2.3 Vorolanib, Multi-Kinase Inhibitor of Angiogenesis ............................................................. 13 
2.4 Nivolumab ......................................................................................................................... 16 
2.5 Rationale for Combinatorial Therapy Against PD-1 and VEGF ......................................... 16 
2.6    Correlative Science Background .................................................................................... 17 
3. OBJECTIVES and ENDPOINTS ....................................................................... 18 
3.1. Objectives ......................................................................................................................... 18 
3.2. Endpoints ......................................................................................................................... 19 
4. Patient Selection .............................................................................................. 19 
4.1. Inclusion Criteria ............................................................................................................... 19 
4.2. Exclusion Criteria ............................................................................................................. 21 
4.3. Inclusion of Underrepresented Populations ..................................................................... 24 
4.4. Number of Patients and Replacement of Patients Who Discontinue Early ...................... 24 
5. ENROLLMENT Procedures ............................................................................. 24 
5.1. Registration Procedures ................................................................................................... 24 
5.2. Screen-Failures ................................................................................................................ 26 
6. SCHEDULE OF ASSESSMENTS ..................................................................... 27 
6.1. Study Calendar ................................................................................................................. 27 
6.2. Screening Visit Assessments ........................................................................................... 31 
6.3. Cycle 1, Day 1 Assessments ............................................................................................ 32 
6.4. Cycle 1, Day 8 Assessments (Phase I - Dose Escalation ONLY) ..................................... 32 
6.5. Cycle 1, Day 15 Assessments .......................................................................................... 33 
6.6. Cycle 1, Day 22 Assessments (Phase I - Dose Escalation ONLY) ................................... 33 
6.7. Cycle 1, Day 29 Assessments .......................................................................................... 34 
6.8. Cycle 1, Day 43 Assessments .......................................................................................... 34 
6.9. Cycle 1, Day 56 Assessments .......................................................................................... 35 
6.10. Cycles 2+, Day 1 and Day 29 Assessments ................................................................... 35 
6.11. Cycles 2+, Day 15 and Day 43 Assessments ................................................................. 36 
6.12. Cycles 2+, Day 56 Assessments .................................................................................... 37 
6.13. End-of-Treatment / Withdrawal Assessments ................................................................ 37 
6.14. Follow-Up Visit Assessments (28-Day and 100-Day) ..................................................... 38 
7. Study Procedures ............................................................................................ 39 
7.1. Informed Consent ............................................................................................................. 39 
7.2. Physical Examination ....................................................................................................... 39 
7.3. Performance Status .......................................................................................................... 39 
7.4. Vital Signs, Body Weight, and Oxygen Saturation ........................................................... 39 
7.5. Review of Concomitant Medications and Adverse Events ............................................... 39 
7.6. Surveillance and Expedited Reporting of Dose Limiting Toxicity ...................................... 40 
7.7. Complete Blood Count with Differential ............................................................................ 40 
7.8. Blood Chemistry ............................................................................................................... 40 
7.9. Thyroid Function Testing .................................................................................................. 40 
7.10. Hepatitis Testing ............................................................................................................. 40 
7.11. ECG ................................................................................................................................ 40 
7.12. Urinalysis ........................................................................................................................ 40 


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7.13. Pregnancy Test ............................................................................................................... 40 
7.14. Disease Assessment by CT/MRI .................................................................................... 41 
7.15. Tumor Tissue and Correlative Blood Samples ............................................................... 41 
7.16. Handling of Biological Samples ...................................................................................... 42 
7.17. Specimen Banking ......................................................................................................... 42 
8. PROTOCOL Treatment .................................................................................... 42 
8.1. Dose Level Summary ....................................................................................................... 42 
8.2. Oral Vorolanib ................................................................................................................... 43 
8.3. Nivolumab Infusion ........................................................................................................... 43 
8.4. Discontinuation of Protocol-Indicated Treatment .............................................................. 45 
8.5. Treatment Beyond Progression ........................................................................................ 46 
8.6. Duration of Follow-Up ....................................................................................................... 47 
8.7. Withdrawal from Study ..................................................................................................... 47 
9. Concomitant Treatment ................................................................................... 47 
9.1. Prohibited or Restricted Treatments ................................................................................. 47 
9.2. Permitted Therapy ............................................................................................................ 48 
9.3. Hematopoietic Growth Factors and Transfusion Support ................................................. 48 
9.4. Clarifications about Steroid Use including Hormones ...................................................... 49 
9.5. Palliative Local Radiotherapy ........................................................................................... 49 
10. Adverse Event Management ......................................................................... 50 
10.1. Definition of Dose-Limiting Toxicity ................................................................................. 50 
10.2. Dose Modifications and Delays of vorolanib .................................................................. 52 
10.3. Dose Modifications of Nivolumab ................................................................................... 55 
10.4. Criteria for Dose Delays of Nivolumab ........................................................................... 55 
10.5. Criteria to Resume Nivolumab Treatment ...................................................................... 56 
10.6. Criteria to Permanently Discontinue Nivolumab Treatment ............................................ 57 
10.7. Management Algorithms for Immuno-Oncology Agents ................................................. 58 
10.8. Guidelines for the Management of Infusion Reactions ................................................... 59 
11. Drug Formulation, Supply and Storage ....................................................... 60 
11.1. Description of Vorolanib .................................................................................................. 60 
11.2. Packaging of Vorolanib ................................................................................................... 61 
11.3. Handling and Storage of Vorolanib ................................................................................. 61 
11.4. Description of Nivolumab ................................................................................................ 61 
11.5. Packaging of Nivolumab ................................................................................................. 61 
11.6. Handling and Storage of Nivolumab ............................................................................... 61 
11.7. Drug Accountability and Compliance Check ................................................................... 62 
12. Safety Reporting of Adverse Events ............................................................ 62 
12.1. General ........................................................................................................................... 62 
12.2. Risks Associated with Vorolanib ..................................................................................... 63 
12.3. Risks Associated with Nivolumab ................................................................................... 64 
12.4. Adverse Event (AE) ........................................................................................................ 64 
12.5. Serious Adverse Event (SAE) ........................................................................................ 64 
12.6. Assessment of Adverse Events ...................................................................................... 65 
12.7. Expectedness ................................................................................................................. 65 
12.8. Attribution ....................................................................................................................... 65 
12.9. Specific Instructions for Recording Adverse Events ....................................................... 66 
12.10. Diagnosis versus Signs and Symptoms ....................................................................... 66 
12.11. Deaths .......................................................................................................................... 66 


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12.12. Pre-existing Medical Conditions ................................................................................... 66 
12.13. Hospitalizations for Medical or Surgical Procedures .................................................... 66 
12.14. Pregnancies in Female Patients ................................................................................... 67 
12.15. Pregnancies in Female Partners of Male Patients ....................................................... 67 
12.16. Overdose ...................................................................................................................... 67 
12.17. Post-Study Adverse Events .......................................................................................... 67 
12.18. Serious Adverse Events ............................................................................................... 68 
12.19. Institutional Review Board ............................................................................................ 68 
12.20. Food and Drug Administration (FDA) ........................................................................... 68 
12.21. Expedited 7 and 15 Day Reporting Requirements for IND ........................................... 68 
12.22. Xcovery (Equinox Sciences) ........................................................................................ 69 
12.23. Bristol-Myers Squibb .................................................................................................... 70 
13. DATA SAFETY AND MONITORING ................................................................ 70 
13.1. Data Management and Reporting .................................................................................. 70 
13.2. Meetings ......................................................................................................................... 71 
13.3. Monitoring ....................................................................................................................... 71 
13.4. Data Handling and Record Keeping ............................................................................... 72 
14. REGULATORY CONSIDERATIONS ............................................................... 72 
14.1. Protocol Review and Amendments ................................................................................ 72 
14.2. Informed Consent ........................................................................................................... 73 
14.3. Ethics and GCP .............................................................................................................. 73 
14.4. Confidentiality ................................................................................................................. 74 
14.5. Study Termination ........................................................................................................... 74 
15. MULTI-CENTER GUIDELINES ....................................................................... 74 
15.1. Pre-Study Documentation .............................................................................................. 74 
15.2. Protocol Review and Amendments ................................................................................ 75 
15.3. Study Documentation ..................................................................................................... 75 
15.4. Records Retention .......................................................................................................... 75 
15.5. Publication ...................................................................................................................... 75 
16. StatISTICAL CONSIDERATIONS ................................................................... 76 
16.1. Phase I (Dose-Escalation) Design ................................................................................. 76 
16.2. Phase II (Dose-Expansion) Design ................................................................................ 76 
16.3. Data Analysis Plan ......................................................................................................... 78 
16.4. Anti-Tumor Activity Analyses .......................................................................................... 78 
17. REFERENCES ................................................................................................ 78 
 
TABLES 
TABLE 1:  Comparison of Objective Response Rates (ORR) after PD-1 / VEGF Inhibition 
in patients with Previously Treated Renal Cell Carcinoma (RCC) ...................................... 17 
TABLE 2:  Dose Escalation Summary ................................................................................ 42 
TABLE 3:  Vorolanib Dose Modifications for Hematologic Toxicities ................................... 53 
TABLE 4:  Methods of Contraception ................................................................................. 86 
TABLE 5:  Response Criteria for Evaluation of TARGET Lesions ...................................... 90 
TABLE 6:  Response Criteria for Evaluation of NON-TARGET Lesions ............................. 90 
TABLE 7:  Overall Response Status for Patients with Baseline Measurable Disease ........ 91 
TABLE 8:  Best Overall Response when Confirmation of CR and PR Required ................ 92 
 


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APPENDICES 
APPENDIX 1 Cockcroft-Gault Formula .............................................................. 82 
APPENDIX 2 ECOG Performance Status ........................................................... 83 
APPENDIX 3 New York Heart Association (NYHA) Functional Classification 84 
APPENDIX 4 ......................................................................................................... 85 
APPENDIX 5 Acceptable Contraception ............................................................ 86 
APPENDIX 6 Response Evaluation Criteria in Solid Tumors (RECIST v1.1) .. 88 
APPENDIX 7 Guidelines for the Management of Immune-Related Adverse 
Events (irAEs) ...................................................................................................... 93 
 
 
 


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1.  SYNOPSIS 
 
Trial Title 
Phase 1/2 Study to Evaluate the Safety, and Preliminary Activity of Nivolumab in 
Combination with Vorolanib in Patients with Refractory Thoracic Tumors. 
Phase 
and 
Overall 
Trial 
Design 
This is a two-agent, open-label, non-randomized, Phase 1/2 dose escalation 
and dose expansion study of combinatorial oral vorolanib plus infusional 
nivolumab in patients with Non-Small Cell Lung Cancer (NSCLC) naïve to 
checkpoint inhibitor therapy, NSCLC who have progressed on checkpoint 
inhibitor therapy, Small Cell Lung Cancer (SCLC) who have progressed on 
platinum-based chemotherapy, and thymic carcinoma. 
Trial Sites 
Vanderbilt University Medical Center, Stanford University, University of Chicago, 
Fox Chase Cancer Center, Emory University, Baptist Clinical Research Institute, 
and Providence Cancer Institute. 
Concept 
and 
Rationale 
The successful development of therapeutic agents targeting the PD-1/PD-L1 
axis has been a major therapeutic advancement in oncology. In particular, 
nivolumab, a potent, highly selective, fully humanized monoclonal antibody 
against PD-1, has been approved for the treatment of NSCLC patients. The 
ORR in many tumor types are generally in the range of 19-25%. Thus, 
combination with other therapies is necessary to further increase the response 
rate and efficacy. The potential for increased efficacy of combining anti-
angiogenic therapy with immunotherapy is supported by preclinical evidence in 
NSCLC, where the combination significantly inhibited tumor growth compared to 
each single agent alone, as well as increased the tumor infiltration of immune 
cells. Preliminary data from one phase Ib study observed a longer median 
progression-free survival when bevacizumab was added to nivolumab (9 
months) compared to single agent nivolumab (4 months in squamous and 5 
months in nonsquamous histology) maintenance therapy. 
Thymic epithelial tumors are rare cancers, which are classified as either 
thymomas or thymic carcinomas. The latter is usually more aggressive and less 
responsive to chemotherapy and has a higher probability of producing distant 
metastases. The 5-year overall survival rate for thymic carcinomas is only 30%-
50%.  Complete and radical surgical resection remains the standard therapeutic 
approach for localized disease and is currently the only potentially curative 
option. Patients with unresectable or recurrent disease usually receive palliative 
chemotherapy. Although the data are limited, angiogenesis appears to have a 
role in the development and progression of thymic epithelial tumors. For thymic 
carcinomas in particular, one study observed that VEGF was expressed in a 
majority of tumors, and VEGF expression and microvessel density was 
associated with invasiveness. Sunitinib, a multi-targeted TKI that inhibits 
VEGFR, KIT, and PDGFR, achieved a >90% disease control rate in patients 
with thymic cancers who were refractory to platinum-based chemotherapy. 
Based on this study, sunitinib is recommended as second-line therapy.  Several 
studies have found high PD-1/PD-L1 expression in thymic epithelial tumors 
suggesting that targeting the PD-1/PD-L1 pathway is a potential 
immunotherapeutic approach. 
 
It is known that tumor cells secrete VEGF-A which, in addition to promoting 
angiogenesis, decreases dendritic cell expression of co-stimulatory molecules 
and T cell priming, and also encourages the formation of myeloid-derived 
suppressor cells (MDSCs). It has been shown that sunitinib, a VEGFR, PDGFR, 


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CSF1R, Kit and Flt-3 inhibitor, reduces infiltration by MDSC and regulatory T 
lymphocytes, thereby potentially enhancing the efficacy of immunotherapy. 
Initial combinations with TKI of VEGFR and PD-1 inhibitors were not well 
tolerated at the full doses of both single agents in renal cell carcinoma. Thus, it 
is desirable to have a VEGFR inhibitor with lower toxicity for combination with 
immunotherapy. 
Vorolanib is a small molecule indolinone inhibitor of a family of type III and type 
V receptor tyrosine kinases characterized by an extracellular domain containing 
several immunoglobulin-like domains, a membrane spanning region, and a 
cytoplasmic split kinase domain (1). Included in this family are receptors for 
three isoforms of vascular endothelial cell growth factors (VEGFR 1,2,3), two 
isoforms of platelet derived growth factor (PDGFR α and β), stem cell factor (c-
Kit), colony-stimulating factor 1 receptor (CSF1R), Fms-related tyrosine kinase 3 
like receptor (Flt-3), and ligand for the receptor tyrosine kinase (RET).  Vorolanib 
is a novel analog of sunitinib with similar kinase profiles. It was designed to 
lower the toxicity by changing the PK/PD of sunitinib. Phase I clinical data 
suggested safety and tolerability with only three grade 3 adverse events 
including hypertension and pain with a 36% ORR in TKI resistant and naïve 
patient with RCC(2). In addition, combination trial of vorolanib and everolimus in 
the phase I was tolerated at full doses of both drugs in patients with RCC some 
of whom experience a partial response.  We propose to test in a Phase I/Phase 
II study to evaluate the safety, and preliminary activity of nivolumab in 
combination with vorolanib in patients with refractory thoracic tumors. 
Protocol 
Treatment 
and  
Mechanisms 
 
Vorolanib is an oral angiogenesis inhibitor being developed to treat malignant 
solid tumors and age-related macular degeneration (AMD). Vorolanib is not 
approved or marketed in any country.  The study will provide vorolanib to each 
site.  This drug is taken orally once daily at the dosage determined in phase I 
dose escalation. 
 
Nivolumab (OPDIVO) is a human immunoglobulin G4 (IgG4) monoclonal 
antibody that binds to the PD-1 receptor found on T cells. Nivolumab infusion is 
approved for a variety of indications, the study will provide nivolumab to each 
site for infusion every 2 weeks at a flat dose of 240 mg. 
 
Of note: If the patient has not exhibited evidence of disease progression (non-
PD) and is undergoing treatment in cycles 3+, then nivolumab will be 
administered every 4 weeks at a flat dose of 480 mg. 
 
 
Treatment 
Schedule 
Treatment will consist of cycles lasting 8 weeks (56 days) each.   
 
All patients are scheduled to receive oral vorolanib once daily (QD) on a 
continuous dosing schedule as determined by the recommended phase I 
combination dose. 
 
All patients are scheduled to receive nivolumab as a 30 minute intravenous 
infusion every two weeks (i.e. on Days 1, 15, 29, and 43 of each 56-day cycle) 
for the first two treatment cycles. After which, the treatment schedule can 
change to every four weeks (i.e., on Days 1 and 29 of each 56-day cycle) if the 
patient is not exhibiting disease progression. 
 


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Objectives and 
Endpoints 
mary Objectives: 
Phase I: To assess the safety and tolerability of nivolumab and vorolanib in 
combination in patients with refractory NSCLC naïve to checkpoint inhibitor 
therapy, NSCLC progressed on prior checkpoint inhibitor therapy considered 
primary refractory, NSCLC progressed on prior checkpoint inhibitor therapy 
considered acquired resistance, SCLC progressed on platinum-based 
chemotherapy, and thymic carcinoma.  
Phase II: To evaluate the efficacy as measured by response to the combination 
nivolumab and vorolanib in patients with refractory NSCLC naïve to checkpoint 
inhibitor therapy, NSCLC progressed on prior checkpoint inhibitor therapy 
considered primary refractory, NSCLC progressed on prior checkpoint inhibitor 
therapy considered acquired resistance, SCLC progressed on platinum-based 
chemotherapy, and thymic carcinoma as compared to historical controls.   
 
    Secondary Objectives: 
Phase I: To assess antitumor activity of this novel combination.   
Phase II: To assess the effects of tumor PD-L1 status and tumor mutation 
burden (TMB) on the response to combinatorial treatment vorolanib and 
nivolumab. 
 
Exploratory Objectives: 
To assess the effects of combinatorial treatment on specific pharmacodynamic 
and pharmacogenetic biomarkers.  
 
mary Endpoints: 
Phase 2 recommended combination dose will be determined when >1/3 or >2/6 
dose limiting toxicities measured using CTCAE criteria version 5.0 
Phase 2 best response will be measured by RECIST v1.1  
 
    Secondary Endpoints: 
Phase II progression free survival at six months and one year intervals, duration 
of response, disease control rate, overall survival at one year, and ORR as 
related to PD-L1 status measured as <1%, 1-49%, and >50%. 
      
      Exploratory Endpoints:  
To assess the effects of combinatorial treatment on specific pharmacodynamic 
and pharmacogenetic biomarkers, including but not limited to circulating levels 
of serum CSF1 and VEGF, protein expression using CyTOF, and multiplex 
immunofluorescence. 
Main 
Inclusion/
Exclusion 
Criteria 
Main Inclusion Criteria: 
Patients must be refractory or refuse  first-line therapy 
NSCLC patients may have received up to three prior treatment regimens, 
except patients with EGFR, ALK, ROS1 and BRAF positive NSCLC must have 
progressed on at least one TKI and are not limited in the number of prior 
regimens they have received 
Patients with non-small cell lung cancer will be allowed to enter following 
progression on prior checkpoint inhibitor therapy or if they refuse standard 
platinum-based chemotherapy 
Treatment with prior bevacizumab or ramucirumab is allowed 
Thymic carcinoma patients may have received any number of prior lines of 
therapy 


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SCLC patients must have progressed on platinum-based chemotherapy and 
may have received up to three prior lines of therapy provided that no prior 
regimen contains an oral VEGF TKI; prior regimens can include an anti-PD-1 or 
PD-L1 agent. 
Main Exclusion Criteria: 
Prior treatment with VEGF TKI is not allowed but prior bevacizumab or 
ramucirumab is allowed in the NSCLC or thymic cohorts 
Prior treatment with checkpoint inhibitor therapy in patients with thymic 
carcinoma is not allowed 
Overall 
Trial 
Design 
Dose-Escalation Phase: 
Standard 3+3 design with the following intended dose levels: 
Dose 
 Level 
 
Vorolanib 
Oral 
continuous QD  
 
Nivolumab 
I.V. 
Days 1, 15, 29, and 43 (each cycle) 
 
-1 
 
100 mg 
 
240 mg 
 
1 
 
200 mg 
 
240 mg 
 
2 
 
300 mg 
 
240 mg 
 
3 
 
400 mg 
 
240 mg 
 
1 cycle = 56 days (8 weeks) 
 
The first cohort of patients will be started at dose level 1.  At least 3 patients will 
be studied at each dose level and evaluated for toxicity.  If 0 of 3 patients 
experience a dose-limiting toxicity (DLT), the dose will be escalated.  If 1 of 3 
patients experiences a DLT, 3 additional patients will be treated.  If none of the 
additional patients develop a DLT, the dose will be escalated, otherwise 
escalation ceases.  If > 2 of 3, or > 2 of 6, patients experience a DLT, the 
Recommended Combination Dose (RCD) has been exceeded. 
  
Dose-Expansion Phase: 
In the phase 2 dose-expansion portion of the study, additional patients (about 
159 total additional patients) will be split into five cohorts (about 21-41 evaluable 
patients/cohort), consisting of patients with refractory NSCLC either naïve to or 
progressed on checkpoint inhibitor therapy (primary refractory and acquired 
resistance), SCLC progressed on platinum-based chemotherapy, and thymic 
carcinoma, who will be treated at the RCD determined in the phase 1 portion of 
the study. Primary refractory is defined as radiographic progression of disease ≤ 
12 weeks after initiation of treatment (+2 week window permitted for radiograph 
scheduling). Acquired resistance includes achieving RECIST defined partial, 
complete response, OR stable disease for at least 12 weeks (+2 week window 
permitted for radiograph scheduling) followed by radiographic progression of 
disease.  


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Number of 
Patients 
Up to 177 patients:  Approximately 9-18 evaluable patients in Dose Escalation; 
and about 159 evaluable patients in five Dose Expansion cohorts, consisting of 
Non-Small Cell Lung Cancer naïve to checkpoint inhibitor therapy (n=39), Non-
Small Cell Lung Cancer primary refractory to prior checkpoint inhibitor therapy 
(n=21), Non-Small Cell Lung Cancer acquired resistance to prior checkpoint 
inhibitor therapy (n=21), Small Cell Lung Cancer (n=37) and Thymic carcinoma 
(n=41).  
Study 
Assessments 
See the Schedule of Assessments in Section 6. 
 


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2.  BACKGROUND AND RATIONALE 
 
2.1.  Introduction 
The successful development of therapeutic agents targeting the programmed cell death protein 1 
(PD-1) and programmed death-ligand 1 (PD-L1) axis has been a major therapeutic advancement in 
oncology. In particular, nivolumab, a potent, highly selective, fully humanized monoclonal antibody 
against PD-1, has been approved for the treatment of metastatic renal cell carcinoma, melanoma, 
urothelial, head and neck, Hodgkin Lymphoma and Non-small cell lung cancer (NSCLC) patients.  It 
has also shown promising activities in a number of other tumor types such as gastric carcinoma and 
triple-negative breast cancer. 
The objective response rates of immune checkpoint inhibitors in PD-L1 positive NSCLC are 
approximately 25-40% and in other tumor types without PD-L1 selection response rates are 
generally in the range of 10-25% (1). Thus, combination with other therapies is necessary to further 
increase the response rate and efficacy in PD-L1 negative, as well as PD-L1 positive, patients. 
Non-Small Cell Lung Cancer 
Non-small cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancers diagnosed. 
The overall 5-year survival rate is only 17%; prognosis is worse for patients that are diagnosed with 
distant metastases, where 5-year survival rates are less than 5% (3). Cytotoxic chemotherapy for 
the treatment of metastatic disease has clearly hit a plateau in terms of improving clinical outcome. 
Additionally, the development of targeted therapies directed towards specific oncogenic drivers has 
been associated with meaningful improvements in survival, but only in a minority of patients whose 
tumors harbor those specific mutations (e.g., epidermal growth factor receptor and anaplastic 
lymphoma kinase alteration) (4-6).  
To overcome these therapeutic limitations, investigators have explored the use of anti-angiogenic 
agents. The main driver for angiogenesis in NSCLC is the development of hypoxia within a growing 
tumor. Hypoxia activates the hypoxia-inducible factor-1A (HIF-1a) and HIF-2a that in turn activates 
multiple intracellular signaling pathways leading to the generation and release of pro-angiogenic 
factor from within the tumor and stroma (7,8). Thus, inhibition of this pathway could be a viable 
treatment option for NSCLC. Indeed, two monoclonal antibodies, bevacizumab and ramucirumab, 
are FDA approved therapies when administered in combination with chemotherapy. 
As mentioned above, the anti-PD1 immunotherapy nivolumab is approved for patients with 
advanced NSCLC. Depending on subtype, the median overall survival was 9.2 or 12.2 months, 
which was an improvement over cytotoxic chemotherapy (6 and 9.4 months) (9-11). Despite this 
improvement in clinical outcome, the response rates were minimal at 20% suggesting there is room 
to develop new therapeutic strategies to increase tumor response. 
The potential for increased efficacy of combining anti-angiogenic therapy with immunotherapy is 
supported by preclinical evidence in NSCLC, where the combination significantly inhibited tumor 
growth compared to each single agent alone, as well as increased the tumor infiltration of immune 
cells (12). Multiple trials investigating angiogenesis inhibitors (e.g., bevacizumab, ramucirumab, and 
nintedanib) administered in combination with immunotherapies (e.g., nivolumab, ipilimumab, 
pembrolizumab, and atezolizumab) in NSCLC are either ongoing or planned (13). Preliminary data 
from one phase Ib study observed a longer median progression-free survival when bevacizumab 
was added to nivolumab (9 months) compared to single agent nivolumab (4 months in squamous 
cell and 5 months in nonsquamous histology) maintenance therapy (14). Despite this improvement, 
the response rates were minimal (8% for the combination versus 10% single-agent nivolumab) and 
similar between the two treatment arms comparing maintenance therapy. 
 
 


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Thymic Carcinoma 
Thymic epithelial tumors are rare cancers, which are classified as either thymomas or thymic 
carcinomas. The latter is usually more aggressive and less responsive to chemotherapy and has a 
higher probability of producing distant metastases. The 5-year overall survival rate for thymic 
carcinomas is only 30%-50% (15).  
Due to the rarity of thymic carcinomas, sufficiently powered clinical trials that aid in the development 
of international guidelines concerning the treatment of these patients do not exist (16,17). Complete 
and radical surgical resection remains the standard therapeutic approach for localized disease and 
is currently the only potentially curative option. Patients with unresectable or recurrent disease 
usually receive palliative chemotherapy. National Comprehensive Cancer Network (NCCN) 
recommended first-line chemotherapeutic regimens include platinum-based combinations based on 
data from small phase II trials that showed excellent disease control rates of 71%-100% (18). 
Despite this success, tumor response rates were minimal (21%-25%) suggesting the need for new 
therapies.  
 
Although the data are limited, angiogenesis appears to have a role in the development and 
progression of thymic epithelial tumors (19-21). For thymic carcinomas in particular, one study 
observed that vascular endothelial cell growth factor (VEGF) was expressed in a majority of tumors, 
and VEGF expression and microvessel density was associated with invasiveness (20). Also, the 
microvessel density of thymic cancers was higher than both noninvasive and invasive thymomas, 
suggesting that thymic carcinomas are extremely vascular and could benefit from anti-angiogenic 
therapies. Indeed, sunitinib, a multi-targeted tyrosine kinase inhibitor (TKI), that inhibits VEGFR, 
stem cell factor (KIT), and platelet derived growth factor receptor (PDGFR), achieved a >90% 
disease control rate in patients with thymic cancers who were refractory to platinum-based 
chemotherapy (19). Based on this study, sunitinib is recommended as second-line therapy. 
However, there is room for improvement as the response rate to sunitinib monotherapy was 
minimal at 26% and the median progression free survival (PFS) was 7.2 months.  
 
Several studies have examined PD-1/PD-L1 expression in thymic epithelial tumors. A recent study 
observed that alterations in PD-L1 gene copy number was increased compared to normal in a 
subset of patients, and in those patients with high copy number gain, immunohistochemical (IHC) 
expression of PD-L1 was also higher (22). Furthermore, this study showed that high PD-L1 
expression is associated with a favorable clinical outcome suggesting that targeting the PD-1/PD-
L1 pathway is a potential immunotherapeutic approach.  
 
Based on the above data, one would hypothesize that a treatment regimen combining an 
antiangiogenic agent with immunotherapy could be efficacious, and potentially synergistic, in patients 
with thymic carcinoma. 
2.2 Targeting Angiogenesis 
Angiogenesis, the process that describes the formation of new blood vessels, is increased in 
tumors, and thus has become a target of anti-tumor drug development. Tumor cells secrete growth 
factors, such as VEGF and PDGF, which induce angiogenesis in order to support tumor growth. 
These growth factors interact with cell surface receptors (e.g., VEGFR and PDGFR) inducing a 
cascade of signaling events that lead to formation of tumor blood vessels. 
Although the VEGF pathway plays a significant role in the development of tumor blood vessels, 
tyrosine kinase inhibitors that target a single protein in the pathway is associated with a modest 
survival benefit most likely due to the development of tumor resistance induced by up-regulation of 
other pathways that stimulate angiogenesis (7). Thus, the use of TKIs that simultaneously inhibit 
multiple angiogenic pathways have been developed with the hypothesis that inhibiting multiple 
targets with one therapy leads to increased clinical benefit. Sorafenib and sunitinib are two multi-
targeted TKIs that have received FDA approval for the treatment of multiple cancers, including renal 
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Both sorafenib and sunitinib along with several emerging TKIs have been evaluated in thoracic 
cancers, yet none are currently FDA approved (23). However, the NCCN guidelines recommend 
sunitinib as second-line therapy for thymic carcinomas. The monoclonal antibodies bevacizumab 
and ramucirumab that inhibit VEGF-A and VEGFR2, respectively, remain the only FDA approved 
antiangiogenic therapies in thoracic cancers.  
2.3 Vorolanib, Multi-Kinase Inhibitor of Angiogenesis 
Vorolanib is an oral multi-kinase inhibitor of VEGFR, PDGFR, colony-stimulating factor 1 receptor 
(CSF1R), stem cell factor (c-Kit), and FMS-like tyrosine kinase 3 (FLT3) that is intended for the 
treatment of solid tumors and pathologic angiogenesis in diseases such as neovascular “wet” age-
related macular degeneration (AMD), and von Hippel-Lindau Disease. 
The binding of vorolanib to its target receptors (VEGF and PDGF) results in angiogenesis inhibition. 
Vorolanib is structurally related to sunitinib and has been designed to improve upon the safety 
profile without compromising the efficacy of sunitinib.  The expectation is that an improved safety 
profile will allow continuous daily dosing to deliver a stronger anti-angiogenic effect and permit 
combination modalities currently precluded by safety issues for sunitinib. 
Vorolanib is a small molecule indolinone inhibitor of a family of type III and type V receptor tyrosine 
kinases characterized by an extracellular domain containing several immunoglobulin-like domains, a 
membrane spanning region, and a cytoplasmic split kinase domain (1). Included in this family are 
receptors for three isoforms of vascular endothelial cell growth factors (VEGFR 1,2,3), two isoforms 
of platelet derived growth factor (PDGFR α and β), stem cell factor (c-Kit), colony-stimulating factor 
1 receptor, FMS-related tyrosine kinase 3 like receptor, and ligand for the receptor tyrosine kinase 
(RET).   
The combined effect on VEGFR and PDGFR allows these drugs to target endothelial cells and 
pericytes, respectively.  Endothelial cell proliferation necessary for new vessel formation is 
dependent on VEGF.  The PDGF dependent pericytes are important for the stabilization of 
neovasculature (24). As such, the combined effect on these two targets (VEGFR and PDGFR) with 
nearly equal potency is thought to contribute to the increased efficacy of sunitinib over other 
tyrosine kinase inhibitors such as sorafenib that primarily target VEGF (25). In addition to the 
primary targets of VEGFR and PDGFR, CSF1R blockage reprograms tumor-infiltrating 
macrophages and might improve responses to T cell checkpoint inhibitor therapy.  
Due to the unique binding mode and chemical scaffold of sunitinib it binds to receptor tyrosine 
kinases (RTKs) via the Type I binding mode where the kinase is in active conformation.  In contrast, 
the two other VEGFR inhibitors approved by FDA (sorafenib and pazopanib) bind to RTKs via the 
Type II binding mode where the kinase is in an inactive conformation.  The Type I inhibitors are less 
likely to have resistant mutations compared to Type II inhibitors. 
Vorolanib is developed on the same chemical scaffold as sunitinib.  Importantly, like sunitinib, 
Vorolanib is able to target the angiogenic regulators VEGFR and PDGFR with similar potency. The 
potent effect of both vorolanib and sunitinib on inhibition of phosphorylation of VEGFR2 and PDGFR 
was confirmed in cell based assays.  In targeting the VEGF and PDGF receptors, vorolanib is 
expected to disrupt tumor angiogenesis and to be active in a broad spectrum of solid tumors. 
Preclinical Experience 
 
In a diverse panel of human tumor nude mouse xenograft models vorolanib displayed comparable 
activity to sunitinib with respect to tumor growth inhibition. Models of renal cell, colon, pancreatic, 
melanoma, and leukemia were studied. In these studies, the minimum effective dose that gave at 
least 50% inhibition of tumor growth in a sensitive model was 40 mg/kg twice a day (BID). The dose 
of vorolanib that induced a maximum effect (complete tumor stasis or regression) in most xenograft 
models was 160 mg/kg BID. Vorolanib has also been tested in a rat model of choroidal 
neovascularization (CNV), and it was observed to inhibit CNV at both 10 and 30 mg/kg ONCE A 
DAY.  


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Comparisons of exposures for vorolanib in toxicokinetic studies with exposures achieved at the 
maximum effective dose in mouse models also predict a large safety window for vorolanib. At a 150 
mg/kg dose of vorolanib in nude mice (Study X82-NCL-010 and X82-NCL-018), an area under the 
plasma concentration time curve (AUC) of 33,844 ng.hr/ml was observed. Accounting for BID 
dosing, the exposure at an optimum efficacious dose in mice would then be about 67,688 ng.hr/ml. 
The toxicokinetic studies in female rats (most sensitive gender) established an STD10 of 160,418 
ng.hr/ml. This relatively safe exposure in rats is 2.4 times the maximum efficacious exposure in mice 
and 9.6 times the exposure needed to inhibit tumor growth by 53% in the 786-O renal carcinoma 
xenograft model. Taken together, these data suggest a very high safety window for vorolanib, if 
translatable to man, would permit maximally effective dosing with reduced toxicity. 
Likewise the 39 week dog study at 12.5, 25, or 50 mg/kg/day of vorolanib concluded that the only 
adverse effect was tubular degeneration/atrophy in the testes at >12.5 mg/kg/day observed at 
interim or terminal sacrifice. Other minor, nonadverse, vorolanib-related effects included reduced 
intraluminal sperm in epididymis in one male at 12.5 mg/kg/day (interim sacrifice only) and yellow 
discoloration of the hair coat, minor protein concentration changes, decreased testis and epididymis 
weights, cellular debris and/or reduced intraluminal sperm in the epididymis, increased 
extramedullary hematopoiesis in the spleen, and hypocellular bone marrow for animals given >25 
mg/kg/day. Based on these results, the no observed adverse effect level (NOAEL) of vorolanib, 
when administered for at least 39 weeks, is 50 mg/kg/day for females and was not achieved for 
males.  
Clinical Experience 
As of January 2017, vorolanib has been administered to humans in ongoing Phase 1 and Phase 2 
studies. The clinical development plan for 2016 includes continuing a Phase 1 study to assess the 
early clinical safety, tolerability, and preliminary pharmacokinetics of vorolanib in patients with 
advanced solid tumors (no new patients will be enrolled, but there are patients that remain on 
study). This study evaluated vorolanib at doses from 50 to 800mg QD.  MTD was not reached at 
800mg, but absorption seemed to reach plateau at 400 – 800mg.  Thus, 400mg QD was the 
recommended dose. The Phase 1 study to evaluate the safety and preliminary biologic 
activity/efficacy of vorolanib in subjects with neovascular age-related macular degeneration (AMD) 
has been completed. Doses at up to 200mg QD were well tolerated. In addition, a pharmacokinetic 
study has been performed in elderly healthy volunteer subjects and a further bioequivalence study 
in healthy subjects aged 18 and above. A Phase 2b double masked, placebo controlled study was 
initiated in March 2015 to investigate the potential efficacy of vorolanib in previously treated patients 
with wet AMD. In oncology, there is an ongoing single agent Phase 1 study and a Phase 2/3 
combination study with everolimus in RCC subjects in China, and there are ongoing Phase 1/2 
combination studies with everolimus and docetaxel being conducted under Investigator INDs in US 
(2).  
Preliminary Clinical Efficacy 
Data regarding antitumor activity of vorolanib includes that available from the March 2016 version of 
the vorolanib Investigator’s Brochure, including results from Clinical trial Protocol X82-CLI-101, a 
Phase 1, First in Human, Dose-Escalation Study to Evaluate the Safety, Tolerability, and 
Pharmacokinetics of X-82 in Patients with Advanced Solid Tumors [NCT01296581]. 
Of the 52 patients that had been treated, 46 were considered to be evaluable for efficacy [received 
at least 2 cycles of therapy (1 cycle for patients with PD) and had a post-baseline response 
assessment with a response of complete response (CR), partial response (PR), stable disease 
(SD), or progressive disease (PD)] at the time of the data cut-off: 1 patient had a CR, 1 patient had 
a PR, 24 had SD, and 20 had PD as their best response. 
The patient with a CR had adenocarcinoma of the pancreas.  This patient was treated with vorolanib 
400 mg capsule daily and was on study for 6 cycles before developing PD.  This patient had a small 


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lesion at baseline and had previously been treated with adjuvant 5-fluorouracil and radiation, ending 
approximately 2.5 months prior to starting vorolanib. 
The patient with a PR had a Hurthle cell carcinoma.  This patient was treated with vorolanib 100 mg 
tablet daily and was on study for 16 cycles before developing PD.  The patient had received prior 
radiation therapy and surgery.  In addition, this patient had received one prior systemic agent 
(dovitinib/TKI258) and had been on that treatment for 11½ months. 
Of the patients with SD as best response, 11 were on vorolanib for ≥ 6 cycles, 5 of whom were on 
VOROLANIB for ≥ 12 cycles, with 3 remaining on treatment as of the cut-off.  These 3 patients have 
been on study for 25+ (carcinoid-low grade neuroendocrine) cycles.  The latter patient was initially 
treated with the 200 mg capsule BID, then switched to 50 mg tablet daily, and then 100 mg tablet 
daily).  The two latter patients had PD beginning approximately 13 and 15 months after starting 
treatment, but were allowed to remain on study because it was considered to be in their best 
interest.  In the case of the latter patient, PD was based on an increase in tumor size from nadir, 
with little further change since then and comparable to baseline. 
Anticipated Clinical Risk 
The current risk profile for vorolanib is based on safety data collected from nonclinical studies and 
clinical experience with vorolanib, as well as from labeling from similar products, sunitinib (Sutent®), 
sorafenib (Nexavar®), pazopanib (Votrient®), and axitinib (Inlyta®). 
The pathology findings from the toxicology studies for vorolanib include adrenal cortical changes, 
lymphoid depletion, pancreatic changes, and bone marrow hypocellularity.  Laboratory findings 
include changes in red blood cell counts, hemoglobin, hematocrit, lower white blood cell and 
lymphocyte counts, lowering calcium, higher platelet counts, hyperglycemia, and increases in 
aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase, creatine 
kinase, and potassium.  The toxicity studies also indicate increased toxicities in female rats 
compared with male rats, likely related to increased drug exposure.  These findings were not 
observed in dogs.  A phototoxicity study in guinea pigs demonstrated sensitivity to light when 
exposed to vorolanib. 
As of Jan 2016, the most frequent (≥ 10%) drug-related adverse events reported with vorolanib from 
the first-in-human oncology Phase 1 single-agent study include: fatigue, nausea, diarrhea, hair color 
changes, vomiting, asthenia, rash, and peripheral edema, mostly grade 1 or 2.  Ten patients have 
reported Grade 3 treatment-related AEs including acute pancreatitis, lymphocyte count decrease, 
neutropenia, diarrhea and fatigue, nausea, proteinuria, neutrophil count decreased and anemia.  
There have not been any Grade 4 treatment-related AEs.  While not a consistent finding, some 
patients have had decreases in platelets and hemoglobin. Some patients receiving vorolanib in a 
study in subjects with age-related macular degeneration had increased transaminases.  No subjects 
have met Hy’s law criteria.  Improvement in transaminases have been documented in all cases, 
either during a dose pause, permanent drug discontinuation, or with continued dosing. 
Adverse events considered serious, unexpected and possibly related to vorolanib from these 
studies are acute pancreatitis and deep vein thrombosis.  In addition, severe adverse events 
reported to the sponsor from studies from other sponsors or from investigator-sponsored IND 
studies and that were considered to be related to vorolanib by the investigator include cerebral 
infarction (resulting in facial weakness and slurred speech; temporary memory loss), fistula 
(between colon and tumor)/pleural effusion, infections, pulmonary embolism, low platelet count, and 
hemorrhage (intraperitoneal bleed with an outcome of death).  The original assessment by the 
investigator for the hemorrhage was that the event was unrelated to vorolanib and was due to a 
mesenteric mass invading major vessels.  However, because of the association of bleeding with this 
class of drugs, the causality assessment was changed to being possibly related to vorolanib.  These 
events were from combination studies with everolimus or docetaxel, with the exception of the 
temporary memory loss, which was from a single agent study in China. 


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Approved vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR TKIs) have 
a well characterized adverse event profile.  The cardiotoxic effects include a high incidence of 
hypertension, less frequent occurrence of impaired cardiac function [decreased left ventricular 
ejection fraction (LVEF) or congestive heart failure], QT prolongation/Torsades de Pointes and 
cardiac ischemia/infarction.  Other warnings or precautions include hepatotoxic effects, including 
liver failure; thyroid dysfunction, hemorrhage and thrombosis/thrombotic/thromboembolic events, 
thrombotic microangiopathy, hand-foot syndrome and other severe dermatologic toxicities (including 
erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, necrotizing fasciitis), 
gastrointestinal perforation/fistula, osteonecrosis of the jaw, proteinuria, reversible posterior 
leukoencephalopathy syndrome, tumor lysis syndrome, and serious infections. The 
recommendations to temporarily interrupt treatment with the TKI before major surgery because of 
the possibility of impaired wound healing and to monitor for adrenal insufficiency in case of stress 
such as surgery, trauma or severe infection because of adrenal toxicity in non-clinical studies. 
Warnings about fetal harm when administered to a pregnant woman and that safety and 
effectiveness have not been established in pediatric patients (due to the possibility of increased 
toxicity in developing organs).  One label also warns about increased toxicity in combination with 
other anticancer agents. 
The most common adverse events (>20%) noted in at least one of the labels for the approved TKIs 
are fatigue, asthenia, fever, diarrhea, nausea, mucositis/stomatitis, vomiting, decreased 
appetite/anorexia, weight loss, dyspepsia, abdominal/ gastrointestinal pain, constipation, 
hypertension, peripheral edema, rash/desquamation, hand-foot syndrome, skin discoloration, dry 
skin, hair color changes, alopecia, altered taste, dysphonia, headache, back ache, musculoskeletal 
pain, arthralgia, myalgia, extremity pain, tumor pain, cough, dyspnea, and bleeding. 
 
2.4 Nivolumab 
Immune checkpoint inhibitors include agents that block negative regulators of T cell responses. 
Immune checkpoints are terms for molecules such as programmed death-1 programmed death-
ligands 1) and 2 that downregulate the host anti-tumor immune response, and are expressed in 
many cancer types.  Thus, these molecules play a key role in evading anti-tumor immunity. PD-1 is 
a negative regulatory molecule expressed by activated T and B lymphocytes.  Binding of PD-1 to its 
ligands, PD-L1 and PD-L2, results in the down-regulation of lymphocyte activation.  Inhibition of the 
interaction between PD-1 and its ligands promotes immune responses and antigen-specific T-cell 
responses to both foreign antigens as well as self-antigens. 
Nivolumab (also referred to as BMS-936558 or MDX1106) is a human monoclonal antibody 
[HuMAb; immunoglobulin G4 (IgG4)-S228P] that targets the PD-1 cluster of differentiation 279 
(CD279) cell surface membrane receptor. In the United States, nivolumab has been FDA approved 
for the treatment of patients with forms of melanoma, non-small cell lung cancer, renal cell 
carcinoma, classical Hodgkin lymphoma, and squamous cell carcinoma of the head and neck.  
Additional information is presented in the full prescribing information (26).  
 
2.5 Rationale for Combinatorial Therapy Against PD-1 and VEGF 
The evidence to suggest that there is a complex relationship between angiogenesis and the 
immune system is growing (summarized in reference (13)). There is also literature that provides 
evidence to suggest that antiangiogenic agents can stimulate the immune system, and vice versa 
(27). Thus, combination regimens that include an antiangiogenic agent and immunotherapy could 
be synergistic when targeting tumors.  
It is known that tumor cells secrete VEGF-A which, in addition to promoting angiogenesis, 
decreases dendritic cell co-stimulatory molecule expression and T cell priming, and also 
encourages the formation of myeloid-derived suppressor cells (MDSCs).  It has been shown that 
sunitinib (a VEGFR, PDGFR, CSF1R, Kit, and Flt-3 inhibitor) reduces infiltration by MDSC and T 




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vorolanib include downregulation of T regulatory cells and increased antigen presentation by dendritic 
cells (31).  In addition to preclinical data supporting changes in the adaptive immune response, 
inhibition of these pathways can also alter the innate immune system including immune repressive 
macrophages (28, 32).  Thus studying the immune system as a whole monitoring changes in both 
the innate and adaptive immune response after treatment with combination vorolanib and nivolumab 
may yield important biologic answers on how the immune system responds to this novel combined 
treatment and provide putative clinical markers that could be monitored for response to treatment.   
 
Mass cytometry is a technique similar to flow cytometry, which allows for analysis of individual cells 
as measured by time of flight for specific metal tagged antibodies that can capture clear detection of 
up to 30-40 markers per individual cell.  Recently, mass cytometry was utilized to analyze the immune 
profile of peripheral blood in patients with stage IV melanoma who were undergoing treatment with 
checkpoint inhibitor therapy (33). The immune profiling from these patients suggested that differences 
in specific T cell subsets could be detected in the peripheral blood and that the numbers of T cells in 
relation to the tumor burden might be predictive of those patients who would respond to checkpoint 
inhibitor therapy (33). 
 
Though mass cytometry will give significant insight to the changing immune milieu, only multiplexed 
immunofluorescence (IF) or immunohistochemistry will yield information in a spatial context important 
to understand the response to treatment with combined VEGF/PDGF inhibitor and nivolumab. In 
tumors such as melanoma, the presence of T cell infiltrate at the tumor margin has been suggestive 
as a marker of a response (34).  In lung cancer, typical patient samples obtained for diagnosis are 
FNA or core biopsies which yield limited materials for correlative studies.  Given that technology such 
as multiplex IF requires less material for analysis we hope to augment the amount of data yielded 
from each precious patient sample using this technique (35). We will characterize presence or 
expression of PD-1, PD-L1, PD-L2; T cell infiltrate by CD3, CD4, Foxp3, and CD8; T cell effector 
function by Granzyme B; markers of macrophages, and B cells.  
 
Circulating angiogenic factors such as soluble VEGF and CSF1 can be produced by tumors and has 
been found in lung cancer cell lines (36, 37). CSF1 is known to be necessary for osteoclastogenesis 
and important in stimulating macrophages to promote an immunsuppressive environment that allows 
tumor growth (38).  Vorolanib has activity blocking CSF1 and therefore it will be important to 
determine if pretreatment levels or levels during therapy with vorolanib and nivolumab correlate with 
tumor response. We will measure soluble VEGF and CSF1 prior to and after treatment with vorolanib 
and nivolumab to determine if levels correlate with response, PFS, or overall survival (OS).  
 
 
 
 
3.  OBJECTIVES AND ENDPOINTS 
 
3.1.  Objectives 
Primary Objectives: 
• Phase I: To assess the safety and tolerability of nivolumab and vorolanib in combination in patients 
with NSCLC naïve to checkpoint inhibitor therapy, NSCLC progressed on prior checkpoint inhibitor 
therapy considered primary refractory, NSCLC progressed on prior checkpoint inhibitor therapy 
considered acquired resistance, and thymic carcinoma.  
• Phase II: To evaluate the efficacy as measured by response to the combination nivolumab and 
vorolanib in patients with refractory NSCLC naïve to checkpoint inhibitor therapy, NSCLC 
progressed on prior checkpoint inhibitor therapy considered primary refractory, NSCLC progressed 
on prior checkpoint inhibitor therapy considered acquired resistance, small cell lung cancer, and 
thymic carcinoma as compared to historical controls.   
 


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    Secondary Objectives: 
• 
Phase II: To assess the effects of tumor PD-L1 status and tumor mutation burden (TMB) on the 
response to combinatorial treatment vorolanib and nivolumab. 
 
Exploratory Objectives: 
• 
To assess the effects of combinatorial treatment on specific pharmacodynamic and 
pharmacogenetic biomarkers.  
 
3.2.  Endpoints 
 
Primary Endpoints: 
• 
Phase 2 recommended combination dose will be determined when >1/3 or >2/6 dose limiting 
toxicities measured using CTCAE criteria version 5.0 
• 
Phase 2 best response will be measured by RECIST v1.1 at end of cycle 1 and confirmed at 
cycle 2 
 
   Secondary Endpoints: 
• 
Phase II progression free survival at six months and one year intervals, duration of response, 
disease control rate, overall survival at one year, and objective response rate (ORR) as related to 
PD-L1 status measured as <1%, 1-49%, and >50%. 
      
   Exploratory Endpoints:  
• 
To measure the effects of this novel combination on the immune system, we will use mass 
cytometry of peripheral blood that can distinguish 30 markers per individual cell to measure 
components of the immune system before, two weeks after initial treatment, at the end of the first 
cycle, and at time of progression and correlate these changes with response to therapy as 
determined by RECIST v1.1.  
• 
To determine if the presence or spatial location of CD4, CD8, Foxp3 Tregs, B cells and 
macrophages in pre-treatment tumor biopsy correlate with response we will perform multiplex 
immunofluorescence. 
• 
To assess effects of the novel combination on circulating CSF1 and VEGF concentrations we will 
perform ELISA on pretreatment and posttreatment peripheral blood. 
 
4.  PATIENT SELECTION 
 
Questions regarding patient eligibility must be addressed and resolved by the investigator in consultation 
with the sponsor-investigator or designee prior to enrollment. 
 
4.1.  Inclusion Criteria 
  
Patients must meet all of the following inclusion criteria to be eligible for enrollment into the study: 
1. 
Signed and dated written informed consent. 
2. 
Male or female ≥ 18 years of age. 
3. 
Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. 
4. 
Having progressed on at least one prior line of therapy, or refused chemotherapy, 
histologically or cytologically confirmed diagnosis of one of the following:   
Dose Escalation and Expansion Cohorts: 


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• 
Checkpoint Inhibitor Naïve Non-Small Cell Lung Cancer patients must have 
progressed on front-line  cytotoxic chemotherapy or have refused chemotherapy and 
may have received up to three prior treatment regimens for stage IV disease 
provided no regimens included an anti-PD1 or PD-L1 agent or an oral VEGF TKI. 
Prior bevacizumab or ramucirumab is allowed.  
• 
Progressed on Checkpoint Inhibitor Non-Small Cell Lung Cancer patients must have 
progressed on front-line or second checkpoint inhibitor therapy and may have 
received up to three prior treatment regimens for stage IV disease provided no 
regimens included an oral VEGF TKI. Prior bevacizumab or ramucirumab is allowed.  
• 
Patients with EGFR, ALK, ROS1 and BRAF NSCLC must have progressed on an 
oral TKI and may have received an unlimited number of prior regimens. 
• 
Thymic carcinoma patients must not be eligible for surgical resection at the time of 
enrollment and may have received any number of prior lines of therapy provided no 
regimens included an anti-PD1 or PD-L1 agent or an oral VEGF TKI. Prior 
bevacizumab or ramucirumab is allowed. 
• 
Small Cell Lung Cancer patients must have progressed on platinum-based 
chemotherapy and may have received up to three prior lines of therapy for stage IV 
disease provided no prior regimen included an oral VEGF TKI; prior regimens can 
include an anti-PD-1 or PD-L1 agent. 
5. 
At least one measureable lesion as defined by RECIST 1.1 which can be followed by CT or 
MRI. 
6. 
Adequate organ function  prior to first dose of protocol-indicated treatment, including: 
• 
Absolute neutrophil count (ANC) ≥ 1,500/µL 
• 
Platelets ≥ 100,000/µL 
• 
Hemoglobin ≥ 9.0 g/dL 
• 
Serum creatinine ≤ 1.5 times institutional upper limit of normal (ULN), or  
calculated creatinine clearance ≥ 40 mL/min (per the Cockcroft-Gault formula)  
• 
Total bilirubin ≤ 1.5 x ULN 
(except subjects with Gilbert Syndrome, who must have total bilirubin < 3.0 mg/dL) 
• 
Alanine aminotransferase and aspartate aminotransferase ≤ 2.5 x ULN, (≤ 5.0 x ULN 
with documented liver metastases)  
7. 
Women must not be breastfeeding. 
8. 
Women of childbearing potential (WOCBP) must have a negative serum pregnancy test 
within 24 hours prior to receiving first dose of protocol-indicated treatment. 
• 
WOCBP is defined as any female who has experienced menarche who has not 
undergone surgical sterilization (hysterectomy or bilateral oophorectomy) or is not 
postmenopausal. 
 
• 
Menopause is defined clinically as 12 months of amenorrhea in a woman over 45 
years of age in the absence of other biological or physiological causes. 
 
• 
If menopausal status is considered for the purpose of evaluating childbearing 
potential, women < 55 years of age must have a documented serum follicle 
stimulating hormone (FSH) level within laboratory reference range for 
postmenopausal women, in order to be considered postmenopausal and not of 
childbearing potential. 


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9. 
Women of childbearing potential must agree to follow instructions for acceptable 
contraception Appendix 5 from the time of signing consent, and for 23 weeks after their last 
dose of protocol-indicated treatment.  
10. 
Men not azoospermic who are sexually active with WOCBP must agree to follow instructions 
for acceptable contraception (Appendix 5), from the time of signing consent, and  
for 31 weeks after their last dose of protocol-indicated treatment.  
 
 
4.2.  Exclusion Criteria  
 
Patients meeting any of the following criteria will not be permitted to enter the trial:  
1. 
≤ 28 days before first dose of protocol-indicated treatment: 
 
• 
Anti-cancer treatment with bevacizumab. 
 
• 
Major surgery requiring general anesthesia or significant traumatic injury. 
 
2. 
≤ 14 days before first dose of protocol-indicated treatment: 
 
• 
Anti-cancer therapy with an approved or investigational agent (including 
chemotherapy, hormonal therapy, targeted therapy, immunotherapy, or biological 
therapy).  
 
• 
Radiosurgery or radiotherapy.  (Note:  A tumor lesion situated in a previously 
irradiated area is considered a measureable/target lesion only if subsequent disease 
progression has been documented in the lesion.) 
 
• 
Initiation of a new erythropoietin, darbepoietin, and/or bisphosphonate therapy.  (See 
Section 9.3.) 
 
• 
Minor surgery.  (Note:  Placement of a vascular access device is not considered 
minor or major surgery.) 
 
• 
Serious or uncontrolled infection. 
 
• 
Infection requiring parenteral antibiotics.  (Note:  Patients with a non-serious infection 
under active treatment and controlled with oral antibiotics initiated at least 10 days 
prior to initiation of protocol-indicated treatment are not excluded – e.g. urinary tract 
infection controlled with oral antibiotics.) 
 
• 
Unexplained fever > 38.0 ºC. 
 
3. 
≤ 7 days before first dose of protocol-indicated treatment: 
 
• 
Receipt of granulocyte colony-stimulating factor (G-CSF) or granulocyte-macrophage 
colony stimulating factor (GM-CSF).  (See Section 9.3.) 
 
4. 
Concurrent use of any medications or substances (e.g. herbal supplement or food) known to 
be a strong inhibitor or strong inducer of CYP3A4.   
 
• 
Although corticosteroids are considered to be strong inducers of CYP3A4, 
physiologic replacement doses of corticosteroids ≤ 10 mg daily prednisone or 
equivalent are allowed (Section 9).  
 


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5. 
Inadequate recovery from toxicity attributed to prior anti-cancer therapy. 
 
• 
With the exception of alopecia, fatigue, or peripheral neuropathy, patients must have 
recovered to ≤ Grade 1 (NCI-CTCAE v5.0) residual toxicity prior to first dose of 
protocol-indicated treatment. 
• 
Patients requiring replacement therapy (e.g. prednisone or thyroid replacement 
therapy) for endocrine disorders from prior checkpoint inhibitor therapy are allowed 
 
6. 
Known history of allergy or intolerance which, in the opinion of the investigator, was an 
unacceptable adverse reaction attributed by the investigator to any prior anti-neoplastic 
therapy specifically targeting vascular endothelial growth factor or the VEGF receptor.  
 
7. 
Known history of allergy or intolerance which, in the opinion of the investigator, was an 
unacceptable adverse reaction attributed by the investigator to any prior anti-neoplastic 
therapy specifically targeting T-cell costimulation or immune checkpoint pathways – i.e. 
nivolumab (OPDIVO), pembrolizumab (KEYTRUDA), atezolizumab (TECENTRIQ), 
ipilimumab (YERVOY), etc. 
 
8. 
Non-healing wounds on any part of the body. 
 
9. 
Known or suspected clinically significant active bleeding. 
  
10. 
Inability to swallow oral medication; or the presence of a poorly controlled gastrointestinal 
disorder that could significantly affect the absorption of oral study drug – e.g. Crohn’s 
disease, ulcerative colitis, chronic diarrhea (defined as > 4 loose stools per day), 
malabsorption, or bowel obstruction.  
 
11. 
NSCLC patients with radiographic evidence of major airway or blood vessel invasion by 
cancer, radiographic evidence of intra-tumor cavitation, or gross hemoptysis (≥ one teaspoon) 
within the preceding 2 months. 
 
12. 
Significant cardiovascular disease or condition including: 
 
• 
Congestive heart failure (CHF) that is uncontrolled on current therapy. 
 
• 
Class III or IV cardiovascular disease according to the New York Heart Association 
(NYHA) Functional Criteria.   
 
• 
Uncontrolled arrhythmia. 
 
• 
Severe conduction disturbance (e.g. 3rd degree heart block). 
 
• 
Unstable angina pectoris (i.e. last episode ≤ 6 months prior to first dose of protocol-
indicated treatment). 
 
• 
Uncontrolled (per investigator judgment) hypertension. 
 
• 
Myocardial infarction within 6 months prior to starting trial treatment. 
 
• 
QTcF >450 ms in men, or >470 ms in women.  
 
13. 
Deep vein thrombosis or pulmonary embolism ≤ 4 weeks before first dose of protocol-
indicated treatment, unless adequately treated and stable. 
 
• 
Patients receiving therapeutic non-coumarin anticoagulation are eligible, provided 
they are on a stable dose (per investigator judgment) of anticoagulant. 


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14. 
Patients with active interstitial lung disease and non-infectious pneumonitis or a history of 
active interstitial lung disease or pneumonitis requiring treatment with steroids or that may 
interfere with the detection or management of suspected drug-related pulmonary toxicity. 
Patients with lung cancer with a remote history (> 3 months ago) of pneumonitis following 
chemo-radiation treatment that has resolved are allowed. 
 
• 
Note:  Patients with Chronic Obstructive Pulmonary Disease (COPD) whose disease 
is controlled (per investigator judgment) at trial entry are not excluded. 
 
15. 
CNS metastasis, unless asymptomatic and stable with no change in CNS disease status for 
at least two (2) weeks prior to initiating protocol-indicated treatment. 
 
• 
Anticonvulsant and/or corticosteroid prophylaxis (≤ 10 mg/day prednisone or 
equivalent daily) will be allowed if patient is on a stable or decreasing dose of such 
treatment for at least 14 days prior to initiating protocol-indicated treatment.   
 
16. 
Any condition requiring systemic treatment with either corticosteroids (> 10 mg/day 
prednisone or equivalent daily) or other immunosuppressive medications within 14 days prior 
to initiating protocol-indicated treatment. 
 
• 
In the absence of active autoimmune disease:  Subjects are permitted the use of 
corticosteroids with minimal systemic absorption (e.g. topical, ocular, intra-articular, 
intranasal, and inhalational) ≤ 10 mg/day prednisone or equivalent daily; and 
physiologic replacement doses of systemic corticosteroids ≤ 10 mg/day prednisone 
or equivalent daily (e.g. hormone replacement therapy needed in patients with 
hypophysitis).   
 
17. 
Active, known or suspected autoimmune disease.  
 
• 
Subjects with type I diabetes mellitus; hypothyroidism; or endocrine disorders 
requiring hormone replacement even if due to prior immunotherapy; skin disorders 
such as vitiligo, psoriasis or alopecia not requiring systemic treatment; or conditions 
not expected by the investigator to recur in the absence of an external trigger are 
permitted to enroll. 
 
18. 
Uncontrolled (per investigator judgment) type I or type II diabetes mellitus. 
 
19. 
Known positive test for Human Immunodeficiency Virus (HIV) or known Acquired 
Immunodeficiency Syndrome (AIDS). 
 
20. 
Any active Hepatitis B or Hepatitis C infection. 
 
• 
Hepatitis B and C testing required ≤ 28 days prior to initiating protocol-indicated 
treatment, including at least:  Hepatitis B surface antigen (HBV sAg); and  
Hepatitis C virus antibody (HCV Ab) or Hepatitis C virus RNA (HCV RNA).  
21. 
Solid tumor transplantation  
 
22. 
Immunization with any attenuated live vaccine within 1 week prior to initiating protocol-
indicated treatment. 
 
23. 
Active second malignancy or history of a previous second malignancy within the last 2 years 
that could in the opinion of the investigator interfere with their assessment of study treatment. 
 
• 
Exceptions include the following permitted conditions – provided a complete 
remission was achieved at least 2 years prior to initiating protocol-indicated treatment 
AND no additional therapy (with the exception of allowable anti-estrogen/androgen 


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therapy or bisphosphonates) is ongoing or required during the trial period:  non-
melanoma skin cancers (e.g. basal or squamous cell); superficial bladder cancer; or 
carcinoma in situ of the prostate, cervix, or breast. 
24. 
Known psychiatric condition, social circumstance, or other medical condition reasonably 
judged by the investigator to unacceptably increase the risk of study participation; or to 
prohibit the understanding or rendering of informed consent or anticipated compliance with 
and interpretation of scheduled visits, treatment schedule, laboratory tests and other study 
requirements. 
 
 
4.3.  Inclusion of Underrepresented Populations 
Women and men of all races and ethnic groups are eligible for this trial.  There is no bias towards 
gender, age, or race in the clinical trial outlined. 
 
4.4.  Number of Patients and Replacement of Patients 
Who Discontinue Early 
Up to 177 patients [approximately 9-18 evaluable patients in Dose Escalation; and about 159 
evaluable patients in five Dose Expansion cohorts, consisting of Checkpoint Inhibitor naïve Non-
Small Cell Lung Cancer (n=39), Non-Small Cell Lung Cancer primary refractory to prior checkpoint 
inhibitor therapy (n=21), Non-Small Cell Lung Cancer adaptive resistance to prior checkpoint 
inhibitor therapy (n=21),  Small Cell Lung Cancer progressed on platinum-based chemotherapy 
(n=37), and Thymic carcinoma (n=41)] are anticipated to enroll in this study at Vanderbilt 
University Medical Center and other study sites. 
 
In general, it is intended that patients will be treated until confirmed disease progression or 
intolerable toxicity.  The criteria for patient discontinuation are listed in Section 8.4.   
 
For purpose of ensuring appropriate opportunity to determine the recommended combination dose 
(RCD) of vorolanib in combination with nivolumab, a subject who is withdrawn from the study 
before completion of the first 28 days after initiating protocol-indicated treatment on Cycle 1, Day 1 
for a as reason other than a DLT will be replaced. 
 
Additionally, if a patient discontinues protocol treatment for reasons clearly not related to protocol 
treatment (in the judgement of the sponsor-investigator), after completing less than 75% of 
scheduled oral doses of vorolanib or less than 2 planned infusions of nivolumab over the first 28 
days after initiating protocol-indicated treatment on Cycle 1, Day 1, then that patient will be 
considered not evaluable for response to overall protocol-indicated treatment and may be replaced 
with a new patient.   
5.  ENROLLMENT PROCEDURES 
 
5.1.  Registration Procedures 
The Vanderbilt-Ingram Cancer Center (VICC) Multi-Institutional Coordinating Office will coordinate 
enrollment onto the study.   
 
Guidelines for VICC and Participating Institutions 
 
Prior to registration, a copy of the IRB approval at the site will be requested and kept on file at the 
Vanderbilt-Ingram Cancer Center (VICC) Coordinating Center. Eligible participants will be entered 
on study centrally at the VICC Coordinating Center. All sites should email the Coordinating Center 
at 
 to verify slot availability prior to enrollment.  


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All patients MUST be registered with the VICC prior to the start of protocol treatment. 
Registration can only be conducted during the business hours of 8AM – 5PM Central 
Standard Time Monday through Friday.  
 
1) All sites must email the VICC CTSR Coordinating Center at Coordinating.Center@vumc.org to 
notify of upcoming registration and ensure slot availability. The following information should be 
included in your email: 
 
o 
Study number 
o 
Patient initials 
o 
Disease type  
o 
Anticipated consent date 
o 
Anticipated start date  
 
2) If a subject ID number is required prior to patient enrollment (i.e. at screening due to sample 
collection requirement), the site must submit the following documents with their email 
notification to the Coordinating Center: 
 
• 
Copy of the patient’s signed and dated Informed Consent including documentation of the 
consent process. 
• 
HIPAA authorization form (if separate from the main consent form) 
• 
VICC Patient Enrollment Form 
 
The Coordinating Center will then provide a subject ID number via email. 
 
3) Email the following documents to the Coordinating Center for eligibility review and patient 
enrollment (
 
 
• 
Copy of the patient’s signed and dated Informed Consent, including documentation of the 
consent process. 
• 
HIPAA authorization form (if separate from the main consent form) 
• 
VICC Patient Enrollment Form 
• 
Eligibility supporting documents such as pathology reports, laboratory tests, etc. or EMR 
access. Note: all source documents should be de-identified and screening/subject ID 
number added prior to sending. 
• 
Tissue Registration Form (if applicable – see Lab Manual) 
• 
Signed and completed Eligibility Checklist. To be eligible for registration to the study, 
the participant must meet each inclusion and exclusion criterion listed in the 
eligibility checklist.  
 
Note: All study documents should be received 24-48 hours prior to the patient’s anticipated start 
date. Same day treatment registrations will only be accepted with prior notice and discussion with 
the Coordinating Center. Please email the Coordinating Center if enrollment is needed sooner. 
 
Upon satisfactory review of eligibility documents submitted, the Coordinating Center will approve 
enrollment and issue a subject ID number if one was not issued at screening. Once 


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registration/enrollment confirmation from Coordinating Center is received, proceed with protocol 
procedures. 
 
Please contact the assigned Study Contact with any questions regarding this process. You can 
also reach out to your assigned Clinical Research Associate (CRA) once the study is activated.  
 
Issues that would cause treatment delays should be discussed with the sponsor-investigator or 
designee 
Any requests for eligibility exceptions and/or deviations must be approved in writing by the 
Protocol Chair and the VICC DSMC. Changes to the protocol will not be implemented without 
agreement from the sponsor-investigator, except where necessary to eliminate an immediate 
hazard to the patient.   
 
As is generally accepted, standard of care procedures performed prior to consent, but within the 
protocol defined screening window for each assessment, can be used for study purposes.  All 
research-only procedures must be performed after the consent date. 
 
5.2.  Screen-Failures 
A patient found not eligible for the trial after giving informed consent is considered a screening-
failure.  The enrollment form and eligibility checklist must be completed and sent to the sponsor-
investigator or designee to confirm the outcome of the screening process. 
 
Re-screening and re-enrollment of a subject who has discontinued the study as a pre-treatment 
failure (i.e. subject has not received protocol-indicated treatment) is permitted.  
 
A consented patient previously reported to the coordinating center as pre-treatment failure must be 
re-consented prior to undergoing re-screening.  
 
 






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8. One standard 12-lead electrocardiogram (ECG) using local site equipment during Screening; and at EOT and Follow-up visits.  Additional ECGs as 
clinically indicated per patient’s study physician. 
 
9. Macroscopic urinalysis to include specific gravity, pH, glucose, protein, ketones, and blood.  Increased frequency of urinalysis and urine 
microscopics (e.g. RBC, WBC, casts, and crystals) as clinically indicated per patient’s study physician. 
 
10. For women of childbearing potential:  Serum pregnancy test required during Screening.  A woman of childbearing potential is defined as any female 
who has experienced menarche who has not undergone surgical sterilization (hysterectomy or bilateral oophorectomy) or is not postmenopausal.   
Menopause is defined clinically as 12 months of amenorrhea in a woman over 45 in the absence of other biological or physiological causes.   
 
Postmenopausal status in females < 55 years of age should be confirmed with a serum follicle-stimulating hormone level within laboratory reference 
range for postmenopausal women (if the patient’s postmenopausal status is considered for childbearing potential and study-required contraception – 
Appendix 5). 
 
11. Baseline evaluation of disease status by CT or MRI within 28 days prior to initiating protocol treatment on Cycle 1, Day 1.  Baseline and subsequent 
scans to include imaging of the chest and abdomen.  Additional sites of known or suspected disease (e.g. pelvis) should be imaged during 
screening and subsequent scans.  Re-scanning to occur every 8 weeks (± 7 days) after initiating protocol treatment on Cycle 1, Day 1.  (The ± 7 day 
scan window is intended to facilitate flexibility in scheduling re-scans during Week 8 of each 56 day cycle, prior to initiation of treatment on Day 1 of 
every new cycle.) 
 
Patients with known or suspected CNS metastasis must have imaging of the head by CT or preferable MRI during screening (and thereafter, while 
on-study, at least every 3 months ± 7 days since prior head imaging, if a CNS lesion is detected on baseline imaging). 
 
Scanning on the same day as infusion with nivolumab is discouraged but allowed, provided scan results receive appropriate RECIST review prior to 
initiating a new cycle of study treatment (e.g. first re-scan is discouraged, but permitted on Cycle 2, Day 1, prior to nivolumab infusion later that 
same day).  Additional disease evaluations or increased scan frequency may be performed according to the medical judgment of the patient’s study 
physician, in accordance with the following:  In the event of suspected Progressive Disease, a CT/MRI is to be performed as soon as possible.  In 
the event of a Complete or Partial Response, a confirmatory CT/MRI is to be performed no earlier than 28 days after the first assessment of CR/PR. 
 
12. On Cycle 1, Day 1:  Physical exam, Hematology and Blood Chemistry, serum lipase and amylase, and Urinalysis need not be repeated if already 
completed ≤ 7 days prior to first dose of protocol-indicated treatment. 
 
13. Requesting FFPE sample from either a standard of care biopsy performed within 28 days prior to Cycle 1, Day 1 or archival tissue if available to 
confirm histologic subtype, progression of disease, and for correlative studies (sample optional and not required for study participation). 
 
14. Pharmacogenetic/Pharmacodynamic blood collection. In Cycle 1 blood will be collected on Day 1, Day 29, and End of Therapy for correlative 
studies. To accommodate scheduling, may occur within - 3 days but blood collection is requested to take place prior to infusion of nivolumab on the 
day treatment.   
 
15. Beginning with Cycle 1, Day 43 (i.e. beyond the DLT assessment period intended for conclusion with the Day 29 visit):  In order to accommodate 
scheduling, visits and procedures may occur with flexibility of ± 3 days.  (Note that a minimum of 12 days is required between successive nivolumab 
infusions.) 
 
16. All patients are scheduled to receive oral vorolanib once daily (QD) on a continuous dosing schedule.  The study will provide vorolanib to the site. 
 


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17. All patients are scheduled to receive nivolumab every 2 weeks, as a 30 minute intravenous infusion on Days 1, 15, 29, and 43 of each 56 day (8 
week) cycle.  The study will provide nivolumab to the site. 
 
18. After the first 16 weeks (2 cycles), if a patient in any cohort has not experienced disease progression (non-PD response), patients with continued 
clinical benefit can switch to treatment with 480 mg nivolumab every 4 weeks on Days 1 and 29 of each 56-day cycle.  
 
19. Reasonable effort should be made to complete EOT procedures on the day it is decided a patient will no longer receive protocol-indicated treatment.  
These procedures must be completed subsequent to and not later than 14 days after investigator decision to permanently discontinue protocol-
indicated treatment with vorolanib or nivolumab (whichever treatment occurs last) and prior to any subsequent anti-cancer therapy.   
 
20. At End-of-Treatment, CT/MRI required only if the previous CT/MRI was done > 28 days before.  At the 28 day Follow-Up visit, CT/MRI scan required 
only if disease progression not already documented by CT/MRI done at or before the prior EOT visit.  If a patient discontinues the study for reason 
other than progressive disease confirmed by CT or MRI (e.g. adverse event), then CT or MRI scans involving sites of known or suspected disease 
must be continued every 8 weeks (± 7 days) until disease progression is confirmed by imaging. 
 
21. Follow-up clinic visit to be completed 28 days (+7 days) after patient’s final protocol-indicated treatment with vorolanib or nivolumab (whichever 
occurs last).  Documented attempt(s) should be made for patient return to the study clinic.  It will not be considered a protocol deviation if the patient 
is physically unable to return for the follow-up visit; such circumstance should be recorded in the study documents, and as much of the follow-up 
information as possible should be obtained via feasible patient contact and from local and outside facilities. 
Given the potential risk for delayed immune-related toxicities, safety follow-up must be performed for at least 100 days (+7 days) after the last dose 
of study drug administration. The extended safety follow-up may be performed either via a clinic visit or telephone call with a subsequent site visit 
requested in case any concerns are noted during the telephone call. 
 
22. Cycle 1 Day 8 and 22 visits in Phase I (Dose Escalation) ONLY. 
 
 
 
 
 
 


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6.2.  Screening Visit Assessments 
Prior to performing any study-based procedures, patient informed consent must be obtained. 
 
The following procedures must be completed ≤ 28 days prior to a patient’s first dose of protocol-
indicated treatment: 
 
• 
Baseline evaluation of disease status by CT or MRI; to include at least the chest and 
abdomen, with additional sites of known or suspected disease (e.g. pelvis) as clinically 
indicated per patient’s study physician. 
 
• 
For patients with known or suspected CNS metastasis:  Baseline imaging of the head by 
CT or preferable MRI. 
 
• 
Hepatitis B and C testing:  Hepatitis B surface antigen; and Hepatitis C virus antibody or 
RNA. 
  
• 
Requesting FFPE sample from either a standard of care biopsy performed within 28 days 
prior to Cycle 1, Day 1 or archival tissue if available to confirm histologic subtype, 
progression of disease, and for correlative studies (sample optional and not required for 
study participation).  
 
• 
Medical history and Demographics. 
 
• 
Physical exam. 
 
• 
ECOG performance status. 
 
• 
Weight. 
 
• 
Vital Signs:  blood pressure, heart rate and temperature. 
 
• 
Oxygen Saturation by pulse oximetry. 
(To be done at least at rest, with any additional measurements per local site’s standard of 
care / treating physician discretion.) 
 
• 
Concomitant medication (prescription and over-the-counter drugs taken at least 14 days 
prior to intended Cycle 1, Day 1 dosing) and Adverse Event review. 
 
• 
Complete Blood Count (CBC) with differential (including white blood cell count with 
differential, hemoglobin, hematocrit, and platelet count). 
 
• 
Blood Chemistry [including sodium, potassium, chloride, bicarbonate or carbon dioxide, 
blood urea nitrogen, creatinine, glucose, total bilirubin, AST, ALT, alkaline phosphatase, 
calcium, albumin, and total protein]. 
 
• 
Serum amylase and lipase. 
 
• 
Thyroid stimulating hormone (with additional free T3 and free T4, if TSH is abnormal). 
 
• 
12-lead ECG (single recording on local equipment), with additional ECGs as clinically 
indicated, per patient’s study physician. 
 
• 
Macroscopic Urinalysis, including specific gravity, pH, glucose, protein, ketones, and 
blood.  (Microscopic analysis only if clinically indicated per patient’s study physician.) 
 
• 
Serum Pregnancy Test in women of childbearing potential (as defined in Section 7.13). 
 
 


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6.3.  Cycle 1, Day 1 Assessments 
On Cycle 1, Day 1, the following procedures must be completed, unless previously  
completed ≤ 7 days prior to a patient’s first dose of protocol-indicated treatment: 
 
• 
Physical Exam. 
 
• 
Complete Blood Count with differential (including white blood cell count with differential, 
hemoglobin, hematocrit, and platelet count). 
 
• 
Blood Chemistry [including sodium, potassium, chloride, bicarbonate or carbon dioxide, 
blood urea nitrogen, creatinine, glucose, total bilirubin, AST, ALT, alkaline phosphatase, 
calcium, albumin, and total protein]. 
 
• 
Serum amylase and lipase 
 
• 
Macroscopic Urinalysis, including specific gravity, pH, glucose, protein, ketones, and 
blood. (Microscopic analysis only if clinically indicated per patient’s study physician.) 
On Cycle 1, Day 1, the following procedures must be completed, unless previously  
completed ≤ 3 days prior to a patient’s first dose of protocol-indicated treatment.  
• 
Peripheral blood for pharmacogenetics and pharmacodynamics analysis 
 
On Cycle 1, Day 1, the following procedures will be completed: 
 
• 
ECOG performance status. 
 
• 
Weight. 
 
• 
Vital Signs:  blood pressure, heart rate and temperature. 
(To be done at least prior to initiation of nivolumab infusion, with any additional recordings 
per local site’s standard of care / treating physician discretion.) 
 
• 
Oxygen Saturation by pulse oximetry.   
(To be done at least at rest, prior to initiation of nivolumab infusion, with any additional 
measurements per local site’s standard of care / treating physician discretion.) 
• 
Concomitant medication and Adverse Event review. 
 
• 
Surveillance for and expedited reporting of Dose Limiting Toxicity– see  
Section 10.1 for DLT definition. 
 
• 
Initiate once daily oral vorolanib. 
 
• 
Nivolumab infusion. 
 
6.4.  Cycle 1, Day 8 Assessments (Phase I - Dose 
Escalation ONLY) 
• 
Weight. 
• 
Oxygen Saturation by pulse oximetry.   
(To be done at least at rest, prior to initiation of nivolumab infusion, with any additional 
measurements per local site’s standard of care / treating physician discretion.) 
 
• 
Concomitant medication and Adverse Event review. 
 


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• 
Surveillance for and expedited reporting of Dose Limiting Toxicity (DLT) – see  
Section 10.1 for DLT definition.  
 
• 
Complete Blood Count with differential (including white blood cell count with differential, 
hemoglobin, hematocrit, and platelet count). 
 
• 
Blood Chemistry [including sodium, potassium, chloride, bicarbonate or carbon dioxide, 
blood urea nitrogen, creatinine, glucose, total bilirubin, AST, ALT, alkaline phosphatase, 
calcium, albumin, and total protein]. 
 
• 
Continue once daily (QD) oral vorolanib. 
 
6.5.  Cycle 1, Day 15 Assessments 
• 
Physical Exam. 
 
• 
ECOG performance status. 
 
• 
Weight. 
 
• 
Vital Signs:  blood pressure, heart rate and temperature. 
(To be done at least prior to initiation of nivolumab infusion, with any additional recordings 
per local site’s standard of care / treating physician discretion.) 
 
• 
Oxygen Saturation by pulse oximetry. 
(To be done at least at rest, prior to initiation of nivolumab infusion, with any additional 
measurements per local site’s standard of care / treating physician discretion.) 
 
• 
Concomitant medication and Adverse Event review. 
• 
Surveillance for and expedited reporting of Dose Limiting Toxicity– see  
Section 10.1 for DLT definition.  
 
• 
Complete Blood Count with differential (including white blood cell count with differential, 
hemoglobin, hematocrit, and platelet count). 
 
• 
Blood Chemistry [including sodium, potassium, chloride, bicarbonate or carbon dioxide, 
blood urea nitrogen, creatinine, glucose, total bilirubin, AST, ALT, alkaline phosphatase, 
calcium, albumin, and total protein]. 
 
• 
Continue once daily oral vorolanib. 
 
• 
Nivolumab infusion. 
 
6.6.  Cycle 1, Day 22 Assessments (Phase I - Dose 
Escalation ONLY) 
• 
Weight. 
• 
Oxygen Saturation by pulse oximetry.   
(To be done at least at rest, prior to initiation of nivolumab infusion, with any additional 
measurements per local site’s standard of care / treating physician discretion.) 
 
• 
Concomitant medication and Adverse Event review. 
 
• 
Surveillance for and expedited reporting of Dose Limiting Toxicity – see  
Section 10.1 for DLT definition.  
 


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• 
Complete Blood Count with differential (including white blood cell count with differential, 
hemoglobin, hematocrit, and platelet count). 
 
• 
Blood Chemistry [including sodium, potassium, chloride, bicarbonate or carbon dioxide, 
blood urea nitrogen, creatinine, glucose, total bilirubin, AST, ALT, alkaline phosphatase, 
calcium, albumin, and total protein]. 
 
• 
Continue once daily oral vorolanib. 
 
6.7.  Cycle 1, Day 29 Assessments 
In order to properly evaluate the DLT period, the Cycle 1, Day 29 visit should occur 28 days after 
Cycle 1, Day 1. 
• 
Physical Exam. 
 
• 
ECOG performance status. 
 
• 
Weight. 
 
• 
Vital Signs:  blood pressure, heart rate and temperature. 
(To be done at least prior to initiation of nivolumab infusion, with any additional recordings 
per local site’s standard of care / treating physician discretion.) 
 
• 
Oxygen Saturation by pulse oximetry. 
(To be done at least at rest, prior to initiation of nivolumab infusion, with any additional 
measurements per local site’s standard of care / treating physician discretion.) 
 
• 
Concomitant medication and Adverse Event review. 
 
• 
Surveillance for and expedited reporting of Dose Limiting Toxicity – see  
Section 10.1 for DLT definition. 
 
• 
Complete Blood Count with differential (including white blood cell count with differential, 
hemoglobin, hematocrit, and platelet count). 
 
• 
Blood Chemistry [including sodium, potassium, chloride, bicarbonate or carbon dioxide, 
blood urea nitrogen, creatinine, glucose, total bilirubin, AST, ALT, alkaline phosphatase, 
calcium, albumin, and total protein]. 
 
• 
Thyroid stimulating hormone (with additional free T3 and free T4, if TSH is abnormal). 
 
• 
Macroscopic Urinalysis, including specific gravity, pH, glucose, protein, ketones, and blood. 
(Microscopic analysis only if clinically indicated per patient’s study physician.) 
• 
Peripheral blood samples will be drawn for pharmacogenetics and pharmacodynamics 
studies.  
• 
Continue once daily oral vorolanib. 
 
• 
Nivolumab infusion. 
 
6.8.  Cycle 1, Day 43 Assessments 
In the absence of delayed dosing (e.g. due to an adverse event), every reasonable effort should 
be made to remain on a consistent schedule of 8 Week (56-day) cycles; but for purpose of 
accommodating holidays, scheduling limitations, etc., subsequent protocol activities beginning with 


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Cycle 1, Day 43 may occur with permissible scheduling flexibility (unless otherwise noted by 
protocol) of up to every ± 3 days.   
 
• 
Physical Exam  
 
• 
ECOG performance status  
 
• 
Weight 
• 
Vital Signs:  blood pressure, heart rate and temperature. 
(To be done at least prior to initiation of nivolumab infusion, with any additional recordings 
per local site’s standard of care / treating physician discretion.) 
 
• 
Oxygen Saturation by pulse oximetry.   
(To be done at least at rest, prior to initiation of nivolumab infusion, with any additional 
measurements per local site’s standard of care / treating physician discretion.) 
 
• 
Concomitant medication and Adverse Event review. 
 
• 
Complete Blood Count with differential (including white blood cell count with differential, 
hemoglobin, hematocrit, and platelet count). 
 
• 
Blood Chemistry [including sodium, potassium, chloride, bicarbonate or carbon dioxide, 
blood urea nitrogen, creatinine, glucose, total bilirubin, AST, ALT, alkaline phosphatase, 
calcium, albumin, and total protein]. 
 
• 
Continue once daily oral vorolanib. 
 
• 
Nivolumab infusion. 
 
6.9.  Cycle 1, Day 56 Assessments 
CT/MRI re-scanning:  
 
• 
Ideally performed on Cycle 1, Day 56, but for purpose of scheduling flexibility:  Scan 
completion permitted anytime during Week 8 of Cycle 1 (i.e. during Days 50-56 of Cycle 
1); or alternatively as late as prior to nivolumab treatment on overall Day 57 (i.e. Cycle 2, 
Day 1), provided such scan results receive appropriate RECIST review prior to initiating 
nivolumab in the new cycle. 
 
• 
Evaluation of disease status by CT or MRI to include at least the chest and abdomen, with 
additional sites of known or suspected disease (e.g. pelvis) as clinically indicated per 
patient’s study physician. 
 
6.10.  Cycles 2+, Day 1 and Day 29 Assessments 
For patients that continue beyond Cycle 1, the following assessments will occur on  
Day 1 and Day 29 of each additional cycle: 
• 
Physical Exam 
 
• 
ECOG performance status. 
 
• 
Weight. 
 
• 
Vital Signs:  blood pressure, heart rate and temperature. 


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(To be done at least prior to initiation of nivolumab infusion, with any additional recordings 
per local site’s standard of care / treating physician discretion.) 
 
• 
Oxygen Saturation by pulse oximetry.   
(To be done at least at rest, prior to initiation of nivolumab infusion, with any additional 
measurements per local site’s standard of care / treating physician discretion.) 
 
• 
Concomitant medication and Adverse Event review. 
 
• 
Complete Blood Count with differential (including white blood cell count with differential, 
hemoglobin, hematocrit, and platelet count). 
 
• 
Blood Chemistry [including sodium, potassium, chloride, bicarbonate or carbon dioxide, 
blood urea nitrogen, creatinine, glucose, total bilirubin, AST, ALT, alkaline phosphatase, 
calcium, albumin, and total protein]. 
 
• 
Day 1 only: Serum amylase and lipase. 
 
• 
Macroscopic Urinalysis, including specific gravity, pH, glucose, protein, ketones, and blood.  
(Microscopic analysis only if clinically indicated per patient’s study physician.) 
• 
Thyroid stimulating hormone (with additional free T3 and free T4, if TSH is abnormal). 
• 
Continue once daily oral vorolanib. 
 
• 
Nivolumab infusion. 
 
6.11.  Cycles 2+, Day 15 and Day 43 Assessments 
For patients that continue beyond Cycle 1, the following assessments will occur on  
Day 15 and Day 43 of each additional cycle: 
 
• 
Physical Exam  
 
• 
ECOG performance status  
 
• 
Weight 
• 
Vital Signs:  blood pressure, heart rate and temperature. 
(To be done at least prior to initiation of nivolumab infusion, with any additional recordings 
per local site’s standard of care / treating physician discretion.) 
 
• 
Oxygen Saturation by pulse oximetry.   
(To be done at least at rest, prior to initiation of nivolumab infusion, with any additional 
measurements per local site’s standard of care / treating physician discretion.) 
 
• 
Concomitant medication and Adverse Event review. 
 
• 
Complete Blood Count with differential (including white blood cell count with differential, 
hemoglobin, hematocrit, and platelet count). 
 
• 
Blood Chemistry [including sodium, potassium, chloride, bicarbonate or carbon dioxide, 
blood urea nitrogen, creatinine, glucose, total bilirubin, AST, ALT, alkaline phosphatase, 
calcium, albumin, and total protein]. 
 
• 
Continue once daily oral vorolanib. 
 
• 
Nivolumab infusion.  


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• 
Of note: If the patient has not exhibited evidence of disease progression (non-PD) and is 
undergoing treatment in cycles 3+, then nivolumab infusion will be NOT be administered 
on Day 15 or Day 43.  
 
6.12.  Cycles 2+, Day 56 Assessments 
CT/MRI re-scanning: 
 
• 
Ideally performed on Cycle x, Day 56, but for purpose of scheduling flexibility:  Scan 
completion permitted anytime during Week 8 of each cycle (i.e. during cycle Days 50-56); 
or alternatively as late as prior to nivolumab treatment on Cycle x, Day 1, provided such 
scan results receive appropriate RECIST review prior to initiating nivolumab in the new 
cycle. 
 
• 
Evaluation of disease status by CT or MRI to include at least the chest and abdomen, 
with additional sites of known or suspected disease (e.g. pelvis) as clinically indicated per 
patient’s study physician. 
 
• 
Additional disease evaluations or increased scan frequency may be performed according 
to the medical judgment of the patient’s study physician, in accordance with the following:  
In the event of suspected Progressive Disease, a CT/MRI is to be performed as soon as 
possible.  In the event of a Complete or Partial Response, a confirmatory CT/MRI is to be 
performed no earlier than 28 days after the first assessment of CR/PR. 
 
• 
Regarding brain scans, please note patients with known or suspected CNS metastasis 
must have baseline imaging of the head by CT or preferable MRI during screening; and 
thereafter, while on-study, at least every 3 months ± 7 days since prior head imaging – if 
a CNS lesion was detected on baseline imaging. 
 
6.13.  End-of-Treatment / Withdrawal Assessments 
Reasonable effort should be made to complete End-of-Treatment / Withdrawal procedures on the 
day it is decided that a patient will no longer receive protocol-indicated treatment. 
 
The following EOT procedures must be completed subsequent to and not later than 14 days after 
investigator decision to permanently discontinue protocol-indicated treatment with vorolanib / 
nivolumab (whichever treatment occurs last) and prior to any subsequent anti-cancer therapy: 
 
• 
Physical Exam. 
 
• 
ECOG Performance Status. 
 
• 
Weight. 
 
• 
Vital Signs:  blood pressure, heart rate and temperature. 
 
• 
Oxygen Saturation by pulse oximetry.   
(To be done at least at rest, with any additional measurements per local site’s standard of 
care / treating physician discretion.) 
 
• 
Concomitant medication and Adverse Event review. 
 
• 
Complete Blood Count with differential (including white blood cell count with differential, 
hemoglobin, hematocrit, and platelet count). 
 
• 
Blood Chemistry [including sodium, potassium, chloride, bicarbonate or carbon dioxide, 
blood urea nitrogen, creatinine, glucose, total bilirubin, AST, ALT, alkaline phosphatase, 
calcium, albumin, and total protein]. 


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• 
Peripheral blood will be drawn for pharmacogenetic and pharmacodynamics testing. 
 
• 
Thyroid stimulating hormone (with additional free T3 and free T4, if TSH is abnormal). 
 
• 
12-lead ECG (single recording on local equipment), with additional ECGs as clinically 
indicated, per patient’s study physician. 
 
• 
Macroscopic Urinalysis, including specific gravity, pH, glucose, protein, ketones, and 
blood. (Microscopic analysis only if clinically indicated per patient’s study physician.)  
  
• 
Disease evaluation by CT/MRI (only if the previous CT/MRI was done > 28 days before).   
 
 
6.14.  Follow-Up Visit Assessments (28-Day and 100-
Day) 
Documented attempt(s) should be made for patient return to the study clinic.  It will not be 
considered a protocol deviation if the patient is physically unable to return for the follow-up visit; 
such circumstance should be recorded in the study documents, and as much of the follow-up 
information as possible should be obtained via feasible patient contact and from local and outside 
facilities.   
 
A Follow-up clinic visit is to be completed 28 days (+7 days) after patient’s final protocol-indicated 
treatment with vorolanib or nivolumab (whichever occurs last), in order to undergo the following 
assessments: 
 
• 
Physical Exam. 
 
• 
ECOG Performance Status. 
 
• 
Weight. 
 
• 
Vital Signs:  blood pressure, heart rate and temperature. 
 
• 
Oxygen Saturation by pulse oximetry.   
(To be done at least at rest, prior to initiation of nivolumab infusion, with any additional 
measurements per local site’s standard of care / treating physician discretion.) 
 
• 
Concomitant medication and Adverse Event review. 
 
• 
Complete Blood Count with differential (including white blood cell count with differential, 
hemoglobin, hematocrit, and platelet count). 
 
• 
Blood Chemistry [including sodium, potassium, chloride, bicarbonate or carbon dioxide, 
blood urea nitrogen, creatinine, glucose, total bilirubin, AST, ALT, alkaline phosphatase, 
calcium, albumin, and total protein]. 
 
• 
Thyroid stimulating hormone (with additional free T3 and free T4, if TSH is abnormal). 
 
• 
12-lead ECG (single recording on local equipment), with additional ECGs as clinically 
indicated, per patient’s study physician. 
 
• 
Macroscopic Urinalysis, including specific gravity, pH, glucose, protein, ketones, and 
blood.  (Microscopic analysis only if clinically indicated per patient’s study physician.) 
 
If a patient discontinues the study for reason other than progressive disease confirmed by CT or 
MRI (e.g. adverse event), then CT or MRI scans of the chest and abdomen (and any additional 
sites of known or suspected disease) must be continued not later than every 8 weeks (± 7 days) 
until disease progression is confirmed by imaging. 


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Given the potential risk for delayed immune-related toxicities, safety follow-up must be performed 
up to 100 days (+7 days) after the last dose of study drug. 
 
7.  .STUDY PROCEDURES 
 
7.1.  Informed Consent 
Informed consent must be obtained before any study-specific screening assessments are 
performed.  Screening assessments are to be performed within 28 days prior to Day 1 of Cycle 1 
unless otherwise noted.  Assessments performed as standard of care within the screening window 
may be used for screening.  Baseline characteristics include but are not limited to:  demographics, 
medical and surgical history, extent of disease, prior anti-cancer treatment, and tumor histology. 
 
7.2.  Physical Examination 
Physical examinations to be performed within 28 days prior to initiating protocol treatment; on Day 
1 (unless previously completed ≤ 7 days prior to a patient’s first dose of protocol-indicated 
treatment) and Day 15, Day 29, and Day 43; and at the End-of-Treatment or 28-day Follow-Up 
visit. 
 
7.3.  Performance Status  
Eastern Cooperative Oncology Group performance status to be recorded during Screening; on 
Days 1, 15, 29 and 43 of each cycle; and at the EOT and Follow-up visits. 
 
7.4.  Vital Signs, Body Weight, and Oxygen Saturation 
Vital Signs to include:  blood pressure, heart rate and temperature. 
 
Oxygen saturation by pulse oximetry to be done at least at rest, with any additional recordings per 
local site’s standard of care / treating physician discretion.  (Note:  If additional recordings of pulse 
oximetry follow patient exertion, then the extent of exertion preceding measurement of oxygen 
saturation should be based on judgment of the patient’s study physician, and should remain 
consistent for each individual subject throughout the study.) 
 
On days of measurement occurring on day of nivolumab administration, then Vital Signs, weight 
and Oxygen Saturation to be done at least pre-dose (i.e. prior to initiation of nivolumab infusion), 
with any additional time points per local institutional standard / treating physician discretion). 
 
 
7.5.  Review of Concomitant Medications and Adverse 
Events 
Review and capture of all concomitant medications will be performed at each visit as indicated in 
Section 6.  Concomitant medications include prescription medications and over-the-counter 
preparations used by a patient within at least 14 days prior to first dose of protocol-defined 
treatment and continuing through at least the 28-day Follow-Up study visit.  After signing the 
informed consent, adverse events will be collected as detailed in protocol Section 12.  All adverse 
events will be recorded at least until 28 days after a patient’s final protocol-directed treatment with 
vorolanib or nivolumab (whichever occurs last) or until initiation of another anti-cancer therapy – 
whichever occurs first. 


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7.6.  Surveillance and Expedited Reporting of Dose 
Limiting Toxicity 
For dose-escalation only:  Dedicated surveillance and expedited reporting of Dose Limiting Toxicity 
are required for 28 days after initiating protocol-indicated treatment.  On Cycle 1, Day 29, 
satisfactory completion of the physical exam and the safety labs is required to help detect 
evidence of past or present DLT as having occurred during the first 28 days of protocol-indicated 
treatment.  If intolerable delayed toxicity attributable (per sponsor-investigator judgement) to 
protocol treatment is detected past Day 28, then the 28-Day DLT window may possibly be 
extended.  See protocol Section 10.1 for definition of DLT and toxicities which if experienced 
during the first 28 days after initiating protocol-indicated treatment shall be considered dose 
limiting. 
 
7.7.  Complete Blood Count with Differential 
Hematology includes white blood cell count with differential, hemoglobin, hematocrit, and platelet 
count. 
 
7.8.  Blood Chemistry 
Local blood chemistry results to include sodium, potassium, chloride, bicarbonate or carbon 
dioxide, blood urea nitrogen, creatinine, glucose, total bilirubin, AST, ALT, alkaline phosphatase, 
calcium, albumin, and total protein. 
 
7.9.  Thyroid Function Testing 
Thyroid stimulating hormone (with additional free T3 and free T4, if TSH is abnormal) to be done at 
Screening and every eight weeks; and at the EOT and Follow-up visits. 
 
7.10.  Hepatitis Testing 
Hepatitis B and C testing at Screening (≤ 28 days prior to initiating protocol-indicated treatment):  
Hepatitis B surface antigen; and Hepatitis C virus antibody or RNA. 
 
7.11.  ECG 
Standard 12-lead electrocardiogram, single tracing, using local site equipment during Screening; 
and at EOT and Follow-up visits.  Additional ECGs as clinically indicated per patient’s study 
physician. 
 
7.12.  Urinalysis 
Macroscopic urinalysis to include specific gravity, pH, glucose, protein, ketones, and blood.  
Increased frequency of urinalysis and urine microscopics (e.g. RBC, WBC, casts, and crystals) as 
clinically indicated per patient’s study physician. 
 
7.13.  Pregnancy Test 
Serum pregnancy test for women of childbearing potential required during Screening.  Subsequent 
pregnancy test – either serum or urine – to be done if clinically indicated per study physician. 
 


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A woman of childbearing potential is defined as any female who has experienced menarche who 
has not undergone surgical sterilization (hysterectomy or bilateral oophorectomy) or is not 
postmenopausal.   Menopause is defined clinically as 12 months of amenorrhea in a woman over 
45 in the absence of other biological or physiological causes. 
 
Postmenopausal status in females < 55years of age should be confirmed with a serum follicle-
stimulating hormone level within laboratory reference range for postmenopausal women (if the 
patient’s postmenopausal status is considered for childbearing potential and study-required 
contraception). 
 
7.14.  Disease Assessment by CT/MRI 
Baseline evaluation of disease status by CT or MRI within 28 days prior to initiating protocol 
treatment on Cycle 1, Day 1.   
 
Baseline and subsequent scans to include imaging at least of the chest and abdomen.  Additional 
sites of known or suspected disease (e.g. pelvis) per judgement of patient’s study physician should 
be imaged during screening and subsequent scans.   
 
Re-scanning ideally performed on Cycle x, Day 56, but for purpose of scheduling flexibility:  Re-
scanning completion permitted anytime during Week 8 of each cycle (i.e. during cycle Days 50-
56); or alternatively as late as prior to nivolumab treatment on Cycle x, Day 1, provided such scan 
results receive appropriate RECIST review prior to initiating nivolumab in the new cycle. 
 
Patients with known or suspected CNS metastasis must have imaging of the head by CT or 
preferable MRI during screening (and thereafter, while on-study, at least every 3 months ± 7 days 
since prior head imaging, if a CNS lesion is detected on baseline imaging). 
 
CT/MRI scanning on the same day as infusion with nivolumab is allowed, provided scan results 
receive appropriate RECIST review prior to initiating a new cycle of study treatment (e.g. first re-
scan is permitted as late as Cycle 2, Day 1, prior to nivolumab infusion later that same day).   
 
Additional disease evaluations or increased scan frequency may be performed according to the 
medical judgment of the patient’s study physician, in accordance with the following:  In the event of 
suspected Progressive Disease, a CT/MRI is to be performed as soon as possible.  In the event of 
a Complete or Partial Response, a confirmatory CT/MRI is to be performed no earlier than 28 days 
after the first assessment of CR/PR. 
 
At End-of-Treatment, CT/MRI required only if the previous CT/MRI was done > 28 days before. 
 
At the 28-day Follow-Up visit, CT/MRI scan required only if disease progression not already 
documented by CT/MRI done at or before the prior EOT visit. 
 
If a patient discontinues the study for reason other than progressive disease confirmed by CT or 
MRI (e.g. adverse event), then CT or MRI scans of involving sites of known or suspected disease 
must be continued every 8 weeks (± 7 days) until disease progression is confirmed by imaging or 
up to 100 days after last dose. 
 
7.15.  Tumor Tissue and Correlative Blood Samples 
Biopsy confirming progression of disease and histology is requested to be analyzed for PD-L1 and 
exploratory endpoints.  If biopsy specimen not available at time of progression prior to entry on 
study, archival tissue is requested to be analyzed for PD-L1 expression and exploratory biologic 
correlates. 
 




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2 
 
300 mg 
 
240 mg 
 
3 
 
400 mg 
 
240 mg 
1 cycle = 56 days (8 weeks) 
The first cohort of patients will be started at dose level 1.  At least 3 patients will be studied at each 
dose level and evaluated for toxicity.  If 0 of 3 patients experience a dose-limiting toxicity, the dose 
will be escalated.  If 1 of 3 patients experiences a DLT, 3 additional patients will be treated.  If none 
of the additional patients develop a DLT, the dose will be escalated, otherwise escalation ceases.  
If > 2 of 3, or > 2 of 6, patients experience a DLT, the RCD has been exceeded. 
 
In the phase 2 dose-expansion portion of the study, additional patients (about 159 total additional 
patients) will be split into five cohorts (about 21-41 evaluable patients/cohort), consisting of 
patients with checkpoint naïve NSCLC, previously progressed on checkpoint inhibitor therapy 
NSCLC, SCLC previously progressed on platinum based chemotherapy, and thymic carcinoma, 
who will be treated at the Recommended Combination Dose determined in the phase 1 portion of 
the study. 
 
8.2.  Oral Vorolanib 
The study will supply vorolanib to each site. 
 
Patients are scheduled to take an oral dose of vorolanib once each day continuously until 
development of progressive disease or unacceptable adverse event.  
 
Vorolanib should be taken whole with food, at approximately the same time each day, 
approximately 24 hours (± 2 hours) apart.  Unless as additionally directed by protocol, once daily 
dosing with vorolanib may occur in the morning, afternoon, or evening. Foods along with 
medications and herbal supplements that are known modulators of CYP3A4 should not be taken 
with vorolanib and are listed in Appendix 4. 
 
Missed doses of vorolanib can be made up during the same day as soon as the patient 
remembers (or, as additionally directed by the clinical team).  However, if the previous dose was 
taken < 6 hours in the past, or if the next scheduled dose is due < 6 hours in the future, then the 
missed dose should be skipped.  Patients with emesis must not take a replacement dose. 
 
Each patient receiving vorolanib will be treated at the assigned dose, unless dose-reduction is 
necessary as specified in Section 10.  There will be no intra-patient dose-escalation of vorolanib. 
 
8.3.  Nivolumab Infusion 
All patients are scheduled to receive 240 mg of nivolumab by 30 minute intravenous 
infusion on Days 1, 15, 29, and 43 of each 56 day (8 week) Cycle. The study will supply 
nivolumab to each site. 
 
Nivolumab will be given every two weeks, with no less than 12 days between successive 
nivolumab infusions. 
 
Of note: If the patient has not exhibited evidence of disease progression (non-PD) and is 
undergoing treatment in cycles 3+, then 480 mg of nivolumab by 30 minute intravenous infusion 
will be administered on Days 1 and Day 29 of each 56 day (8 week) Cycle.  
 


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Every effort should be made to target infusion timings to be as close to scheduled duration as 
possible.  But given the variability of infusion pumps, time windows of ± 10 minutes for the duration 
of scheduled infusions are permitted.  (Additionally, prolongation of infusion duration for the 
purpose of managing suspected or actual adverse event such as infusion reaction will not be 
considered a protocol deviation.) 
 
Nivolumab will be prepared and administered consistent with the product label: 
 
• 
Visually inspect drug product solution for particulate matter and discoloration prior to 
administration.  Nivolumab is a clear to opalescent, colorless to pale-yellow solution. 
Discard the vial if the solution is cloudy, discolored, or contains extraneous particulate 
matter other than a few translucent-to-white, proteinaceous particles.  Do not shake the 
vial. 
 
• 
Preparation: 
 
 Withdraw the required volume of nivolumab and transfer into an intravenous 
container. 
 Dilute nivolumab with either 0.9% Sodium Chloride Injection, USP or 5% 
Dextrose Injection, USP to prepare an infusion with a final concentration ranging 
from 1 mg/mL to 10 mg/mL. 
 Mix diluted solution by gentle inversion.  Do not shake. 
 Discard partially used vials or empty vials of nivolumab. 
 
• 
Storage of Infusion: 
 
 The product does not contain a preservative. 
 After preparation, store the nivolumab infusion either:  At room temperature for 
no more than 8 hours from the time of preparation (this includes room 
temperature storage of the infusion in the IV container and time for administration 
of the infusion), or under refrigeration at 2°C to 8°C (36°F to 46°F) for no more 
than 24 hours from the time of infusion preparation. 
 Do not freeze. 
 
 
 
• 
Administration: 
 
 Administer the infusion over 30 minutes through an intravenous line containing a 
sterile, non-pyrogenic, low protein binding in-line filter (pore size of 0.2 
micrometer to 1.2 micrometer). 
 Do not co-administer other drugs through the same intravenous line. 
 Flush the intravenous line at end of infusion. 
 
For all nivolumab infusions, an appropriate dosing history will be recorded, e.g.: 
• 
Total dose and volume administered 
• 
Start and stop time of infusion 
• 
Infusion interruption or termination and reason for such actions. 
 
Subjects should be carefully monitored for infusion reactions during nivolumab administration.  If 
an acute infusion reaction is noted, subjects should be managed according to Section 10.9. 
 


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There are no pre-medications recommended for nivolumab prior to Day 29 of the first cycle (i.e. 
the intended DLT evaluation period). 
 
Doses of nivolumab may be interrupted, delayed, or discontinued (e.g. Section 10) depending on 
how well the subject tolerates the treatment. 
 
Dose reductions or dose escalations of nivolumab are not permitted. 
 
8.4.  Discontinuation of Protocol-Indicated Treatment 
All patients will initiate the study via receipt of vorolanib in combination with nivolumab.   
 
The visit schedule for protocol treatment will apply until vorolanib treatment in combination with 
nivolumab has been permanently discontinued.  Once this has occurred, an End-of-Treatment visit 
will be performed within 14 days after the decision of permanent discontinuation, prior to any 
subsequent anti-cancer therapy. 
 
After the EOT visit, the patient will continue to be followed until 28 days (+7 days) after the last 
dose of protocol-indicated treatment, at which time the Follow-Up visit must be completed. 
 
Reasons for permanent discontinuation of a patient’s protocol-indicated treatment include any of 
the following: 
 
• 
Inability to tolerate vorolanib in combination with nivolumab.  Please note:  Within the 
study, a patient will not receive nivolumab as an exclusive ‘single-agent’ therapy.  
Therefore, a patient must permanently discontinue the study if unable to tolerate 
vorolanib. 
 
• 
Patient withdraws consent to participate. 
 
• 
Occurrence of an AE considered by the investigator to require treatment discontinuation. 
 
• 
Toxicity requiring discontinuation as outlined in Section 10. 
 
• 
Progressive Disease, verified by CT/MRI according to RECIST v1.1. 
 
• 
Treatment failure not meeting the criteria for PD, but considered by the investigator to 
require treatment discontinuation (e.g. clinical progression). 
 
• 
Requirement for a significant surgical procedure.  Note:  Patients requiring a minor 
surgical procedure (e.g. port placement, skin abscess drainage) may continue at the 
investigator's discretion following discussion with the sponsor-investigator or designee.  A 
brief interruption in therapy may be considered. 
 
• 
An intercurrent illness which, in the opinion of the investigator, would prevent completion 
of trial-related evaluations. 
 
• 
The investigator judges it necessary due to medical reasons (e.g. significant deterioration 
in performance status). 
 
• 
Required use of a prohibited concomitant medication, as defined in Section 9.  Note: 
subject to discussion with and approval by the sponsor-investigator, inadvertent isolated 
receipt of a prohibited concomitant medication (e.g. incidental to acute management of an 
adverse event) does not require permanent discontinuation. 
 
• 
The patient becomes pregnant during treatment.  (Cases of pregnancy that occur during 
maternal or paternal exposures to study treatment should be reported.  Data on fetal 


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outcome and breast-feeding may be collected for regulatory reporting and drug safety 
evaluation.) 
 
• 
Significant deviation from the protocol or eligibility criteria.  Such patients will be 
considered protocol violations and may be discontinued from treatment after discussion 
with the sponsor-investigator. 
 
• 
Noncompliance with trial procedures may require discontinuation after discussion with the 
sponsor-investigator. 
 
• 
Termination of the trial by the sponsor-investigator or regulatory authority. 
 
8.5.  Treatment Beyond Progression 
Accumulating evidence indicates a minority of subjects treated with immunotherapy may derive 
clinical benefit despite initial evidence of progressive disease.   
 
With written permission from the sponsor-investigator, subjects will be permitted to continue 
treatment beyond initial RECIST 1.1 defined PD as long as they meet the following criteria 
determined by the investigator: 
 
• 
Investigator-assessed clinical benefit from protocol-indicated treatment 
 
• 
Subject is tolerating nivolumab 
 
• 
Stable performance status. 
 
The assessment of clinical benefit should take into account whether the subject is clinically 
deteriorating and unlikely to receive further benefit from continued treatment.  
 
Treatment beyond progression will not delay an imminent intervention to prevent serious 
complications of disease progression (e.g. CNS metastases). 
 
A radiographic assessment/ scan should be performed within 6 weeks of initial investigator-
assessed progression to determine whether there has been a decrease in the tumor size or 
continued PD.  The assessment of clinical benefit should be balanced by clinical judgment as to 
whether the subject is clinically deteriorating and unlikely to receive any benefit from continued 
treatment with nivolumab. 
 
For the subjects who continue nivolumab study therapy beyond progression, further progression is 
defined as an additional 10% increase in tumor burden from time of initial PD.  This includes an 
increase in the sum of diameters of all target lesions and/ or the diameters of new measurable 
lesions compared to the time of initial PD.  Nivolumab treatment should be discontinued 
permanently upon documentation of further progression. 
 
New lesions are considered measureable at the time of initial progression if the longest diameter is 
at least 10 mm (except for pathological lymph nodes which must have a short axis of at least15 
mm).  Any new lesion considered non-measureable at the time of initial progression may become 
measureable and therefore included in the tumor burden if the longest diameter increases to at 
least 10 mm (except for pathological lymph nodes which must have a short axis of at least 15 
mm).  In situations where the relative increase in total tumor burden by 10% is solely due to 
inclusion of new lesions which become measurable, these new lesions must demonstrate an 
absolute increase of at least 5 mm. 
 
For statistical analyses, it is intended that subjects who continue treatment beyond initial 
investigator-assessed, RECIST 1.1-defined progression will be considered to have investigator-


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assessed progressive disease at the time of the initial progression event after having it confirmed 
on repeat imaging. 
 
8.6.  Duration of Follow-Up 
In general, it is intended that patients will be treated until disease progression or intolerable 
toxicity.  Criteria for patient discontinuation include those listed in Section 8.4.  Patients should be 
assessed when it is decided the patient will no longer receive protocol-indicated treatment; and 
assessed again 28 days (+ 7 days) after patient’s final protocol-indicated treatment with vorolanib / 
nivolumab. There will be a 100day follow up visit for all patients.  
 
 
8.7.  Withdrawal from Study 
Patients may withdraw from the study at any time at their own request, or they may be withdrawn 
at any time at the discretion of the investigator or sponsor-investigator for safety, or behavioral 
reasons; or the inability of the subject to comply with the protocol-required schedule of study visits 
or procedures, or an inability to maintain voluntary informed consent.  The EOT and the Follow-Up 
visits should be performed to the extent possible and the Investigator should ensure any serious 
adverse event (SAE) is followed as described in Section 12. 
 
Reasons for withdrawal from the study might include but are not limited to any of the following:   
 
• 
The patient withdraws consent to participate in treatment, follow-up, or survival monitoring. 
 
• 
The investigator judges it necessary due to medical reasons. 
 
• 
Subject is lost to follow-up. 
 
• 
Study is terminated for any reason. 
 
9.  CONCOMITANT TREATMENT 
 
9.1.  Prohibited or Restricted Treatments 
The following medications are prohibited during the study: 
• 
Immunosuppressive agents (except to treat a drug-related adverse event). 
• 
Systemic corticosteroids >10 mg daily prednisone equivalent (except to treat a drug-
related adverse event).  
• 
Other than vorolanib and nivolumab, any other concurrent anti-neoplastic therapy (i.e. 
chemotherapy, hormonal therapy, immunotherapy, extensive non-palliative radiation 
therapy, or standard or investigational agents for treatment of NSCLC, SCLC, or thymic 
carcinoma).  
 
• 
Vorolanib is primarily metabolized by CYP3A4 and to a lesser extent by CYP2D6 and 
CYP2C9 based on in vitro studies using human liver microsome.  Therefore, concurrent 
use of any medication, herbal supplement or food known to be a strong inhibitor or strong 
inducer of CYP3A4 is prohibited unless there are no therapeutic alternatives. A list of 
medications and foods which are common strong modulators of CYP3A4 and CYP2C9 are 
included in Appendix 4. 
• 
Hematopoietic growth factors and transfusion support – as per Section 9.3. 


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• 
Caution should be used regarding the use of herbal medications as there may be as yet 
unknown interactions with nivolumab.  Discontinuation of the use of herbal medications 
prior to study enrollment is encouraged. 
• 
Immunization with any attenuated live vaccine.  Note:  The inactivated seasonal influenza 
vaccine (intramuscular injection) can be given to patients while on therapy without 
restriction.  Influenza vaccines containing live virus or other clinically indicated 
vaccinations for infectious diseases (i.e. pneumovax, varicella, etc.) may be permitted, but 
must be discussed in writing with the sponsor-investigator and may require a study drug 
washout period prior to and after administration of the vaccine. 
• 
Drugs that are known to cause hepatictoxicity should be used with caution 
 
9.2.  Permitted Therapy 
In the absence of active autoimmune disease:  Subjects are permitted the use of corticosteroids 
with minimal systemic absorption (e.g. topical, ocular, intra-articular, intranasal, and inhalational) ≤ 
10 mg/day prednisone or equivalent daily; and physiologic replacement doses of systemic 
corticosteroids ≤ 10 mg/day prednisone or equivalent daily (e.g. hormone replacement therapy 
needed in patients with hypophysitis).   
 
A brief (less than 3 weeks) course of corticosteroids for prophylaxis (e.g. contrast dye allergy) or 
for treatment of non-autoimmune conditions (e.g. delayed-type hypersensitivity reaction caused by 
a contact allergen) is permitted. 
 
Regular concomitant use of bisphosphonates and RANK-L inhibitors for prevention or reduction of 
skeletal-related events in patients with bone metastases is allowed if initiated > 2 weeks prior to 
first dose of protocol-indicated treatment.   
 
Prior palliative radiotherapy must have been completed > 2 weeks prior to first dose of protocol-
indicated treatment. 
 
All concomitant (non-oncological) therapies with the exception of vitamins, appetite stimulants, or 
nutrient supplements, starting or changing must be recorded in the eCRF during the screening and 
treatment period, starting from the date of signature of informed consent (to include concomitant 
medications include prescription medications and over-the-counter preparations used by a patient 
within at least 14 days prior to first dose of protocol-defined treatment), and ending at the EOT 
visit.  After the EOT visit, only concomitant therapy indicated for treatment of an AE has to be 
reported.  Trade name, indication, dose and dates of administration will be documented. 
 
Patients may receive their current concomitant medication and any medication considered 
necessary for the welfare of the patient during trial, except as otherwise restricted or prohibited per 
protocol (e.g. if con med is restricted by Section 4 Inclusion/Exclusion Criteria, or Section 9.1).  
 
9.3.  Hematopoietic Growth Factors and Transfusion 
Support 
• 
Packed red blood cell and platelet transfusions should be administered only if clinically 
indicated, and should be avoided during the first 28 days after the start of a patient’s first 
dose of vorolanib / nivolumab. 
 
• 
Use of granulocyte colony-stimulating factor (G-CSF) or granulocyte-macrophage colony 
stimulating factor (GM-CSF) is prohibited unless the patient experiences a hematologic 
DLT.  Per eligibility criteria, G-CSF or GM-CSF should not be administered ≤ 7 days before 
first dose of protocol-indicated treatment.  At the discretion of the treating physician, 


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patients may receive G-CSF or GM-CSF after the completion of the first 28 days after the 
start of a patient’s first dose of vorolanib / nivolumab if neutropenia occurs.  Therapeutic 
use of G-CSF / GM-CSF should follow standard ASCO guidelines.  
 
• 
Patients who enter the trial on stable doses (initiated > 14 days prior to initiating trial 
treatment) of erythropoietin, darbepoietin, and/or bisphosphonates may continue this 
treatment; and patients may start such treatment during the trial (after the first 28 days of 
trial treatment) at the discretion of the treating physician if clinically indicated. 
 
9.4.  Clarifications about Steroid Use including 
Hormones 
Data indicate that corticosteroids have an adverse effect on T cell function and that they inhibit and 
damage lymphocytes.  Furthermore, as with all immunotherapies intended to augment cell-
mediated immunity, there is a risk that concomitant immunosuppression such as with steroids will 
counteract the intended benefit of the proposed trial treatment.  However, studies with anti-CTLA-4 
antibodies indicate that short-term use of steroids may be employed without compromising clinical 
outcomes. 
 
Therefore, allowable steroid use during this trial includes the following: 
 
• 
Prophylaxis and treatment of toxicities attributed to protocol-indicated treatment [e.g. 
immune-related adverse events (irAEs)] 
• 
Adrenal replacement steroid doses ≤ 10 mg daily prednisone or equivalent 
• 
Corticosteroids with minimal systemic absorption (e.g. topical, ocular, intra-articular, 
intranasal, and inhalational) ≤ 10 mg/day prednisone or equivalent daily 
• 
Steroid therapy for contrast reaction prophylaxis 
• 
Hormonal therapy (e.g. Megace) for appetite stimulation 
• 
Hormonal contraceptive therapy 
• 
Hormone replacement therapy for hypophysitis and hypothyroidism. 
 
Other steroid use may be allowed upon discussion with and written agreement from the sponsor-
investigator. 
 
9.5.  Palliative Local Radiotherapy 
The potential for overlapping toxicities with radiotherapy and vorolanib/nivolumab is currently 
unknown. Per eligibility criteria, prior therapeutic or palliative radiation therapy must be completed 
> 2 weeks prior to first dose of vorolanib/nivolumab.  After beginning trial treatment, palliative 
radiotherapy is generally not recommended while receiving vorolanib/nivolumab. 
 
However, local radiotherapy of isolated lesions with palliative intent (e.g. bleeding, pain, 
compression, etc.) is permitted if considered medically necessary by the treating physician.  The 
irradiated area should be as small as possible, and the total dose delivered must be in a palliative 
range according to institutional standards.  Irradiated lesions will be followed for disease 
progression but will not be accounted for in the evaluation of the response.  Radiotherapy other 
than palliative radiotherapy for symptom control is not allowed concomitantly with the 
administration of protocol-indicated treatment.  
 
Patients requiring palliative radiotherapy should be assessed for disease progression.  If palliative 
radiotherapy is needed to control pain, the site(s) of disease causing pain should be present at 
baseline; otherwise, painful lesion(s) requiring radiotherapy should be considered as a sign of 
disease progression. 


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Administration of additional vorolanib/nivolumab to patients who experienced PD at the time of 
palliative radiotherapy should follow guidelines specified in Section 8.5. 
 
If palliative radiotherapy is required, then vorolanib/nivolumab should be withheld for at least 1 
week before, during, and 1 week after radiation.  Patients should be closely monitored for any 
potential toxicity during and after receiving radiotherapy, and AEs considered related to 
radiotherapy should resolve to Grade ≤1 prior to resuming vorolanib/nivolumab. 
 
If a treatment cycle is interrupted for more than 28 days, the decision to continue will be made by 
the investigator in agreement with the sponsor-investigator.  Continuous interruption of >28 days 
due to palliative radiotherapy will not be allowed. 
 
Only non-target bone lesions that do not include lung tissue in the planned radiation field may 
receive palliative radiotherapy while on trial treatment.  Details of palliative radiotherapy should be 
documented in the source records and eCRF.  Details in the source records should include: dates 
of treatment, anatomical site, dose administered and fractionation schedule, and AEs. 
 
10.  ADVERSE EVENT MANAGEMENT 
 
Patients should be instructed to notify their study team at the first occurrence of any adverse 
symptom.  In addition to dose delays according to protocol guidance, investigators are encouraged 
to employ best supportive care according to local institutional clinical practice. 
 
Recognizing that new knowledge will be acquired and unforeseen safety issues may arise in the 
course of the study, the management guidelines are not exhaustive and do not represent the full 
spectrum of care or treatment options described.   
 
In general, an adverse event related to study treatment that results in a dose delay should be 
present on the day of intended study treatment (i.e. a delayed toxicity that develops mid-cycle, but 
which is no longer present or has resolved to an acceptable grade on the day of intended dosing, 
generally does not require a delay in treatment – unless, for example, the occasion involves 
retrospective detection of a prior event of sufficient grade to, regardless of duration, require delay 
or discontinuation). 
 
In the event of multiple toxicities, treatment delay should be based on the worst toxicity observed. 
 
Even if protocol-indicated dosing is interrupted, tumor scans and other visits, assessments and 
procedures should continue per protocol (i.e. per timeline in place prior to the dose interruption). 
  
10.1.  Definition of Dose-Limiting Toxicity 
When classified by the sponsor-investigator as possibly, probably or definitely related to 
vorolanib; or to the combination of vorolanib + nivolumab:  any of the following events 
occurring during the first 28 days after first dose of protocol-indicated treatment will be considered 
a dose-limiting toxicity (DLT): 
 
1) Non-Hematologic DLT: 
 
• 
Any ≥ Grade 4 non-hematological toxicity. 
 


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• 
Grade ≥ 3 total bilirubin or hepatic transaminases [ALT (SGPT) or AST (SGOT)] with 
the following exceptions: 
 
 Grade 3 elevated ALT/AST lasting for ≤ 7 days, in the absence of elevated 
direct bilirubin that is both > ULN and more than 35% increased over baseline, 
will not be considered a DLT. 
 
 For patients with a Grade 1 hepatic transaminase level at baseline  
(i.e. ALT or AST), same respective hepatic transaminase level must increase to 
> 7.5 × ULN to be considered a DLT. 
 
 For patients with a Grade 2 hepatic transaminase level at baseline  
(i.e. ALT or AST), same respective hepatic transaminase level must increase to 
> 10 × ULN to be considered a DLT. 
 
• 
Grade ≥ 3 of the following: 
 Pneumonitis 
 Adrenal Insufficiency 
 Immune-mediated hepatitis 
 Colitis 
 
• 
Immune-mediated encephalitis 
• 
Grade 3 other non-hematologic toxicity lasting > 3 days despite optimal supportive care 
with the exception of: 
 
 
Grade 3 fatigue 
 
 Grade 3 symptomatic rash that resolves to ≤ Grade 1 within 3 weeks; or a 
Grade 3 asymptomatic rash 
 
 Grade 3 tumor flare (defined as local pain, irritation or rash localized at sites of 
known or suspected tumor) 
 
 Transient (resolves within 6 hours of onset) Grade 3 infusion-related AE 
 
 Grade 3/4 elevation in serum amylase and/or lipase not associated with clinical 
or radiological evidence of pancreatitis. 
 
• 
Any clinically meaningful (per investigator judgement) Grade 3 non-hematologic 
laboratory value if: 
 
 Medical intervention (other than electrolyte repletion) is required to treat the 
patient, OR 
 
 The abnormality leads to hospitalization, OR 
 
 The abnormality persists for >1 week. 
 
2) Hematologic DLT: 
 
• 
Grade ≥ 3 febrile neutropenia [ANC < 1000 /mm3 with either a single temperature of  
> 38.3 ºC (101 ºF), or a sustained temperature of ≥ 38 ºC (100.4 ºF) for > 1 hour]. 
 
• 
Grade 4 neutropenia (ANC < 500 /mm3) lasting > 5 days. 
 
• 
Grade 4 anemia lasting > 5 days despite optimum management by transfusions.  
 


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• 
Grade 4 thrombocytopenia (platelets < 25,000 /mm3) if associated with: 
 
 A bleeding event that requires an elective platelet transfusion, OR 
 
 A life-threatening bleeding event which results in urgent intervention and 
admission to an Intensive Care Unit. 
 
• 
Any Grade 5 hematologic or non-hematologic toxicity.   
 
3) Inability to initiate Cycle 1, Day 29 treatment within protocol-specified allowances due to 
adverse event that is possibly, probably, or definitely related to protocol-indicated treatment. 
 
Note:  Subjects who have experienced a DLT do not automatically require discontinuation of 
protocol-indicated treatment, unless the nature or severity of the DLT is also an adverse event that 
would require permanent discontinuation of treatment as elsewhere defined by the protocol.  
Rather, a patient who has experienced a DLT should be evaluated for consideration of an 
appropriate dose hold or dose modification which, if consistent with the protocol, would allow 
continued dosing under revised circumstance. 
 
For purpose of ensuring appropriate opportunity to determine the maximum tolerated dose (MTD) 
of vorolanib in combination with nivolumab, a subject who is withdrawn from the study prior to 
completing the DLT assessment window (i.e. first 28 days after initiating protocol-indicated 
treatment on Cycle 1, Day 1) for reasons other than a DLT will be considered not evaluable for 
DLT and will be replaced.  
 
Additionally, if a patient discontinues study treatment for reasons clearly not related to protocol-
indicated treatment (in the judgement of the sponsor-investigator), after completing less than 75% 
of scheduled oral doses of vorolanib and/or less than 2 planned infusions of nivolumab over the 
first 28 days after initiating protocol-indicated treatment on Cycle 1, Day 1, then that patient will be 
considered not evaluable for response to overall protocol-indicated treatment and may be replaced 
with a new patient.   
 
 
10.2.  Dose Modifications and Delays of vorolanib 
Dose modifications for hematologic and non-hematologic toxicities considered related to vorolanib 
by the patient’s study physician are described below in Sections 10.2.1 and 2. 
 
Vorolanib treatment may be delayed for up to 4 weeks from the last dose.  If vorolanib is 
interrupted for more than 28 days, written permission to continue vorolanib must be obtained from 
the sponsor-investigator subsequent to consultation with the investigator and study physician. 
 
Vorolanib dose levels are indicated in Section 8.1.  Note the lowest dose of vorolanib allowed on 
study is 100 mg QD.  Accordingly, a patient unable to tolerate vorolanib at a minimum dose of 
100 mg QD would be unable to continue the study. 
 
For each dose reduction of vorolanib, reduce the current vorolanib dose by 100 mg daily. 
 
During the initial 28 days after first dose of protocol-indicated treatment on Cycle 1, Day 1:  Dose 
reductions of vorolanib are to be avoided for patients enrolled in the Phase 1 dose escalation part 
of the study, and are permitted only by written permission from the sponsor-investigator.  (The data 
from such a dose-reduced patient would normally not be applicable toward dose-escalation 
decisions.)  At other times, dose reductions of vorolanib for adverse events may take place at any 
time as otherwise consistent with the protocol. 
 


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In general and unless otherwise specified by the protocol, dose reductions of vorolanib for 
management of adverse event(s) within a given patient should be considered permanent:  Once 
the dose of VOROLANIB has been reduced in a given patient, all subsequent cycles in the same 
patient should be ordinarily administered at the reduced dose level (unless additional dose 
reduction is required).   
 
Accordingly, intrapatient dose re-escalation of vorolanib in a given patient will not ordinarily be 
allowed, unless there is discussion and written agreement between the investigator and the 
sponsor-investigator (e.g. as part of an appropriate evaluation of the combinatorial setting in 
which, after strategic dose intervention involving one or more particular agent, any potentially 
overlapping toxicity between vorolanib and nivolumab is ultimately judged best attributed to one 
individual drug, but unlikely or not related to the other drug). 
 
Note that whereas intrapatient dose re-escalation (e.g. following an adverse event) of vorolanib in 
a given patient will not be ordinarily be allowed, intrapatient dose escalation of vorolanib may be 
allowed by the sponsor-investigator, to the extent that such action involves an early-enrolling 
patient, who is tolerating treatment and who was assigned to an early vorolanib dose level which 
was ultimately found to be below the maximum tolerated dose (MTD) level of the vorolanib + 
nivolumab combination.  Once the MTD of vorolanib + nivolumab is established by the study, early 
patients who initially enrolled at vorolanib dose levels below the MTD, may optionally be dose 
escalated to the MTD dose level upon written agreement between the patient’s treating physician, 
the local site’s principal investigator and the sponsor-investigator. 
 
For purpose of any necessary definition, “baseline value” is defined as the most immediately 
known value in place prior to patient’s first receipt of vorolanib on Cycle 1, Day 1. 
 
In the event of an adverse event deemed by the study physician as unrelated to vorolanib, the 
study physician may nevertheless optionally choose to precautionarily interrupt vorolanib for up to 
28 days, but no dose reduction of vorolanib should occur.   
 
If vorolanib is held for adverse event, tolerated treatment with nivolumab should continue as 
scheduled until vorolanib is permanently discontinued – at which time the patient must also 
permanently discontinue the study (per Section 8.4:  a patient must permanently discontinue the 
study if unable to tolerate vorolanib; within the study, a patient will not receive nivolumab as an 
exclusive ‘single-agent’ therapy.) 
 
1.  Vorolanib Dose Adjustments for Hematologic Toxicity 
For hematologic adverse events deemed by the patient’s study physician as possibly, probably, 
or definitely related to vorolanib, treatment with vorolanib should be held according to Table 3, 
with subsequent monitoring and re-evaluation of ANC and platelets at an interval deemed 
appropriate by the patient’s study physician. 
 
If ANC and/or platelets do not recover to ≤ Grade 2 within 4 weeks, then the patient will be 
discontinued from the trial unless the treating physician and PI agree that continued treatment at 
lower doses is in the best interest of the patient, and written permission is obtained from the 
sponsor-investigator. 
 
TABLE 3:  Vorolanib Dose Modifications for Hematologic Toxicities 




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writing that continued treatment at a reduced dose of vorolanib is in the best interest of 
the patient.  
 
• 
If a Grade 4 non-hematologic toxicity related to vorolanib occurs, vorolanib will be 
permanently discontinued.  
 
• 
Specific Recommendations for Rash, Nausea, Vomiting and Diarrhea:  
For patients with Grade 3 rash, nausea, vomiting, and/or diarrhea related to vorolanib:   
Vorolanib should be held and supportive care initiated.  If the Grade 3 toxicity lasts  
≤ 7 days, patients may restart vorolanib at a reduced dose when the toxicity reduces 
to ≤ Grade 1. 
 
• 
Specific Recommendations for drug induced Liver Function Test Abnormalities:  
For patients with Grade 3 liver enzyme elevations (i.e. AST/ALT) related to vorolanib:   
Vorolanib should be held until the value(s) recover to ≤ Grade 1.  Patients with 
elevated ALT ≥ 3 x ULN in conjunction with a bilirubin ≥ 2 x ULN may continue 
vorolanib if a correctable cause of the liver test elevations can be documented as 
unrelated to vorolanib; otherwise, the patient must permanently discontinue 
vorolanib.  
 
• 
Specific Recommendations for the Treatment of Hypertension:  
Treatment of hypertension should be based on the patient, and the patient’s clinical status.  
General recommendations for initial management of hypertension (HTN) include:  
 
1. 
For hypertension that is persistent in the judgement of the patient’s study 
physician (e.g. consistent blood pressure readings of > 140/90), consider initiating 
an ACE inhibitor (e.g. benazepril, lisinopril), an angiotensin II receptor blocker 
(ARB, e.g. losartan), a thiazide diuretic (e.g. HCTZ), or a dihydropyrimidine 
calcium channel blocker (e.g. amlodipine).  Titrate to BP control with dose 
escalation of the chosen medication or, if additional agents are needed, choose a 
second agent from the recommended list.  
 
2. 
For patients with blood pressure > 160/90, consider initiating combinatorial 
therapy with an ACE inhibitor + a dihydropyrimidine calcium channel blocker.  
 
 
 
10.3.  Dose Modifications of Nivolumab 
Dose reductions or dose escalations of nivolumab are not permitted.  Nivolumab will be managed 
by dose holds.  
  
10.4.  Criteria for Dose Delays of Nivolumab 
Because of the potential for clinically meaningful nivolumab-related adverse events requiring early 
recognition and prompt intervention, management algorithms have been developed for suspected 
AEs of selected categories.  For example, please see Protocol Appendix 7, regarding guidelines 
for the management of immune-related adverse events (irAEs). 
 
If deemed by the investigator as possibly, probably, or definitely related to nivolumab, then 
nivolumab administration should be delayed for the following: 
 
• 
Any Grade ≥ 2 non-skin, drug-related AE, with the following exceptions: 
 


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 Grade 2 drug-related fatigue or laboratory abnormalities do not require treatment 
delay. 
 
• 
Grade 3 skin, drug-related AE. 
 
• 
Any Grade 3 drug-related laboratory abnormality, with the following exceptions for 
lymphopenia, leukopenia, AST, ALT, total bilirubin, or asymptomatic amylase or lipase: 
 
 Grade 3 lymphopenia or leukopenia does not require dose delay. 
 
 If a subject has a baseline AST, ALT, or total bilirubin that is within normal limits, 
delay dosing for drug-related Grade ≥ 2 toxicity. 
 
 If a subject has baseline AST, ALT, or total bilirubin within the Grade 1 toxicity 
range, delay dosing for drug-related Grade ≥ 3 toxicity. 
 
 Any Grade ≥ 3 drug-related amylase or lipase abnormality not associated with 
symptoms or clinical manifestations of pancreatitis does not require dose delay.  
The sponsor-investigator should be consulted for such Grade ≥ 3 amylase or 
lipase abnormalities. 
 
• 
Any AE, laboratory abnormality, or intercurrent illness which, in the judgment of the 
investigator, warrants delaying the dose of nivolumab. 
 
Subjects who require delay of nivolumab should be re-evaluated weekly or more frequently 
if clinically indicated and resume nivolumab dosing when re-treatment criteria are met. 
 
 
10.5.  Criteria to Resume Nivolumab Treatment 
Subjects may resume treatment with nivolumab when the AE(s) deemed by the investigator as 
possibly, probably, or definitely related to nivolumab treatment resolve to Grade ≤ 1 or 
baseline value (i.e. the most immediately known value in place prior to patient’s first receipt of 
nivolumab on Cycle 1, Day 1) with the following exceptions: 
 
• 
Subjects may resume nivolumab treatment in the presence of Grade 2 fatigue. 
  
• 
Subjects who have not experienced a Grade 3 nivolumab-related skin AE may resume 
nivolumab treatment in the presence of Grade 2 skin toxicity.  
 
• 
Subjects with baseline Grade 1 AST/ALT or total bilirubin who require dose delays for 
reasons other than a 2-grade shift in AST/ALT or total bilirubin may resume nivolumab 
treatment in the presence of Grade 2 AST/ALT OR total bilirubin. 
 
• 
Subjects with combined Grade 2 AST/ALT AND total bilirubin values meeting 
discontinuation parameters (Section 10.6) should have nivolumab treatment permanently 
discontinued. 
 
• 
Nivolumab-related pulmonary toxicity, diarrhea, or colitis, must have resolved to baseline 
before nivolumab treatment is resumed.  Subjects with persistent Grade 1 pneumonitis 
after completion of a steroid taper over at least 1 month may be eligible for nivolumab 
retreatment at the discretion of the investigator, with written permission from the sponsor-
investigator. 


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• 
Subjects with nivolumab-related endocrinopathies adequately controlled with only 
physiologic hormone replacement may resume nivolumab treatment with written 
permission from the sponsor-investigator. 
 
If nivolumab treatment is delayed for > 6 weeks, the subject must permanently discontinue 
nivolumab therapy, except as otherwise specified (e.g. Section 10.6, where the delay is due to 
the need for a prolonged steroid taper in order to manage drug-related adverse events, or the 
delay is not drug related) and written permission to resume treatment is granted by the sponsor-
investigator. 
   
10.6.  Criteria to Permanently Discontinue Nivolumab 
Treatment 
If deemed by the investigator as possibly, probably, or definitely related to nivolumab 
treatment, treatment with nivolumab should be permanently discontinued for the following: 
 
• 
Any Grade 2 drug-related uveitis, eye pain or blurred vision that does not respond to 
topical therapy and does not improve to Grade 1 severity within the re-treatment period 
OR requires systemic treatment.  
• 
Any Grade 2 drug-related AST or ALT > 3 x ULN concurrent with total bilirubin > 2 x ULN.   
• 
Any Grade 3 non-skin, drug-related adverse event lasting > 7 days, with the following 
exceptions for drug-related laboratory abnormalities, uveitis, pneumonitis, bronchospasm, 
hypersensitivity and infusion reactions, and endocrinopathies: 
 
 Grade 3 drug-related uveitis, pneumonitis, bronchospasm, hypersensitivity reaction, 
colitis or infusion reaction of any duration requires discontinuation. 
 
 Grade 3 drug-related endocrinopathies, except adrenal insufficiency, adequately 
controlled with only physiologic hormone replacement do not require 
discontinuation. Patients with grade 3 adrenal insufficiency must permanently 
discontinue nivolumab. 
 
 Grade 3 drug-related laboratory abnormalities do not require treatment 
discontinuation except: 
 
o 
Grade 3 drug-related thrombocytopenia > 7 days or associated with bleeding 
requires discontinuation. 
 
o 
Immune mediated hepatitis or any drug-related liver function test (LFT) 
abnormality that meets the following criteria requires discontinuation:  
 
 
AST or ALT > 8 x ULN. 
 
 
Total bilirubin > 5 x ULN. 
 
Concurrent AST or ALT > 3 x ULN and total bilirubin > 2 x ULN.   
 
• 
Immune-mediated encephalitis 
• 
Any Grade 4 drug-related adverse event or laboratory abnormality, except for the 
following events which do not require discontinuation: 
 


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 Isolated Grade 4 amylase or lipase abnormalities not associated with symptoms or 
clinical manifestations of pancreatitis and decrease to < Grade 4 within 1 week of 
onset.  
 
 Isolated Grade 4 electrolyte imbalances/abnormalities not associated with clinical 
sequelae and corrected with supplementation/appropriate management within 72 
hours of onset. 
 
 Grade 4 neutropenia ≤ 7 days 
 
 Grade 4 lymphopenia or leukopenia. 
 
 Grade 4 drug-related endocrinopathy adverse events (except hypophysitis), such as 
adrenal insufficiency, ACTH deficiency, hyper- or hypothyroidism, or glucose 
intolerance, which resolve or are adequately controlled with physiologic hormone 
replacement (corticosteroids, thyroid hormones) or glucose-controlling agents, 
respectively, may not require discontinuation after discussion with and written 
approval from the sponsor-investigator.  Occurrence of Grade 4 hypophysitis requires 
discontinuation. 
 
• 
Any dosing interruption lasting > 6 weeks with the following exceptions: 
 
 Dosing delays or interruptions to allow for prolonged steroid tapers to manage drug-
related adverse events are allowed.  Prior to re-initiating treatment in a subject with a 
dosing interruption lasting > 6 weeks, written permission must be obtained from the 
sponsor-investigator.  Tumor assessments should continue as per protocol even if 
dosing is interrupted or delayed. 
 
 Dosing interruptions or delays lasting > 6 weeks that occur for non-drug-related 
reasons may be allowed if approved in writing by the sponsor-investigator.  Prior to 
re-initiating treatment in a subject with a dosing interruption lasting > 6 weeks, the 
sponsor-investigator must be consulted.  Tumor assessments should continue as per 
protocol even if dosing is interrupted. 
 
• 
Any adverse event, laboratory abnormality, or intercurrent illness which, in the judgment of 
the investigator, presents a substantial clinical risk to the subject with continued nivolumab 
dosing. 
 
10.7.  Management Algorithms for Immuno-Oncology 
Agents 
Immuno-oncology (I-O) agents are associated with adverse events (AEs) that can differ in severity 
and duration than AEs caused by other therapeutic classes.  In this protocol, nivolumab is 
considered an immuno-oncology agent.  Early recognition and management of AEs associated 
with an immuno-oncology agent may mitigate severe toxicity.  
 
Management Algorithms have been developed to assist investigators in assessing and managing 
the following groups of AEs:  
 
 
• 
Gastrointestinal  
• 
Renal  
• 
Pulmonary  


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• 
Hepatic  
• 
Endocrinopathy  
• 
Skin  
• 
Neurological 
• 
Myocarditis 
 
For the above events deemed by the patient’s study physician to be possibly, probably or definitely 
related to nivolumab, Management Algorithms are found in Appendix 7.   
 
The guidance provided in these algorithms should not replace the Investigator’s medical judgment 
but should complement it. 
 
10.8.  Guidelines for the Management of Infusion 
Reactions 
Nivolumab can cause severe infusion reactions, which have been reported in less than 1.0% of 
patients in clinical trials.  In patients receiving nivolumab as a single agent, infusion-related 
reactions occurred in 6.4% (127/1994) of patients.  In patients receiving nivolumab with 
ipilimumab, infusion-related reactions occurred in 2.5% (10/407) of patients.  
 
Since nivolumab contains only human immunoglobulin protein sequences, it is unlikely to be 
immunogenic and induce infusion or hypersensitivity reactions.  However, if such a reaction were 
to occur, it might manifest with fever, chills, rigors, headache, rash, pruritus, arthralgias, hypo- or 
hypertension, bronchospasm, or other symptoms of allergic-like reactions.  
 
Discontinue nivolumab in patients with severe or life-threatening infusion reactions.  
Interrupt or slow the rate of infusion in patients with mild or moderate infusion reactions. 
 
Infusion reactions should be graded according to NCI CTCAE 5.0 guidelines. 
 
All Grade 3 or 4 infusion reactions will be evaluated as to whether or not the event is a DLT.  All 
infusion reactions that are serious adverse events (per Section 12) must be rapidly reported as 
such, via notification procedures described in Section 12. 
 
Treatment recommendations are provided below and may be modified based on local treatment 
standards and guidelines as appropriate: 
 
• 
For Grade 1 symptoms:  
 
 Mild reaction; infusion interruption not indicated; intervention not indicated. 
 
 Remain at bedside and monitor subject until recovery from symptoms.  The 
following prophylactic premedications are recommended for future infusions: 
diphenhydramine 50 mg (or equivalent) and/or paracetamol 325 to 1000 mg 
(acetaminophen) at least 30 minutes before additional nivolumab administrations. 
 
• 
For Grade 2 symptoms:  
  
 Moderate reaction requires therapy or infusion interruption but responds promptly 
to symptomatic treatment (e.g. antihistamines, non-steroidal anti-inflammatory 
drugs, narcotics, corticosteroids, bronchodilators, IV fluids); prophylactic 
medications indicated for ≤ 24 hours. 
 


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 Stop the nivolumab infusion, begin an IV infusion of normal saline, and treat the 
subject with diphenhydramine 50 mg IV (or equivalent) and/or paracetamol 325 to 
1000 mg (acetaminophen); remain at bedside and monitor subject until resolution 
of symptoms.  Corticosteroid or bronchodilator therapy may also be administered 
as appropriate.   
 
 If the infusion is interrupted, then restart the infusion at 50% of the original infusion 
rate when symptoms resolve; if no further complications ensue after 30 minutes, 
the rate may be increased to 100% of the original infusion rate.  Monitor subject 
closely.  If symptoms recur then no further nivolumab will be administered at that 
visit.  Administer diphenhydramine 50 mg IV, and remain at bedside and monitor 
the subject until resolution of symptoms.  The amount of study drug infused must 
be recorded on the electronic case report form (eCRF).   
 
 The following prophylactic premedications are recommended for future infusions: 
diphenhydramine 50 mg (or equivalent) and/or paracetamol 325 to 1000 mg 
(acetaminophen) should be administered at least 30 minutes before additional 
nivolumab administrations.  If necessary, corticosteroids (recommended dose: up 
to 25 mg of IV hydrocortisone or equivalent) may be used. 
 
• 
For Grade 3 or Grade 4 symptoms:   
 
 Severe reaction, Grade 3:  prolonged (i.e. not rapidly responsive to symptomatic 
medication and/or brief interruption of infusion); recurrence of symptoms following 
initial improvement; hospitalization indicated for other clinical sequelae (e.g. renal 
impairment, pulmonary infiltrates).  Grade 4:  life threatening; pressor or ventilatory 
support indicated.  
 
 Immediately discontinue infusion of nivolumab.   
 
 Begin an IV infusion of normal saline, and treat the subject as follows.  
Recommend bronchodilators, epinephrine 0.2 to 1 mg of a 1:1,000 solution for 
subcutaneous administration or 0.1 to 0.25 mg of a 1:10,000 solution injected 
slowly for IV administration, and/or diphenhydramine 50 mg IV with 
methylprednisolone 100 mg IV (or equivalent), as needed. 
 
 Subject should be monitored until the investigator is comfortable that the symptoms 
will not recur.  Nivolumab will be permanently discontinued.  Investigators 
should follow their institutional guidelines for the treatment of anaphylaxis.  Remain 
at bedside and monitor subject until recovery from symptoms.  
 
 In the case of late-occurring hypersensitivity symptoms (e.g. appearance of a 
localized or generalized pruritus within 1 week after treatment), symptomatic 
treatment may be given (e.g. oral antihistamine, or corticosteroids). 
 
11.  DRUG FORMULATION, SUPPLY AND STORAGE 
 
11.1.  Description of Vorolanib 
Vorolanib is an oral multi-kinase vascular endothelial growth factor receptor (VEGFR)/platelet 
derived growth factor receptor (PDGFR)/colony-stimulating factor 1 receptor (CSF1R)/FMS like 
tyrosine kinase 3 (FLT3) inhibitor under investigation for the treatment of solid tumors and for the 


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treatment of pathologic angiogenesis in diseases such as neovascular “wet” age-related macular 
degeneration (AMD), and von Hippel-Lindau Disease.  Binding of vorolanib to its target receptors 
(VEGF and PDGF) results in angiogenesis inhibition. 
 
11.2.  Packaging of Vorolanib 
The study will supply vorolanib to each site. 
 
Oral vorolanib drug product was originally formulated as capsules and has more recently been 
formulated as orange tablets with a dosage strength of 100 mg (oblong tablets) of vorolanib drug 
substance. The tablets are coated with a colored, nonfunctional, globally accepted film coating.  
The formulation was changed to improve absorption. 
 
11.3.  Handling and Storage of Vorolanib 
Vorolanib tablets (100 mg) are packaged in 60 cc round, white HDPE bottles containing a 
pharmaceutical desiccant canister, closed with a white polypropylene child resistant cap and foil 
induction inner seal. 
 
Vorolanib should be stored at room temperature (15ºC - 30ºC/59ºF - 86ºF). 
 
11.4.  Description of Nivolumab 
Nivolumab (OPDIVO®) is a programmed death receptor-1 (PD-1) blocking antibody that is 
currently FDA approved for BRAF V600 wild-type unresectable or metastatic melanoma; BRAF 
V600 mutation-positive unresectable or metastatic melanoma; unresectable or metastatic 
melanoma, in combination with ipilimumab; metastatic non-small cell lung cancer and progression 
on or after platinum-based chemotherapy; advanced renal cell carcinoma after prior anti-
angiogenic therapy; and classical Hodgkin lymphoma that has relapsed or progressed after 
autologous hematopoietic stem cell transplantation (HSCT) and post-transplantation brentuximab 
vedotin . 
 
11.5.  Packaging of Nivolumab 
The study will supply nivolumab to each site. 
 
Nivolumab is typically available as nivolumab injection:  100 mg/10 mL (10 mg/mL) solution in a 
single-dose vial. 
 
Nivolumab drug product should be visually inspected for particulate matter and discoloration prior 
to administration. OPDIVO is a clear to opalescent, colorless to pale-yellow solution.  Discard the 
vial if the solution is cloudy, discolored, or contains extraneous particulate matter other than a few 
translucent-to-white, proteinaceous particles.  Do not shake the vial. 
 
11.6.  Handling and Storage of Nivolumab 
Nivolumab product does not contain a preservative.  Nivolumab will be prepared according to the 
product label.  After preparation, nivolumab infusion should be stored either: 
 
• 
At room temperature for no more than 8 hours from the time of preparation.  This includes 
room temperature storage of the infusion in the IV container and time for administration of 
the infusion, or 
 


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• 
Under refrigeration at 2°C to 8°C (36°F to 46°F) for no more than 24 hours from the time 
of infusion preparation. 
 
• 
Do not freeze. 
 
11.7.  Drug Accountability and Compliance Check 
The Investigator is responsible for ensuring accountability for vorolanib and nivolumab, including 
maintenance of adequate drug accountability records. 
 
Drug accountability records should include an appropriate inventory of vorolanib and nivolumab 
including: 
 
• 
Confirmation that vorolanib and nivolumab supplied by the study was delivered to the trial 
site 
 
• 
Record of each dose of vorolanib and nivolumab dispensed 
 
• 
Return of unused vorolanib and nivolumab provided by the study to the sponsor-
investigator or designee, or documentation of destruction at site (if drug destruction by the 
site is authorized by sponsor-investigator or designee). 
 
Records should specify relevant dates, quantities, batch numbers, use-by dates and patient 
numbers, as applicable. 
 
The Investigator, or designee, should maintain records that adequately document: 
 
• 
That patients were provided the doses specified by the clinical trial protocol, and 
 
• 
That all vorolanib and nivolumab provided by the study was fully reconciled. 
 
 
12.  SAFETY REPORTING OF ADVERSE EVENTS 
 
12.1.  General 
Each adverse event will be graded according to the NCI’s Common Terminology Criteria for 
Adverse Events (NCI CTCAE), Version 5.0, dated November 27, 2017, currently locatable via the 
following URL:  
<https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_Q
uick_Reference_8.5x11.pdf >. 
 
For events not listed in the CTCAE, severity will be designated as mild, moderate, severe or life 
threatening, or fatal which respectively correspond to Grades 1, 2, 3, 4, and 5 on the NCI CTCAE, 
with the following definitions: 
 
• 
Mild:  An event not resulting in disability or incapacity and which resolves without 
intervention; 
 
• 
Moderate:  An event not resulting in disability or incapacity but which requires 
intervention; 
 
• 
Severe:  An event resulting in temporary disability or incapacity and which requires 
intervention; 
 


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• 
Life-threatening:  An event in which the patient was at risk of death at the time of the 
event; 
 
• 
Fatal:  An event that results in the death of the patient. 
 
Information on all adverse events, whether serious or not, 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.  
 
Reporting period:  Adverse events experienced by participants will be collected and reported 
from initiation of protocol-indicated treatment (to also include events after signing consent but 
before initiation of protocol-indicated treatment if an adverse event is at least possibly related to a 
study procedure such as a biopsy, or to the withholding of a medication prohibited by protocol), 
throughout the study, and within 100 days after the last dose of protocol-indicated treatment.  
Participants who experience an adverse event related to a study procedure and/or protocol-
indicated treatment beyond 100 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.  
 
All laboratory test results and vital signs captured as part of the study should be recorded following 
institutional procedures.  Laboratory test results and vital signs that constitute SAEs should be 
documented and reported as such.   
 
• 
Any laboratory test result or vital sign considered by the investigator to be clinically 
significant or meeting the definition of an SAE; 
 
• 
Any laboratory or vital sign abnormality that required the subject to have protocol-
indicated treatment to be discontinued or interrupted; 
 
• 
Any laboratory or vital sign abnormality that required the subject to receive specific 
corrective therapy.  
 
Baseline disease-related signs and symptoms which are initially recorded as medical history, will 
subsequently be recorded as adverse events during the trial if they worsen in severity or increase 
in frequency. 
 
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 
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. 
 
12.2.  Risks Associated with Vorolanib 
• 
The most frequent (≥ 10%) drug-related adverse events reported with vorolanib as of 14 
Jan 2016 from the first-in-human oncology Phase 1 single-agent study include fatigue, 
nausea, diarrhea, hair color changes, vomiting, asthenia, rash, and peripheral edema.  
 
• 
While not a consistent finding, some patients have had decreases in laboratory values 
(e.g. platelets and hemoglobin).  Some patients receiving vorolanib in a study in subjects 
with age-related macular degeneration (AMD) had increased transaminases.  No subjects 
have met Hy’s law criteria.  Improvement in transaminases have been documented in all 
cases, either during a dose pause, permanent drug discontinuation, or with continued 
dosing. 
 
• 
A more detailed safety profile of vorolanib is provided in the investigator’s brochure (2).  
 


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12.3.  Risks Associated with Nivolumab 
• 
Most common adverse reactions (≥20%) of nivolumab as a single agent in patients were:  
fatigue, rash, musculoskeletal pain, pruritus, diarrhea, nausea, asthenic conditions, cough, 
dyspnea, constipation, decreased appetite, back pain, arthralgia, upper respiratory tract 
infection, pyrexia. 
 
• 
A more detailed safety profile of nivolumab is provided in the product labels, currently 
locatable online via following: 
 
Nivolumab (OPDIVO): 
< https://packageinserts.bms.com/pi/pi_opdivo.pdf  >. 
 
12.4.  Adverse Event (AE) 
An AE is any unfavorable and unintended sign, symptom, or disease temporally associated with 
the use of an investigational medicinal product (IMP) or other protocol-imposed intervention, 
regardless of attribution.  Progressive disease will not be considered an adverse event.  
An adverse event includes the following: 
 
• 
AEs not previously observed in the patient that emerge during the protocol-specified AE 
reporting period, including signs or symptoms that were not present prior to the AE 
reporting period. 
 
• 
Complications that occur as a result of protocol-mandated interventions (e.g. invasive 
procedures such as biopsy). 
 
• 
If applicable, AEs that occur prior to assignment of study treatment associated with 
medication washout, no treatment run-in, or other protocol-mandated intervention. 
 
• 
Pre-existing medical conditions (other than the condition being studied) judged by the 
investigator to have worsened in severity or frequency or changed in character during the 
protocol-specified AE reporting period. 
 
• 
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.  
 
 
 
12.5.  Serious Adverse Event (SAE) 
An AE should be classified as an SAE if the following criteria are met: 
• 
It results in death (i.e. the AE actually causes or leads to death). 
 
• 
It is life threatening (i.e. the AE, in the view of the investigator or sponsor-investigator, 
places the patient at immediate risk of death.  It does not include an AE that, had it 
occurred in a more severe form, might have caused death.) 
 
• 
It requires or prolongs inpatient hospitalization. 
 
• 
It results in persistent or significant disability/incapacity (i.e. the AE results in 
substantial disruption of the patient’s ability to conduct normal life functions). 
 
• 
It results in a congenital anomaly/birth defect in a neonate/infant born to a mother 
exposed to the investigational product 
 


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• 
It is considered a significant medical event by the investigator or sponsor-investigator 
based on medical judgment (e.g. may jeopardize the patient or may require 
medical/surgical intervention to prevent one of the outcomes listed above). 
 
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. 
 
• 
Emergency outpatient treatment for an event not fulfilling the serious criteria outlined 
above and not resulting in an inpatient admission lasting ≥ 24 hours. 
 
• 
Respite care. 
 
12.6.  Assessment of Adverse Events 
All AEs and SAEs, whether volunteered by the patient, discovered by study personnel during 
questioning, or detected through physical examination, laboratory test, or other means, will be 
reported appropriately.  Each reported AE or SAE will be described by its duration (i.e. start and 
end dates), regulatory seriousness criteria if applicable, suspected relationship to the 
investigational treatment (see following guidance), and actions taken. 
 
To ensure consistency of AE and SAE causality assessments, investigators should apply the 
following general guidelines: 
 
• 
Yes 
There is a reasonable causal relationship between the investigational treatment and the 
adverse event.  There is a plausible temporal relationship between the onset of the AE 
and administration of the investigational treatment, and the AE cannot be readily explained 
by the patient’s clinical state, intercurrent illness, or concomitant therapies; and/or the AE 
follows a known pattern of response to the investigational treatment; and/or the AE abates 
or resolves upon discontinuation of the investigational treatment or dose reduction and, if 
applicable, reappears upon re-challenge.   
 
• 
No 
There is no reasonable causal relationship between the investigational treatment 
administered and the adverse event.  Evidence exists that the AE has an etiology other 
than the investigational treatment (e.g. pre-existing medical condition, underlying disease, 
intercurrent illness, or concomitant medication); and/or the AE has no plausible temporal 
relationship to administration of the investigational treatment. 
 
12.7.  Expectedness 
Expected:  Expected adverse events are those that have been previously identified as resulting 
from administration of the agent.  An adverse event is generally considered expected when it 
appears in the current adverse event list, investigator’s brochure, package insert, protocol; or is 
included in the informed consent document as a potential risk. 
 
• 
Unexpected:  An adverse event is generally considered unexpected when it varies in 
nature, intensity or frequency from information provided in the current adverse event list, 
the investigator’s brochure, package insert, or protocol; or is not listed in the investigator’s 
brochure, package insert, protocol, or informed consent document as a potential risk. 
 
12.8.  Attribution 


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The investigator must attempt to determine if there exists reasonable possibility that an adverse 
event or serious adverse event is related to the use of the investigational treatment.  Attribution of 
adverse events should be described as unrelated; or unlikely, possibly, probably, or definitely 
related to the investigational treatment: 
Attribution   
Description 
Unrelated   
AE is clearly NOT related to the intervention. 
Unlikely  
 
AE is doubtfully related to the intervention. 
Possible  
 
AE may be related to the intervention. 
Probable  
 
AE is likely related to the intervention. 
Definite  
 
AE is clearly related to the intervention. 
 
For additional purpose of any applicable binary regulatory reporting, an event should be 
considered Unrelated to study treatment when its attribution is felt by the investigator to be either 
Unrelated or Unlikely related to investigational treatment.  Similarly, an event should be 
considered Related to study treatment, when its attribution is felt to be either Possibly, Probably, 
or Definitely related to investigational treatment. 
 
12.9.  Specific Instructions for Recording Adverse Events 
Investigators should use correct medical terminology/concepts when reporting AEs or SAEs.  
Avoid colloquialisms and abbreviations.  All adverse events will be captured on the appropriate 
study-specific electronic case report forms (eCRFs).  
 
12.10.  Diagnosis versus Signs and Symptoms 
If known at the time of reporting, a diagnosis should be reported rather than individual signs and 
symptoms (e.g. record only liver failure or hepatitis rather than jaundice, asterixis, and elevated 
transaminases).  However, if a constellation of signs and/or symptoms cannot be medically 
characterized as a single diagnosis or syndrome at the time of reporting, it is acceptable to report 
the information that is currently available.  If a diagnosis is subsequently established, it should be 
reported as follow-up information. 
 
12.11.  Deaths 
All deaths that occur during the protocol-specified AE reporting period, regardless of attribution, 
will be reported to the appropriate parties.  When recording a death, the event or condition that 
caused or contributed to the fatal outcome should be reported as the single medical concept.  If 
the cause of death is unknown and cannot be ascertained at the time of reporting, report 
“Unexplained Death.”  Deaths that occur during the protocol specified adverse event reporting 
period that are attributed by the investigator solely to progression of disease should be recorded 
only in the study eCRF. 
 
12.12.  Pre-existing Medical Conditions 
A pre-existing medical condition is one that is present at the start of the study.  Such conditions 
should be reported as medical and surgical history.  A pre-existing medical condition should be re-
assessed throughout the trial and reported as an AE or SAE only if the frequency, severity, or 
character of the condition worsens during the study.  When reporting such events, it is important 
to convey the concept that the pre-existing condition has changed by including applicable 
descriptors (e.g., “more frequent headaches”). 
 
12.13.  Hospitalizations for Medical or Surgical Procedures 
Any AE that results in hospitalization ≥ 24 hours or prolonged hospitalization should be 
documented and reported as an SAE.  If a patient is hospitalized to undergo a medical or surgical 


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procedure as a result of an AE, the event responsible for the procedure, not the procedure itself, 
should be reported as the SAE.  For example, if a patient is hospitalized to undergo coronary 
bypass surgery, record the heart condition that necessitated the bypass as the SAE. 
 
Hospitalizations for the following reasons do not require reporting: 
• 
Hospitalization or prolonged hospitalization for diagnostic or elective surgical procedures 
for pre-existing conditions, 
• 
Hospitalization or prolonged hospitalization required to allow efficacy measurement for the 
study, or 
• 
Hospitalization or prolonged hospitalization for scheduled therapy of the target disease of 
the study. 
12.14.  Pregnancies in Female Patients 
Female patients of childbearing potential will be instructed to immediately inform the investigator 
if they become pregnant during the study or within 23 weeks after the last dose of protocol-
indicated treatment.  The coordinating center SAE form reporting the pregnancy should be 
completed by the investigator immediately (i.e., no more than 24 hours after learning of the 
pregnancy) and submitted via fax or email.    Unless otherwise agreed to and approved by the 
sponsor-investigator, investigator and the IRB, the patient should discontinue protocol-indicated 
treatment. Bristol-Myers Squibb will be notified within 24 hours of this knowledge and patient 
pregnancies monitored.   
 
The investigator or medical designee should counsel the patient, discussing the risks of the 
pregnancy and the possible effects on the fetus.  Monitoring of the patient should continue until 
conclusion of the pregnancy.  Any SAEs associated with the pregnancy (e.g. an event in the 
fetus, an event in the mother during or after the pregnancy, or a congenital anomaly/birth defect in 
the child) should be reported on the coordinating center SAE form. 
 
12.15.  Pregnancies in Female Partners of Male Patients 
Male patients will be instructed through the informed consent form to immediately inform the 
investigator if their partner becomes pregnant during the study or within 31 weeks after 
completing protocol-indicated treatment.  Male patients who received study treatment should not 
attempt to father a child until 31 weeks after stopping study treatment.  The coordinating center 
SAE form reporting the pregnancy should be completed by the investigator immediately (i.e., no 
more than 24 hours after learning of the pregnancy) and faxed or emailed to the sponsor-
investigator.  Attempts should be made to collect and report details of the course and outcome of 
any pregnancy in the partner of a male patient exposed to study drug.  The pregnant partner may 
be asked to sign an Authorization for Use and Disclosure of Pregnancy Health Information to 
allow for follow-up on her pregnancy.  Once the authorization has been signed, the investigator or 
designee will update the coordinating center SAE form with additional information on the course 
and outcome of the pregnancy.  An investigator or medical designee who is contacted by the 
male patient or his pregnant partner may provide information on the risks of the pregnancy and 
the possible effects on the fetus, to support an informed decision in cooperation with the treating 
physician and/or obstetrician. 
 
12.16.  Overdose 
An overdose is defined as the accidental or intentional administration of any dose of a product 
that is considered both excessive and medically important. All occurrences of overdose must be 
reported as an SAE. 
 
12.17.  Post-Study Adverse Events 
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IND 
Events meeting the following criteria must be submitted to the FDA as expedited IND Safety 
Reports according to the following guidance and timelines: 
 
7 Calendar Day Telephone or Fax Report 
 
The sponsor-investigator is required to notify the FDA of any fatal or life-threatening AE that is 
unexpected and suspected by the sponsor-investigator to be possibly, probably or definitely 
related to protocol-indicated treatment.  The sponsor-investigator must notify the FDA of such 
events as soon as possible but in no case later than 7 calendar days after the sponsor-
investigator’s initial receipt of the information. 
 
15 Calendar Day Written Report 
 
The sponsor-investigator is required to notify the FDA and all participating investigators, in a 
written IND Safety Report, of any serious unexpected adverse event suspected by the sponsor-
investigator to be possibly, probably, or definitely related to protocol-indicated treatment.  The 
sponsor-investigator must notify the FDA of such events no later than 15 calendar days after the 
sponsor-investigator’s initial receipt of the information. 
 
Written IND Safety reports should include an Analysis of Similar Events in accordance with 
regulation 21 CFR § 312.32.  All safety reports previously filed by the sponsor-investigator with 
the IND concerning similar events should be analyzed and the significance of the new report in 
light of the previous, similar reports commented on. 
 
Written IND safety reports with analysis of similar events are to be submitted to the FDA and all 
participating investigators as soon as possible but not later than 15 calendar days after the 
sponsor-investigator determines that the information qualifies for reporting.   
 
The sponsor-investigator must submit each IND safety report in a narrative format or on FDA 
Form 3500A or in an electronic format that FDA can process, review, and archive.  FDA will 
periodically issue guidance on how to provide the electronic submission (e.g., method of 
transmission, media, file formats, preparation and organization of files).   
 
Each notification to FDA must bear prominent identification of its contents, i.e., “IND Safety 
Report,” and must be transmitted to the review division in the Center for Drug Evaluation and 
Research (CDER) or in the Center for Biologics Evaluation and Research (CBER) that has 
responsibility for review of the IND.  
 
Upon request from FDA, the sponsor-investigator must submit to FDA any additional data or 
information that the agency deems necessary, as soon as possible, but in no case later than 15 
calendar days after receiving the request. 
 
 
12.22.  Xcovery (Equinox Sciences) 
If a Vorolanib event originating from any non–Xcovery sponsored study requires expedited safety 
reporting to the FDA, then Xcovery will need a copy of the final 7 or 15-day MedWatch report via 
email to 
, no later than calendar day 4 for a 7-day report and no later than 
calendar day 10 for a 15-day report, when possible, for submission to Competent Authorities, and 
any central/local ECs, and investigators as applicable per U.S. specific regulatory reporting 
requirements.  
 
The Safety Reporting specialist will generate an Expedited Safety Report/Cross Report 
Investigator Letter Template and will distribute the Safety Cross-Report packet (Expedited Safety 




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supports more than 99,000 projects and 128,000 users. More information about the consortium 
and system security can be found at 
  
 
Specified members at each participating site will submit all pertinent regulatory documents to the 
Coordinating Center for storage in a secure location. 
 
The Principal Investigator or designee at each site will inform the Coordinating Center as defined 
in the Safety and Data Exchange Agreement (SDEA) of any serious adverse event, and will also 
inform the site’s local IRB in accordance with each institution’s IRB policy.  The investigator is 
responsible for the detection and documentation of events meeting the criteria and definition of an 
AE or SAE, as provided in this protocol.  During the study when there is a safety evaluation, the 
treating investigator or site staff will be responsible for detecting, documenting, and reporting AEs 
and SAEs, as detailed in the protocol.  If any problem is identified related to the conduct of this 
research, the VICC Data Safety and Monitoring Committee (DSMC) will be formally asked to 
review the study and the situation that required DSMC intervention. 
 
13.2.  Meetings 
This trial will be monitored by the VICC Thoracic Oncology research team.  The team is composed 
of Medical Oncologists, Research Nurses, Data Managers, and Regulatory Specialists. The team 
meets on a monthly basis to discuss all AEs/SAEs, accrual, compliance, safety issues, adherence 
to protocol, etc. pertaining to cancer studies conducted by the thoracic team.  This particular study 
will be thoroughly reviewed during these meetings.  These monthly meetings are intended to have 
minutes recorded for review on a monthly basis by the Physician Leader of the thoracic oncology 
research team. 
 
In addition, monthly teleconferences between participating sites and the Thoracic Oncology 
research team at Vanderbilt are intended to discuss relevant issues related to the trial (e.g. 
AEs/SAEs, accrual, compliance, safety issues, adherence to protocol, reviews). 
 
13.3.  Monitoring  
This trial will be monitored continuously by the study’s Protocol Chair and by the Thoracic 
Oncology research team at Vanderbilt.   
 
Additionally, the Vanderbilt-Ingram Cancer Center (VICC) oversees patient safety and data 
monitoring for its investigator-initiated and NIH-NCI funded clinical trials through its Data and 
Safety Monitoring Committee (DSMC). The purpose of the DSMC is to ensure the efficient 
implementation and management of VICC Data and Safety Monitoring Plan (DSMP). The 
Committee maintains authority to intervene in the conduct of studies as necessary to ensure 
clinical research performed at VICC achieves the highest quality standards.  
 
The VICC DSMC meets on a quarterly basis and ad hoc to discuss data and safety monitoring of 
clinical trials and to oversee the VICC DSMP. Internal audits for compliance with adverse event 
reporting, regulatory and study requirements, and data accuracy and completion are conducted 
according to the VICC DSMP according to study phase and risk. The committee reviews all serious 
adverse events (SAE) on Vanderbilt sponsored, investigator-initiated studies on a quarterly basis 
and provides DSMC SAE review reports to the Vanderbilt IRB. 
 
The investigator will allow the VICC-DSMC designee access to all pertinent medical records, as 
required by federal regulations, in order to allow for the verification of data gathered in the 
electronic data case report forms (eCRFs) and for the review of the data collection process.  The 
VICC-DSMC designee will review various aspects of the trial including, but not limited to:  
screening and enrollment logs; compliance with the protocol and with the principles of Good 
Clinical Practice; completion of case report forms; source data verification; study drug 
accountability and storage; facilities and staff. The investigator and the investigational site staff 


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must be available to meet with the VICC-DSMC designee in order to discuss the progress of the 
trial, make necessary corrections to case report form entries, respond to data clarification requests 
and respond to any other trial-related inquiries of the Research Compliance Coordinator. 
 
Additionally, the Coordinating Center has responsibilities to health authorities to take all reasonable 
steps to ensure the proper conduct of the study as regards to ethics, protocol adherence, integrity, 
validity of the data recorded on the CRFs, and adherence to regulations regarding Good Clinical 
Practice (GCP) and the protection of human subjects. 
 
In accordance with applicable regulations, GCP, and Coordinating Center procedures, sites will be 
contacted prior to the start of the study to review with the site staff the protocol, study requirements, 
and their responsibilities to satisfy regulatory, ethical, and Coordinating Center requirements.  
 
During the course of the study, the Coordinating Center will routinely monitor sites for protocol 
compliance, compare CRFs with individual subjects’ original source documents, assess drug 
accountability, and ensure that the study is being conducted according to the pertinent regulatory 
requirements. The review of subjects’ medical records will be performed in a manner to ensure that 
subjects’ confidentiality is maintained. Monitoring visits will primarily be conducted remotely, and 
sites are required to provide the appropriate source documentation in order to allow for proper 
oversight per GCP. Investigators must agree to cooperate with the Coordinating Center to ensure 
that any problems detected are resolved. 
 
In addition to the above, the FDA may review the conduct or results of the study at the 
investigational site.  
 
In accordance with HIPAA and associated privacy regulations, a subject’s authorization to use 
personally identifiable health information may be required from each subject before 
commencement of research activities. This authorization document must clearly specify what 
parties will have access to a subject’s personal health information, for what purpose and for what 
duration. 
  
13.4.  Data Handling and Record Keeping 
An electronic case report form (eCRF) is required and must be completed for each included 
participant.  The completed dataset should not be made available in any form to third parties, 
except for authorized representatives of appropriate Health/Regulatory Authorities, without written 
permission from Vanderbilt. 
 
To enable evaluations and/or audits from health authorities and Vanderbilt, each site investigator 
agrees to keep records including:  The identity of all participants (sufficient information to link 
records; e.g., hospital records), all original signed informed consent forms, copies of all source 
documents, and detailed records of drug disposition.  To comply with international regulations, the 
records should be retained by the investigator in compliance with regulations. 
 
During data entry, range and missing data checks will be performed remotely online.  The checks 
to be performed will be documented in the Data Monitoring Plan for the study.  A summary report 
(QC Report) of these checks together with any queries resulting from manual review of the eCRFs 
will be generated for each site and transmitted to the site and the site monitor.  Corrections will be 
made by the study site personnel.  This will be done on an ongoing basis. 
 
 
14.  REGULATORY CONSIDERATIONS 
 
14.1.  Protocol Review and Amendments 


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Information regarding study conduct and progress will be reported to the Institutional Review 
Board (IRB) per current institutional standards. 
 
The trial will not be initiated until there is approval by the local IRB of the protocol, informed 
consent document and any other material used to inform the patient about the nature of the trial.  
The IRB should be duly constituted according to local regulatory requirements.  The investigator 
will inform the IRB of the progress of the trial at least yearly. 
 
Any changes to the protocol will be made in the form of a written amendment and must be 
approved by the sponsor-investigator and the local IRB prior to local implementation.  All 
amendments will also be submitted as necessary to the FDA by the sponsor-investigator (or 
designee). 
 
Protocol changes to eliminate an immediate hazard to a trial patient may be implemented by the 
investigator immediately.  The investigator must then immediately inform the local IRB; and the 
sponsor-investigator (or designee), who will communicate as appropriate with the FDA. 
 
The sponsor-investigator (or designee) is responsible for the coordination and development of all 
protocol amendments, and will disseminate this information to the participating centers. 
 
14.2.  Informed Consent 
The investigator (or designee) will explain to each subject 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 subject 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 
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 subject should read and consider the statement before 
signing and dating it, and will be given a copy of the document.  No subject 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 subjects’ medical history. 
 
14.3.  Ethics and GCP 
This study will be carried out in compliance with the protocol and Good Clinical Practice, as 
described within: 
 
1. ICH Harmonized Tripartite Guidelines for Good Clinical Practice 1996. 
2. US 21 Code of Federal Regulations dealing with clinical studies (including parts 50 and 
56 concerning informed consent and IRB regulations). 
3. 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 within the above 
and thereby to adhere to the principles of Good Clinical Practice with which the above conform. 
 


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14.4.  Confidentiality 
It is the responsibility of the investigator to insure that the confidentiality of all patients participating 
in the trial and all of their medical information is maintained.  Case report forms (CRFs) and other 
documents submitted to regulatory authorities must not contain the name of a trial patient.  All 
patients in the trial will be identified by a unique identifier which will be used on all CRFs and any 
other material submitted to regulatory authorities.  All case report forms and any identifying 
information must be kept in a secure location with access limited to the study staff directly 
participating in the trial. 
 
14.5.  Study Termination 
The sponsor-investigator reserves the right to terminate the study at any site and at any time.  
Reasons for study termination may include, but are not limited to, the following: 
 
• 
Investigator non-compliance with the protocol, GCP or regulatory requirements 
• 
Insufficient enrollment 
• 
Safety concerns 
• 
Decision by suppliers to modify or discontinue the availability, development or 
manufacture of protocol-indicated treatment 
• 
A request to discontinue the study by the IRB or FDA. 
 
The sponsor-investigator will promptly notify investigators, the IRB and FDA if the study is 
terminated for any reason. 
 
 
15.  MULTI-CENTER GUIDELINES 
15.1.  Pre-Study Documentation 
Prior to initiating the trial, the investigator will secure and provide to the Coordinating Center 
essential documents, including but not limited to: 
 
• 
A signed FDA Form 1572 
• 
A current curriculum vitae for the Principal Investigator and each sub-investigator listed on 
the FDA Form 1572 
• 
A copy of the current medical license of the Principal Investigator and each sub-
investigator listed on the FDA Form 1572 
• 
A completed Financial Disclosure Form for the investigator and all sub- investigators listed 
on the FDA 1572 
 
• 
A letter from the IRB stipulating approval of the protocol, the informed consent document 
and any other material provided to potential trial participants with information about the 
trial (e.g. advertisements) 
• 
A copy of the informed consent document approved by both the sponsor and local IRB 
• 
The current IRB membership list for the reviewing IRB 
• 
Current laboratory certification for the reference laboratory and curriculum vitae of the 
laboratory director 
• 
A list of current laboratory normal values for the reference laboratory. 
• 
A copy of the signed Delegation of Authority Log 
• 
Protocol training documentation for study staff  
• 
The drug destruction SOP for each participating site  
• 
A copy of the fully executed contract must be on record  


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15.2.  Protocol Review and Amendments 
Information regarding study conduct and progress will be reported to the Institutional Review 
Board (IRB) per the current institutional standards of each participating center. 
 
Any changes to the protocol will be made in the form of an amendment and must be approved by 
the IRB of each institution prior to local implementation.   
 
The sponsor-investigator (or designee) is responsible for the coordination and development of all 
protocol amendments.  Once approved by the sponsor-investigator, Vanderbilt will disseminate this 
information to the participating centers. 
 
15.3.  Study Documentation 
Each participating site is responsible for submitting copies of all relevant regulatory documentation 
to the Coordinating Center.  The required documents include, but are not limited to the following: 
local IRB approvals (i.e., protocol, consent form, amendments, patient brochures and recruitment 
material, etc.), each participant’s informed consent, enrollment form, eligibility checklist, summary 
of unanticipated problems or protocol deviations, and documentation of expertise of the 
investigators.  The Coordinating Center will provide each participating site with a comprehensive 
list of the necessary documents.  It is the responsibility of the participating sites to maintain copies 
of all documentation submitted to the Coordinating Center. 
 
The requirements for data management, submissions, and monitoring are outlined below.  The 
participating sites will submit all the research related information (source documents and research 
records – IRB approval documents, patient registration list, CRF info, toxicity assessments, tumor 
measurements / responses, etc.) within 2 weeks of the patient’s visit to the assigned Coordinating 
Center Monitor (CRA).  The CRA will check if data was entered into REDCap within 1 week of 
receiving the information. Personnel from the VICC Clinical Trial Shared Resource Coordinating 
Center will monitor the trial remotely and may periodically visit the investigative site to assure 
proper conduct of the trial and proper collection of the data.  The investigators at other sites will 
allow the monitor to review all source documents used in the preparation of the case reports. 
 
15.4.  Records Retention 
U.S. FDA regulations (21 CFR §312.62[c]) require that records and documents pertaining to the 
conduct of this study and the distribution of investigational drug, including CRFs, consent forms, 
laboratory test results, and medication inventory records, must be retained by each Principal 
Investigator for 2 years after marketing application approval.  If no application is filed, these 
records must be kept 2 years after the study is discontinued and the U.S. FDA and the applicable 
national and local health authorities are notified.  
 
Following closure of the study, each participating center will maintain a copy of all site study 
records in a safe and secure location.  The Coordinating Center will inform the investigator at each 
site at such time that the records may be destroyed. 
 
15.5.  Publication 
It is understood that any manuscript or releases resulting from the collaborative research must be 
approved by the sponsor-investigator and will be circulated to applicable participating 
sites/investigators prior to submission for publication or presentation. 
 
 




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study in the future. This design yields a type I error rate of 10% and power of 80% when 
the true response rate is 35%.  
 
• 
NSCLC naïve to checkpoint inhibitor therapy (n = 39):  A two-stage MinMax design 
described by Simon will ensure that the number of the total patients exposed to the 
combination nivolumab and X-82 is minimized. Initially, 23 eligible patients will be entered 
into the study.  If there are less than 6 responses in these first 23 patients, the trial will be 
terminated with the conclusion that there is little evidence to suggest that the overall 
response rate would reach 45%, i.e., a 20% RR improvement (45% vs. null hypothesis 
RR = 25%), If there are six or more than six responses in these first 23 patients, the trial 
will continue until 39 patients have been treated. If there are less than 14 responses in 
these 39 patients then the NSCLC group will be terminated, otherwise a phase III study 
may be conducted in the future. This design provides 90% statistical power to detect a 
difference of 20% (45% vs. 25%) with a significance level less than 0.10 (type I error). 
 
• 
NSCLC primary refractory to checkpoint inhibitor therapy (n = 21): A two-stage 
MinMax design described by Simon will ensure that the number of the total patients 
exposed to vorolanib + nivolumab is minimized (39). The design is based on assuming a 
response rate of 25% improvement or less would not be considered of interest for future 
study.  The design has 90% power to detect the response rate of 40% versus 15% at the 
1-sided 10% level, i.e., a 25% RR improvement (40% vs. null hypothesis RR = 15%). 
Initially 15 patients will be accrued and assessed for response.  If there are less than 3 
responses in the first 15 evaluable patients, then accrual to this cohort will be terminated 
with the conclusion that there is little evidence to rule out an improvement in response 
rate of 25%. If there is at least 3 responses in the first 15 patients, the cohort will continue 
until 21 evaluable patients have been treated.  If the study continues past the first stage 
and 6 or more responses are observed, then this would be considered evidence to rule 
out the response rate of 25%.  This design yields a type I error rate of 10% and power of 
90% when the true response rate is 40%.  
 
• 
NSCLC acquired resistance to checkpoint inhibitor therapy (n = 21): A two-stage 
MinMax design described by Simon will ensure that the number of the total patients 
exposed to vorolanib + nivolumab is minimized (39). The design is based on assuming a 
response rate of 25% improvement or less would not be considered of interest for future 
study.  The design has 90% power to detect the response rate of 40% versus 15% at the 
1-sided 10% level, i.e., a 25% RR improvement (40% vs. null hypothesis RR = 15%). 
Initially 15 patients will be accrued and assessed for response.  If there are less than 3 
responses in the first 15 evaluable patients, then accrual to this cohort will be terminated 
with the conclusion that there is little evidence to rule out an improvement in response 
rate of 25%. If there is at least 3 responses in the first 15 patients, the cohort will continue 
until 21 evaluable patients have been treated.  If the study continues past the first stage 
and 6 or more responses are observed, then this would be considered evidence to rule 
out the response rate of 25%.  This design yields a type I error rate of 10% and power of 
90% when the true response rate is 40%. 
 
• 
SCLC progressed on platinum-based chemotherapy (n = 37): The sample size 
estimation was completed using the Simon’s MinMax design (39). If there are less 
than 3 responses in the first 18 evaluable patients, the trial will be terminated with the 
conclusion that there is little evidence to suggest that the ORR would reach 30%, i.e., a 
15% ORR improvement (30% vs. null hypothesis ORR = 15%), If there are at 
least 3 responses in the first 18 evaluable patients, the trial will continue 
until 37 evaluable patients have been treated. If 9 or more of these 37 patients respond, 
additional evaluation in this indication may be warranted. This design provides 80% 
statistical power to detect a difference of 15% with a significance level less than 
0.10 (type I error). 


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16.3.  Data Analysis Plan 
.  
The ORR and DCR will be summarized by binomial response rate and their corresponding two-
sided 95% exact Cis using Clopper-Pearson method. For lifetime data analyses, e.g., PFS, 
Kaplan-Meier product-limit estimates will be prepared.  The 95% CIs for the 6-month and 12-
month PFS and survival rates will be estimated and reported. Duration of Response (DOR) will 
also be assessed using KM product-limit method. Median value of Duration of Response (DOR), 
along with two-sided 95% CI using Brookmeyer and Crowley method will be reported.   
 
As exploratory analysis, the Fisher’s exact test as well as the Wilcoxon rank sum test will be 
applied to examine the correlation between the baseline covariates and toxicities outcomes. 
 
Safety will be examined on an ongoing basis during the study.  Data will be listed and/or 
summarized and tabulated.  Descriptive statistics, including means, standard deviations, and 
ranges for continuous parameters, as well as percents and frequencies for categorical parameters, 
will be presented. 
 
Adverse events will be tabulated.  NCI toxicity Grade 3 and Grade 4 laboratory abnormalities will 
be listed, and summary statistics will be provided for all laboratory values. 
 
16.4.  Anti-Tumor Activity Analyses 
Antitumor activity will be assessed by ORR, as well as progression-free survival (PFS), duration of 
response (DOR), disease control rate (DCR), and 1-year survival.  In addition, correlation between 
the biomarkers and clinical outcomes will be evaluated. 
 
The analyses involving response will be based on definitions of responses according to RECIST 
v1.1.  Data will be listed for all evaluable patients, including by dose level for the dose escalation 
portion. 
 
Objective response is defined as a complete or partial response, as determined by investigator 
assessment using RECIST v1.1 and confirmed by repeat assessments > 4 weeks after initial 
documentation.  Disease control is defined as a complete or partial response or stable disease, as 
determined by investigator assessment.  PFS will be defined as the time from study treatment 
initiation (Cycle 1 Day 1) to the first occurrence of documented disease progression or death from 
any cause during the study, whichever occurs first.  For patients who do not have documented 
progressive disease or death during the study, PFS will be censored at the day of the last tumor 
assessment or at time of initiation of subsequent therapy.  One-year survival will be evaluated from 
the first dose of study treatment. 
 
 
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39.  Simon R. Optimal two-stage designs for phase II clinical trials. Control Clin Trials [Internet]. 1989 Mar 
[cited 2017 Aug 3];10(1):1–10. Available from: http://www.ncbi.nlm.nih.gov/pubmed/2702835 


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APPENDIX 1 
Cockcroft-Gault Formula 
Cockcroft-Gault Formula 
The following formula may be used for estimated creatinine clearance rate (eCCR) using 
Cockcroft-Gault formula.  The use of on-line calculators or formulas which are institution 
standards for eCCR and differ slightly may also be used.  The calculations and results 
must be filed in the patient’s chart. 
 
 
 
 
 
 
 
 
 
 
 
 
 
When serum creatinine is measured in mg/dL; 
(
)
(
) [
]
(
)
mg/dL
in 
 
Creatinine
 
Serum
72
 
 
85
.0
kilograms
in 
 
Mass
Age
140
eCCR
⋅
⋅
⋅
−
=
Female
if
 
When serum creatinine is measured in µmol/L; 
(
)
(
)
(
)
µmol/L
in 
 
Creatinine
 
Serum
Constant
kilograms
in 
 
Mass
Age
140
eCCR
⋅
⋅
−
=
 
Where Constant is 1.23 for men and 1.04 for women. 




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APPENDIX 3 
New York Heart Association (NYHA) Functional Classification 
 
 
 
 


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APPENDIX 4 
Prohibited Medications and Food 
The following list describes medications and foods which are common strong inhibitors of CYP3A4. 
This list should not be considered all-inclusive. Consult individual drug labels for specific information 
on a compound’s propensity to inhibit CYP3A4.
Boceprevir 
Conivaptan 
Grapefruit juice 
Lopinavir 
Mibefradil 
Posaconazole 
Telaprevir 
Voriconazole 
Ritonavir 
Indinavir 
Nelfinavir 
Saquinavir 
Clarithromycin 
Telithromycin 
Chloramphenicol 
Ketoconazole 
Itraconazole 
Nefazodone 
Amprenavir 
Aprepitant 
Atazanavir 
Ciprofloxacin 
Darunavir 
Diltiazem 
Erythromycin 
Fluconazole 
Fosamprenavir 
Imatinib 
Verapamil 
Avasimibe 
Carbamazepine 
Phenytoin 
Rifampin 
St. John’s wort
 
The following list describes medications and foods which are common inhibitors, inducers, and 
substrates of CYP2C9. This list should not be considered all-inclusive. Consult individual drug 
labels for specific information on a compound’s propensity to inhibit or induce CYP2C9.
CYP2C9 Substrates 
Major 
Celecoxib 
Lmoxicam 
Diclofenac 
Ibuprofen 
Piroxicam 
Meloxicam 
Phenytoin 
Fluvastatin 
Sulfonylurea 
Glibenclamide 
Glimepiride 
Glipizide 
Tolbutamide 
Irbesartan 
 
 
 
Losartan 
Warfarin 
 
Minor 
Amitriptyline 
Omeprazole 
Miconazole 
Pitavastatin 
Pheylbutazone 
Rosiglitazone 
Sertraline 
Sildenafil 
Sulfinpyrazone 
Tamoxifen 
THC
 
 


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APPENDIX 5 
Acceptable Contraception 
 
Women of childbearing potential must have a negative serum or urine pregnancy test within 24 hours 
prior to the start of nivolumab.  Women must not be breastfeeding. 
“Women of childbearing potential” (WOCBP) is defined as any female who has experienced menarche 
who has not undergone surgical sterilization (hysterectomy or bilateral oophorectomy) or is not 
postmenopausal.  
Menopause is defined clinically as 12 months of amenorrhea in a woman over 45 years of age in the 
absence of other biological or physiological causes.  If menopausal status is considered for the purpose 
of evaluating childbearing potential, women < 55 years of age must have a documented serum follicle 
stimulating hormone (FSH) level within laboratory reference range for postmenopausal women, in order 
to be considered postmenopausal and not of childbearing potential.  
• 
Women of childbearing potential (WOCBP) will be instructed to adhere to acceptable 
contraception from the time of signing consent, and for 23 weeks after their last dose of 
protocol-indicated treatment.  
• 
Men who are not azoospermic and who are sexually active with WOCBP will be instructed 
to adhere to acceptable contraception from the time of signing consent, and for  
31 weeks after their last dose of protocol-indicated treatment.  
These durations have been calculated using the upper limit of the half-life for nivolumab (25 days); and 
are based on the protocol requirement that WOCBP use contraception for 5 half-lives plus 30 days, and 
men who are sexually active with WOCBP use contraception for 5 half-lives plus 90 days. 
Women of child bearing potential (WOCBP) and men able to father children who are sexually active with 
WOCBP must agree to use acceptable contraception.  A study physician or clinical designee shall counsel 
such participants on the importance of pregnancy prevention, the implications of an unexpected 
pregnancy, and the use of highly effective methods of contraception.  Highly effective methods of 
contraception have a failure rate of < 1% per year when used consistently and correctly. 
• 
At a minimum, applicable subjects must agree to the use of 2 methods of contraception, 
with 1 method being highly effective and the other method being either highly effective or 
less effective, as listed below in Table 4: 
 
TABLE 4:  Methods of Contraception 
 
HIGHLY EFFECTIVE methods of contraception: 
 
• 
Male condoms with spermicide 
 
• 
Hormonal methods of contraception including combined oral contraceptive 
pills, vaginal ring, injectables, implants and intrauterine devices (IUDs) such 
as Mirena® by WOCBP subject or male subject’s WOCBP partner.  Female 
partners of male subjects participating in the study may use hormone based 
contraceptives as one of the acceptable methods of contraception since they 
will not be receiving study drug 
 
• 
Nonhormonal IUDs, such as ParaGard® 


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• 
Tubal ligation 
 
• 
Vasectomy 
 
• 
Complete Abstinence* 
 
* Complete abstinence is defined as complete avoidance of heterosexual 
intercourse and is an acceptable form of contraception for all study 
drugs.  Subjects who choose complete abstinence are not required to 
use a second method of contraception, but female subjects of 
childbearing potential must continue to have pregnancy tests.  
Acceptable alternate methods of highly effective contraception must be 
discussed in the event that the subject chooses to forego complete 
abstinence. 
 
 
LESS EFFECTIVE methods of contraception: 
 
• 
Diaphragm with spermicide 
 
• 
Cervical cap with spermicide 
 
• 
Vaginal sponge 
 
• 
Male Condom without spermicide  
 
• 
Progestin only pills by WOCBP subject or male subject’s WOCBP partner 
 
• 
Female Condom*. 
 
* A male and female condom must not be used together. 
 
 
UNACCEPTABLE methods of contraception: 
 
• 
Periodic abstinence (calendar, symptothermal, post-ovulation methods) 
 
• 
Withdrawal (coitus interruptus) 
 
• 
Spermicide only  
 
• 
Lactation amenorrhea method (LAM) 
 
 


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APPENDIX 6 
Response Evaluation Criteria in Solid Tumors (RECIST v1.1) 
 
Measurability of tumor at baseline 
 
Definitions 
At baseline, tumor lesions/lymph nodes will be categorized measurable or non-measurable as 
follows: 
 
Measurable: 
 
Tumor lesions:  Must be accurately measured in at least one dimension (longest diameter in the 
plane of measurement is to be recorded) with a minimum size of: 
• 
10 mm by CT scan (CT scan slice thickness no greater than 5 mm) 
 
• 
10 mm caliper measurement by clinical exam (lesions which cannot be accurately 
measured with calipers should be recorded as non-measurable) 
 
• 
20 mm by chest X-ray 
Malignant lymph nodes:  To be considered pathologically enlarged and measurable, a lymph 
node must be ≥ 15 mm in short axis 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. See also notes below on “Baseline documentation of target and non-
target lesions” for information on lymph node measurement. 
 
Non-measurable: 
 
All other lesions, including small lesions (longest diameter < 10 mm or pathological lymph nodes 
with 10 to < 15 mm short axis) as well as truly non-measurable lesions. Lesions considered truly 
non-measurable include: leptomeningeal disease, ascites, pleural or pericardial effusion, 
inflammatory breast disease, lymphangitic involvement of skin or lung, abdominal 
masses/abdominal organomegaly identified by physical exam that is not measurable by 
reproducible imaging techniques. 
 
Special considerations regarding lesion measurability: 
 
Bone lesions, cystic lesions, and lesions previously treated with local therapy require particular 
comment: 
 
Bone lesions 
• 
Bone scan, PET scan or plain films are not considered adequate imaging 
techniques to measure bone lesions. However, these techniques can be used to 
confirm the presence or disappearance of bone lesions 
 
• 
Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue 
components, that can be evaluated by cross sectional imaging techniques such as 
CT or MRI can be considered as measurable lesions if the soft tissue component 
meets the definition of measurability described above 
 
• 
Blastic bone lesions are non-measurable 
 


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Cystic lesions 
• 
Lesions that meet the criteria for radiographically defined simple cysts should not 
be considered as malignant lesions (neither measurable nor non-measurable) 
since they are, by definition, simple cysts 
 
• 
“Cystic lesions” thought to represent cystic metastases can be considered as 
measurable lesions, if they meet the definition of measurability described above. 
However, if non-cystic lesions are present in the same patient, these are preferred 
for selection as target lesions 
 
Lesions with prior local treatment 
• 
Tumor lesions situated in a previously irradiated area, or other loco-regional 
therapy, are usually not considered measurable unless there has been 
demonstrated progression in the lesion. Study protocols should detail the 
conditions under which such lesions would be considered measurable 
 
Specifications by methods of measurements 
 
Measurement of lesions 
 
All measurements should be recorded in metric notation, using calipers if clinically assessed. All 
baseline evaluations should be performed as close as possible to the treatment start and never 
more than 4 weeks before the beginning of the treatment. 
 
Method of assessment 
 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging based evaluation should 
always be done rather than clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam.  
• 
Clinical lesions:  Clinical lesions will only be considered measurable when they are superficial 
and ≥10 mm diameter as assessed using calipers (e.g. skin nodules).  For the case of skin 
lesions, documentation by color photography including a ruler to estimate the size of the 
lesion is suggested.  As noted above, when lesions can be evaluated by both clinical exam 
and imaging, imaging evaluation should be undertaken since it is more objective and may 
also be reviewed at the end of the study 
• 
Chest X-ray:  Chest CT is preferred over chest X-ray, particularly when progression is an 
important endpoint, since CT is more sensitive than X-ray, particularly in identifying new 
lesions.  However, lesions on chest X-ray may be considered measurable if they are clearly 
defined and surrounded by aerated lung 
• 
CT, MRI:  CT is the best currently available and reproducible method to measure lesions 
selected for response assessment.  This guideline has defined measurability of lesions on CT 
scan based on the assumption that CT slice thickness is 5 mm or less.  When CT scans have 
slice thickness greater than 5 mm, the minimum size for a measurable lesion should be twice 
the slice thickness. MRI is also acceptable in certain situations (e.g., for body scans) 
• 
Ultrasound:  Ultrasound is not useful in assessment of lesion size and should not be used as 
a method of measurement 
• 
Endoscopy, laparoscopy:  The utilization of these techniques for objective tumor evaluation is 
not advised.  However, they can be useful to confirm complete pathological response when 








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APPENDIX 7 
Guidelines for the Management of Immune-Related Adverse Events (irAEs) 
 
These general guidelines constitute guidance to the Investigator.  The guidance applies to all 
immuno-oncology (I-O) agents and regimens. 
 
Where applicable the Approved Label should be used in combination with the protocol and IB for 
guidance around dose modifications and discontinuation. 
 
A general principle is that differential diagnoses should be diligently evaluated according to standard 
medical practice.  Non-inflammatory etiologies should be considered and appropriately treated. 
 
Corticosteroids are a primary therapy for immuno-oncology drug-related adverse events.  The oral 
equivalent of the recommended IV doses may be considered for ambulatory patients with low-grade 
toxicity.  The lower bioavailability of oral corticosteroids should be taken into account when switching 
to the equivalent dose of oral corticosteroids. 
 
Consultation with a medical or surgical specialist, especially prior to an invasive diagnostic or 
therapeutic procedure, is recommended. 
 
The frequency and severity of the related adverse events covered by these algorithms will depend 
on the immuno-oncology agent or regimen being used 
 
Investigators should refer to the most current version of the IB or Approved Label for current 
recommendations for management of a specific Adverse Event of interest. 
  
 
 
 
 
 
 
 
 
 
 
 
 


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1 
Name of participant:  
Age:  
The following is given to you to tell you about this research study. Please read this form with care and ask any 
questions you may have about this study. Your questions will be answered. Also, you will be given a copy of this 
consent form. 
What is the purpose of this study? 
You are being asked to participate in this research study because you have been diagnosed with Non-Small Cell Lung 
Cancer (NSCLC), Small Cell Lung Cancer (SCLC), or Thymic Carcinoma. Your disease has not responded to standard 
therapy, or has returned or progressed after standard therapy; or no standard therapy is currently available for your 
disease. 
The purpose of this study is to learn if the investigational drug called vorolanib can help your condition when used in 
combination with the immunotherapy drug nivolumab. 
Investigational means vorolanib is still being tested in research studies and has not yet been approved by regulatory 
health authorities, such as the U.S. Food and Drug Administration (FDA). Vorolanib blocks new blood vessel growth to 
reduce the possibility of tumor growth. 
Nivolumab (also known as OPDIVO®) and other anti-PD-1/PD-L1 drugs are approved by the FDA to be used alone for 
the treatment of patients with metastatic NSCLC whose cancer has spread after treatment with platinum-based 
chemotherapy. Drugs that block PD-1 or PD-L1 (these are proteins found in normal and cancer cells of your body) can 
help immune cells find cancer cells to attack them. 
The addition of vorolanib to nivolumab may lead to increased side effects. There is the possibility that these side 
effects could require delays or lower doses of the scheduled study drug treatments. It is also possible that the 
combination of vorolanib and nivolumab may not offer an additional benefit compared to nivolumab alone. 
Nivolumab increases the ability of the immune system to attack cells such as cancer. 
This research study was developed at Vanderbilt University Medical Center (VUMC). Katy Beckermann, PhD, MD at 
the Vanderbilt-Ingram Cancer Center (VICC) is the sponsor-investigator of this study (also known as the study chair). 
This study will be conducted at Vanderbilt University Medical Center and up to approximately 4-6 other academic 
medical centers in the United States. Overall, up to approximately 177 patients are expected to enroll in this study. 
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This study is partially funded by Equinox Sciences, LLC, which is affiliated with Xcovery Holdings, Inc. Equinox is the 
company that makes and is supplying vorolanib for use in this study. Equinox/Xcovery could benefit financially from 
this research study. This study is partially supported by Bristol-Myers Squibb. Bristol-Myers Squibb is the company 
that makes and is supplying nivolumab (Opdivo) for use in this study. 
 
You do not have to be in this research study. You may choose not to be in this study and get other treatments 
without changing your healthcare, services or other rights. You can stop being in this study at any time. If we learn 
something new that may affect the risks or benefits of this study, you will be told so that you can decide whether or 
not you still want to be in this study. Your medical record will contain a note saying you are in a research study. 
Anyone you authorize to receive your medical record will also get this note. 
 
What will happen and how long will you be in the study? 
 
If you qualify and agree to participate, your time in this research study will be followed in “Cycles”. Each treatment 
Cycle lasts 8 weeks (56 days). 
 
All patients enrolling in this study are scheduled to receive treatment with vorolanib and nivolumab: 

Vorolanib: Once every day. 

Nivolumab: Once every two weeks on Days 1, 15, 29 and 43 during each 8 week (56-day) treatment cyclefor 
the first two treatment cycles. After which, the treatment schedule can change to every four weeks (i.e., on 
Days 1 and 29 of each 56-day cycle) if the patient is not exhibiting disease progression. 
 
 
Vorolanib is an oral drug, which you will take by mouth. You will take vorolanib with food, at about the same time 
each day, approximately 24 hours (± 2 hours) apart. You will write down when you take your vorolanib every day on a 
drug diary we will give you. Also, if you have a blood pressure cuff at home, you will be asked to take and record your 
blood pressure. 
 
Nivolumab will be given by IV, infused into a vein in your arm (or similar site). Each nivolumab infusion is scheduled to 
take about 30 minutes. All patients are scheduled to receive the same dosage of nivolumab (240mg during each 
nivolumab infusion). 
 
Dose Escalation: In the early part of the study (called Dose Escalation), approximately 9-18 total patients in groups of 
about 3-6 patients per group will receive increasingly higher doses of vorolanib. The purpose of Dose Escalation is to 
find the highest dose of vorolanib that does not cause unacceptable side effects when VOROLANIB is used in 
combination with nivolumab. You and your study team will know the dose of VOROLANIB that you will receive, but 
your study doctor cannot choose your vorolanib dose level. Thus, you may receive a dose of vorolanib that is higher 
or lower than other patients in the study. 
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Dose Expansion: After the highest safe dose of vorolanib (called the maximum tolerated dose / MTD, or the 
recommended combination dose / RCD) is identified during Dose Escalation, the second part of the study (called Dose 
Expansion) will then use this dose of VOROLANIB to enroll up to about 90 total additional patients, in order to further 
examine the safety of vorolanib in combination with nivolumab, and to help initially understand if vorolanib + 
nivolumab does or does not work against Non-Small Cell Lung Cancer, Small Cell Lung Cancer and Thymic Carcinoma. 
In Dose Expansion, about 20-41 patients will enroll into each of the disease categories. 
 
In this study we will look at genes (DNA) in your blood and tumor tissue to see how they affect health and disease. 
Genes are the instruction manual for your body. The genes you get from your parents decide what you look like and 
how your body behaves. They can also tell us a person’s risk for certain diseases and how they will respond to treatment. 
 
If you decide to participate in the study, you must first sign this consent form. Before you are treated, your study 
doctor will need to determine if you are eligible to take part in this study. By signing this form, you agree to follow the 
instructions given by the research staff during the study. 
 
After reviewing and signing this consent form, you will be asked to undergo tests and procedures to find out if it is 
okay for you to take part in the research study. This is called screening. Some of these tests and procedures are likely 
to be part of the regular care you would receive even if you were not participating in the study. You may have had 
some of these tests or procedures recently done. If this is the case, these tests or procedures may not need to be 
repeated. 
 
After these tests are reviewed, it is possible you will not be able to be in the study. There may be other reasons why 
you are unable to be in this study. These reasons will be discussed with you by your study doctor or the clinic staff.  
 
 
Side effects and risks that you can expect if you take part in this study: 
 
This is the first time that vorolanib will be given in combination with nivolumab. 
 
Therefore, there may be new side effects for vorolanib and nivolumab together in combination, which have not been 
reported for either drug when given alone. The study has been designed to monitor closely for side effects, but 
unexpected side effects are possible. The long-term effects of vorolanib and nivolumab are unknown. 
 
As with any new drug exposure, there is a risk of allergic reactions that can be fatal. These reactions can start shortly 
after taking a new drug. Symptoms might include skin itching and redness, difficulty breathing and/or low blood 
pressure and may be severe in some cases. 
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4 
 
 
You may experience one or more of the risks indicated below from being in this study. Some risks described in this 
consent document, if severe, may cause death. In addition to these risks, there may be other unexpected and 
possibly severe, life-threatening or fatal side effects that could occur. 
 
Tell your study doctor about any side effects you are experiencing and seek medical attention when necessary. 
 
 
Risks of VOROLANIB 
 
Based on findings in human patients who have taken vorolanib alone, risks of vorolanib may include the following: 
 
Common (≥ 10%) risks of VOROLANIB may include: 
 

Diarrhea 

Nausea 

Vomiting 

Fatigue 

Hair color changes 

Rash 

Weakness 

Edema/ edema peripheral (fluid build-up, including in arms, legs, hands, and/or feet) 

Dysgeusia (altered sense of taste) 

Alanine and/or Aspartate aminotransferase increased (high levels of liver enzymes in the blood, which can 
indicate liver damage or injury). 
 
Less Common (≤ 10%) risks of VOROLANIB may include: 
 

Anemia (low red blood cells, which could cause you to feel fatigued) 

Granulocytopenia (low numbers of granulocytes, a type of white blood cell; can increase the risk of infection) 

Leukopenia (low white blood cells, which can increase the risk of infection)

Neutropenia (low numbers of neutrophils, a type of white blood cell; can increase the risk of infection) 

Thrombocytopenia (low platelets in the blood, which can increase the risk of bleeding) 

Dry eye 

Abdominal pain 

Ascites (extra fluid in the abdominal cavity, between the chest and the diaphragm) 

Constipation 

Dyspepsia (feeling of indigestion, burning, pain or discomfort in the upper abdomen) 

Dysphagia (difficulty swallowing) 

Gait disturbance (changes in the way you walk) 
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5 
 
 

Mucosal inflammation (oral or gastrointestinal mucositis), causing tenderness or pain in tissues like the inside 
of the mouth, or anus 

Blood creatinine increased (can indicate kidney stress or injury) 

Lymphocyte blood count decreased (can increase risk of infection) 

Waist circumference increased 

Weight increased or decreased 

Anorexia 

Decreased appetite 

Dehydration 

Hypertriglyceridemia (high levels of fatty acids; may cause shortness of breath, nausea, vomiting) 

Hypomagnesemia (low magnesium; may cause weakness, muscle cramps, irregular heartbeat, tremors, or 
confusion) 

Arthralgia (joint pain) 

Muscular weakness 

Muscle spasms 

Myalgia (muscle pain) 

Dizziness 

Headache 

Peripheral neuropathy (numbness, tingling and/or pain in the extremities) 

Parosmia (altered sense of smell) 

Proteinuria (protein in the urine, which can be a sign of kidney damage) 

Dyspnea exertional (shortness of breath during exercise) 

Epistaxis (nose bleed) 

Alopecia (hair loss, including possible eyelash/eyebrows) 

Dermatitis bullous (skin blisters) 

Dry skin 

Erythema (red patches on the skin) 

Hair growth abnormal 

Photosensitivity reaction (sensitivity to sunlight) 

Pruritus (itching) 

Rash erythematous (red rash) 

Urticaria (hives, or patches of skin with raised itchy bumps that are red or skin-colored) 

Hypertension (high blood pressure) 

Urinary retention (inability to completely empty the bladder) 

Increased cholesterol (LDL) 

Gingivitis 

Skin discoloration 

Palmar-Plantar erythrodysesthesia (hand-foot syndrome) 
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6 
 
 

Abnormal nails 

Dysphonia (difficulty speaking) 

Hypothyroidism 

Hypophosphatemia (low levels of phosphate) 

Hypocalcemia (low levels of calcium) 

Hyponatremia (low levels of sodium) 

Urinalysis abnormalities (increased white blood count) 

Increased bilirubin and GGT (gamma-glutamyl transferase) 

Cardiac arrhythmias (atrial, ventricular) 

QT prolongation (irregular heart rhythms) 
 
Serious events considered related or at least possibly related to vorolanib have included: 
 

Acute pancreatitis (inflammation of the pancreas) symptoms of which include severe upper abdominal 
burning pain, nausea, and vomiting 

Deep vein thrombosis (DVT), a blood clot that forms in a vein deep in the body which can break off and travel 
through the bloodstream to an artery in the lungs, blocking blood flow (may be life threatening) 

Cerebral infarction (stroke), resulting may result in facial weakness and slurred speech; memory loss 

Fistula (unusual or abnormal connection between a tumor and an organ; usually a result of an injury or 
surgery) 

Pleural effusion (build-up of fluid around the lungs) 

Infections 

Pulmonary embolism (blood clot in a major blood vessel in the lungs), often caused by a blood clot in the legs 
or elsewhere in the body that travels to the lungs, causing sudden shortness of breath, or sharp chest pain 
worsened by coughing or taking a deep breath; without prompt treatment, can be life-threatening 

Low platelet count (which could increase the risk of bleeding) 

Hemorrhage (bleeding in the abdomen involving a tumor invading a major blood vessel), that could cause 
death 

Hypertensive crisis (severe increase in blood pressure that can damage organs) and acute pain (pain that 
begins suddenly) 
 
In the body, one target of VOROLANIB is called the vascular endothelial growth factor receptor (VEGFR), which is 
involved in the growth of new blood vessels (angiogenesis). Currently, other drugs are FDA approved which also 
target VEGFR. Because VOROLANIB has similarities to these other drugs, it is possible that side effects seen in these 
other drugs may also be observed when patients take VOROLANIB. 
 
The most common side effects (>20%) noted in at least one of the prescribing information labels for these approved 
drugs which are similar to VOROLANIB include: 
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7 
 
 

Fatigue 

Asthenia (weakness) 

Fever 

Diarrhea 

Nausea 

Mucositis/stomatitis (inflammation of mucus membranes; for example inside the mouth, which may appear 
red, inflamed and may bleed) 

Vomiting 

Decreased appetite/anorexia 

Weight loss 

Dyspepsia (feeling of indigestion, burning, pain or discomfort in the upper abdomen) 

Abdominal/ gastrointestinal pain 

Constipation 

Hypertension (high blood pressure) 

Peripheral edema (fluid build-up in the arms, legs, hands, and/or feet) 

Rash with or without skin peeling (desquamation) 

Hand-foot syndrome (reddening, swelling, numbness and peeling of skin on the hand palms and feet soles) 

Skin discoloration 

Dry skin 

Hair color changes 

Alopecia (hair loss) 

Altered taste 

Dysphonia (hoarse voice, or other difficulty speaking) 

Headache 

Back ache 

Musculoskeletal pain 

Arthralgia (joint pain) 

Myalgia (muscle pain) 

Extremity pain (pain in the arms, legs, hands, feet, fingers, and/or toes) 

Tumor pain 

Cough 

Dyspnea (shortness of breath) 

Bleeding. 
 
Serious side effects previously seen with drugs similar to vorolanib include: 
 

Heart problems, such as reduced ability to pump blood (including decreased ejection fraction or congestive 
heart failure), impaired heart function and rhythm; or heart ischemia/infarction (heart attack) 
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8 
 
 

Liver damage or failure (hepatotoxicity) 

Thyroid dysfunction (imbalance in the thyroid hormones) 

Hemorrhage (serious bleeding, often requiring transfusion), including bleeding into the tumor 

Thrombosis / thrombotic / thromboembolic events (formation of blood clots in blood vessels), including a 
blood clot forming in a vein deep in the body (deep vein thrombosis / DVT) which can break off and travel 
through the bloodstream to an artery in the lungs (pulmonary embolism / PE) blocking blood flow (may be life 
threatening); tell your study doctor immediately about sudden shortness of breath, or sharp chest pain 
worsened by coughing or taking a deep breath; without prompt treatment, can be life-threatening 

Thrombotic microangiopathy (blood clots in small blood vessels that can affect the kidneys and other organs) 

Hand-foot syndrome (reddening, swelling, numbness and peeling of skin on the hand palms and feet soles) 

Severe rash or severe skin reactions that can be life-threatening (such as erythema multiforme, Stevens- 
Johnson syndrome, and toxic epidermal necrolysis) 

Serious infections, including necrotizing fasciitis (serious rapid skin infection often caused by bacteria; 
requires treatment to prevent wider damage or death of tissue) 

Hole in the intestine (gastrointestinal perforation), or an abnormal passage between an organ and other 
tissues (fistula), which can be caused by tumor shrinkage 

Osteonecrosis of the jaw (breaking down of the bone in the jaw) 

Proteinuria (protein in the urine, which can be a sign of kidney damage); if severe can cause swelling 
(nephrotic syndrome) 

Reversible posterior leukoencephalopathy syndrome (neurological changes associated with headaches, 
mental status changes and possible seizures) 

Tumor lysis syndrome (complications from rapid break down of tumor cells). 
 
Based on studies in animals, potential risks of vorolanib may include: 
 

Changes to the adrenal glands (tissue above the kidneys which makes hormones), which could cause changes 
to levels of hormones in the blood such as steroids 

Lymphoid depletion (changes to / shrinkage of lymph nodes), which can indicate abnormal changes to the 
immune system 

Changes to the pancreas 

Bone marrow hypocellularity (can indicate a reduced ability to produce appropriate levels of cells needed to 
transport oxygen, clot the blood, and fight infection) 

Changes in red blood cell counts, hemoglobin, and hematocrit (can indicate reduced ability of the blood to 
properly transport oxygen to the body tissues) 

Lower white blood cell and absolute lymphocyte counts (can indicate a reduced ability to fight infections) 

Higher platelet counts in the blood 

Changes to blood levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and/or alkaline 
phosphatase (may indicate liver stress or damage, or bone problems) 

Changes to blood levels of creatine kinase (indicating possible damage to muscles, including the heart) 
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9 
 
 

Changes in blood concentrations of sugars, elements and minerals (such as glucose, calcium and potassium). 
 
Risks of Nivolumab (also known as OPDIVO®) 
 
The following information is provided in the FDA approved Prescribing Information (version dated August 2018) for 
nivolumab, also known as Opdivo®. 
 
What is the most important information I should know about Opdivo? 
Opdivo is a medicine that may treat your melanoma, lung cancer, kidney cancer, blood cancer, head and neck cancer, 
colon or rectal cancer, liver cancer, or bladder cancer by working with your immune system. Opdivo can cause your 
immune system to attack normal organs and tissues in many areas of your body and can affect the way they work. 
These problems can sometimes become serious or life-threatening and can lead to death. These problems may 
happen anytime during treatment or even after your treatment has ended. 
 
Call or see your study doctor right away if you develop any symptoms of the following problems or these symptoms 
get worse: 
 
Lung problems (pneumonitis). Symptoms of pneumonitis may include: 

New or worsening cough 

Chest pain 

Shortness of breath. 
 
Intestinal problems (colitis) that can lead to tears or holes in your intestine. Signs and symptoms of colitis may 
include: 

Diarrhea (loose stools) or more bowel movements than usual 

Blood in your stools or dark, tarry, sticky stools 

Severe stomach-area (abdomen) pain or tenderness. 
 
Liver problems (hepatitis). Signs and symptoms of hepatitis may include: 

Yellowing of your skin or the whites of your eyes 

Severe nausea or vomiting 

Pain on the right side of your stomach area (abdomen) 

Drowsiness 

Dark urine (tea colored) 

Bleeding or bruising more easily than normal 

Feeling less hungry than usual 

Decreased energy 
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10 
 
 
Hormone gland problems (especially the thyroid, pituitary, adrenal glands, and pancreas). Signs and symptoms that 
your hormone glands are not working properly may include: 

Headaches that will not go away or unusual headaches 

Extreme tiredness 

Weight gain or weight loss 

Dizziness or fainting 

Changes in mood or behavior, such as decreased sex drive, irritability, or forgetfulness 

Hair loss 

Feeling cold 

Constipation 

Voice gets deeper 

Excessive thirst or lots of urine. 
 
Kidney problems, including nephritis and kidney failure. Signs of kidney problems may include: 

Decrease in the amount of urine 

Swelling in your ankles 

Blood in your urine 

Loss of appetite. 
 
Skin Problems. Signs of these problems may include: 

Rash 

Skin blistering 

Itching 

Ulcers in mouth or other mucous membranes. 
 
Inflammation of the brain (encephalitis). Signs and symptoms of encephalitis may include: 

Headache 

Fever 

Tiredness or weakness 

Confusion 

Memory problems 

Sleepiness 

Seeing or hearing things that are not really there (hallucinations) 

Seizures 

Stiff neck. 
 
Problems in other organs. Signs of these problems may include: 

Changes in eyesight 
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11 
 
 

Severe muscle weakness 

Severe or persistent muscle or joint pains 

Chest pain 
 
Getting medical treatment right away may keep these problems from becoming more serious. Your study doctor 
will check you for these problems during treatment with Opdivo. Your study doctor may treat you with corticosteroid 
or hormone replacement medicines. Your study doctor may also need to delay or completely stop treatment with 
OPDIVO, if you have severe side effects. 
 
What should I tell my study doctor before receiving Opdivo? Before you receive Opdivo, tell your study doctor if 
you: 

Have immune system problems such as Crohn’s disease, ulcerative colitis, or lupus 

Have had an organ transplant 

Have lung or breathing problems 

Have liver problems 

Have any other medical conditions 

Are pregnant or plan to become pregnant. It is unknown at this time if Opdivo is harmful to a fetus. 
 Females who are able to become pregnant should use an acceptable method of birth control during 
and for 23 weeks after your last dose of Opdivo (more about this below). Talk to your study doctor 
about birth control methods that you can use during this time. 
 Tell your study doctor right away if you become pregnant during treatment with Opdivo. 

Are breastfeeding or plan to breastfeed. It is not known if Opdivo passes into your breast milk. Do not 
breastfeed during treatment with Opdivo and for 23 weeks after your last dose. 
 
Tell your study doctor about all the medicines you take, including prescription and over-the-counter medicines, 
vitamins, and herbal supplements. Know the medicines you take. Keep a list of them to show your study doctor and 
pharmacist when you get a new medicine. 
 
Nivolumab may cause one or more of the side effects listed below. This information is based on data from 
cancer subjects in other clinical trials with nivolumab. In addition, there may be side effects that are not yet 
known that may occur. You should tell your doctor or nurse right away about any possible side effects you 
experience. 
 
Very common side effects of nivolumab are: [≥1/10 or ≥10%] 
 

Diarrhea 

Fatigue 

Itching 

Rash 
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12 
 
 
 
Common side effects of nivolumab include: [≥ 1/100 to < 1/10 or ≥ 1% to <10%] 
 

Abdominal pain 

Alkaline phosphatase increased: lab test result associated with liver or bone abnormalities 

Allergic reaction/hypersensitivity 

ALT increased: lab test result associated with abnormal liver function 

Amylase increased: lab test result associated with pancreas inflammation 

AST increased: lab test result associated with abnormal liver function 

Bilirubin (liver function blood test) increased 

Chills 

Constipation 

Cough 

Creatinine increased: lab test result associated with decreased kidney function 

Decreased appetite 

Dizziness or vertigo (feeling off balance which can lead to dizziness) 

Dry mouth 

Dry skin 

Fever 

Headache 

High blood pressure 

Increased blood sugar 

Inflammation of the colon 

Inflammation of the mouth 

Infusion related reaction 

Joint pain or stiffness 

Lipase increased: lab test result associated with pancreas inflammation 

Loss of color (pigment) from areas of skin 

Lung inflammation (pneumonitis - see details below) 

Musculoskeletal pain 

Nausea 

Redness (of the skin) 

Shortness of breath 

Sodium levels in the blood low 

Swelling, including face, arms, and legs 

 Thyroid gland function decreased/thyroid stimulating hormone increased (lab test associated with abnormal 
thyroid function) 

Thyroid gland function increased 

Tingling, burning, numbness or weakness, possibly in arms, legs, hands and feet 

Upper respiratory tract infection 

Vomiting 
 
Uncommon side effects of nivolumab include: [≥ 1/1,000 to < 1/100 or ≥0.1% to <1%] 
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13 
 
 
 

Adrenal gland function decreased 

Bronchitis 

Cranial nerve disorder 

Diabetes 

Dry eye 

Hair loss 

Heart rate increase 

Heart rhythm abnormal 

Hives 

Inflammation of the eye 

Inflammation of the kidney 

Inflammation of the pancreas 

Inflammation of the pituitary gland 

Inflammation of the stomach 

Inflammation of the thyroid gland 

Liver inflammation 

Low blood pressure 

Lung infiltrates, associated with infection or inflammation 

Pituitary gland function decreased 

Psoriasis: characterized by patches of abnormal, scaly skin 

Renal (kidney) failure or kidney injury 

Respiratory failure 

Vision blurred 
 
Rare side effects of nivolumab include: [≥ 1/10,000 to < 1/1,000 or ≥0.01% to <0.1%] 
 

Anaphylactic reaction (severe allergic reaction) 

Damage to the protective covering of the nerves in the brain and spinal cord 

Diabetes complications resulting in excess blood acids and diabetic coma 

Guillain-Barre syndrome, an autoimmune disorder associated with progressive muscle weakness orparalysis 

Inflammation of blood vessels 

Inflammation of the brain, potentially life-threatening or fatal 

Inflammation of the heart 

Muscle inflammation 

Myasthenic syndrome (neurologic syndrome characterized by muscle weakness) including myasthenia 
gravis, a nerve disease that may cause weakness of eye, face, breathing, and swallowing muscles. 

Pemphigoid: blistering of the skin or mouth caused by the immune system attacking healthy tissue 

Rhabdomyolysis: muscle fiber released into the blood stream which could damage yourkidneys 

Rosacea: acne-like skin condition resulting in redness of face 

Sarcoidosis, a disease involving abnormal collections of inflammatory cells (granulomas) in organs such 
as lungs, skin, and lymph nodes 
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14 
 
 

Stevens Johnson syndrome: inflammatory disorder of skin and mucous membranes, resulting in blistering 
and shedding of skin 

Toxic epidermal necrolysis: a potentially fatal disease characterized by blistering and peeling of the top 
layerof skin resembling a severe burn 

Histiocytic necrotizing lymphadenitis or Kikuchi lymphadenitis: disorder of the lymph nodes which causes 
the lymph nodes to become enlarged, inflamed and painful, commonly affecting lymph nodes of the 
neck and possibly associated with fever or muscle and joint pains. 

Vogt Koyanagi Harada syndrome; a disease that affects the pigmented tissue; this may affect the eye leading 
to swelling, pain and/or blurred vision; the ear leading to hearing loss, ringing in the ears and /or the skin 
leading to loss of skin color 
 
 
Lung Inflammation (pneumonitis): It is possible that nivolumab may cause inflammation of the tissues of the 
lung. This adverse effect has been reported infrequently in patients treated with nivolumab. While many 
patients with x-ray or CT abnormalities have not developed any symptoms, some patients have developed mild 
to severe symptoms and in rare cases, death has occurred as a result of their lung inflammation. Signs and 
symptoms of lung inflammation may include difficulty breathing, pain or discomfort while breathing, chest pain, 
cough, shortness of breath, increased rate of breathing, fever, low blood oxygen levels, or fatigue. 
 
Your study doctor and nurse will watch you closely for changes in your ability to breathe and for other signs or 
symptoms that might show you are developing this type of lung inflammation and will perform regular tests 
including physical exams, measurement of oxygen levels through non-invasive testing (i.e., pulse oximeter), 
blood tests, chest x-rays and/or CT scans. 
 
 
Please inform your study doctor or nurse AT ONCE if you experience any of the following: 

Any new or increased shortness of breath 

Any new or increased chest pain 

Any new or increased pain/difficulty while breathing 

Any new or increased cough or any significant change in your type of cough; for example, any new or 
increased mucous or blood in your cough 

Any change in the amount of oxygen you require 

Any fever, fatigue, or other symptoms that occur at the same time as any changes to your breathing or 
other lung symptoms 
 
 
 
Reproductive Risks 
 
Female patients: 
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15 
 
 
Patients should not become pregnant while on this study because the study treatments in this study could affect 
an unborn baby. Breast-feeding and pregnant women are not allowed to take part in the study. Due to unknown 
risks and potential harm to an unborn child/infant, you should not become pregnant or nurse a baby while on this 
study. Females able to have a child must have a negative pregnancy test prior to enrolling in the study. Female 
patients must meet 1 of the following conditions: 

Patient is postmenopausal – i.e. amenorrheic (no menstrual period) without alternative medical cause – 
for at least 1 year prior to the date of signed informed consent. Note: If menopausal status is considered 
for the purpose of evaluating childbearing potential, then postmenopausal status in females < 55 years of 
age will be confirmed with a blood test for follicle stimulating hormone (FSH level). 

Patient is surgically sterile (i.e. patient has had a bilateral oophorectomy, or a complete hysterectomy), or 
patient’s partner is surgically sterile (i.e. has had a vasectomy), or 

If of childbearing potential, female patient agrees to practice 2 methods of acceptable contraception 
(with 1 method being highly effective and the other method being either highly effective or less effective, 
as listed in the below table) at the same time, from the time of signing the informed consent, and for 23 
weeks after patient’s last dose of vorolanib or nivolumab (whichever dose occurs last), or 

Patient agrees to practice true abstinence (defined as complete avoidance of heterosexual intercourse), 
when this is in line with the preferred and usual lifestyle of the patient. 
 
Female patients of childbearing potential must use acceptable contraception from time of signing consent until 23 
weeks after the last dose of study medication. 
 
Male patients: 
You should not father a child while on this study because the study treatments in this study could affect an 
unborn baby. Participation in this study may affect your ability to father a child. For future childbearing, you may 
wish to consider banking sperm prior to beginning this study. Due to unknown risks and potential harm to an 
unborn child/infant, you should not get a partner pregnant while you are getting the study treatment. Male 
patients must meet 1 of the following conditions: 

Patient is surgically sterile (has had a vasectomy), or patient’s sexual partner is not a woman able to have 
children, or 

Patient agrees to practice 2 methods of acceptable contraception (with 1 method being highly effective 
and the other method being either highly effective or less effective, as listed in the below table) at the 
same time, from the time of signing the informed consent, and for 31 weeks after patient’s last dose of 
VOROLANIB or nivolumab (whichever dose occurs last), or 

Patient agrees to practice true abstinence (defined as complete avoidance of heterosexual intercourse), 
when this is in line with the preferred and usual lifestyle of the patient. 
 
Male patients who are not surgically sterile and who are sexually active with women of child bearing potential 
must use acceptable contraception from the time of signing consent until 31 weeks after the last dose of study 
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16 
 
 
medication. 
All patients (male or female): 

If your partner becomes pregnant during this study, you must tell the study doctor immediately. The 
study doctor will advise you of the possible risks to your unborn child and discuss options for managing 
the pregnancy with you. For female patients who become pregnant while on this study, the study 
treatment will be stopped immediately and the pregnancy will be followed until conclusion. For partners 
of male patients who become pregnant, we will ask for permission to follow the pregnancy. We may also 
request information on pregnancy outcomes and breast-feeding. Bristol-Meyers Squibb, the maker of 
nivolumab, will receive this information. 
 
Methods of Contraception 
 
HIGHLY EFFECTIVE methods of contraception: 

Male condoms with spermicide 

Hormonal methods of contraception including combined oral contraceptive pills, vaginal 
ring, injectables, implants and intrauterine devices (IUDs) such as Mirena®.  Female 
partners of male patients participating in the study may use hormone based contraceptives 
as one of the acceptable methods of contraception since they will not be receiving study 
drug. 

Nonhormonal IUDs, such as ParaGard®. 

Tubal ligation. 

Vasectomy. 

Complete Abstinence*. 
* Complete abstinence is defined as complete avoidance of heterosexual intercourse and 
is an acceptable form of contraception for all study drugs. Subjects who choose 
complete abstinence are not required to use a second method of contraception, but 
female subjects of childbearing potential must continue to have pregnancy tests. 
Acceptable alternate methods of highly effective contraception must be discussed in 
the event that the patient chooses to stop complete abstinence. 
LESS EFFECTIVE methods of contraception: 

Diaphragm with spermicide. 

Cervical cap with spermicide. 

Vaginal sponge. 

Male Condom without spermicide. 

Progestin only pills by female patient able to have children, or by male patient’s partner 
who is a female able to have children. 
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17 
 
 
 
 
Other Risks 
 
Allergic Reaction 
It is possible to have an allergic reaction to the study treatment. If you have a very bad allergic reaction, you 
could die. Some things that happen during an allergic reaction that could be a sign or symptom of a life- 
threatening allergic reaction (anaphylaxis) are: rash, having a hard time breathing, wheezing, a sudden drop in 
blood pressure (making you feel dizzy or lightheaded), swelling around the mouth, throat, or eyes, a fast pulse or 
sweating. 
 
You should get medical help and contact the study doctor or study staff if you have any of these or any other side 
effects during the study. 
 
Computed Tomography Scans (CT Scans) 
CT scans are used to create images of internal bones and organs using radiation. 
The contrast solution that may be given for a CT scan may cause an allergic reaction (rare). Severe allergic 
reactions can be life threatening. CT contrast solution can cause kidney damage, especially if you are diabetic, 
dehydrated (lost body water) or elderly. CT contrast is used in scans to highlight specific parts of the body. 
 
During CT scans, you will lie still on a table that slides into a tunnel slightly wider than your body. People who feel 
anxiety in confined spaces (claustrophobia) may feel uncomfortable in the narrow cylinder. If you feel 
uncomfortable in confined spaces, please tell your doctor. Your doctor may give you a medication in an effort to 
make you feel more comfortable in a confined space. 
 
Radiation Risks 
Participation in this research study could involve exposure to radiation from two CT scans of your chest and 
abdomen, and possibly your pelvis and head (depending on where your cancer is located). This radiation exposure 
is not necessary for your medical care and is for research purposes only. The total amount of radiation that you 
could receive by participating in this study is equal to your body receiving about 8 years of radiation from your 
natural surroundings or about 50% of the exposure allowed for radiation workers in one year. 
 
Magnetic Resonance Imaging (MRI) 
This is a medical imaging technique used to investigate the anatomy of the body and its risks include 
claustrophobia, discomfort due to lying still for a prolonged period of time, and other factors which will be 
described to you and discussed with you by the MRI staff. 
 
Blood Draw Risks 

Female Condom*. 
* A male and female condom must not be used together.
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18 
 
 
When you give blood, you may feel faint, or experience mild pain, bruising, irritation or redness at the site. In rare 
cases, you may get an infection. 
 
Risk of Loss of Confidentiality 
One risk of giving samples for this research may be the release of your name that could link you to the stored 
samples and/or the results of the tests run on your samples. This may cause problems with insurance or getting a 
job. 
 
The Genetic Information Nondiscrimination Act (GINA) may help protect you from health insurance or 
employment discrimination based on genetic information. 
 
The law provides that health insurance companies and group health plans 
 may not ask for genetic information from this research and 
 may not use genetic information when making decision about eligibility or premiums 
 
The law will not stop health insurance companies from using genetic information to decide whether to pay claims. 
The law also will not help you get other types of insurance (such as: life, disability or long-term care). 
 
Despite the GINA protections and the best efforts of the research team, there may still be a risk if information 
about you were to become known to people outside of this study. 
 
To minimize this risk, we will remove your name and any other information that could directly identify you from 
your materials. We will replace this information with codes. We will keep a master list that links those codes to 
your materials. Only certain project staff can access this master list. We will keep the samples in locked freezers in 
locked buildings. We will keep health information and research data on secure computers. These computers have 
many levels of protection. 
 
Your name and other information that could directly identify you (such as address or social security number) will 
not be placed into any database. However, because your genetic information is unique to you, there is a small 
chance that someone could trace it back to you. The risk of this happening is very small, but may grow in the 
future. Researchers will always have a duty to protect your privacy and to keep your information confidential. 
 
Risks that are not known: 
 
Because this treatment is investigational, meaning non-FDA approved, there may be risks that we do not know about 
at this time. 
 
Good effects that might result from this study: 
 
a)
The benefits to science and humankind that might result from this study: 
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19 
 
 
This research may contribute to the understanding of cancer and its treatment, and may eventually lead 
to improvements in treatment. 
 
b)
The benefits you might get from being in this study: 
There may or may not be a direct benefit to you as a result of your participation in the study. 
 
Procedures to be followed: 
Screening 
 
The following must be completed ≤ 28 days prior to your first dose of study treatment: 
 

Scan of your disease by CT or MRI. Scanning to include at least your chest and abdomen, with any 
additional areas (such as the pelvis) as deemed appropriate by your study doctor. Also, if it is known 
or suspected by your study doctor that your disease has spread to your brain or spinal cord (CNS 
metastasis), you will have a scan of your head by CT or if preferable MRI. 
 

Blood sample (about 1/3 tablespoon) will be tested for Hepatitis B and Hepatitis C (infectious diseases 
primarily involving the liver, which are caused by the hepatitis B and C viruses). Patients with 
Hepatitis B or uncontrolled Hepatitis C are not eligible to receive the study treatment. 

Please note that if test results show that you are positive for Hepatitis B or C, the study staff 
will tell you the results. We would talk with you before and after testing, and these test 
results will be given to you only in person. You should know that the study staff must give 
your name to the Tennessee Department of Health if you test positive for Hepatitis B or C 
because this is the law. If others find out you have one or more of these viruses, it may cause 
mental stress, unfair treatment from other people, problems with being able to get insurance 
or find a job, or other unknown problems. It is important to seek medical care if you have 
these diseases. 
 
Your study team will request a sample of your tumor tissue. The purpose of this important tissue is to hel p 
understand why different patients do or do not respond to the study treatment. 
 

Your demographics (for example, age, race and gender) will be reviewed. You will be asked about 
your past and current health, including any past treatments for your condition. 

You will have a physical exam. Your weight and vital signs will be recorded (blood pressure, heart rate 
and temperature). 

Oxygen saturation: The oxygen level in your blood will be measured by pulse oximetry. (A small non- 
invasive device similar to a clothespin will gently squeeze a body part, for example finger or earlobe, 
in order to measure the oxygen saturation in your blood.) 

Your health will be assessed by questions about your ability to carry out daily activities. 
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
You will be asked about any problems you are having and the medicines you are taking, including all 
prescriptions and over-the-counter medicines. 

Urine test (about ¼ cup of urine will be collected) to check your kidney function. 

Blood will be drawn (about ½ tablespoon) to check the following: 
 Check your Blood Cell Counts (numbers of each type of blood cell). 
 Check your Chemistries (proteins, elements and minerals in your blood). 
 Check your Thyroid function (hormone levels in the blood). 
 Women Only: During screening, a blood pregnancy test will be done during for women who 
can have children (about ⅓ tablespoon of blood will be drawn). This pregnancy test must be 
negative for you to take part in the study. Women who are pregnant or breast feeding may 
not take part in the study. If you are a post-menopausal woman (a woman who can no longer 
become pregnant), a portion of the above blood collected for blood chemistries may be used 
to also measure follicle stimulating hormone (FSH) to confirm your post-menopausal status. 

12-Lead Electrocardiogram (ECG) to check the electrical activity of your heart, using 12 sticky pads 
attached to the surface of your skin. 
 
Treatment 
 
If, based on the results of the above screening tests and procedures, you qualify and choose to participate in the 
study, you will return to your study doctor's office to begin treatment. 
 
Cycle 1, Day 1 

Your health will be assessed by questions about your ability to carry out daily activities. 

Your weight, vital signs (blood pressure, heart rate and temperature), and oxygen saturation will be 
recorded. 

You will be asked about any problems you are having and the medicines you are taking, including all 
prescriptions and over-the-counter medicines. 

Blood will be drawn (about 2 tablespoon) for the following: 
 Blood sample for research to look for possible differences in genes (also known as DNA) that 
may influence how different patients do or do not respond to the study treatment. 
 Blood samples to study biomarkers for research. (Biomarkers are biological indicators of how 
your body and illness may be reacting to the drugs that you are receiving.) 

You will start taking oral vorolanib by mouth (once per day). 

You will receive your first dose of nivolumab by a 30 minute infusion into a vein. 
 
The following will be done, unless already completed ≤ 7 days prior to your first dose of vorolanib/nivolumab: 

Physical exam. 

Blood will be drawn (about ½ tablespoon) to check the following: 
 Check your Blood Cell Counts (numbers of each type of blood cell) 
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21 
 
 
 Check your Chemistries (proteins, elements and minerals in your blood) 

Urine test (about ¼ cup of urine will be collected) to check your kidney function. 
 
Cycle 1, Day 8 (Only if you are in the dose escalation part of this study will you have this visit) 

You will be asked about any problems you are having and the medicines you are taking, including all 
prescriptions and over-the-counter medicines. 

Your weight, vital signs (blood pressure, heart rate and temperature), and oxygen saturation will be 
recorded 

Blood will be drawn (about ½ tablespoon) to check the following: 
 Check your Blood Cell Counts (numbers of each type of blood cell) 
 Check your Chemistries (proteins, elements and minerals in your blood) 
 
Cycle 1, Day 15 

Physical exam. 

Your health will be assessed by questions about your ability to carry out daily activities. 

Your weight, vital signs (blood pressure, heart rate and temperature), and oxygen saturation will be 
recorded. 

You will be asked about any problems you are having and the medicines you are taking, including all 
prescriptions and over-the-counter medicines. 

Blood will be drawn (about ½ tablespoon) to check the following: 
 Check your Blood Cell Counts (numbers of each type of blood cell) 
 Check your Chemistries (proteins, elements and minerals in your blood) 
 

Nivolumab infusion by a 30 minute infusion into a vein. 
 
Cycle 1, Day 22 (Only if you are in the dose escalation part of this study will you have this visit) 

You will be asked about any problems you are having and the medicines you are taking, including all 
prescriptions and over-the-counter medicines. 

Your weight, vital signs (blood pressure, heart rate and temperature), and oxygen saturation will be 
recorded 

Blood will be drawn (about ½ tablespoon) to check the following: 
 Check your Blood Cell Counts (numbers of each type of blood cell) 
 Check your Chemistries (proteins, elements and minerals in your blood). 
 
Cycle 1, Day 29 

Physical exam. 

Your health will be assessed by questions about your ability to carry out daily activities. 
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22 
 
 

Your weight, vital signs (blood pressure, heart rate and temperature), and oxygen saturation will be 
recorded. 

You will be asked about any problems you are having and the medicines you are taking, including all 
prescriptions and over-the-counter medicines. 

Blood will be drawn (about ½ tablespoon) to check the following: 
 Check your Blood Cell Counts (numbers of each type of blood cell) 
 Check your Chemistries (proteins, elements and minerals in your blood). 
 Check your Thyroid function (hormone levels in the blood). 

Blood will be drawn (about 2 tablespoon) for the following: 
 Blood sample for research to look for possible differences in genes (also known as DNA) that 
may influence how different patients do or do not respond to the study treatment. 
 Blood samples to study biomarkers for research. (Biomarkers are biological indicators of how 
your body and illness may be reacting to the drugs that you are receiving.) 

Urine test (about ¼ cup of urine will be collected) to check your kidney function. 

Nivolumab infusion by a 30 minute infusion into a vein. 
 
Cycle 1, Day 43 

Physical exam. 

Your health will be assessed by questions about your ability to carry out daily activities. 

Your weight, vital signs (blood pressure, heart rate and temperature), and oxygen saturation will be 
recorded. 

You will be asked about any problems you are having and the medicines you are taking, including all 
prescriptions and over-the-counter medicines. 

Blood will be drawn (about ½ tablespoon) to check the following: 
 Check your Blood Cell Counts (numbers of each type of blood cell) 
 Check your Chemistries (proteins, elements and minerals in your blood) 

Nivolumab infusion by a 30 minutes infusion into a vein. 
 
Cycle 1, between Days 50-56: 

Standard of Care re-scanning of your disease by CT or MRI to occur during Week 8 (ideally on Day 56), 
prior to initiating Cycle 2 treatment. Scanning to include at least your chest and abdomen, with 
additional sites of known or suspected disease (for example, pelvis) as clinically indicated according to 
your study doctor. Additional scans or increased scan frequency may be performed according to the 
medical judgment of your study doctor. 

Also, if a baseline scan done during screening previously showed that your disease had spread to your 
brain or spinal cord (CNS metastasis), standard of care re-scanning of your head by CT or by 
preferable MRI will be done at least every 3 months since your prior head scan. 
 
Additional Cycles, Day 1 
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23 
 
 
In general, you may continue to receive treatment on this study as long as you tolerate treatment and your disease 
does not get worse (progress). All additional cycles will continue as outlined above with the exception that we will no 
longer collect blood samples for genetics (Pharmacogenetics) and biomarkers (Pharmacodynamics) 
 
Cycle 2+: 
After the first 16 weeks (2 cycles), if you have not experienced disease progression (non-PD response), patients with 
continued clinical benefit can switch to treatment with 480 mg nivolumab every 4 weeks on Days 1 and 29 of each 56- 
day cycle. 
 
End-of-Treatment and Follow-up 
 
You may stop study treatment based on your disease assessments, or if you are having side effects that make you 
unable to tolerate study therapy. Based on discussions between you and your study doctor, you may discontinue for 
other reasons including your decision to stop being treated. 
 
End-of-Treatment / Withdrawal Assessments 
The following must be completed subsequent to and not later than 14 days after you permanently discontinue study 
treatment with vorolanib/ nivolumab (whichever treatment occurs last) and prior to any subsequent anti-cancer 
therapy: 

Physical Exam. 

Your health (ability to carry out your daily activities) will be assessed. 

Your weight, vital signs (blood pressure, heart rate and temperature), and oxygen saturation will be 
recorded. 

You will be asked about any problems you are having and the medicines you are taking, including all 
prescriptions and over-the-counter medicines. 

12-Lead Electrocardiogram (ECG) to check the electrical activity of your heart, using 12 sticky pads 
attached to the surface of your skin. 

Urine test (about ¼ cup of urine will be collected) to check your kidney function. 

Blood will be drawn (about ½ tablespoon) for the following: 
 Check your Blood Cell Counts (numbers of each type of blood cell) 
 Check your Chemistries (proteins, elements and minerals in your blood) 
 Check your Thyroid function (hormone levels in the blood) 

Blood will be drawn (about 2 tablespoon) for the following: 
 Blood sample for research to look for possible differences in genes (also known as DNA) that 
may influence how different patients do or do not respond to the study treatment. 
 Blood samples to study biomarkers for research. (Biomarkers are biological indicators of how 
your body and illness may be reacting to the drugs that you are receiving.) 

If prior scans done > 28 days before: Re-scanning of your disease by CT or MRI. This scan would be 
done for research purposes. Scanning to include at least your chest and abdomen, with additional 
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24 
 
 
sites of known or suspected disease (for example, pelvis) as clinically indicated according to your 
study doctor. Additional scans may be performed according to the medical judgment of your study 
doctor (including possible head imaging, if medically appropriate to repeat). Also, if you stop the 
study for reason other than progressive disease confirmed by CT or MRI (for example, stopping the 
study treatment because of side effects), then CT or MRI scans involving sites of known or suspected 
disease must be continued every 8 weeks (± 7 days) until disease progression is confirmed by imaging. 
These scans will be done as part of your standard care. 
 
28-Day Follow-Up Visit Assessments 
You will be asked to return to the study clinic 28 days after your final treatment with VOROLANIB or nivolumab 
(whichever occurs last), in order to undergo the following: 
 

Physical Exam. 

Your health (ability to carry out your daily activities) will be assessed. 

Your weight, vital signs (blood pressure, heart rate and temperature), and oxygen saturation will be 
recorded. 

You will be asked about any problems you are having and the medicines you are taking, including all 
prescriptions and over-the-counter medicines. 

12-Lead Electrocardiogram (ECG) to check the electrical activity of your heart, using 12 sticky pads 
attached to the surface of your skin. 

Urine test (about ¼ cup of urine will be collected) to check your kidney function. 

Blood will be drawn (about ½ tablespoon) for the following: 
 Check your Blood Cell Counts (numbers of each type of blood cell) 
 Check your Chemistries (proteins, elements and minerals in your blood) 
 Check your thyroid function (hormone levels in the blood). 
 
100-Day Follow-Up Visit Assessment 
100 days after your final treatment with vorolanib or nivolumab (whichever occurs last), you will be contacted either 
by a clinic visit, or by a telephone call from a member of your study team. If you are having any possible side effects 
after stopping the study treatment, you may be asked to have more tests done to check your heath (such as repeating 
some or all of the above items previously done during your 28-Day follow-up assessment). 
 
Long-Term Follow-Up 
After you complete all of the planned study visits, you will be contacted approximately every 3 months (± 14 days) 
after your final treatment with vorolanib or nivolumab (whichever occurs last), in order to determine your health 
status. Contact could be by a variety of methods, including via telephone, clinic visit, medical records, or publicly 
available information. This will continue until death, end of the study, until you withdraw consent for this 
communication, or for a maximum of 2 years after your final treatment with vorolanib/ nivolumab – whichever comes 
first. 
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25 
 
 
 
Leftover Specimens 
Any leftover study tissue or blood samples may be stored for future research studies. Any studies that use these 
leftover samples will be approved by an Institutional Review Board. 
 
Your samples and information about you may be made available to others to use for research. To protect your 
privacy, we will not release your name. You will not receive any benefit as a result of the tests done on your samples. 
These tests may help us learn more about the causes, risks, treatments, or how to prevent this and other health 
problems. 
 
Your samples may be used to make new products or tests. These may have value and may be developed and owned 
by the study staff, Vanderbilt University, and/or others. If this happens, there are no plans to provide money to you. 
 
 
Payments for your time spent taking part in this study or expenses: 
 
You will not be paid for participating in this study. 
 
Costs to you if you take part in this study: 
If you agree to take part in this research study, you and/or your insurance will not have to pay for the tests and 
treatments that are being done only for research. 
However, you are still responsible for paying for the usual care you would normally receive for the treatment of your 
illness. This includes treatments and tests you would need even if you were not in this study. These costs will be 
billed to you and/or your insurance. 
You have the right to ask what it may cost you to take part in this study. If you would like assistance, financial 
counseling is available through the Vanderbilt Financial Assistance Program. The study staff can help you contact this 
program. You have the right to contact your insurance company to discuss the costs of your routine care (non- 
research) further before choosing to be in the study. You may choose not to be in this study if your insurance does 
not pay for your routine care (non-research) costs and your doctor will discuss other treatment plans with you. 
 
 
Payment in case you are injured because of this research study: 
 
 
If it is determined by Vanderbilt and the Investigator that an injury occurred as a direct result of the tests or 
treatments that are done for research, then you and/or your insurance will not have to pay for the cost of immediate 
medical care provided at Vanderbilt to treat the injury. 
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26 
 
 
There are no plans for Vanderbilt to pay for any injury caused by the usual care you would normally receive for 
treating your illness or the costs of any additional care. There are no plans for Vanderbilt to give you money for the 
injury. 
 
Who to call for any questions or in case you are injured: 
 
If you should have any questions about this research study or if you feel you have been hurt by being a part of this 
study, please feel free to contact Katy Beckermann, PhD, MD at (615) 936-8422. If you cannot reach the research staff, 
please page the study doctor at (615) 322-5000. 
 
For additional information about giving consent or your rights as a person in this study, to discuss problems, concerns, 
and questions, or to offer input, please feel free to call the Vanderbilt University Institutional Review Board Office at 
(615) 322-2918 or toll free at (866) 224-8273. 
 
 
Reasons why the study doctor may take you out of this study: 
 
The study doctor, sponsor, supporters Bristol-Myers Squibb or Equinox/ Xcovery, or a regulatory authority (FDA, 
Institutional Review Board, etc.) may choose to end your participation in this study without your consent. This could 
happen for reasons such as: 
 

The study doctor feels it is not in your best interest to continue in the study 

You fail to follow the study doctor’s instructions 

You experience an adverse reaction that requires other medical treatment 

You become pregnant, or 

The sponsor, supporters: Equinox/ Xcovery or Bristol-Myers Squibb, or the FDA or other regulatory authority 
stops the study for any reason. 
 
If you are removed from the study, the reason will be explained to you. 
 
What will happen if you decide to stop being in this study? 
 
If you decide to stop being part of the study, you should tell your study doctor. Deciding to not be part of the study 
will not change your regular medical care in any way. 
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27 
 
 
Clinical Trials Registry: 
 
A description of this clinical trial will be available on www.ClinicalTrials.gov, as required by U.S. Law. This Web site will 
not include information that can identify you. At most, the Web site will include a summary of the results. You can 
search this Web site at any time. 
Clinical Trials Reporting Program: 
Vanderbilt’s NCI-Designated Cancer Center or the Sponsor registers National Cancer Institute (NCI)-supported clinical 
trials with NCI though their Clinical Trials Reporting Program (CTRP) to provide study related information. The data 
provided will include the following identifiable information that may identify you: birth month/year and five -digit zip 
code. NCI uses the data to manage and enhance the nation’s investment in cancer research. 
 
Confidentiality: 
 
All efforts, within reason, will be made to keep your personal information in your research record confidential but 
total confidentiality cannot be guaranteed. Your information and samples will be given a unique code instead of your 
name to help protect your identity. Dr. Beckermann, her staff at Vanderbilt and other authorized people will be the 
only people who know your personal information. Results of this study may be presented in meetings or in 
publications. Your identity will not be released in those presentations. Your study records will be secured in the 
clinical trials office. Your research data will be kept for an unknown period of time. Your tissue and blood samples will 
be kept in locked storage and may be used or stored indefinitely from the end of the study. Any samples that are not 
needed will be destroyed. 
 
Vanderbilt may share your information, without identifiers, to others or use it for other research projects not listed in 
this form. Vanderbilt, Dr. Beckermann and her staff will comply with any and all laws regarding the privacy of such 
information. There are no plans to pay you for the use or transfer of this de-identified information. 
 
This study may have some support from the National Institutes of Health (NIH). If so, your study information is 
protected by a Certificate of Confidentiality. This Certificate allows us, in some cases, to refuse to give out your 
information even if requested using legal means. 
 
It does not protect information that we have to report by law, such as child abuse or some infectious diseases. The 
Certificate does not prevent us from disclosing your information if we learn of possible harm to yourself or others, or 
if you need medical help. 
 
Disclosures that you consent to in this document are not protected. This includes putting research data in the medical 
record or sharing research data for this study or future research. Disclosures that you make yourself are also not 
protected. 
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28 
 
 
Privacy: 
 
Any samples and information about you may be made available to others to use for research. To protect your privacy, 
we will not release your name. You will not receive any benefit as a result of the tests done on your samples. These 
tests may help us learn more about the causes, risks, treatments, or how to prevent this and other health problems. 
 
Your samples may be used to make new products or tests. These may have value and may be developed and owned 
by the study staff, Vanderbilt University, and/or others. If this happens, there are no plans to provide money to you. 
 
Study results: 
You have the right to see and copy the PHI we gather on you for as long as the study doctor or research site holds this 
data. To ensure the scientific quality of the research study, you will not be able to review some of your research data 
until after the research study is finished. 
 
Authorization to Use/Disclose Protected Health Information 
 
All efforts, within reason, will be made to keep your protected health information (PHI) private. PHI is your health 
information that is or has been gathered or kept by Vanderbilt as a result of your healthcare. This includes data 
gathered for research studies that can be traced back to you. Using or sharing (“disclosure”) such data must follow 
federal privacy rules. By signing the consent for this study, you are agreeing (“authorization”) to the uses and likely 
sharing of your PHI. If you decide to be in this research study, you are also agreeing to let the study team use and 
share your PHI as described below. 
 
As part of the study, Dr. Beckermann and her study team may share the results of your study and/or non-study 
linked blood and other tissue samples and related records, medical histories, physical examinations, laboratory 
tests, x-rays, CT/MRI scans, ECG results, and any other data created or collected during the study, as well as parts of 
your medical record, to the groups named below. These groups may include people from the Federal Government 
Office for Human Research Protections, the Vanderbilt University Medical Center Institutional Review Board, 
domestic and foreign drug regulatory agencies such as the Food and Drug Administration, National Institutes of 
Health, National Cancer Institute, representatives of Equinox/Xcovery, Bristol-Myers Squibb, Scientific Review 
Committees, Medicare and Insurance companies for billing purposes, etc. Federal privacy rules may not apply to 
these groups; they have their own rules and codes to assure that all efforts, within reason, will be made to keep 
your PHI private. 
 
The study results will be kept in your research record for at least six years after the study is finished. At that time, the 
research data that has not been put in your medical record will be kept for an unknown length of time . Any research 
data that has been put into your medical record will be kept for an unknown length of time. 
 
Unless told otherwise, your consent to use or share your PHI does not expire. If you change your mind, we ask that 
you contact Dr. Beckermann in writing and let her know that you withdraw your consent. Her mailing address is: Katy 
Beckerman, PhD, MD, Vanderbilt-Ingram Cancer Center, 777 Preston Research Building, 2220 Pierce Avenue, 
Nashville, TN 37232. At 
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29 
 
 
that time, we will stop getting any more data about you. But, the health data we stored before you withdrew your 
consent may still be used for reporting and research quality. 
 
You have the right to see and copy the PHI we gather on you for as long as the study doctor or research site holds this 
data. To ensure the scientific quality of the research study, you will not be able to review some of your research data 
until after the research study is finished. 
 
If you decide not to take part in this research study, it will not affect your treatment, payment or enrollment in any 
health plans or affect your ability to get benefits. You will get a copy of this form after it is signed. 
 
 
 
If you decide not to take part in this research study, it will not affect your treatment, payment or enrollment in any 
health plans or affect your ability to get benefits. You will get a copy of this form after it is signed. 
 
 
STATEMENT BY PERSON AGREEING TO BE IN THIS STUDY 
 
I have read this consent form and the research study has been explained to me verbally. All my questions have been 
answered, and I freely and voluntarily choose to take part in this study. 
 
 
 
Date 
Signature of patient/volunteer 
Consent obtained by: 
 
 
Date 
Signature 
 
 
 
Printed Name and Title 
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