Clinical trial NCT04197310
Conditions: Carcinoid Tumor Carcinoid Tumor of GI System Neuroendocrine Tumors
Keywords: Carcinoid Tumor Carcinoid Tumor of GI System Neuroendocrine Tumors
Sponsor: Dana-Farber Cancer Institute
Start date: 2019-12-26; Completion date: 2024-01-31
Enrollment: 19 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This research study, is studying the combination of cabozantinib and nivolumab in treating advanced carcinoid tumors.

\- Carcinoid tumor is another term used to refer to neuroendocrine tumors that arise in organs such as the gastrointestinal tract, lungs, or thymus.

Detailed description:
This is open-label, single-arm, phase II research study, studying the combination of cabozantinib and nivolumab in treating advanced carcinoid tumors. Carcinoid tumor is another term used to refer to neuroendocrine tumors that arise in organs such as the gastrointestinal tract, lungs, or thymus.

* The research study procedures include screening for eligibility and study treatment including evaluations and follow up visits.
* Cabozantinib will be administered orally, once daily
* Nivolumab will be administered intravenously, every two weeks
* The target enrollment for this study is 35 participants.
* The U.S. Food and Drug Administration (FDA) has not approved cabozantinib or nivolumab for treating carcinoid tumors.

Arms: arm 1: The research study procedures include screening for eligibility and study treatment including evaluations and follow up visits.

* Cabozantinib will be administered at a dose of 40mg orally, once daily
* Nivolumab will be given at a dose of 240mg every 14 days, intravenously

Retreat Phase (Optional)

* Participants may elect to stop nivolumab and cabozantinib with confirmed CR after at least 24 weeks of treatment.
* Participants who elect to stop and then the condition progresses after stopping study treatment may be eligible to resume nivolumab and cabozantinib therapy.
* This resumption will be termed as a retreatment second course phase and is available only while the study remains open and the subject meets specified criteria.
Interventions: intervention 1: Nivolumab intervention 2: Cabozantinib
Intervention descriptions: intervention 1: 240mg, intravenously, Day 1 and 15 of a 28 day cycle intervention 2: 40mg, orally, Daily for a 28 day cycle

Protocol documents:
Prot_SAP_000.pdf: 
Page 1
NCI Protocol #:  NCT04197310
DF/HCC Protocol #:  19-403
TITLE: Phase II trial of cabozantinib in combination with nivolumab for advanced carcinoid 
tumors
Coordinating Center:
Dana-Farber Cancer Institute/ Harvard Cancer Center
Principal Investigator (PI):
Kimberly Perez, MD
Dana-Farber Cancer Institute
Kimberly_Perez@dfci.harvard.edu
Other Investigators:
Jennifer Chan, MD, MPH
Dana-Farber Cancer Institute
JAng@partners.org
Matthew Kulke, MD
Boston Medical Center
Matthew.Kulke@bmc.org
Statistician:
Project Manager: 
Hui Zheng, PhD
Alexandra Bird
Massachusetts General Hospital
Dana-Farber Cancer Institute
HZHENG1@mgh.harvard.edu
Alexandra_Bird@dfci.harvard.edu
Responsible Research Nurses:
 
Christopher Graham, RN
Dana-Farber Cancer Institute
Christopher_Graham@dfci.harvard.edu
Mark Sawin, RN
Lauren Ritterband, RN
Dana-Farber Cancer Institute
Dana-Farber Cancer Institute
Mark_Sawin@dfci.harvard.edu
Lauren_Ritterband@dfci.harvard.edu
NCI-Supplied Agent(s):  N/A
Other Agent(s): Cabozatinib – Exelixis; Nivolumab – Bristol-Myers Squibb 
IND #:  144470
IND Sponsor:  Kimberly Perez, MD


DF/HCC Protocol #: 19-403
Protocol Version Date: 20-May-2022
2
Protocol Type / Version # / Version Date:   Version #6.0 / 20-May-2022


DF/HCC Protocol #: 19-403
Protocol Version Date: 20-May-2022
3
SCHEMA
Diseases: 
Well-differentiated 
Neuroendocrine Tumors of 
non-pancreatic (i.e, 
carcinoid)  origin 
 
Treatment:
Nivolumab intravenously every 2 weeks
AND
Cabozantinib  orally daily
                 
                               28 day cycle
Stage I: safety run-in (N= 18);
If more than 3 patients 
demonstrate response measured 
by RECIST 1.1 criteria then, 
Stage II: expansion (N= 17)


DF/HCC Protocol #: 19-403
Protocol Version Date: 20-May-2022
4
TABLE OF CONTENTS
1
OBJECTIVES......................................................................................................................8
1.1
Study Design............................................................................................................8
1.2
Primary Objective(s)................................................................................................8
1.3
Secondary Objective(s)............................................................................................8
1.4
Exploratory Objective(s)..........................................................................................8
2
BACKGROUND .................................................................................................................9
2.1
Introduction..............................................................................................................9
2.2
Rationale ................................................................................................................10
2.3
IND Agent(s) .........................................................................................................11
2.4
Correlative Studies Background ............................................................................11
3
PARTICIPANT SELECTION...........................................................................................13
3.1
Eligibility Criteria..................................................................................................13
3.2
Exclusion Criteria ..................................................................................................15
3.3
Inclusion of Women and Minorities ......................................................................17
4
REGISTRATION ..............................................................................................................18
4.1
General Guidelines for DF/HCC Institutions ........................................................18
4.2
Registration Process for DF/HCC Institutions.......................................................18
4.3
General Guidelines for Other Investigative Sites ..................................................18
4.4
Registration Process for Other Investigative Sites.................................................18
5
TREATMENT PLAN........................................................................................................19
5.1
Treatment Regimen................................................................................................19
5.2
Pre-Treatment Criteria ...........................................................................................20
5.3
Agent Administration.............................................................................................21
5.4
General Concomitant Medication and Supportive Care Guidelines......................21
5.5
Criteria for Taking a Participant Off Protocol Therapy.........................................25
5.6
Duration of Follow Up...........................................................................................27
5.7
Criteria for Taking a Participant Off Study ...........................................................27
6
DOSING DELAYS/DOSE MODIFICATIONS ...............................................................27
6.1
Dosing/Delays/Omission/Modification .................................................................27
6.2
Dose Levels............................................................................................................28
6.3
Hematologic Toxicities..........................................................................................28
6.4
Diarrhea/Colitis......................................................................................................29
6.5
Hepatobiliary Disorders.........................................................................................30
6.6
Elevated Amylase and/or Lipase ...........................................................................32
6.7
Fatigue, Anorexia and Weight loss Disorders .......................................................32
6.8
Stomatitis and Mucositis........................................................................................33
6.9
Palmar-plantar erythrodysesthesia (PPE) syndrome..............................................33
6.10
Other dermatologic disorders.................................................................................34
6.11
GI perforation/fistula and non-GI fistula formation ..............................................35


DF/HCC Protocol #: 19-403
Protocol Version Date: 20-May-2022
5
6.12
Treatment-emergent hypertension .........................................................................35
6.13
Thromboembolic Event .........................................................................................37
6.14
Hemorrhagic Events...............................................................................................38
6.15
Proteinuria..............................................................................................................38
6.16
Hypophosphatemia ................................................................................................39
6.17
Osteonecrosis of the Jaw........................................................................................40
6.18
QTcF Prolongation.................................................................................................40
6.19
Pulmonary Toxicity ...............................................................................................40
6.20
Neurologic Events..................................................................................................41
6.21
Endocrinopathy including hypophysitis and adrenal insufficiency.......................41
6.22
Thyroid Dysfunction..............................................................................................42
6.23
Creatinine Levels/ Renal Insufficiencies ...............................................................42
6.24
Infusion Reactions .................................................................................................42
6.25
Fever ......................................................................................................................44
6.26
Management of other toxicities attributable to cabozantinib.................................44
6.27
Management of other toxicities attributable to nivolumab....................................45
7
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ............................46
7.1
Adverse Events Lists..............................................................................................46
7.2
Adverse Event Characteristics...............................................................................46
7.3
Adverse Event Reporting.......................................................................................47
7.4
Routine Adverse Event Reporting .........................................................................47
7.5
Expedited Reporting to BMS.................................................................................48
7.6
Expedited Reporting to Exelexis ...........................................................................48
8
PHARMACEUTICAL INFORMATION..........................................................................49
8.1
Cabozantinib ..........................................................................................................49
8.2
Nivolumab..............................................................................................................52
9
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ........................................54
9.1
Correlative Science Objectives..............................................................................54
9.2
Hypothesis: ............................................................................................................55
9.3
Archival Tissue......................................................................................................56
9.4
Fresh Tissue Biopsy...............................................................................................56
9.5
Blood Collection....................................................................................................58
9.6
Stool Collection .....................................................................................................58
9.7
Statistical Considerations.......................................................................................59
9.8
Additional analysis.................................................................................................59
10
STUDY CALENDAR .......................................................................................................59
11
MEASUREMENT OF EFFECT .......................................................................................61
11.1
Antitumor Effect – Solid Tumors ..........................................................................61
11.2
Other Response Parameters ...................................................................................68
12
DATA REPORTING / REGULATORY REQUIREMENTS...........................................70
12.1
Data Reporting.......................................................................................................70


DF/HCC Protocol #: 19-403
Protocol Version Date: 20-May-2022
6
12.2
Data Safety Monitoring..........................................................................................71
13
ETHICAL ASPECTS ........................................................................................................71
13.1
Local Regulations ..................................................................................................71
13.2
Informed Consent...................................................................................................71
13.3
Institutional Review Board/Ethics Committee ......................................................72
14
CONDITIONS FOR MODIFYING THE PROTOCOL ...................................................72
15
CONDITIONS FOR TERMINATING THE STUDY ......................................................72
15.1
Collaborative Agreements Language.....................................................................72
16
STATISTICAL CONSIDERATIONS...............................................................................73
16.1
Study Design/Endpoints ........................................................................................73
16.2
Sample Size, Accrual Rate and Study Duration ....................................................73
16.3
Analysis Plan .........................................................................................................74
16.4
Interim Monitoring Plan ........................................................................................75
16.5
Evaluation of Toxicity ...........................................................................................75
17
PUBLICATION PLAN .....................................................................................................75
REFERENCES ..............................................................................................................................77
APPENDIX A
PERFORMANCE STATUS CRITERIA ..................................................80
APPENDIX B GI ADVERSE EVENT MANAGEMENT ALGORITHM ..................................81
APPENDIX C BIOSPECIMEN PREPARATION........................................................................90
APPENDIX d multi-center guidelines...........................................................................................92
1
INTRODUCTION .............................................................................................................93
1.1
Purpose...................................................................................................................93
2
GENERAL ROLES AND RESPONSIBILITIES .............................................................93
2.1
External Site...........................................................................................................93
3
DF/HCC REQUIREMENTS FOR MULTI-CENTER PROTOCOLS .............................93
3.1
Protocol Revisions and Closures ...........................................................................94
3.2
Informed Consent Requirements ...........................................................................94
3.3
IRB Re-Approval...................................................................................................94
3.4
DF/HCC Multi-Center Protocol Confidentiality ...................................................94
3.5
Participant Registration and Randomization .........................................................95
3.6 
Data Management..................................................................................................96
3.7
 Protocol Reporting Requirements.........................................................................96
4
MONITORING: QUALITY CONTROL..........................................................................97
4.1
Ongoing Monitoring of Protocol Compliance.......................................................97


DF/HCC Protocol #: 19-403
Protocol Version Date: 20-May-2022
7
4.2
Monitoring Reports................................................................................................97
4.3
Accrual Monitoring................................................................................................97
5
AUDITING: QUALITY ASSURANCE ...........................................................................98
5.1
DF/HCC Internal Audits........................................................................................98
5.2
Audit Notifications.................................................................................................98
5.3
Audit Reports.........................................................................................................98
5.4
External Site Performance .....................................................................................98


DF/HCC Protocol #: 19-403
Protocol Version Date: 20-May-2022
8
1
OBJECTIVES
1.1
Study Design
This is an open-label, single-arm, phase 2 study of nivolumab given in combination with 
cabozantinib.  Nivolumab will be administered every two weeks at a dose of 240 mg given 
intravenously.  Cabozantinib will be administered orally, once daily at a dose of 40 mg.
1.2
Primary Objective(s) 
To evaluate the efficacy of cabozatinib in combination with nivolumab, as defined by objective 
response rate (ORR) according to RECIST 1.1, in patients with advanced carcinoid tumors. 
1.3
Secondary Objective(s)
1.3.1
To evaluate the safety and tolerability of cabozantinib in combination with 
nivolumab in patients with advanced carcinoid tumors.
1.3.2
To evaluate the ORR of cabozantinib in combination with nivolumab in 
patients with advanced carcinoid tumors according to immune-related 
response criteria (irRC).
1.3.3
To evaluate the duration of response in patients with advanced carcinoid 
tumors receiving the combination of cabozantinib and nivolumab.
1.3.4
To evaluate progression-free survival of patients with advanced carcinoid 
tumors treated with the combination of cabozantinib and nivolumab. 
1.3.5
To evaluate overall survival of patients with advanced carcinoid tumors 
treated with the combination of cabozantinib and nivolumab. 
1.4
Exploratory Objective(s)
1.4.1
To explore whether baseline tumor immune cell infiltration and PD-L1 and 
PD-L2 staining correlates with response to therapy.
1.4.2
To explore whether changes in circulating immune cell profile correlates with 
response to therapy.
1.4.3
To explore whether changes in the level of angiogenic and inflammatory 
blood biomarkers during therapy correlate with efficacy of therapy.


DF/HCC Protocol #: 19-403
Protocol Version Date: 20-May-2022
9
2
BACKGROUND
2.1
Introduction
Neuroendocrine neoplasms are a relatively rare heterogeneous group of malignancies. These 
tumors arise from neuroendocrine cells located throughout the body.  In current clinical practice 
neuroendocrine neoplasms are divided into two groups based on clinical behavior, histology, and 
proliferation rate: well differentiated (low grade to intermediate grade) neuroendocrine tumors 
(NET) and poorly differentiated (high grade) neuroendocrine carcinomas (NEC). This 
dichotomization is clinically relevant for therapeutic and prognostics purposes, though imprecise 
as the behavior (metastatic potential, local invasion, recurrence after resection) can be very 
heterogeneous. Furthermore, there are distinctions in the management of well-differentiated 
neuroendocrine tumors arising in the pancreas versus non-pancreatic primary sites, including 
organs such as thymus, lung, and the gastrointestinal tract.  Well-differentiated neuroendocrine 
tumors arising in non-pancreatic sites have historically been classified as carcinoid tumors.  
Current therapeutic options for carcinoid tumors include somatostatin analogs, everolimus, and 
the radiolabeled somatostatin analog lutetium-177 dotatate.  These therapies have been shown to 
improve progression-free survival for patients with advanced stage disease, but the benefit is 
finite. As such, newer therapeutic options are needed to manage this very heterogeneous disease. 
2.1.1
The PD-1/PD-L1 pathway in cancer
The role of intact immune surveillance in controlling neoplastic transformation and growth has 
been well-described. (Restifo) There is recent evidence demonstrating a correlation between 
tumor-infiltrating lymphocytes (TILs) in cancer tissue and clinical outcomes. (Mlecnik) The 
PD-1 receptor ligand interaction is a major pathway hijacked by tumors to suppress immune 
control. The normal function of PD-1, expressed on the cell surface of activated T-cells under 
healthy conditions, is to down-modulate unwanted or excessive immune responses, including 
autoimmune reactions. PD-1 is an Ig superfamily member related to CD28 and CTLA-4 which 
has been shown to negatively regulate antigen receptor signaling upon engagement of its 
ligands (PD-L1 and/or PD-L2). PD-1 is expressed on activated lymphocytes including 
peripheral CD4+ and CD8+ T-cells, B-cells, T regs, natural killer cells, and a subset of 
macrophages and dendritic cells. The ligands for PD-1 (PD-L1 and PD-L2) are constitutively 
expressed or can be induced in a variety of cells types. PD-L1 serves to dampen unwarranted T-
cell function in peripheral tissues and PD-L2 controls immune T-cell activation in lymphoid 
organs. Most healthy tissues express few PD-L1 ligands, a variety of cancer demonstrate an 
abundant level, thus suggesting that the PD-1/PD-L1 pathway plays a critical role in tumor 
immune evasion and is therefore considered an attractive target for therapeutic intervention. 
(Intlekofer)
The PD-1/PD-L1 pathway in neuroendocrine tumors
The new generation of immunotherapy treatment, check-point inhibitors, has not yet been 
proven to be effective in patients with NETs. Prior analysis of interferon in NET, a classic 
immune-modulatory drug, demonstrated an ability to stimulate T-cell function, control the 
secretion of tumor products and inhibit tumor growth by activation of the T-cell response 
against the tumor and angiogenesis inhibition in NETs (Oberg). Efforts to better characterize the 


DF/HCC Protocol #: 19-403
Protocol Version Date: 20-May-2022
10
immune response in NET have been undertaken, and several studies have demonstrated an 
association between expression of PD-L1, presence of TILs, and clinical outcome. Lamarca and 
colleagues recently demonstrated that 30% of a 109 patient cohort of SINETs showed 
expression of PD-L1 within tumor cells and/or TILs, together with a high rate of TIL presence. 
In this cohort, 17.2% demonstrated a concomitant presence of CD8+ lymphocyte aggregate and 
PD-L1 expression. (Lamarca) Other studies have demonstrated similar results, with high grade 
or well differentiated grade 3 NETs consistently demonstrating a higher expression of PD-L1 
when compared to grade 1 or 2 NET. (Lamarca, Cavalcanti, da Silva).  In contrast, in another 
cohort of patients with NET, including 64 with small intestinal NET (SINET) and 21 with 
pancreatic NET, no membranous expression of PD-L1 was identified in the SINETs group, and 
11% was noted in the PNET cohort. Both groups, however, showed T-cell tumor infiltrate. (da 
Silva). 
The therapeutic use of immune checkpoint inhibitors and NETs is currently under investigation. 
The results of the first completed study was presented at the ESMO 2017 Annual Conference. 
The Keynote-028 study evaluated the use of pembrolizumab for patients with PD-L1 positive 
advanced carcinoid or pancreatic NET. The study screened 276 patients for the presence of PD-
L1; 36% were positive (carcinoid N=25; pancreatic NET N=16). Three carcinoid patients (12%; 
95% CI, 3-31%) and one PNET (6%; 95% CI, 0-30%) had an objective response; stable disease 
rates were 60% (n=15) and 88% (n=14) respectively. Duration of response ranged between 6.9 
to 11.1 months for the carcinoid responders; and 17.6 months for the PNET responder. 
(Mehnert) Other clinical trials are currently evaluating the role of checkpoint inhibitors and 
focusing on NETs that are both well-differentiated and poorly differentiated, and studies are 
also evaluating checkpoint inhibitors in combination with other immunomodulatory agents 
(NCT03167853, NCT02955069, NCT03095274, NCT03074513).
2.1.2
Cabozatinib in carcinoid tumors
Cabozantinib is an orally administered drug that is classified as a small-molecule tyrosine 
kinase inhibitor (TKI). It is a reversible competitive inhibitor of tyrosine kinase receptors 
including VEGFR2, MET, AXL, and RET.  Cabozantinib has demonstrated efficacy in advance 
renal cell carcinoma and metastatic medullary thyroid cancer. (Choueiri, Brose) We recently 
demonstrated in a phase II trial of patients with advanced carcinoid and pancreatic 
neuroendocrine tumors (NET) that treatment with single agent cabozantinib was associated with 
encouraging response rates and progression-free survival [2].  The objective response rate, as 
measured by RECIST 1.1, was 15% in patients with both carcinoid tumors (6/41) and pancreatic 
NET (3/20). (Chan)  The CABINET study, a randomized, phase III placebo-controlled clinical 
trial, is currently open to enrollment and will further evaluate the efficacy of cabozantinib in 
patients with advanced pancreatic NET and carcinoid tumors previously treated with everolimus  
(NCT03375320).
 
2.2
Rationale
Although NET is not typically considered to be an immunogenic malignancy, an increasing body 
of preclinical and clinical evidence suggests that modulation of the immune system can influence 
disease outcome. In particular, anti-PD-1/PD-L1 antibodies have demonstrated clinical efficacy, 


DF/HCC Protocol #: 19-403
Protocol Version Date: 20-May-2022
11
and two PD-1 inhibitors (nivolumab and pembrolizumab) are FDA approved for the treatment of 
multiple cancer types. (Brahmer) Although immune checkpoint inhibitors have made an 
enormous impact on therapeutic strategies, there remain many tumor types and subsets of tumor 
types in which therapeutic benefit has not been clearly demonstrated. This suggests that there may 
be additional immunosuppressive factors causing resistance to immunotherapy, and other agents 
must be added to anti-PD-1/PD-L1 treatment in order to enhance the benefit of immunotherapy.
Treatment with cabozantinib has been associated with immunomodulatory changes.  In a phase 
II study of patients with triple negative breast cancer, for example, significant and persistent 
increases in circulating CD3+ T-lymphocytes were observed after treatment with cabozantinib, 
driven primarily by increase in CD8+CD4–cytotoxic T-lymphocytes. (Tolaney)   Moreover, there 
was a significant decrease in circulating CD14+ monocytes, an immunosuppressive myeloid-
derived population. These changes in circulating immune cells provides rationale for combining 
cabozantinib with immune checkpoint inhibitors as an innovative treatment strategy.  Similar 
treatment strategies are being proposed in other malignancies, including urothelial and 
genitourinary malignancies (NCT02496208) and renal cell carcinoma (NCT03141177). 
Neuroendocrine tumors provide another ideal platform upon which to perform such a study. 
Given the single agent activity of cabozantinib in NET, and the potential immunomodulatory 
potential of cabozantinib, we propose a phase II study to evaluate the antitumor activity of 
cabozantinib plus nivolumab (anti-PD-1 monoclonal antibody) in patients with advanced 
carcinoid tumors.
2.3
IND Agent(s)
2.3.1
Cabozatinib – refer to the Investigator’s Brochure (IB)/ approved labeling for 
detailed background information. 
2.3.2
Nivolumab - refer to the Investigator’s Brochure (IB for detailed background 
information. 
2.4
Correlative Studies Background
The importance of the tumor microenvironment and immune surveillance in the natural history 
of cancer has proved to be significant in our therapeutic strategy. However, less than half of 
patients with solid tumors will derive benefit from these drugs alone. (Ribas) Thus, it is 
imperative to examine the mechanisms of antitumor immunity evasion in the tumor 
microenvironment to direct immunotherapy treatment. This effort can be moved forward by the 
discovery and validation of prognostic and predictive biomarkers. 
Although multiple cancers have demonstrated a sensitivity to immunotherapy, there are subsets 
that do not appear to respond. The lack of a significant T-cell infiltrate and low expression of 
immune checkpoint molecules may explain the reason that certain non-inflamed tumor 
phenotypes are associated with de novo resistance to anti-PD-1 / anti-PD-L1 drugs. For this 
group of patients, therapeutic strategies that promote an increase in cytotoxic T-cell infiltration, 


DF/HCC Protocol #: 19-403
Protocol Version Date: 20-May-2022
12
such as anti-angiogenic therapies, may be relevant to successfully overcoming T-cell exclusion 
and improve the likelihood of benefit of PD-1 blockers. 
Tolaney and colleagues recently published their experience in triple negative breast cancer with 
single-agent cabozantinib. Although the study did not meet its pre-specified endpoint, there were 
notable notable biomarker changes after treatment with cabozantinib which included: significant 
and durable increases in plasma placental growth factor, vascular endothelial growth factor 
(VEGF), VEGF-D, stromal cell-derived factor 1a, and carbonic anhydrase IX, and circulating 
CD3+ cells and CD8 + T lymphocytes, and decreases in plasma soluble VEGF receptor 2 and 
CD14+ monocytes (all p<.05). There was a significant increase in the fraction of circulating 
CD3+ cells and CD3 + CD4-CD8+ T lymphocytes at days 22 and 64 (p=.04 and p=.01, 
respectively), and a decrease in percentage of CD14+ monocytes at days 22 and 64 (p=.01). 
(Tolaney) Although none of these findings, except baseline soluble MET levels, were associated 
with outcome measures, this is the first description of cabozantinib induced modulation of 
immune cells in the clinical setting. We propose analysis of potential biomarkers of cabozantinib 
and nivolumab activity in carcinoid and the impact on the immune environment. We intend to 
explore changes in angiogenic/inflammatory biomarkers during treatment, the characteristics of 
potential immune biomarkers and expression of immune checkpoint molecules, and TILs to 
explore the activity of cabozantinib and nivolumab in carcinoid tumors.  


DF/HCC Protocol #: 19-403
Protocol Version Date: 20-May-2022
13
3
PARTICIPANT SELECTION
3.1
Eligibility Criteria 
3.1.1
Patients with locally unresectable or metastatic well-differentiated 
neuroendocrine tumor of non-pancreatic (ie, carcinoid) origin
3.1.2
Participants must have measurable disease, defined as at least one lesion that 
can be accurately measured in at least one dimension (longest diameter to be 
recorded for non-nodal lesions and short axis for nodal lesions) as ≥20 mm 
with conventional techniques or as ≥10 mm with spiral CT scan, MRI, or 
calipers by clinical exam.  See Section 11 for the evaluation of measurable 
disease.
3.1.3
Patients must have evidence of radiographic disease progression within the 
past 12 months. 
3.1.4
Patients who have received at least one line of therapy, which can include 
somatostatin analog therapy.  Participants should be adequately recovered 
from acute toxicities of prior treatment.
-
Prior somatostatin analog therapy is allowed.  Continuation of 
somatostatin analog therapy is allowed provided that the dose has been 
stable for 2 months.
-
Prior chemotherapy: Participants must have been off treatment with 
cytotoxic chemotherapy for at least 14 days prior to registration.  
-
Prior biologic therapy: Patients must have discontinued all biologic 
therapy at least 28 days prior to registration.  Duration may be shorted to 
14 days for agents with short half-lives.
-
Prior radiolabeled somatostatin analog therapy: Participants must have 
completed radiolabeled somatostatin analog therapy at least 6 weeks prior 
to registration. 
-
Prior hepatic artery embolization or ablative therapies is allowed if 
measurable disease remains outside the treated area or there is documented 
disease progression in a treated site.  Prior liver-directed or ablative 
treatment must be completed at least 28 days prior to registration.
-
Prior radiation therapy: Radiation therapy must be completed per the 
following timelines
i) Radiotherapy to the thoracic cavity or abdomen within 4 weeks prior to
registration.
ii) Radiotherapy to bone lesions within 2 weeks prior to registration.
iii) Radiotherapy to any other site within 4 weeks prior to registration.
NOTE: In all cases, there must be complete recovery and no ongoing 
complications from prior radiotherapy.
3.1.5
Age ≥ 18 years.  


DF/HCC Protocol #: 19-403
Protocol Version Date: 20-May-2022
14
3.1.6
ECOG performance status ≤1 (Karnofsky ≥60%, see Appendix A)
3.1.7
Participants must have normal organ and marrow function as defined below:
-
absolute neutrophil count
≥1,500/mcL
-
platelets
≥100,000/mcL
-
total bilirubin
≤1.5 × institutional upper limit of normal 
(ULN)
(or 2.0 x ULN in patients with documented 
Gilbert’s Syndrome)
-
AST (SGOT)/ALT (SGPT)
≤2.5 × ULN or ≤ 3 × ULN for participants 
with documented liver metastases
-
creatinine
Or 
      creatinine clearance
<1.5 × ULN  
≥40 mL/min (using Cockcroft-Gault 
formula) for participants with creatinine 
levels above institutional normal
-
Urine protein/creatinine ratio 
(UPCR)
-
PT/INR or partial 
thromboplastin time (PTT) test 
≤ 1
< 1.3  the laboratory ULN within 7 days 
before the first dose of study treatment.
3.1.8
Negative urine pregnancy test for women of childbearing potential.
3.1.9
Participant must be able to swallow pills.
3.1.10 The participant is capable of understanding and complying with the protocol 
and has signed the informed consent document.


DF/HCC Protocol #: 19-403
Protocol Version Date: 20-May-2022
15
3.2
Exclusion Criteria
3.2.1
Major surgery (eg, GI surgery, removal or biopsy of brain metastasis) within 8 
weeks before first dose of study treatment. Complete wound healing from 
major surgery must have occurred 1 month before first dose and from minor 
surgery (eg, simple excision, tooth extraction) at least 10 days before first 
dose. Subjects with clinically relevant ongoing complications from prior 
surgery are not eligible.
3.2.2
Participants who are receiving any other investigational agents.
3.2.3
Participants who have received a prior cabozantinib.
3.2.4
Participants who have received prior therapy with an anti-PD-1, anti-PD-L1, 
anti- PD-L2, anti-CD137, or anti-Cytotoxic T-lymphocyte-associated antigen-
4 (CTLA-4) antibody (including nivolumab, pembrolizumab, ipilimumab, and 
any other antibody or drug specifically targeting T-cell co-stimulation or 
checkpoint pathways) 
3.2.5
Participants with known Central Nervous System(CNS) metastases should be 
excluded from this clinical trial because of their poor prognosis and because 
they often develop progressive neurologic dysfunction that would confound 
the evaluation of neurologic and other adverse events.
3.2.6
The participant has tumor in contact with, invading, or encasing major blood 
vessels or radiographic evidence of significant cavitary pulmonary lesions. 
3.2.7
History of allergic reactions attributed to compounds of similar chemical or 
biologic composition to cabozantinib or nivolumab. 
3.2.8
Participants receiving any strong inhibitors or inducers of CYP3A4 within 14 
days prior to registration are ineligible.  Chronic treatment with strong 
inhibitors or inducers of CYP3A4 is not allowed.
3.2.9
Cardiovascular disorders including: 
­
Congestive heart failure (CHF): New York Heart Association (NYHA) 
Class III (moderate) or Class IV (severe) at the time of screening; 
­
Concurrent uncontrolled hypertension defined as sustained blood pressure 
(BP) > 150 mm Hg systolic or > 100 mm Hg diastolic despite optimal 
antihypertensive treatment within 7 days of the first dose of study 
treatment; 
­
Any history of congenital long QT syndrome;
­
QTcF interval >500 msec
­
Any of the following within 6 months before the first dose of study 
treatment: 

unstable angina pectoris; 

clinically-significant cardiac arrhythmias; 


DF/HCC Protocol #: 19-403
Protocol Version Date: 20-May-2022
16

stroke (including transient ischemic attack (TIA), or other    
ischemic event);

myocardial infarction; 
3.2.10 GI disorders particularly those associated with a high risk of perforation or 
fistula formation including:

Tumors invading the GI tract, active peptic ulcer disease, active 
inflammatory bowel disease (eg, Crohn’s disease), active diverticulitis, 
cholecystitis, symptomatic cholangitis or appendicitis, acute 
pancreatitis or acute obstruction of the pancreatic duct or common bile 
duct, or gastric outlet obstruction 

Abdominal fistula, GI perforation, bowel obstruction, intra-abdominal 
abscess within 6 months before screening
3.2.11 Thromboembolic events within 6 months of registration.  
Note: Low dose aspirin ≤ 81 mg/day is allowed. Anticoagulation with 
therapeutic doses of LMWH is allowed in patients who are on a stable dose of 
LMWH for at least 6 weeks prior to registration. Treatment with warfarin is 
not allowed.
3.2.12 The subject has experienced any significant bleeding episodes, including:

Clinically significant gastrointestinal bleeding within 6 months before the 
first dose of study treatment

Clinically significant hemoptysis (> 0.5 teaspoon) within 3 months of the 
first dose of study treatment

Any other signs indicative of pulmonary hemorrhage within 3 months 
before the start of study treatment

Individuals with a history of different malignancy are ineligible except for 
the following circumstances:  Individuals with a history of other 
malignancies are eligible if they have been disease-free for at least 3 years 
or are deemed by the investigator to be at low risk for recurrence of that 
malignancy. 


DF/HCC Protocol #: 19-403
Protocol Version Date: 20-May-2022
17
3.2.13 Participant has an active infection requiring IV antibiotics 
3.2.14 Any active, known, or suspected autoimmune disease.  Participants with type I 
diabetes mellitus, hypothyroidism only requiring hormone replacement, skin 
disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic 
treatment, or conditions not expected to recur in the absence of an external 
trigger (e.g. celiac disease) are permitted to enroll.
3.2.15 Patient has a medical condition that requires chronic systemic steroid therapy 
or on any other form of immunosuppressive medication.  Adrenal replacement 
steroid disease are permitted in the absence of autoimmune disease.
3.2.16 The participant is known to be positive for the human immunodeficiency virus 
(HIV), HepBsAg, or HCV RNA.   HIV-positive participants with non-
detectable viral loads on combination antiretroviral therapy are ineligible 
because of the potential for pharmacokinetic interactions with cabozantinib 
and nivolumab.  
3.2.17 The participant has received a live vaccine within 28 days prior to the first 
dose of trial treatment and while participating in the trial. Examples of live 
vaccines include, but are not limited to, the following: measles, mumps, 
rubella, varicella/zoster, yellow fever, rabies, BCG, and typhoid vaccine. The 
use of the inactivated seasonal influenza vaccine (Fluzone®) is allowed. 
3.2.18 Pregnant or lactating females are excluded from this study because 
cabozantinib and nivolumab are agents with the potential for teratogenic or 
abortifacient effects.  Because there is an unknown but potential risk for 
adverse events in nursing infants secondary to treatment of the mother with 
cabozantinib and nivolumab, breastfeeding should be discontinued if the 
mother is treated with cabozantinib and nivolumab.  These potential risks may 
also apply to other agents used in this study.
3.2.19 Sexually active fertile subjects and their partners must agree to use medically 
accepted methods of contraception (eg, barrier methods, including male 
condom, female condom, or diaphragm with spermicidal gel) during the 
course of the study and following treatment.  Women of childbearing potential 
receiving nivolumab will be instructed to adhere to contraception for a period 
of 5 months after the last dose of nivolumab. Men receiving nivolumab and 
who are sexually active with WOCBP will be instructed to adhere to 
contraception for a period of 7 months after the last dose of nivolumab.  
Contraception must be used for 4 months after last dose of cabozantinib.
3.3
Inclusion of Women and Minorities
Both men and women of all races and ethnic groups are eligible for this trial.


DF/HCC Protocol #: 19-403
Protocol Version Date: 20-May-2022
18
4
REGISTRATION 
4.1
General Guidelines for DF/HCC Institutions
Institutions will register eligible participants in the Clinical Trials Management System (CTMS) 
OnCore. Registrations must occur prior to the initiation of any protocol-specific therapy or 
intervention. Any participant not registered to the protocol before protocol-specific therapy or 
intervention begins will be considered ineligible and registration will be denied.
An investigator will confirm eligibility criteria and a member of the study team will complete the 
protocol-specific eligibility checklist.
Following registration, participants may begin protocol-specific therapy and/or intervention. 
Issues that would cause treatment delays should be discussed with the Overall Principal 
Investigator (PI). If the subject does not receive protocol therapy following registration, the 
subject must be taken off-study in the CTMS (OnCore) with an appropriate date and reason 
entered.  
4.2
Registration Process for DF/HCC Institutions
Applicable DF/HCC policy (REGIST-101) must be followed.  
4.3
General Guidelines for Other Investigative Sites
Eligible participants will be entered on study centrally by the Project Manager at the 
Coordinating Center.  All sites should call the Project Manager at 617-632-5728 to verify dose 
level availabilities.  The required Registration Request Cover Sheet and External Site Subject 
Registration forms will be provided to sites. Following registration, participants should begin 
protocol therapy within 5 days.* Issues that would cause treatment delays should be discussed 
with the Sponsor-Investigator.  If the subject does not receive protocol therapy following 
registration, the subject must be taken off study in the CTMS (OnCore) with an appropriate date 
and reason entered.  
4.4
Registration Process for Other Investigative Sites
To register a participant, the following documents should be completed by the participating site 
and faxed to 617-582-7988 or e-mailed to the Project Manager, 
DanielleE_Stonely@dfci.harvard.edu:

Signed participant consent form

HIPAA authorization form

Eligibility Checklist

Registration Request Coversheet 

External Site Subject Registration form


DF/HCC Protocol #: 19-403
Protocol Version Date: 20-May-2022
19

Screening provider note including medical/ surgical history, ECOG performance 
status, vital signs, and physical exam findings

Pathology report to support inclusion criteria

Laboratory reports including:
o
CBC with differential 
o
Chemistry panel
o
Pregnancy test (if applicable)
o
Thyroid panel
o
Coagulation panel 
o
LDH

Screening radiology reports (CT and/or MRI scans)

Screening EKG
The participating site will then call 617-632-5728 or e-mail 
DanielleE_Stonely@dfci.harvard.edu, the Project Manager to verify eligibility.  The Project 
Manager will follow DF/HCC policy (REGIST-101) and register the participant on the protocol.  
The Project Manager will fax or e-mail the participant study number and confirmation of 
registration to the participating site. The participating site will then register the patient per their 
local requirements. 
5
TREATMENT PLAN
5.1 Treatment Regimen
This is an open-label, single-arm, phase 2 study of nivolumab given every 14 days intravenously 
in combination with cabozantinib given orally once daily for 28 days. Up to 35 participants will 
be enrolled to the study to assess the efficacy of the combination as defined by objective 
response rate (ORR) according to RECIST 1.1, in patients with carcinoid tumors. 
No investigational or commercial agents of therapies other than those described below may be 
administered with the intent to treat the participant’s malignancy. 


DF/HCC Protocol #: 19-403
Protocol Version Date: 20-May-2022
20
Regimen Description
Agent
Premedications; 
Precautions
Dose
Route
Schedule
Cycle 
Length
Nivolumab
Not routinely 
necessary unless 
prior infusion 
reaction. 
240mg
IV 
Every 14 
days 
Cabozantinib
Not necessary
40mg
oral
Continuous, 
once daily*
28 days 
(4 weeks)
*The participant will be requested to maintain a medication diary of each dose of medication.  
The medication diary will be returned to clinic staff at the end of each cycle.
5.2
Pre-Treatment Criteria
5.2.1
Cycle 1, Day 1 
Participants do not need to re-meet eligibility criteria on Cycle 1, Day1 if screening laboratory 
evaluations were completed within 3 days of Cycle 1 Day 1.
-
absolute neutrophil count  ≥1,500/mcL
-
platelets   ≥100,000/mcL
-
hemoglobin   ≥ 9 g/dl 
-
total bilirubin  ≤1.5 × institutional upper limit of normal (ULN) (or 2.0 x ULN in 
patients with documented Gilbert’s Syndrome)
-
AST(SGOT)/ALT(SGPT)  ≤2.5 × institutional ULN or ≤ 3 × institutional ULN for 
participants with documented liver metastases 
-
Creatinine <1.5 ×within normal institutional ULN OR creatinine clearance ≥40 mL/min 
(using Cockcroft-Gault formula) for participants with creatinine levels above institutional 
ULN. 
-
urine protein/creatinine ratio (UPCR) ≤ 1. 
-
Urine pregnancy test in women of child-bearing age
5.2.2
Subsequent Cycles 
­
absolute neutrophil count  ≥1,000/mcL
­
total bilirubin  ≤1.5 × institutional upper limit of normal (ULN) (or 2.0 x ULN in 
patients with documented Gilbert’s Syndrome)
­
AST(SGOT)/ALT(SGPT)  ≤2.5 × institutional ULN or ≤ 3 × institutional ULN for 
participants with documented liver metastases 
­
Urine pregnancy test in women of child-bearing age every 4 weeks (+/- 1 week)


DF/HCC Protocol #: 19-403
Protocol Version Date: 20-May-2022
21
5.3
Agent Administration
On days when Nivolumab and Cabozantinib are administered on the same day (i.e. Day 1 of each 
cycle) the order of agent administration does not matter. 
5.3.1
Nivolumab Administration 
Nivolumab is available as 100 mg vials (10 mg/mL), which include an overfill. It is supplied in 
10 mL type I flint glass vials with butyl stoppers and aluminum seals. Nivolumab injection can 
be infused undiluted (10 mg/mL) or diluted with 0.9% Sodium Chloride Injection, USP (USP to 
a final concentration ranging from 1 mg/mL to 10 mg/mL. The total volume of infusion must not 
exceed 160 mL.) or 5% Dextrose. 
Nivolumab will be administered every 14 days at a dose of 240 mg given intravenously over 30 
minutes (+/- 10 minutes) using a volumetric pump with 0.2 to 1.2 micron pore size, low- protein 
binding polyethersulfone membrane in-line filter. Please refer to the Investigational Brochure for 
further details regarding storage, preparation and administration. Care must be taken to assure 
sterility of the prepared solution as the product does not contain any antimicrobial preservative or 
bacteriostatic agent.
5.3.2
Cabozantinib administration 
Cabozantinib will be administered orally, once daily for 28 days at a dose of 40 mg. 
Cabozantinib should be taken 2 hours after a meal (water is permitted) with a full glass of water 
(8oz/240mL). Participants should continue to fast for 1 hour after taking cabozantinib. 
Participants will be provided with dosing instructions, a drug diary and a sufficient supply of 
cabozantinib for continuous daily dosing. Cabozantinib should be dosed on an outpatient basis 
even on days where Nivolumab and Cabozantinib are dosed together (i.e. Day 1 of each cycle). 
While taking Cabozantinib, participants should avoid consumption of grapefruit and Seville 
oranges. Cabozantinib should not be crushed, chewed, or dissolved in water.
Subjects should be instructed to take their cabozantinib dose at approximately the same time 
every day.  If a subject misses a dose, the dose may be taken later only if it is within 12 hours of 
when the missed dose should have been taken.  The missed dose should not be made up if it is 
within 12 hours of the next scheduled dose.  
Management and dose modifications associated with the above adverse events are outlined in 
Section 6.  
5.4
General Concomitant Medication and Supportive Care Guidelines
5.4.1
Concomitant Medications Guidelines
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed during 
the ongoing trial.  If there is a clinical indication for one of these or other medications or 


DF/HCC Protocol #: 19-403
Protocol Version Date: 20-May-2022
22
vaccinations specifically prohibited during the trial, discontinuation from trial therapy or 
vaccination may be required.  The investigator should discuss any questions regarding this with 
the overall PI.  
Acceptable Concomitant Medications
All treatments that the investigator considers necessary for a subject’s welfare may be administered 
at the discretion of the investigator in keeping with the community standards of medical care and 
documented in the medical record. Selected medications of interest received within 28 days before 
the first dose of trial treatment and 30 days after the last dose of trial treatment, including dosage, 
frequency, route, and dates of administration will be recorded. 
Concurrent use of somatostatin analogs is allowed, provided that the patient has been on a stable 
dose for at least two months.
Concomitant medications that are known to prolong the QTcF interval and should be used with 
caution in subjects who receive cabozantinib until they have permanently discontinued 
cabozantinib treatment (refer to http://www.qtdrugs.org for a list of drugs which have the 
potential to prolong the QTcF interval).
Drugs known to be P-glycoprotein substrates (e.g. fexofenadine, aliskiren, ambrisentan digoxin, 
colchicine, maraviroc, posaconazole, tolvaptan, etc.) should be used with caution as cabozantinib 
can cause increased P-glycoprotein substrate plasma concentrations.
MRP2 inhibitors such as cyclosporine, delavirine, efavirenz, and emtricitabine should be used with 
caution during treatment with cabozantinib as coadministration can cause increased cabozantinib 
plasma concentrations. 
Highly protein-bound medications (e.g. diazepam, furosemide, dicloxacillin, propranolol, etc.) 
should be used with caution during treatment with cabozantinib. 
Bisphosphonates should be used with caution due to the nephrotoxic potential and potential for 
osteonecrosis of the jaw previously described in association with these agents. 
Prohibited Concomitant Medications
Subjects are prohibited from receiving the following therapies during the Screening and Treatment 
Phase of this trial: 

Antineoplastic systemic chemotherapy or biological therapy  

Immunotherapy not specified in this protocol  

Investigational agents other than nivolumab and cabozantinib  

Radiation therapy  

Live vaccines within 28 days prior to the first dose of trial treatment and while participating 
in the trial. Examples of live vaccines include, but are not limited to, the following: 
measles, mumps, rubella, varicella/zoster, yellow fever, rabies, BCG, and typhoid vaccine. 
The use of the inactivated seasonal influenza vaccine (Fluzones, BCG, and ty  

Systemic glucocorticoids should be avoided for any purpose other than to modulate 
symptoms from radiation or an event of clinical interest of suspected immunologic 


DF/HCC Protocol #: 19-403
Protocol Version Date: 20-May-2022
23
etiology. If corticosteroids are required for this purpose, the minimum effective dose 
should be used. 

Full dose oral anticoagulation/antiplatelet therapy is not permitted. Low dose aspirin ≤ 
81mg/day is allowed. Anticoagulation with therapeutic doses of LMWH is allowed in 
patients who are on a stable dose of LMWH for at least 6 weeks. Treatment with warfarin 
is not allowed.

CYP3A4 Inhibitors
Chronic concomitant treatment with strong inhibitors of CYP3A4 is not allowed during on 
this trial. The following drugs are EXAMPLES of strong inhibitors of CYP3A4 and are not 
allowed during treatment with cabozantinib.

Indinavir

Clarithromycin

Ketoconazole
CYP3A4 inhibiting foods such as grapefruit/grapefruit juice and Seville oranges may increase 
plasma concentrations of cabozantinib and should be avoided during treatment with 
cabozantinib.
Because lists of these agents are constantly changing, please consult and review any drugs for 
their potential to inhibit CYP3A4. 

CYP3A4 Inducers
Chronic concomitant treatment with strong inducers of CYP3A4 is not allowed during on 
this trial. The following drugs are EXAMPLES of strong inducers of CYP3A4 and are not 
allowed during treatment with cabozantinib

Rifampin

Carbamazepine
Because lists of these agents are constantly changing, please consult and review any drugs 
for their potential to induce CYP3A4.
5.4.2
Supportive Care Guidelines – general medications 
Patients should receive full supportive care while on this study.  
This includes blood product support, antibiotic treatment, and treatment of other newly diagnosed 
or concurrent medical conditions. All blood products and concomitant medications such as 
antidiarrheals, analgesics, and/or antiemetics received from the first day of study treatment 
administration until 30 days after the final dose must be recorded in the medical records.
Antiemetics may be used at the discretion of the treating physician.
Antiemetic agents, along with supportive care, may be used as clinically appropriate at the first 
sign of nausea and vomiting. 5-HT3 receptor antagonists are recommended over chronic use of 
NK-1 receptor antagonists and dexamethasone due to possible CYP3A4 interactions.
Diarrhea management is per the discretion of the treating physician. 


DF/HCC Protocol #: 19-403
Protocol Version Date: 20-May-2022
24
Diarrhea may need to be managed conservatively with medications such as loperamide, 
diphenoxylate/atropine, deodorized tincture of opium, or octreotide as clinically appropriate at the 
first sign of diarrhea. Treating physicians may wish to instruct patients to notify their physician 
immediately at the first signs of poorly-formed or loose stool or an increased frequency of bowel 
movements.
Patients with severe diarrhea may need to be assessed for intravenous hydration, correction of 
electrolyte imbalances, and dietary adjustments.
Prevention of Skin Toxicity
Patients could be advised to use prophylactic measures for skin care. These measures may include: 
the use of hypoallergenic moisturizing creams, ointment for dry skin, sunscreen with SPF ≥ 30: 
avoidance of exposure of hands and feet to hot water; protection of pressure-sensitive areas of 
hands and feet; and use of thick, cotton gloves and socks to prevent injury and to keep the palms 
and soles dry. Treating physicians may wish to carefully monitor patients with skin disorders for 
signs of infection (e.g. abscess, cellulitis, or impetigo).
Early signs of hand-foot syndrome can include tingling, numbness, and slight redness or mild 
hyperkeratosis. Early manifestations include painful, symmetrical, red and swollen areas on the 
palms and soles. Treating physicians may wish to consider adequate interventions to prevent 
worsening of skin symptoms such as blisters, desquamations, ulcerations, or necrosis of affected 
areas, including aggressive management of symptoms and an early dermatology referral.
Recommendations for treatment of palmar-plantar erythrodysesthesia (hand-foot) syndrome 
include urea 20% cream twice daily and clobetasol 0.05% cream once daily. Analgesics (e.g. 
NSAID, GABA agonist, narcotic) can be used for pain control if needed. 
Prevention of GI Perforation/Fistula and Non-GI Fistula Formation
Treating physicians may wish to consider carefully monitoring patients for episodes of abdominal 
pain, especially in patients with known risk factors for developing GI perforation/fistula or non-
GI fistula, to allow for early diagnosis.
Prevention of Mucositis and Stomatitis
Comprehensive dental examination may be used as a preventative measure to identify any potential 
complications prior to initiation of protocol therapy, and, if indicated, the appropriate correction 
may need to be implemented such as modification of ill-fitting dentures and appropriate care of 
gingivitis. During treatment with cabozantinib, treating physicians may wish to advise patients to 
maintain good oral hygiene and standard local treatments such as non-traumatic cleansing and oral 
rinses (e.g. with a weak solution of salt and baking soda), as well as noting that the oral cavity 
should be rinsed and wiped after meals, and dentures should be cleaned and brushed often to 
remove plaque. 
Prevention of Osteonecrosis of the Jaw (ONJ)
Patients using concomitant antiangiogenic drugs, bisphosphonates, or denosumab may need to be 
monitored for ONJ more frequently, and treating physicians may wish to advise patients who have 
previously been treated with or concomitantly receive these medications to avoid invasive dental 
procedures if possible. In cases where dental procedures are unavoidable, treating physicians may 
wish to consider the risks and benefits of a dental procedure, the extent of the procedure, as well 
as the risk of developing osteonecrosis of the jaw when deciding how long to hold protocol therapy. 


DF/HCC Protocol #: 19-403
Protocol Version Date: 20-May-2022
25
Growth Factors
Blood products and growth factors should be utilized as clinically warranted and following 
institutional policies and recommendations. 
White Blood Cell Growth Factors and other FDA-approved White Blood Cell Growth Factor 
biologics may not be used to avoid dose reductions, delays or to allow for dose escalations 
specified in the protocol.
5.5
Criteria for Taking a Participant Off Protocol Therapy
Duration of therapy will depend on individual response, evidence of disease progression and 
tolerance. In the absence of treatment delays due to adverse event(s), treatment may continue for 
indefinite number or until one of the following criteria applies:
1. Disease progression by RECIST 1.1 Criteria
Although the primary endpoint is ORR as defined by RECIST 1.1, patients may 
remain on protocol therapy until the time of disease progression by irRC criteria. The 
immune criteria allows treatment beyond initial radiographic worsening of disease in 
order to distinguish between pseudoprogression and true disease progression. 
2. Participants who have attained a confirmed complete response (CR) and who have been 
treated for at least 24 weeks on protocol therapy and had at least four treatments with 
nivolumab beyond the date when the initial CR was declared. Participants who stop 
nivolumab with CR may be eligible for additional nivolumab therapy if they progress 
after stopping study treatment. This retreatment is termed the Second Course Phase 
Therapy, as summarized below. 
3. Intercurrent illness that prevents further administration of treatment
4. Unacceptable adverse event(s). If the subject does not recover from his or her toxicities to 
tolerable Grade ≤ 2 within 6 weeks, the subject will have study treatment discontinued 
unless there is unequivocal evidence that the subject is benefitting. In this situation, a 
subject may be able to restart therapy with a dose reduction upon resolution of the 
toxicity and with agreement of the principal investigator / Sponsor.
5. Participant demonstrates an inability or unwillingness to comply with the oral medication 
regimen and/or documentation requirements. OR Significant noncompliance with the 
protocol schedule in the opinion of the investigator. OR Subjects who cannot tolerate the 
minimum protocol-specified dose of study treatment will have study treatment 
discontinued.
6. Participant decides to withdraw from the protocol therapy
7. General or specific changes in the participant's condition render the participant 
unacceptable for further treatment in the judgment of the treating investigator


DF/HCC Protocol #: 19-403
Protocol Version Date: 20-May-2022
26
8. Sexually active subjects who refuse to use medically accepted barrier methods of 
contraception (eg, male condom, female condom) during the course of the study and for 
5 months (women) or 7 months (men) after discontinuation of nivolumab and 4 months 
after discontinuation of cabozantinib
9. Women who become pregnant or are breastfeeding
10. Request by regulatory agencies for termination of treatment of an individual subject or all 
subjects under the protocol
Participants will be removed from the protocol therapy when any of these criteria apply.  The 
reason for removal from protocol therapy, and the date the participant was removed, must be 
documented in the case report form (CRF). Alternative care options will be discussed with the 
participant.
When a participant is removed from protocol therapy and/or is off of the study, the relevant Off-
Treatment/Off-Study information will be updated in OnCore.
Second Course Phase (Retreatment Period)
Participants may elect to stop nivolumab and cabozantinib with confirmed CR after at least 24 
weeks of treatment.
Subjects who stop nivolumab and cabozantinib with CR may be eligible for additional nivolumab 
and cabozantinib therapy if they progress after stopping study treatment.  This retreatment is 
termed the Second Course Phase of this study and is only available if the study remains open and 
the subject meets the following conditions:
o
Stopped initial treatment with nivolumab and cabozantinib after attaining an 
investigator-determined confirmed CR according to RECIST 1.1, was treated for at 
least 24 weeks with nivolumab before discontinuing therapy, and received at least four 
treatments with nivolumab beyond the date when the initial CR was declared
AND
o
experienced an investigator-determined confirmed radiographic disease progression 
after stopping their initial treatment with nivolumab
o
did not receive any anti-cancer treatment other than cabozantinib since the last dose of 
nivolumab
o
meets all other study inclusion/exclusion criteria, as per Section 3.
Subjects who restart treatment will be retreated at the same dose and dose interval as when they 


DF/HCC Protocol #: 19-403
Protocol Version Date: 20-May-2022
27
last received nivolumab.  Visit requirements are as outlined for subjects on the initial treatment 
phase of the trial.  
5.6
 Duration of Follow Up
Participants will be followed for initiation of a new regimen of anti-neoplastic therapy, first 
disease progression event after removal from protocol therapy or until death .  Tumor 
assessments should continue to be performed every 12 weeks on these participants until first 
disease progression event or until death, whichever occurs first. 
Participants removed from protocol therapy for unacceptable adverse event(s) will be followed 
until resolution or stabilization of the adverse event. 
5.7
Criteria for Taking a Participant Off Study
Participants will be removed from study when any of the following criteria apply:

Lost to follow-up

Withdrawal of consent for data submission

Death
The reason for taking a participant off study, and the date the participant was removed, must be 
documented in the case report form (CRF). In addition, the study team will ensure Off 
Treatment/Off Study information is updated in OnCore in accordance with DF/HCC policy 
REGIST-101.
6
DOSING DELAYS/DOSE MODIFICATIONS
6.1
Dosing/Delays/Omission/Modification

The descriptions and grading scales found in the revised NCI Common Terminology Criteria 
for Adverse Events (CTCAE) version 5.0 will be utilized for dose delays and dose 
modifications. 

If multiple adverse events are seen, administer dose based on the greatest reduction required 
for any single adverse event observed. Reductions apply to treatment given in the preceding 
cycle and are based on adverse events observed since the prior dose.

If more than one of these apply, use the most stringent (i.e. the greatest dose reduction).

Dosing interruptions are permitted in the case of medical / surgical events or logistical reasons 
not related to study therapy (e.g., elective surgery, unrelated medical events, patient vacation, 
and/or holidays). Participants held for these reasons require prior approval from the PI and 
should resume therapy within 6 weeks of the scheduled interruption. The reason for 
interruption should be documented in the participant's study record.  


DF/HCC Protocol #: 19-403
Protocol Version Date: 20-May-2022
28

If treatment is withheld > 8 weeks from the last dose of cabozantinib or nivolumab, the patient 
should discontinue study therapy. 

For management of AEs which can be clearly attributed to cabozantinib or nivolumab, 
independent dose modification for either agent is allowed as described. For AEs without clear 
attribution to either study treatment, management of toxicity should include dose modifications 
or delay of both agents. 

Participants who require dose delay should be re-evaluated weekly or more frequently if 
clinically indicated and resume dosing when re-treatment criteria are met.

Delayed doses of nivolumab and cabozantinib should be administered as soon as the participant 
meets criteria to resume treatment.  If a dose has been delayed, the participant should not wait 
until the next scheduled dosing date.

Dosing interruptions will not impact assessments or cycle/day scheduling. 

Restarting of treatment after dose interruption must be discussed with the PI.

In order to standardize the management of adverse events, treatment management algorithms 
recommended for utilization in this study are included in Appendix B.
6.2
Dose Levels
Dose Level
Nivolumab
(IV)
Cabozantinib 
(tablet dose expression)
0 (starting dose)
240 mg
40mg daily
-1
-
20mg daily
Dose reductions are permitted for cabozantinib but not for nivolumab. 
6.3
Hematologic Toxicities
For grade 3 neutropenia with documented infection, grade 3 neutropenia ≥ 5 days, or grade 
4 neutropenia, delay cabozantinib and nivolumab until toxicity resolves to grade ≤ 1, then resume 
cabozantinib with one dose level reduction and nivolumab without dose reduction.  
For grade 3 febrile neutropenia, delay cabozantinib and nivolumab until ANC grade ≤ 1 and 
temperature to ≤ 38.0⁰C, then resume cabozantinib with one dose level reduction and nivolumab 
without dose reduction.
For grade 4 febrile neutropenia, discontinue cabozantinib.  Resume nivoluamb when ANC 
grade ≤ 1.
For grade 3 thrombocytopenia with clinically significant bleeding or grade 4 
thrombocytopenia, continue nivolumab but delay cabozantinib until platelet count ≥ 
100,000/mm3, then resume cabozantinib with one dose level reduction.


DF/HCC Protocol #: 19-403
Protocol Version Date: 20-May-2022
29
For grade 4 anemia, continue nivolumab but delay cabozantinib and use supportive care (e.g. 
red blood cell transfusions) as clinically indicated according to institutional guidelines until 
toxicity resolves to grade ≤ 1, then resume cabozantinib with one dose level reduction.
6.4
Diarrhea/Colitis
Participants experiencing intolerable Grade 2 diarrhea or Grade 3 diarrhea unable to be managed 
with standard antidiarrheal treatments should consult a gastrointestinal (GI) doctor for potential 
endoscopy and biopsy to help distinguish between cabozantinib vs. nivolumab mediated toxicity. 
If a biopsy is performed and: 
.
there is T cell infiltration indicative of nivolumab-induced colitis, nivolumab should be 
held and managed with corticosteroids. Once diarrhea returns to Grade 1, restart 
cabozantinib and nivolumab as indicated in the management table below.  
.
there is no T cell infiltration indicative of nivolumab-induced colitis, when diarrhea 
returns to Grade 1 nivolumab should be resumed at the same dose at the discretion of the 
investigator. Cabozantinib should also be resumed at a reduced dose. 
Treatment may be restarted following the resolution of colitis. In addition, if the patient is being 
managed with corticosteroids, treatment should not be restarted until the steroids have been 
tapered down to a prednisone dose <10 mg/day. Patients who resume treatment should be 
monitored closely for signs of renewed diarrhea. 
Table: Management of Diarrhea/Colitis 
Grade
Management
Grade 1
• Continue nivolumab and cabozantinib. 
• Start Anti-diarrheal agent (e.g., Imodium) – up to 3 agents are 
permitted 
• Close monitoring. 
Grade 2

Hold nivolumab and cabozantinib 

Administer anti-diarrheal agent (e.g., Imodium). 

If symptoms persist > 5 days or recur, initiate therapy with 
Prednisone 60 mg/day or equivalent 

If improved to Grade ≤1 within 8 weeks: 
o
Taper steriods over ≥ 1 month 
o
Restart Nivolumab when corticosteroids have been reduced 
to the equivalent of prednisone ≤ 10 mg/day. 
o
Restart Cabozantinib at a reduced dose when corticosteroids 
have been reduced to the equivalent of prednisone ≤ 10 
mg/day. 
Grade 3
Hold nivolumab and cabozantinib. 
• Treat with IV steroids (1-2 mg/kg/day methylprednisolone or 
equivalent) and convert to oral steroids (prednisone 60 mg/day or 


DF/HCC Protocol #: 19-403
Protocol Version Date: 20-May-2022
30
equivalent) after improvement 
• If improved to Grade ≤1 within 8 weeks:
o
Taper steriods over ≥ 1 month 
o
Restart Nivolumab when corticosteroids have been reduced 
to the equivalent of prednisone ≤ 10 mg/day. 
o
Restart Cabozantinib at a reduced dose when corticosteroids 
have been reduced to the equivalent of prednisone ≤ 10 
mg/day. 
Grade 4

Permanently discontinue nivolumab and hold cabozantinib.

Treat with IV steroids (1−2 mg/kg/day methylprednisolone or 
equivalent) and convert to oral steroids (prednisone 60 mg/day or 
equivalent) after improvement

When symptoms improve to Grade ≤ 1, taper steroids over ≥ 1 
month 

If symptoms are not improving after 48 hours of initiating 
steroids or are worsening, addition of an alternative 
immunosuppressive agent (e.g., mycophenolate or TNF-α 
antagonist) may be considered.

If the subject was unequivocally deriving clinical benefit, the 
subject may be able to resume cabozantinib at reduced dose as 
determined by the investigator. 
6.5
Hepatobiliary Disorders
It is recommended that participants with elevation of ALT, AST, and/or bilirubin have more 
frequent laboratory monitoring of these parameters. If possible, hepatotoxic concomitant 
medications should be discontinued in participants who develop increased values of ALT, AST, 
or bilirubin. 
Guidelines in the following table should be used for dose modifications. 
Transaminase 
elevation
CTCAE v. 5.0
Intervention
≤ Grade 1
AST or ALT > ULN 
to 3.0 x ULN and/or 
Total bilirubin > 
ULN – 1.5x ULN
Continue study treatment, monitor liver function tests (LFTs) weekly 
for at least 4 weeks
Grade 2
AST or ALT > 3.0 to 
</= 5.0 x ULN 
and/or Total bilirubin 
>ULN – 1.5x ULN 
to </= x 3ULN
Hold cabozantinib and nivolumab
Monitor LFTs at least twice weekly until return to baseline or Grade 
</= 1
Consider referral to a hepatologist
If persistent > 5 days, start prednisone 60 mg/day or equivalent. 
When LFTs resolve to baseline or Grade ≤1 and steroid dose is 


DF/HCC Protocol #: 19-403
Protocol Version Date: 20-May-2022
31
Transaminase 
elevation
CTCAE v. 5.0
Intervention
prednisone ≤ 10 mg/day or equivalent, restart nivolumab and 
cabozantinib at a reduced dose.
* Permanently discontinue protocol therapy for conditions fulfilling 
Hy’s law with elevations >3 × ULN of ALT or AST concurrent with 
>2 × ULN total bilirubin without other explanation
Grade 3
AST or ALT > 5.0 to 
≤ 20.0 x ULN and/or 
Total bilirubin > 
ULN – 3.0 x ULN to 
≤10.0 x ULN 
Hold cabozantinib and nivolumab. 
Monitor LFTs every 48−72 hours until LFTs return to baseline or 
Grade ≤1 
Consider referral to hepatologist and liver biopsy to establish etiology 
of hepatic injury 
Start prednisone 60 mg/day or equivalent 
With first occurrence: 
. If LFTs do not resolved to Grade < 3 within 7 days,  permanently 
discontinue nivolumab and continue holding cabozantinib.  
.
When LFTs resolve to baseline or Grade ≤ 1, taper steroids over ≥1 
month. When steroid dose is prednisone ≤ 10 mg/day or equivalent, 
restart Nivolumab and Cabozantinib at a reduced dose. Subjects 
receiving cabozantinib at a daily dose of 20 mg may be restarted at 
the same dose if deemed safe at the discretion of the principal 
investigator. 
If recurs: permanently discontinue nivolumab . If the subject was 
unequivocally deriving clinical benefit, the subject may be able to 
resume cabozantinib at reduced dose as determined by the investigator.  
 
* Permanently discontinue protocol therapy for conditions fulfilling 
Hy’s law with elevations >3 × ULN of ALT or AST concurrent with 
>2 × ULN total bilirubin without other explanation
Grade 4
AST or ALT > 20.0 
x ULN and/or Total 
bilirubin > ULN 10.0 
x ULN 
Permanently discontinue nivolumab and hold cabozantinib and inform 
the principle investigator. 
Obtain hepatology consult and liver biopsy to establish etiology of 
hepatic injury. 
Start prednisone 60 mg/day or equivalent. 
If LFT results do not decrease within 48 hours after initiation of 
systemic steroids, consider addition of an alternative 
immunosuppressive agent (e.g., mycophenolate) to the corticosteroid 
regimen. 
If LFTs resolve to baseline or Grade ≤ 1, taper steroids over ≥1 month. 


DF/HCC Protocol #: 19-403
Protocol Version Date: 20-May-2022
32
Transaminase 
elevation
CTCAE v. 5.0
Intervention
If the subject was unequivocally deriving clinical benefit, the subject 
may be able to resume cabozantinib at reduced dose as determined by 
the investigator. 
6.6
Elevated Amylase and/or Lipase
Patients may develop symptomatic and/or radiographic evidence of pancreatitis, diabetes 
mellitus, or pancreatic dysfunction related to cabozantinib or nivolumab. Amylase and lipase 
should be checked if there is clinical suspicion for pancreatitis. Corticosteroids do not seem to 
alter the natural history of lipase/amylase elevations related to nivolumab. 
Patients with symptomatic or radiographic pancreatitis should discontinue nivolumab and consider 
consulting a gastroenterologist for management. 
Table: Management of elevated amylase and/or lipase
Grade
Management/ Next Dose for Cabozantinib and Nivolumab
≤3
For asymptomatic ≤ grade 3 lipase or amylase elevation, continue protocol 
therapy.  Ensure that participants have associated symptoms consistent with 
pancreatitis, such as abdominal pain, or hyperglycemia or radiographic pancreatic 
inflammation.
4
Hold nivolumab and cabozantinib. 
Ensure that participants have associated symptoms consistent with pancreatitis, 
such as abdominal pain, or hyperglycemia or radiographic pancreatic 
inflammation.
If patient remains asymptomatic, resume treatment when ≤ Grade 1. 
6.7
Fatigue, Anorexia and Weight loss Disorders
Fatigue has been reported during treatment with cabozantinib and nivolumab, the dose 
modifications are recommended for both drugs. Common causes of fatigue such as anemia, 
deconditioning, emotional distress (depression and/or anxiety), nutrition, sleep disturbance, and 
hypothyroidism should be ruled out and/or these causes treated according to standard of care. 
Individual non-pharmacological and/or pharmacologic interventions directed to the contributing 
and treatable factors should be given. Pharmacological management with psychostimulants such 
as methylphenidate should be considered after disease specific morbidities have been excluded. 
Dose reduction of study treatment should be considered when general or pharmacological 
measures have not been successful in reducing symptoms. 


DF/HCC Protocol #: 19-403
Protocol Version Date: 20-May-2022
33

For Grade ≥ 3 fatigue despite optimal management, hold nivolumab and cabozantinib.  
When fatigue improves to ≤ Grade 2, resume treatment with nivolumab at the same dose 
and cabozantinib at one dose level reduction.
Anorexia and weight loss should be managed according to local standard of care including 
nutritional support. Pharmacologic therapy such as megestrol acetate should be considered for 
appetite enhancement.   

For Grade ≥ 3 anorexia and weight loss despite optimal management, delay therapy.  
Treatment with nivolumab and cabozantinib with one dose level reduction may be 
resumed when symptoms improve to grade ≤ 2.  
6.8
Stomatitis and Mucositis  
Refer to Section 5.4 for guidance regarding supportive care of mucositis and stomatitis.
For grade 2 mucositis or stomatitis that is subjectively tolerable, continue cabozantinib and 
nivolumab in addition to providing supportive care.
For grade 2 mucositis or stomatitis that worsens, lasts ≥ 10 days, or interferes with 
adequate nutrition (and supportive care is insufficient), continue nivolumab but delay 
cabozantinib until toxicity improves to grade ≤ 1, then resume cabozantinib with one dose level 
reduction.
For grade 3 mucositis or stomatitis that interferes with adequate nutrition (and supportive 
care is insufficient), continue nivolumab but delay cabozantinib until toxicity improves to grade 
≤ 1, then resume cabozantinib with one dose level reduction.
For grade 4 mucositis or stomatitis that interferes with adequate nutrition (and supportive 
care is insufficient), discontinue cabozantinib permanently, resume nivolumab when toxicity 
improves to grade ≤ 1.
6.9
Palmar-plantar erythrodysesthesia (PPE) syndrome
Palmar-plantar erythrodysesthesia syndrome (also known as hand-foot syndrome), skin rash 
(including blisters, erythematous rash, macular rash, skin exfoliation, dermatitis acneiform, and 
papular rash), pruritus, dry skin, and erythema have been reported in cabozantinib-treated 
participants.  Refer to Section 5.4 for guidance regarding supportive management of skin 
toxicity.
Management of Hand-Foot Syndrome (PPES) Associated with Cabozantinib


DF/HCC Protocol #: 19-403
Protocol Version Date: 20-May-2022
34
CTCAE v.5.0 Grade 
Action To Be Taken 
Grade 1
Cabozantinib treatment may be continued at the current dose if PPES is clinically 
insignificant and tolerable. Otherwise, cabozantinib should be reduced to the next 
lower dose level.a Start urea 20% cream twice daily AND clobetasol 0.05% 
cream once daily. Reassess at least weekly; if PPES worsens at any time or does 
not improve after 2 weeks, proceed to the intervention guidelines for Grade 2.  
Maintain dosing of nivolumab.
Grade 2 
Cabozantinib treatment may be continued if PPES is tolerated. Cabozantinib 
should be dose reduced or interrupted if PPES is intolerable. Continue urea 20% 
cream twice daily AND high potency steroid cream (eg, clobetasol 0.05%) once 
daily and add analgesics (eg, NSAIDs/gamma-aminobutyric acid agonists) for 
pain control if needed. Reassess at least weekly; if PPES worsens or affects 
self-care or is intolerable, proceed to the intervention guidelines for Grade 3.  
Maintain dosing of nivolumab.
Grade 3
Interrupt cabozantinib treatment until severity decreases to Grade 1 or 0. 
Continue treatment of skin reaction with high potency steroid cream (eg, 
clobetasol 0.05%) twice daily AND analgesics. Resume study drug at a reduced 
dose if PPES recovers to Grade ≤ 1. Discontinue subject from study treatment if 
PPES does not improve within 6 weeks.  Maintain dosing of nivolumab.
CTCAE, Common Terminology Criteria for Adverse Events; NSAID, non-steroidal anti-inflammatory drug; PPES, palmar 
plantar erythrodysesthesia syndrome.
a Permitted dose levels are defined by individual protocols.
6.10 Other dermatologic disorders
Treatment-emergent skin rash has been associated with nivolumab. The majority of cases of rash 
have been mild in severity and self-limited, with or without pruritus. 
A dermatologist should evaluate persistent and/or severe rash or pruritus. A biopsy should be 
performed unless contraindicated. Low-grade rash and pruritus irAEs have been treated with 
symptomatic therapy (e.g., antihistamines). Topical or parenteral corticosteroids may be required 
for more severe symptoms. 
Table 5: Management of Skin Rash
Grade
Intervention
≤ Grade 1
No change in dose
Grade 2
Continue protocol therapy and monitor.  
Grade 3
Omit dose of nivolumab and cabozantinib until < grade 1.  
Grade 4
Discontinue nivolumab and hold cabozantinib
If the subject is unequivocally deriving clinical benefit, the subject 
may be able to resume cabozantinib at one dose level below prior dose 
once resolves to grade  1.
. Patients with bullous lesions must be evaluated for vasculitis, Steven-Johnson syndrome, 


DF/HCC Protocol #: 19-403
Protocol Version Date: 20-May-2022
35
Grade
Intervention
TEN, and autoimmune bullous disease including oral lesions of bullous 
pemphigus/pemphigoid.  
. Pruritus may occur with or without skin rash and should be treated symptomatically.  
. Note skin rash typically occurs early and may be followed by additional events particularly 
during steroid taper.  
6.11 GI perforation/fistula and non-GI fistula formation
GI perforation/fistula and non-GI fistula formation have been reported with cabozantinib and 
other approved drugs that inhibit VEGF pathways. 
After starting cabozantinib, subjects should be monitored for early signs of GI perforation such 
as abdominal pain, nausea, emesis, constipation, and fever especially if known risk factors for 
developing GI perforation or fistula are present. 
• Discontinue cabozantinib treatment in participants diagnosed with GI or non-GI 
perforation/fistula. Nivolumab can be resumed after perforation/fistula has healed.
6.12 Treatment-emergent hypertension
Guidelines for hypertension management:

For patients who require a delay of greater than 6 weeks for management of hypertension, 
discontinue cabozantinib.

Patients may have up to 3 agents for management of hypertension prior to any dose reduction 
in cabozantinib.

24 to 48 hours should elapse between modifications of anti-hypertensive therapy.

Treating physicians should not add antihypertensive medications that are strong inducers or 
inhibitors of CYP3A4.


DF/HCC Protocol #: 19-403
Protocol Version Date: 20-May-2022
36
Criteria for dose 
modification
Intervention


DF/HCC Protocol #: 19-403
Protocol Version Date: 20-May-2022
37
BP, blood pressure. 
6.13 Thromboembolic Event
Maintain dosing of nivolumab.
For grade 2 or 3 venous thrombosis requiring anticoagulation, delay cabozantinib. If the 
planned duration of full dose anticoagulation is ≤ 2 weeks, then delay cabozantinib until 
> 140 mm Hg 
(systolic) and < 160 
mm Hg OR > 90 
mm Hg (diastolic) 
and < 110 mm Hg 
Maintain dose of cabozantinib and nivolumab; however, please see below 
for recommendations regarding anti-hypertensive therapy.
Recommended Antihypertensive Therapy

Increase existing antihypertensive therapy or initiate a new 
antihypertensive agent if needed after 24-48 hours of treatment; 
increase dose in stepwise fashion every 24-48 hours until BP is 
controlled or at the maximum dose of therapy.

If BP is still not controlled, add another antihypertensive agent; 
increase dose of this drug as described in Step 1.  

If BP is still not controlled, add a 3rd agent; increase dose of this 
drug as described in Step 1.

If BP is still not controlled after maximal medical management, 
proceed with one dose level reduction. 
≥ 160 mm Hg 
(systolic) OR ≥ 110 
mm Hg (diastolic) 
Maintain dosing of nivolumab.
Delay cabozantinib until systolic BP ≤ 159 mmHg and diastolic BP ≤ 99 
mmHg. Once blood pressure is controlled to this level, resume cabozantinib 
with one dose level reduction and consider the recommended 
antihypertensive therapy outlined above. 
For patients who require a delay of greater than 6  weeks for management 
of hypertension, discontinue cabozantinib.
If the patient requires hospitalization for management of symptomatic systolic BP 
>180 or diastolic BP >110, then discontinue cabozantinib and recommend inpatient 
management as clinically indicated with IV medications.Maintain dosing of 
nivolumab.  Delay cabozantinib until systolic BP ≤ 159 mmHg and diastolic 
BP ≤ 99 mmHg.  Once blood pressure is controlled to this level, resume 
cabozantinib with one dose level reduction and consider the recommended 
antihypertensive therapy outlined above. 
NOTE: Discontinuing or reducing the dose of cabozantinib is expected to cause a 
decrease in BP. The treating physician should monitor the patient for hypotension 
and adjust the number and dose of antihypertensive medication(s) accordingly.
Hypertensive crisis 
or
hypertensive 
encephalopathy
Discontinue cabozantinib treatment.
Hold nivolumab until resolution.


DF/HCC Protocol #: 19-403
Protocol Version Date: 20-May-2022
38
anticoagulation is completed. If the planned duration of full dose anticoagulation is > 2 weeks, 
then resume cabozantinib during anticoagulation therapy if all of the following are met:

The patient must be on a stable dose of LMWH prior to restarting cabozantinib. Warfarin or a 
novel oral anticoagulation drug may not be used for anticoagulation.

The patient must not have any pathological condition that carries a high risk of bleeding. 

The patient must not have had any hemorrhagic events while on study. 
For recurrent/worsening venous thromboembolic events after resuming cabozantinib, 
discontinue cabozantinib.
For grade 4 venous thromboembolic events, discontinue cabozantinib. 
For any grade arterial thromboembolic events including cerebrovascular ischemia, cardiac 
ischemia/infarction, peripheral or visceral arterial ischemia, discontinue cabozantinib.
6.14 Hemorrhagic Events
Maintain dosing of nivolumab.
For grade 2 CNS or pulmonary hemorrhage, discontinue cabozantinib.
For any other grade 3 or 4 hemorrhage, discontinue cabozantinib.
6.15 Proteinuria
Proteinuria is an expected AE with the inhibition of VEGF pathways and has been observed 
in cabozantinib clinical studies. Nephrotic syndrome has been reported with cabozantinib and 
other inhibitors of VEGF pathways. 
Management of Proteinuria:


DF/HCC Protocol #: 19-403
Protocol Version Date: 20-May-2022
39
Severity of Proteinuria 
(UPCR)
Management of Proteinuria
≤ 1 mg/mg
(≤ 113.1 mg/mmol)

No change in  protocol treatment or monitoring
> 1 and < 3.5 mg/mg
(> 113.1 and < 395.9 
mg/mmol)

Consider confirming with a 24-h protein assessment within 7 days

Continue nivolumab dosing

No change in cabozantinib treatment required if UPCR ≤ 2 mg/mg or urine 
protein ≤ 2 g/24 h on 24-h urine collection.

Dose reduce or interrupt cabozantinib treatment if UPCR > 2 mg/mg on 
repeat UPCR testing or urine protein > 2 g/24 h on 24-h urine collection. 
Continue cabozantinib on a reduced dose if UPCR decreases to < 2 mg/mg. 
Consider interrupting cabozantinib treatment if UPCR remains > 2 mg/mg 
despite a dose reduction until UPCR decreases to < 2 mg/mg. Restart 
cabozantinib treatment at a reduced dose after a dose interruption.

Repeat UPCR within 7 days and once per week. If UPCR < 1 mg/mg on 2 
consecutive readings, UPCR monitoring can revert to protocol-specific 
times. (Second reading is confirmatory and can be done within 1 week of 
first reading.) If UPCR remains > 1 mg/mg and < 2 mg/mg for 1 month or 
is determined to be stable (< 20% change) for 1 month, check urine 
protein/creatinine per protocol or as clinically indicated.
≥ 3.5 mg/mg
(≥ 395.9 mg/mmol)

Interrupt cabozantinib and nivolumab treatment pending repeat UPCR 
within 7 days and/or 24-h urine protein. 

If ≥ 3.5 mg/mg on repeat UPCR, continue to interrupt cabozantinib and 
nivolumab treatment and check UPCR every 7 days. If UPCR decreases to 
< 2 mg/mg, restart nivolumab and cabozantinib treatment at a reduced dose 
and monitoring of urine protein/creatinine should continue weekly until the 
UPCR decreases to < 1 mg/mg. If UPCR remains > 1 mg/mg and < 2 
mg/mg for 1 month or is determined to be stable (< 20% change) for 1 
month, check urine protein/creatinine per protocol or as clinically indicated.

If treatment is delayed for more than 6 weeks due to proteinuria, 
discontinue cabozantinib and nivolumab treatment.
Nephrotic syndrome

Discontinue cabozantinib and nivolumab treatment.
RCC, renal cell carcinoma; UC, urothelial carcinoma; UPCR, urine protein/creatinine ratio.
6.16 Hypophosphatemia
Hypophosphatemia has been reported during treatment with cabozantinib. 
Mild hypophosphatemia is usually asymptomatic or symptoms can be non-specific such as 
weakness, bone pain, rhabdomyolysis, or altered mental status. Other causes of 
hypophosphatemia such as poor nutrition, chronic alcoholism, malabsorption, excessive antacid 
use, glucocorticoids use, kidney dysfunction, respiratory alkalosis, vitamin D deficiency should 
be ruled out and/or these causes treated according to standard of care. 


DF/HCC Protocol #: 19-403
Protocol Version Date: 20-May-2022
40
Mild to moderate hypophosphatemia should be managed by oral replacement including food that 
are high in phosphate (diary items, meats, beans) and/or oral phosphate supplements according to 
standard clinical practice guidelines. 
6.17 Osteonecrosis of the Jaw
To minimize the risk of osteonecrosis of the jaw, it is recommended that, if possible, cabozantinib 
be stopped at least 4 weeks prior to dental procedures such as tooth extractions, implants, and 
major jaw surgery whenever possible. Cabozantinib does not need to be held for routine dental 
fillings and cleanings. 
6.18 QTcF Prolongation
For QTcF interval > 500 msecs, (confirm with triplicate EKG) continue nivolumab but delay 
cabozantinib, stop any medications that may prolong the QTcF interval (if possible), and consider 
checking calcium, potassium, and magnesium levels and correcting any abnormalities. Once QTcF 
interval ≤ 500 msecs, correction of electrolyte abnormalities has been considered, and symptoms 
have resolved, cabozantinib may be resumed with one dose level reduction.
6.19 Pulmonary Toxicity
Mild-to-moderate events of pneumonitis have been reported with nivolumab. Patients will be 
assessed for pulmonary signs and symptoms throughout the study. Patients will also have CT 
scans of the chest at every tumor assessment.  
Management of pneumonitis is as summarized in the following table:
Grade
Management
≤1
Continue protocol therapy if radiologic findings only; dose may be held for 
further evaluation per investigator discretion 
2
Hold nivolumab pending evaluation. 
Patient should discontinue nivolumab if prolonged steroids are required unless 
an alternative etiology of findings is identified. 
Withhold cabozantinib until resolved to ≤ Grade 1. 
3
Discontinue nivolumab. 
Withhold cabozantinib until resolved to ≤ Grade 1. 
4
Discontinue nivolumab. 
Withhold cabozantinib until resolved to ≤ Grade 1.
Distinguishing inflammatory pneumonitis is often a diagnosis of exclusion for patients who do 
not respond to antibiotics and have no causal organism identified including influenza. Most 
patients with respiratory failure or hypoxia will be treated with steroids. Bronchoscopy may be 
required and analysis of lavage fluid for lymphocytic predominance may be helpful. Patients 
with new lung nodules should be evaluated for sarcoid like granuloma. Please consider 
recommending seasonal influenza inactivated vaccine for all patients. 


DF/HCC Protocol #: 19-403
Protocol Version Date: 20-May-2022
41
6.20 Neurologic Events
The principal treatments for neurologic toxicity are dose delay, corticosteroids, and IV 
immunoglobulin. Patients with any CNS events including aseptic meningitis, encephalitis, 
symptomatic hypophysitis, myopathy, peripheral demyelinating neuropathy, cranial neuropathy 
(other than peripheral n. VII), Guillain-Barre syndrome, and myasthenia gravis should 
discontinue nivolumab. If reversible posterior leukoencephalopathy syndrome (RPLS) is 
diagnosed then discontinue cabozantinib.
Table: Management of Neurologic Events
Grade
Management
≤1
Continue protocol therapy
2
Hold nivolumab.  Hold cabozantinib.
If treatment with steriods is required, permanently discontinue nivolumab. 
If no treatment with steroids is required, and it has resolved to ≤ Grade 1, resume 
nivolumab and caboantinib at same dose. 
Participants are permitted to resume treatment with nivolumab for peripheral isolated 
CN VII (Bell’s palsy) when stable. 
3
Discontinue nivolumab. Hold cabozantinib. 
If the subject was unequivocally deriving clinical benefit, the subject may be able to 
resume cabozantinib at a lower dose as determined by the investigator. 
4
Discontinue nivolumab. Hold cabozantinib. 
If the subject was unequivocally deriving clinical benefit, the subject may be able to 
resume cabozantinib at a lower dose as determined by the investigator. 
6.21 Endocrinopathy including hypophysitis and adrenal insufficiency
Note all patients with symptomatic pituitary enlargement, exclusive of hormone deficiency, but 
including severe headache or enlarged pituitary on MRI or aseptic meningitis or encephalitis 
should be considered grade 3 events. Isolated thyroid or testosterone deficiency may be treated 
as grade 2 if there are no other associated deficiencies and adrenal function is monitored. 
Table: Management of Endocrinopathy including hypophysitis and adrenal insufficiency
Grade
Management
≤2
Asymptomatic abnormalities do not require dose delay*. 
If symptomatic, hold until on a stable replacement hormone regimen. If treated 
with steroids patients, must be stable off of steroids for two weeks with the 
exception of adrenal replacement therapy. 
3
Hypophysitis: 
Hold nivolumab and cabozantinib* until ≤ Grade 1, then resume at same dose. 
Other endocrinopathies: 
Hold nivolumab and cabozantinib* until ≤ Grade 1 and stable on replacement 
hormones, then resume at same dose. 


DF/HCC Protocol #: 19-403
Protocol Version Date: 20-May-2022
42
4
Discontinue nivolumab. 
Discontinue cabozantinib. If the subject was unequivocally deriving clinical 
benefit, the subject may be able to resume cabozantinib at a lower dose as 
determined by the investigator. 
*Patients must be evaluated to rule out pituitary disease prior to initiating thyroid replacement, and steroids 
including baseline serum: cortisol, ACTH, TSH and free T4
6.22 Thyroid Dysfunction

Cabozantinib and nivolumab do not need to be held for asymptomatic participants. 
Management of thyroid dysfunction should follow accepted clinical practice guidelines.

For grade 3 hyper- or hypothyroidism, delay cabozantinib until toxicity improves to grade 
≤ 2, then resume nivolumab and cabozantinib with one dose level reduction.

For grade 4 hyper-or hypothyroidism, discontinue cabozantinib and nivolumab.
6.23 Creatinine Levels/ Renal Insufficiencies
Table: Management of Creatinine Levels/Renal Insufficiencies
Grade
Management
≤1
Continue protocol therapy. Monitor weekly until return to baseline. 
2-3
(>1.5 
baseline to ≤ 
6 3.0 x ULN)
Hold nivolumab and cabozantinib until ≤ Grade 1. Monitor creatinine every 
2-3 days. Start 0.5 to 1.0 mg/Kg/day methylprednisolone IV or oral 
equivalent. Consider consulting nephrology and obtaining a renal biopsy. 
4 ( >6.0 x 
ULN)
Discontinue nivolumab and hold cabozantinib. Monitor creatinine daily. Start 
1.0 – 2.0 mg/Kg/day methylprednisolone IV or oral equivalent. 
Consult nephrologist and consider obtaining a renal biopsy. 
6.24 Infusion Reactions
All Grade 3 or 4 infusion reactions should be reported within 24 hours to the study PI and 
reported as an SAE if criteria are met. Infusion reactions should be graded according to National 
Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE (version 5.0)) 
guidelines. Treatment recommendations are provided below and may be modified based on local 
treatment standards and guidelines as appropriate: 
Table: Management of Infusion Reaction
Grade
Management
≤1
Continue nivolumab infusion, remain at bedside. Continue cabozantinib. 


DF/HCC Protocol #: 19-403
Protocol Version Date: 20-May-2022
43
Institute prophylactic medications with subsequent infusions. 
2
Hold nivolumab until resolution to ≤ Grade 1. Refer to management and 
rechallenging instructions below. 
Continue cabozantinib. 
3
Discontinue nivolumab. Continue cabozantinib. 
4
Discontinue nivolumab. Continue cabozantinib. 
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 [eg, antihistamines, non-steroidal anti-
inflammatory drugs, narcotics, corticosteroids, bronchodilators, IV fluids]; prophylactic 
medications indicated for ≤ 24 hours). 
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. Restart the infusion at 50% of 
the original infusion rate when symptoms resolve to Grade ≤ 1; if no further complications ensue 
after 30 minutes, the rate may be increased to 100% of the original infusion rate. Monitor 
participant 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 participant 
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 administration. If necessary, corticosteroids (recommended dose: up to 25 mg of IV 
hydrocortisone or equivalent) may be used. 
For Grade 3 or Grade 4 symptoms: 
Grade 3: prolonged [ie, not rapidly responsive to symptomatic medication and/or brief 
interruption of infusion]; recurrence of symptoms following initial improvement; hospitalization 
indicated for other clinical sequelae [eg, renal impairment, pulmonary infiltrates). 
Grade 4: life-threatening; pressor or ventilatory support indicated. 


DF/HCC Protocol #: 19-403
Protocol Version Date: 20-May-2022
44
Immediately discontinue infusion of nivolumab. Begin an IV infusion of normal saline, treat 
with 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. Participant should be monitored until the investigator is comfortable that the symptoms 
will not recur. 
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 pruritis 
within 1 week after treatment), symptomatic treatment may be given (e.g., oral antihistamine, or 
corticosteroids) 
6.25 Fever
Patients with fever should be evaluated as clinically appropriate. Patients may experience 
isolated fever during infusion reactions or up to several days after infusion. Evaluation over the 
course of 1-2 weeks should be done for other autoimmune events that may present as fever. 
Table 16: Management of Fever
Grade
Management
≤1
Continue nivolumab and cabozantinib and monitor. 
2
Hold nivolumab and cabozantinib until ≤ Grade 1 
3
Hold nivolumab and cabozantinib until ≤ Grade 1 
4
Hold nivolumab and cabozantinib until ≤ Grade 1 
6.26 Management of other toxicities attributable to cabozantinib
General guidance for management of non-hematologic toxicity not described above and 
considered at least possibly related to cabozantinib only:


DF/HCC Protocol #: 19-403
Protocol Version Date: 20-May-2022
45
CTCAE v.5.0 Grade
Recommended Guidelines for Managementa
Grade 1 AEs
Add supportive care as indicated. Continue cabozantinib 
treatment at the current dose level if AE is manageable and 
tolerable.  Continue nivolumab
Grade 2 AEs which are 
tolerable and are easily 
managed
Grade 2 AEs which are 
intolerable and cannot be 
adequately managed 
Continue cabozantinib treatment at the current dose level with 
supportive care.  Continue nivoliumab.
At the discretion of the investigator, cabozantinib should be dose 
reduced or interrupted.
Note: It is recommended that dose holds be as brief as possible. 
Grade 3 AEs (except 
clinically non-relevant 
laboratory abnormalities)
Cabozantinib should be interrupted unless the toxicity can be 
easily managed with a dose reduction and optimal medical care.   
Continue nivolumab.
Note: It is recommended that dose holds be as brief as possible.
Grade 4 AEs (except 
clinically non-relevant 
laboratory abnormalities)
Subjects should have cabozantinib interrupted immediately. 
Discontinue cabozantinib unless the following criteria are met: 

Subject is deriving clear clinical benefit as determined by 
the investigator

Toxicity can be managed with a dose reduction following 
recovery to Grade 1 (or baseline) and optimal medical care 
Contiue nivolumab.
AE, adverse event.
a Study treatment dose adjustment is only needed if the toxicity was deemed related to 
cabozantinib treatment or had an unclear relationship to cabozantinib treatment.
6.27 Management of other toxicities attributable to nivolumab
General guidance for management of other non-laboratory adverse events not described above 
attributed to nivolumab only:
Grade
Management/Next Dose for Nivolumab 
≤ 1
Continue protocol therapy. 
2
Hold nivolumab until ≤ Grade 1 OR baseline (exceptions as noted below).  Continue 
cabozantinib.
3
Omit dose of nivolumab if not recurrent (exceptions as noted below).  Continue 


DF/HCC Protocol #: 19-403
Protocol Version Date: 20-May-2022
46
Grade
Management/Next Dose for Nivolumab 
cabozantinib.
4
Discontinue nivolumab therapy.  Continue cabozantinib.
Recommended management:  Low-grade events that are considered drug related and any high-
grade events of unclear etiology should be fully evaluated and treated with systemic 
corticosteroids if an alternative etiology is not identified.
7
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The 
following list of reported and/or potential AEs (Section 7.1) and the characteristics of an 
observed AE (Section 7.2) will determine whether the event requires expedited reporting in 
addition to routine reporting.
7.1
Adverse Events Lists
7.1.1
Expected adverse events for cabozantinib
The general adverse event profile of cabozantinib includes GI symptoms (such as nausea, 
vomiting, and diarrhea), fatigue, anorexia, palmar-plantar erythrodysesthesia (PPE) syndrome, 
skin rash, elevated ALT and AST, increased pancreatic enzymes with rare cases of pancreatitis, 
as well as side effects associated with inhibition of VEGF signaling such as thrombotic events 
(eg, pulmonary embolism [PE] and deep vein thrombosis [DVT]), hypertension, proteinuria, 
hemorrhagic events, and rare cases of gastrointestinal [GI] perforation and rectal/perirectal 
abscess. Additionally, events of arterial thromboembolism (transient ischemic attack [TIA], 
myocardial infarction [MI]) have been reported. For a full listing of safety events please refer to 
the Cabozantinib Investigational Brochure. 
7.1.2
Expected adverse event for nivolumab
The PD-L1/PD-1 pathway is involved in peripheral tolerance; therefore, such therapy may 
increase the risk of immune-related AEs, specifically the induction or enhancement of 
autoimmune conditions. AEs with potentially immune-related causes, including rash, 
hypothyroidism, hepatitis/transaminitis, colitis, myositis, and myasthenia gravis, have been 
observed. 
7.2
Adverse Event Characteristics

CTCAE term (AE description) and grade:  The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
5.0 will be utilized for AE reporting.  All appropriate treatment areas should have access 
to a copy of the CTCAE version 5.0.  A copy of the CTCAE version 5.0 can be 
downloaded from the CTEP web site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.


DF/HCC Protocol #: 19-403
Protocol Version Date: 20-May-2022
47

For expedited reporting purposes only:  
-
AEs for the agent(s) that are listed above should be reported only if the adverse event 
varies in nature, intensity or frequency from the expected toxicity information which 
is provided.
-
Other AEs for the protocol that do not require expedited reporting are outlined in the 
next section (Expedited Adverse Event Reporting) under the sub-heading of Protocol-
Specific Expedited Adverse Event Reporting Exclusions.

Attribution of the AE: 
-
Definite – The AE is clearly related to the study treatment.
-
Probable – The AE is likely related to the study treatment.
-
Possible – The AE may be related to the study treatment.
-
Unlikely – The AE is doubtfully related to the study treatment.
-
Unrelated – The AE is clearly NOT related to the study treatment.
7.3
Adverse Event Reporting 
7.3.1
In the event of an unanticipated problem or life-threatening complications treating 
investigators must immediately notify the Overall PI.
7.3.2
Investigators must report to the Overall PI any adverse event (AE) that occurs after 
the initial dose of study treatment, during treatment, or within 30 days of the last dose 
of treatment on the local institutional SAE form. 
7.3.3
DF/HCC Adverse Event Reporting Guidelines
Investigative sites within DF/HCC will report AEs directly to the DFCI Office for 
Human Research Studies (OHRS) per the DFCI IRB reporting policy. 
7.3.4
Reporting to the Food and Drug Administration (FDA)
The Overall PI, as study sponsor, will be responsible for all communications with the 
FDA. The Overall PI will report to the FDA, regardless of the site of occurrence, any 
serious adverse event that meets the FDA’s criteria for expedited reporting following the 
reporting requirements and timelines set by the FDA.
7.3.5
Reporting to Hospital Risk Management
Participating investigators will report to their local Risk Management office any 
participant safety reports, sentinel events or unanticipated problems that require 
reporting per institutional policy. 
7.4
Routine Adverse Event Reporting
All Adverse Events must be reported in routine study data submissions to the Overall PI on the 


DF/HCC Protocol #: 19-403
Protocol Version Date: 20-May-2022
48
toxicity case report forms.  AEs reported through expedited processes (e.g., reported to the 
IRB, FDA, etc.) must also be reported in routine study data submissions.
7.5
Expedited Reporting to BMS
All SAEs that occur following the subject’s written consent to participate in the study through 
100 days of discontinuation of dosing must be reported to BMS Worldwide Safety, whether 
related or not related to study drug. If applicable, SAEs must be collected that relate to any later 
protocol-specified procedure (eg, a follow-up skin biopsy). Although pregnancy, overdose, 
potential drug-induced liver injury (DILI), and cancer are not always serious by regulatory 
definition, these events must be handled as SAEs.
Any component of a study endpoint that is considered related to study therapy should be reported 
as an SAE (eg, death is an endpoint, if death occurred due to anaphylaxis, anaphylaxis must be 
reported).
All SAEs must be reported to BMS within 24 buiness hours of the awareness of the event. SAEs 
must be recorded on a Medwatch Form 3500A. 
SAE Email Address: Worldwide.Safety@BMS.com 
SAE Facsimile Number: 609-818-3804 
If only limited information is initially available, a follow-up report is required and should include 
the same investigator term(s) initially reported. 
If an ongoing SAE changes in its intensity or relationship to study drug or if new information 
becomes available, a follow-up SAE report should be sent within 24 hours of awareness to BMS 
(or designee) using the same procedure used for transmitting the initial SAE report. 
All SAEs should be followed to resolution or stabilization. 
7.6
Expedited Reporting to Exelexis
As soon as an investigator becomes aware of an AE that meets the definition of ‘serious,’ this 
must be documented on an SAE Report Form or in an electronic database and include the 
following: (i) all SAEs that occur after starting cabozantinib and through 30 days after the 
decision to discontinue study treatment and (ii) any SAEs assessed as related to study treatment 
or study procedures, from the time of informed consent, even if the SAE occurs more than 30 
days after the decision to discontinue study treatment. 
All SAEs that are assessed by the PI as related to drug or study procedure and all 
pregnancy/lactation reports regardless of outcome must be sent to Exelixis within one (1) 
business day of the PI’s knowledge of the event. The reports, on a MedWatch 3500A Form, must 
be sent to drugsafety@exelixis.com or fax 650-837-7392. 

The PI will perform adequate due diligence with regard to obtaining follow-up 
information on incomplete reports. All follow-up information must be sent to Exelixis 


DF/HCC Protocol #: 19-403
Protocol Version Date: 20-May-2022
49
within one (1) business day of the PI’s receipt of the new information. Upon Exelixis 
request, the PI will query for follow-up information. 
 
8
PHARMACEUTICAL INFORMATION
A list of the adverse events and potential risks associated with the investigational agents 
administered in this study can be found in Section 7.1.
8.1
Cabozantinib
8.1.1
Description
Cabozantinib is the (S)-malate salt of cabozantinib, a kinase inhibitor. Cabozantinib (S)-malate is 
described chemically as N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-N’-(4- 
fluorophenyl)cyclopropane-1,1-dicarboxamide, (2S)-hydroxybutanedioate. The molecular 
formula is C28H24FN3O5·C4H6O5 and the molecular weight is 635.6 Daltons as malate salt. 
The chemical structure of cabozantinib (S)-malate salt is: 
 
In vitro biochemical and/or cellular assays have shown that cabozantinib inhibits the tyrosine 
kinase activity of MET, VEGFR-1, -2 and -3, AXL, RET, ROS1, TYRO3, MER, KIT, TRKB, 
FLT-3, and TIE-2. These receptor tyrosine kinases are involved in both normal cellular function 
and pathologic processes such as oncogenesis, metastasis, tumor angiogenesis, drug resistance, 
and maintenance of the tumor microenvironment. 
8.1.2
Form
Cabozantinib/XL184 Tablets 
The manufacturer will provide each investigator with adequate supplies of cabozantinib, which 
will be supplied as 20-mg yellow film-coated tablets. The 20-mg tablets are round. The 
components of the tablets are listed in the table below. The sponsor is requiring pharmacy to 
dispense cabozantinib in original containers; if needed, it is permissible for DF/HCC pharmacy 
to remove and destroy the tablets in excess of the dosing requirement per standard practice, while 
still dispensing the drug in the original container.


DF/HCC Protocol #: 19-403
Protocol Version Date: 20-May-2022
50


DF/HCC Protocol #: 19-403
Protocol Version Date: 20-May-2022
51
Table: Cabozantinib Tablet Components and Composition
Ingredient
Function
%w/w
Cabozantinib Drug Substance (25% drug load as 
free base)
Active Ingredient
31.7
Microcrystalline Cellulose (Avicel PH-102)
Filler
38.9
Lactose Anhydrous (60M)
Filler 
19.4
Hydroxypropyl Cellulose (EXF)
Binder
3.0
Croscarmellose Sodium (Ac-Di-Sol)
Disenegrant
6.0
Colloidal Silicon Dioxide
Glidant
0.3
Magnesium Stearate
Lubricant
0.75
Opadry Yellow Film Coating which includes: 
-
HPMC 
2910/Hypromellose 
6cp
-
Titanium dioxide
-
Triacetin
-
Iron Oxide Yellow
Film Coating
4.00
8.1.3
Storage and Stability
Store cabozantinib at 20°C to 25°C (68°F to 77°F); excursions are permitted from 15°C to 30°C 
(59°F to 86°F) [see USP Controlled Room Temperature]. 
8.1.4
Compatibility
Not applicable 
8.1.5
Handling
Qualified personnel, familiar with procedures that minimize undue exposure to 
themselves and the environment, should undertake the preparation, handling, and safe 
disposal of the chemotherapeutic agent in a self-contained and protective environment. 
8.1.6
Availability
Cabozantinib is an investigational agent and will be supplied free-of-charge from Exelixis. 
8.1.7
Preparation
Not applicable
8.1.8
Administration
Cabozantinib is administered once daily as an oral tablet. Participants will be provided with a 


DF/HCC Protocol #: 19-403
Protocol Version Date: 20-May-2022
52
sufficient supply of study treatment and instructions for taking the study treatment on days 
without scheduled clinic visits. After fasting (with exception of water) for 2 hours, participants 
will take study treatment daily each morning with a full glass of water (minimum of 8 oz/ 240 
mL) and continue to fast for 1 hour after each dose of study treatment. If doses are withheld, the 
original schedule of assessments should be maintained when cabozantinib is restarted. The 
participant should be instructed to not make up the missed doses and to maintain the planned 
dosing schedule. Participants must be instructed to not make up missed doses that are vomited. 
8.1.9
Ordering
Cabozantinib will be provided by Exelixis. 
8.1.10 Accountability
The investigator, or a responsible party designated by the investigator, should maintain a careful 
record of the inventory and disposition of the agent using the NCI Drug Accountability Record 
Form (DARF) or another comparable drug accountability form.  (See the NCI Investigator’s 
Handbook for Procedures for Drug Accountability and Storage.)
The investigator or designee will maintain accurate records of receipt of all study treatment 
including dates of receipt. In addition, accurate records will be kept regarding the date, lot 
number, and how much study treatment is dispensed and used by each subject in the study. 
Reasons for deviation from the expected dispensing regimen must also be recorded. At 
completion of the study, to satisfy regulatory requirements regarding drug accountability, all 
unused study treatment will be reconciled and destroyed according to applicable state, federal, 
and local regulations.
8.1.11 Destruction and Return
At the end of the study, unused supplies of cabozantinib and nivolumab should be destroyed 
according to institutional policies. Expired supplies of cabozantinib and nivolumab will be 
destroyed according to DF/HCC instititutional SOP. Destruction will be documented in the Drug 
Accountability Record Form. 
8.2
Nivolumab
8.2.1
Description
Nivolumab is also referred to as BMS-936558-01 or BMS-936558. Nivolumab is a soluble 
protein consisting of 4 polypeptide chains, which include 2 identical heavy chains and 2 identical 
light chains. The physical and chemical properties of nivolumab are provided in the table below. 
The geometric mean of terminal T-HALF was 25.6 days and the typical clearance was 8.8 mL/h, 
which are consistent with those of full human immunoglobulin antibodies. 


DF/HCC Protocol #: 19-403
Protocol Version Date: 20-May-2022
53
Table: Nivolumab Physical and Chemical Properties 
BMS Number
BMS-936558-01
Other Names
Nivolumab, BMS-936558, MDX1106, ONO-4538, Anti-PD-1
Molecular Weight
146,221 daltons (143,619.17 daltons, protein portion)
Appearance
Clear to opalescent, colorless to pale yellow liquid, light (few) 
particulates may be present
Solution pH
5.5 to 6.5
 
8.2.2
Storage and Stability
Vials of Nivolumab injection must be stored at 2°-8°C (36°-46°F) and protected from light, 
freezing and shaking. Shelf-life surveillance of the intact vials is ongoing. 
The administration of undiluted and diluted solutions of Nivolumab must be completed within 24 
hours of preparation. If not used immediately, the infusion solution may be stored up to 24 hours 
in a refrigerator at 2°-8°C (36°-46°F) and a maximum of 8 hours of the total 24 hours can be at 
room temperature (20°-25°C, 68°-77°F) and room light. The maximum 8-hour period under 
room temperature and room light conditions includes the product administration period. 
CAUTION: The single-use dosage form contains no antibacterial preservative or bacteriostatic 
agent. Therefore, it is advised that the product be discarded 8 hours after initial entry. 
8.2.3
Compatibility 
No incompatibilities between Nivolumab injection and polyvinyl chloride (PVC), non- 
PVC/non-DEHP (di(2-ethylhexyl)phthalate) IV components, or glass bottles have been 
observed. 
8.2.4
Handling 
Qualified personnel, familiar with procedures that minimize undue exposure to themselves and 
the environment, should undertake the preparation, handling, and safe disposal of the 
chemotherapeutic agent in a self-contained and protective environment. 
8.2.5
Availability 
Nivolumab is available as 100 mg vials (10 mg/mL) with a 0.7mL overfill. It is supplied in 10 
mL type I flint glass vials, with butyl rubber stoppers and aluminum seals. 
8.2.6
Preparation 
Nivolumab is available as 100 mg vials (10 mg/mL), which include an overfill. It is supplied in 
10 mL type I flint glass vials, with butyl stoppers and aluminum seals. Nivolumab injection can 
be infused undiluted (10 mg/mL) or diluted with 0.9% Sodium Chloride Injection, USP or 5% 


DF/HCC Protocol #: 19-403
Protocol Version Date: 20-May-2022
54
Dextrose, USP to a final concentration ranging from 1 mg/mL to 10 mg/mL. The total volume of 
infusion must not exceed 160 mL. 
8.2.7
Administration
Nivolumab will be delivered in infusion bags with IV infusion lines over 30 minutes (+/- 10 
minutes) using a volumetric pump with 0.2 to 1.2 micron pore size, low-protein binding 
polyethersulfone membrane in-line filter. 
8.2.8
Ordering
Nivolumab will be provided by BMS.
8.2.9
Accountability
The investigator, or a responsible party designated by the investigator, should maintain a careful 
record of the inventory and disposition of the agent using the NCI Drug Accountability Record 
Form (DARF) or another comparable drug accountability form. (See the NCI Investigator’s 
Handbook for Procedures for Drug Accountability and Storage.) 
The investigator or designee will maintain accurate records of receipt of all study treatment 
including dates of receipt. In addition, accurate records will be kept regarding the date, lot 
number, and how much study treatment is dispensed and used by each subject in the study. 
Reasons for deviation from the expected dispensing regimen must also be recorded. At 
completion of the study, to satisfy regulatory requirements regarding drug accountability, all 
unused study treatment will be reconciled and destroyed according to applicable state, federal, 
and local regulations.
8.2.10 Destruction and Return
At the end of the study, unused supplies of nivolumab should be destroyed according to 
institutional policies. Destruction will be documented in the Drug Accountability Record Form. 
9
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES
9.1
Correlative Science Objectives

To explore whether baseline tumor immune cell infiltration and PD-L1 and PD-L2 staining 
correlates with response to therapy.

To explore whether changes in circulating immune cell profile correlates with response to 
therapy

To explore whether changes in the level of angiogenic and inflammatory blood biomarkers 
during therapy correlate with efficacy of therapy


DF/HCC Protocol #: 19-403
Protocol Version Date: 20-May-2022
55
9.2
Hypothesis: 
Based on what has been described in breast cancer with single agent exposure to Cabozantinib, 
we hypothesize the following:
(1) there will be an increase in CD3+ T-lymphocytes, primarily CD8CD4- cytotoxic T 
lymphocytes 
(2) a decrease in monocytes
(3) impairment of neutrophil recruitment
In all patients in the run-in phase (first 18 patients) for whom tumor is safely accessible, a 
baseline and on-treatment tumor biopsy during cycle 2 is required.  Based on concerns for biopsy 
associated complications, a safety evaluation will be performed after 6 patients have undergone 
an on-treatment biopsy. 
For those undergoing a biopsy the following criteria must be met:

Biopsy should be done only in patients in whom the tumor is safely accessible. 

Due to the risk of perforation and fistula with cabozantinib,
o
transesophageal and transintestinal biopsies should not be performed
o
biopsies should not be performed in areas of prior fistula formation, surgery or 
radiation. 

To minimize risks of bleeding, the on-treatment biopsy should be performed with a 
20 gauge (or smaller) needle.
Serial blood draws for correlative science are required on this trial; blood draws will be obtained 
the first day of cycles 1 and 2 prior to the infusion of study drugs, at the end-of-treatment visit in 
patients who go off study for progressive disease, and all efforts will be made to obtain an 
additional blood draw at the time of progressive disease in patients who went off study for 
anything other than progressive disease.
Summary of Specimens
Research Sampling
Timepoint
Contents
Destination
Archival Tissue
Anytime on study
1 FFPE block or 10-
20 5 micron 
unstained slides
DFCI Clinical 
Research (Dr. Perez)
Baseline
5-7 cores
DFCI Clinical 
Research (Dr. Perez) 
/ DFCI Rodig Lab
Fresh Tissue
End of cycle 2
5-7 cores
DFCI Clinical 
Research (Dr. Perez) 
/ DFCI Rodig Lab
Pre-treatment 
1 Stool sample
Stool Sample 
At time of on 
treatment biopsy
1 Stool sample
CIO Immune 
Assessment Lab of 
Mariano


DF/HCC Protocol #: 19-403
Protocol Version Date: 20-May-2022
56
Blood
Baseline, cycle 2 day 
1, cycle 3 day 1, and 
at progression
5 – Green Top 10 ml 
Sodium Heparin 
tubes (REF 366480)
(PBMCs)
CIO Immune 
Assessment Lab of 
Mariano Severgnini
9.3
Archival Tissue
1
block or 10-20 5 micron unstained, charged slides will be collected for future research. 
9.4
Fresh Tissue Biopsy
Objectives: 

Characterizing immune markers in metastatic well differentiated carcinoid tumors.

Compare MET and phospho-MET expression in tumor tissue at baseline and after tumor 
exposure to the combination of MET and PD-1 inhibition.
Collection and Storage of Fresh Tissue
Tissue biopsy samples will be processed with 4-6 cores put in FFPE as per usual institutional 
practice and a separate core to be put in FFPE to be set to BWH Pathology. 
Details on processing and shipping of samples are provided in Appendix C.
Potential Testing:
Assay 1: Immune population characterization by Multiplex Immunofluorescence (mIF)
Objective: identify subsets of different immune populations (effector/memory CD8 cells, 
T regulatory cells, dendritic cells, tumor associated macrophages, and Tie-2 expressing 
monocytes) and changes in these populations in response to cabozantinib and nivolumab 
at baseline versus 4-6 weeks post initiation of treatment.
Methods: The CIO Tissue Biomarker Laboratory (TBL) led by Dr. Scott Rodig and Ana 
Lako offers multiplex immunofluorescence biomarker imaging for multi-label analysis of 
formalin- FFPE tissue biopsy samples. We use the PerkinElmer’s multiplex biomarker 
imaging systems to precisely measure and quantify multiple fluorescent molecular 
markers simultaneously, even when co-localized within a single tissue section. The data 
for each marker is spectrally unmixed, generating clear and accurate images for each of 
the individual labels in a multi-labeled tissue section with no crosstalk. Specifically, we 
will use the Opal chemistry and multispectral microscopy Vectra™ 3.0 and Polaris™ 
systems (Perkin-Elmer), which includes the Nuance software; analysis will be performed 
using the inForm software. T-cell and other immune cell subpopulations are defined by 
co-expression of specific markers and are evaluated as cell density per tumor tissue 
(number of positive cells by mm square of tumor area. The staining procedure is 


DF/HCC Protocol #: 19-403
Protocol Version Date: 20-May-2022
57
performed by specialized technicians under pathologist supervision, and the scanning and 
analysis is done by senior scientists and a pathologist trained in the use of Vectra and 
InForm.
The following antibodies will be assessed by mIF to identify the presence of the immune 
subsets: 
T Cell Panel: CD4, CD8, FoxP3
Tumor Characteristics Panel: Chromogranin, PD-L1, PD-L2, TIM-3, and LAG-3
Monocyte Panel: CD68, CD 163, Indoleamine 2,3 deosygenase -1 (IDO-1), 
CD11c, CD14, CD16, CD56
Assay 2: CyTOF
Objective: analyze the characteristics of the TILs present in carcinoid tumors
Methods: The CIO Immune Assessment Lab led by Mariano Severgnini and Dr. Emily 
McWilliams offers CyTOF; a single-cell proteomic technology that allows for the 
analysis of 30+ cellular parameters using antibodies tagged with heavy metal isotopes to 
elucidate complex phenotypic and functional characteristics of heterogeneous immune 
populations as well as their activation status and checkpoint marker expression. The 
technology is closely related to flow cytometry, but the readout is based on mass 
spectrometry rather than fluorescence. CyTOF technology currently allows us to analyze 
over 35 parameters in parallel while being significantly less affected by spillover between 
channels, natural background, and cell-based autofluorescence. Each CyTOF panel 
includes 12 immunological core markers: CD3, CD4, CD8, CD11C, CD14, CD16, CD19, 
CD25, CD45, CD56, CD127, and HLA-DR that will identify CD8, CD4 T cells, 
regulatory T cells, B cells, NK cells, and myeloid cell subsets including dendritic cells, 
basophils, and neutrophils. Panels can then be customized on a per trial basis to over 30+ 
parameters including identification of checkpoint molecules (PD-1, PD-L1, etc), and 
markers for memory, activation, trafficking, and cytotoxicity. The samples will be run on 
a CyTOF2 mass cytometer (Fluidigm) housed at DFCI and analyzed by DFCI scientists 
using tools such as Cytobank and Astrolabe.
TILs isolated from the biopsy specimen will be assessed and the following antibodies 
will be used, with the potential to alter based on novel developments in the field of cancer 
immune profiling:
Panels to include: CD8, PD-1, PD-L1, PD-L2, CD4, CD25, CD127
Assay 3: c-Met expression
Objective: Evaluate c-Met and phosphor-c-Met expression in the tumor tissue at   
baseline vs. 4-6 wks post treatment.
Methods: tumor tissue sections will be de-parrafinized prior to antigen retrieval, blocking 
and incubation with primary antibodies to determine: (1) Qualification of c-Met 
expression; (2) association between expression and response to therapy


DF/HCC Protocol #: 19-403
Protocol Version Date: 20-May-2022
58
9.5
Blood Collection
Research blood collection is mandatory for all patients for flow cytometry and potential DNA 
isolation. The samples will be banked in the DFCI CIO Immune Assessment Labfor these and 
future research purposes. These specimens will become the property of the DF/HCC. 
Potential Testing: 
Assay 1: CyTOF
Objective: analyze the characteristics of the PBMCs present in patients with active carcinoid 
tumors.
Methods: Surface staining with a panel of antibotides on PBMCs will be performed utilizing a 
previously developed panel that includes the following: 
Assay 2: Evaluate potential plasma biomarkers of cabozantinib
Objective: conduct an exploratory analysis of potential biomarkers of cabozantinib activity.
Methods: The CIO IAL offers FLEXMAP 3D: Luminex’s most advanced and versatile 
multiplexing platform. Capable of multiplexing up to 500 analytes (cytokines, chemokines, 
growth factors, etc) in a single sample. Analytes of interest will include a panel of circulating 
angiogenic and inflammatory molecules previously identified as potential biomarkers of 
response to therapy. 
Biomarkers specific to anti-VEGF therapy: VEGF, placental-derived growth 
factor (PIGF), VEGF-C, VEGF-D, sVEGFR1, basic granulocyte-macrophage 
colony stimulating factor (GM-CSF), interferon gamma (IFN-gamma), tumor 
necrosis factor alpha (TNF-alpha), and interleukin (IL)-1B, IL-2, IL-6, IL-8, IL-
10, and IL-12 heterodimer p70, and stromal-derived factor 1 alpha. 
Biomarkers specific to cabozantinib activity: HGF, s-MET, s-c-KIT and 
sVEGFR2
 
9.6
Stool Collection
Research stool collection is mandatory for all patients. The samples will be banked in the DFCI 
CIO Immune Assessment Labfor these and future research purposes. These specimens will 
become the property of the DF/HCC.
Each participant will provide two stool samples, one obtained during screening and the other 
between the time of the on treatment biopsy and the next planned treatment visit. Participants 
should be instructed to collect the stool samples once eligibility has been confirmed. This will be 
proceeded and analyzed by the DFCI Center for Immuno-Oncology, Immune Assessment 
Laboratory, under the direction of Mariano Severgnini, PhD. The purpose of which is to evaluate 


DF/HCC Protocol #: 19-403
Protocol Version Date: 20-May-2022
59
participant’s microbiome as a possible predictive marker for immunotherapy treatment.
9.7
Statistical Considerations
All tissue and circulating biomarkers will be correlated with clinical outcome in collaboration 
with our statistician. Descriptive statistics will be provided for all outcome measurements, as 
appropriate. 
9.8
Additional analysis 
The plans for tissue and blood analyses will be altered based on novel developments in the field 
of cancer immune profiling at the time of correlative science. Additional markers or alternative 
technologies (based on scientific developments and/or novel technologies) may also be used, to 
explore potential prognostic or predictive candidate markers/panels or markers related to 
treatment benefit and/or safety, to improve diagnostic tests, or to understand carcinoid biology. 
10
STUDY CALENDAR
Baseline evaluations are to be conducted within 2 weeks prior to start of protocol therapy.  Scans 
and x-rays must be done <4 weeks prior to the start of therapy.  In the event that the participant’s 
condition is deteriorating, laboratory evaluations should be repeated within 48 hours prior to 
initiation of the next cycle of therapy.
Assessments must be performed prior to administration of any study agent. Study assessments 
and agents should be administered within + 3 days of the protocol-specified date, unless 
otherwise noted.


DF/HCC Protocol #: 19-403
Protocol Version Date: 20-May-2022
60
Screening
Cycle 1
Cycle 2
Cycle 3+
End of Treatment 
(Within 30 Days 
of Last Dose)
Safety Follow Up 
(100 Days After 
Last Dose)c
Day 1
Day 
15
Day 
1
Day 
15
Day 
16-
28j
Day 
1
Day 
15
CabozantinibA
X
X
X
X
X
X
NivolumabB
X
X
X
X
X
X
Informed consent
X
Medical history
X
Concurrent 
Medicationsl
X
Physical examd
X
X
X
X
X
X
X
X
X
Vital signse
X
X
X
X
X
X
X
X
X
Performance status
X
X
X
X
X
X
CBC w/diff, pltsf
X
X
X
X
X
X
X
X
X
Serum chemistrya
X
X
X
X
X
X
X
X
X
Urine protein creatinine 
ratio
X
X
X
X
TSH/fT4g
X
X
X
X
Pregnancy Testb
X
Xb
Xb
Xb
Coagulation Panel 
(PT/PTT)
X
LDH
X
EKG 
X
X
X
X
Research Biopsyj
X
X
Research Bloodk
X
X
X
X
Research Stool
Xm
Xn
Adverse event 
evaluation
X-----------------------------------------------------X
X
Tumor measurementsh
X
Tumor measurements are repeated every 8 (+/- 1) weeks for the first 24 
weeks, then every 12 (+/- 1) weeks thereafter as indicated below. 
Documentation (radiologic) must be provided for participants removed 
from study for progressive disease.
X
A: Cabozantinib: 40mg PO days 1-28 of a 28 day cycle 
B: Nivolumab: 240 mg IV on days 1, 15 of a 28 day cycle. 
a.
Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, LDH, 
phosphorus, potassium, total protein, SGOT [AST], SGPT [ALT], sodium.
b.
In female subjects of child-bearing potential as defined in the eligibility criteria, pregnancy test must be 
performed within 24 hours prior to the initial administration of study drug, then every 4 weeks ± 1 week. 
c.
Off-study evaluation. 
-
follow up visits or other contact required in order to identify SAEs during the 100 days following the end of 
study treatment. 
-
Male and Female subjects must be educated on contraception post treatment: women of childbearing potential 
(WOCBP) receiving nivolumab will be instructed to adhere to contraception for a period of 5 months after the 
last dose of nivolumab. Men receiving nivolumab and who are sexually active with WOCBP will be instructed to 
adhere to contraception for a period of 7 months after the last dose of nivolumab.  Contraception must be used 
for 4 months after last dose of cabozantinib.
d.
A complete physical examination will be performed at baseline. A limited physical exam will be completed prior 
to therapy on Days 1 and 15 for Cycles 1 and 2 and on Day 1 of every cycle beginning with cycle 3.
e.
Vital sign assessments include measurements of heart rate, systolic and diastolic blood pressures, respiratory 
rate, temperature and weight.  
f.
Hematology includes: hemoglobin, hematocrit, platelet count, RBC count, WBC count, and percent and absolute 


DF/HCC Protocol #: 19-403
Protocol Version Date: 20-May-2022
61
differential count. Results must be available prior to the administration of study drug. ANC must be ≥1500 for 
eligibility and Cycle 1 Day 1. Subsequent ANC must be ≥1000.
g.
TSH and free T4 will be performed during screening, on Day 1 of Cycles 1-4 and then every other cycle on Day 
1.   
h.
Tumor assessments should consist of 1) CT chest/abdomen/pelvis and/or MRI of the abdomen/pelvis, and 2) any 
other imaging studies (CT neck, plain films, etc.) as clinically  indicated by the treating physician. The same 
radiographic procedures and technique must be used throughout the study for each patient (e.g., if the patient had 
CT chest/abdomen/pelvis performed during screening, then she should subsequently undergo CT performed 
using the same radiologic protocol throughout the remainder of the study). Tumor assessments will be performed 
every 8 weeks (+/- 1 week) calculated from C1D1 for the first 24 weeks, then every 12 weeks (+/- 1 week) 
thereafter.  Additional scans are permitted as clinically indicated. All known sites of disease documented at 
screening should be re-assessed at each subsequent tumor evaluation. Tumor assessments will occur as outlined 
regardless of dose holds or treatment delays. 
i.
End of treatment visit is to occur within 30 days of final administration of study treatment. End of treatment 
assessments do not have to be repeated if the same  assessments were performed within 7 days (28 days for 
tumor assesments) prior to the visit. 
j.
For the first 18 patients during the run-in phase: The first biopsy of a metastatic site should occur during the 2 
weeks before initiating treatment on cycle #1. Please see section 9.2. Preferably, the same metastatic lesion will 
be biopsied twice.
k.
Five 10mL whole blood sample for research will be collected at baseline, C2D1, C3D1, and progression The 
sample will be collected at the end of treatment visit for all patients who discontinue due to progressive disease, 
and all efforts will be made to obtain an additional blood draw at the time of progressive disease in patients who 
went off study for anything other than progressive disease. 
l.
If new medications or changes are prescribed while patient is receiving treatment on study, these medications 
should be recorded.
m.
Stool sample will be collected during screening, prior to C1D1. Sample should be received within 1 day of 
collection.
n.
Stool sample will be collected between the time of the on treatment biopsy and the next planned treatment visit. 
Sample should be received within 1 day of collection.
11
MEASUREMENT OF EFFECT
11.1 Antitumor Effect – Solid Tumors
For the purposes of this study, participants should be re-evaluated for response every 8 weeks 
(+/- 1 week) for the first 24 weeks, then every 12 weeks (+/- 1 week) thereafter.  In addition to a 
baseline scan, confirmatory scans should also be obtained 8 (not less than 4) weeks following 
initial documentation of objective response.
Response and progression will be evaluated in this study using the new international criteria 
proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1) 
[Eur J Ca 45:228-247, 2009].  Changes in the largest diameter (unidimensional measurement) of 
the tumor lesions and the shortest diameter in the case of malignant lymph nodes are used in the 
RECIST criteria.
11.1.1 Definitions
Evaluable for Target Disease response.  Only those participants who have measurable 
disease present at baseline, have received at least one cycle of therapy, and have had their 
disease re-evaluated will be considered evaluable for target disease response.  These 
participants will have their response classified according to the definitions stated below.  
(Note:  Participants who exhibit objective disease progression prior to the end of cycle 1 
will also be considered evaluable.)
Evaluable Non-Target Disease Response.  Participants who have lesions present at 


DF/HCC Protocol #: 19-403
Protocol Version Date: 20-May-2022
62
baseline that are evaluable but do not meet the definitions of measurable disease, have 
received at least one cycle of therapy, and have had their disease re-evaluated will be 
considered evaluable for non-target disease.  The response assessment is based on the 
presence, absence, or unequivocal progression of the lesions. 
11.1.2 Disease Parameters
Measurable disease.  Measurable lesions are defined as those that can be accurately 
measured in at least one dimension (longest diameter  to be recorded) as ≥ 20 mm by 
chest x-ray or ≥10 mm with CT scan, MRI, or calipers by clinical exam.  All tumor 
measurements must be recorded in millimeters (or decimal fractions of centimeters).
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.
Non-measurable disease.  All other lesions (or sites of disease), including small lesions 
(longest diameter <10 mm or pathological lymph nodes with ≥10 to <15 mm short axis), 
are considered non-measurable disease.  Bone lesions, leptomeningeal disease, ascites, 
pleural/pericardial effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, 
abdominal masses (not followed by CT or MRI), and cystic lesions are all considered 
non-measurable.
Note: Cystic lesions that meet the criteria for radiographically defined simple cysts 
should not be considered as malignant lesions (neither measurable nor non-measurable) 
since they are, by definition, simple cysts.
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if non-
cystic lesions are present in the same participant, these are preferred for selection as 
target lesions.
Target lesions.  All measurable lesions up to a maximum of 2 lesions per organ and 5 
lesions in total, representative of all involved organs, should be identified as target 
lesions and recorded and measured at baseline.  Target lesions should be selected on the 
basis of their size (lesions with the longest diameter), be representative of all involved 
organs, but in addition should be those that lend themselves to reproducible repeated 
measurements. It may be the case that, on occasion, the largest lesion does not lend itself 
to reproducible measurement in which circumstance the next largest lesion which can be 
measured reproducibly should be selected. A sum of the diameters (longest for non-nodal 
lesions, short axis for nodal lesions) for all target lesions will be calculated and reported 
as the baseline sum diameters. If lymph nodes are to be included in the sum, then only the 
short axis is added into the sum. The baseline sum diameters will be used as reference to 
further characterize any objective tumor regression in the measurable dimension of the 
disease. 


DF/HCC Protocol #: 19-403
Protocol Version Date: 20-May-2022
63
Non-target lesions.  All other lesions (or sites of disease) including any measurable 
lesions over and above the 5 target lesions should be identified as non-target lesions and 
should also be recorded at baseline. Measurements of these lesions are not required, but 
the presence, absence, or in rare cases unequivocal progression of each should be noted 
throughout follow up. 
11.1.3 Methods for Evaluation of Disease
All measurements should be taken and recorded in metric notation using a ruler, calipers, 
or a digital measurement tool.  All baseline evaluations should be performed as closely as 
possible to the beginning of treatment and never more than 4 weeks before the beginning 
of the treatment.
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 is preferred to evaluation by 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 (e.g., skin nodules and palpable lymph nodes) and ≥10 mm in diameter as 
assessed using calipers (e.g., skin nodules).  In the case of skin lesions, documentation by 
color photography, including a ruler to estimate the size of the lesion, is recommended. 
Chest x-ray.  Lesions on chest x-ray are acceptable as measurable lesions when they are 
clearly defined and surrounded by aerated lung; however, CT is preferable. 
Conventional CT and MRI. This guideline has defined measurability of lesions on CT 
scan based on the assumption that CT thickness is 5mm or less. If CT scans have slice 
thickness greater than 5 mm, the minimum size of a measurable lesion should be twice 
the slice thickness. MRI is also acceptable in certain situations (e.g. for body scans).  
Use of MRI remains a complex issue.  MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which 
greatly impact image quality, lesion conspicuity, and measurement.  Furthermore, the 
availability of MRI is variable globally.  As with CT, if an MRI is performed, the 
technical specifications of the scanning sequences used should be optimized for the 
evaluation of the type and site of disease.  Furthermore, as with CT, the modality used at 
follow-up should be the same as was used at baseline and the lesions should be 
measured/assessed on the same pulse sequence.  It is beyond the scope of the RECIST 
guidelines to prescribe specific MRI pulse sequence parameters for all scanners, body 
parts, and diseases.  Ideally, the same type of scanner should be used and the image 
acquisition protocol should be followed as closely as possible to prior scans.  Body scans 
should be performed with breath-hold scanning techniques, if possible.
FDG-PET. While FDG-PET response assessments need additional study, it is sometimes 


DF/HCC Protocol #: 19-403
Protocol Version Date: 20-May-2022
64
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in 
assessment of progression (particularly possible 'new' disease).  New lesions on the basis 
of FDG-PET imaging can be identified according to the following algorithm: 
(a) Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of 
PD based on a new lesion.
(b)  No FDG-PET at baseline and a positive FDG-PET at follow-up:  If the positive 
FDG-PET at follow-up corresponds to a new site of disease confirmed by CT, this is 
PD.  If the positive FDG-PET at follow-up is not confirmed as a new site of disease 
on CT, additional follow-up CT  scans are needed to determine if there is truly 
progression occurring at that site (if so, the date of PD will be the date of the initial 
abnormal FDG-PET scan).  If the positive FDG-PET at follow-up corresponds to a 
pre-existing site of disease on CT that is not progressing on the basis of the anatomic 
images, this is not PD.
(c)  FDG-PET may be used to upgrade a response to a CR in a manner similar to a 
biopsy in cases where a residual radiographic abnormality is thought to represent 
fibrosis or scarring.  The use of FDG-PET in this circumstance should be 
prospectively described in the protocol and supported by disease-specific medical 
literature for the indication.  However, it must be acknowledged that both approaches 
may lead to false positive CR due to limitations of FDG-PET and biopsy 
resolution/sensitivity.
Note:  A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake 
greater than twice that of the surrounding tissue on the attenuation corrected image.
PET-CT. At present, the low dose or attenuation correction CT portion of a combined 
PET-CT is not always of optimal diagnostic CT quality for use with RECIST 
measurements.  However, if the site can document that the CT performed as part of a 
PET-CT is of identical diagnostic quality to a diagnostic CT (with IV and oral contrast), 
then the CT portion of the PET-CT can be used for RECIST measurements and can be 
used interchangeably with conventional CT in accurately measuring cancer lesions over 
time.  Note, however, that the PET portion of the CT introduces additional data which 
may bias an investigator if it is not routinely or serially performed.  
Ultrasound. Ultrasound is not useful in assessment of lesion size and should not be used 
as a method of measurement. Ultrasound examinations cannot be reproduced in their 
entirety for independent review at a later data and, because they are operator dependent, it 
cannot be guaranteed that the same technique and measurements will be taken from one 
assessment to the next. If new lesions are identified by ultrasound in the course of the 
study, confirmation by CT or MRI is advised. If there is concern about radiation exposure 
from CT, MRI may be used instead of CT in selected instances. 
Endoscopy, Laparoscopy. The utilization of these techniques for objective tumor 
evaluation is not advised. However, such techniques may be useful to confirm complete 
pathological response when biopsies are obtained or to determine relapse in trials where 
recurrence following complete response (CR) or surgical resection is an endpoint.


DF/HCC Protocol #: 19-403
Protocol Version Date: 20-May-2022
65
Tumor markers. Tumor markers alone cannot be used to assess response. If markers are 
initially above the upper normal limit, they must normalize for a participant to be 
considered in complete clinical response.  Specific guidelines for both CA-125 response 
(in recurrent ovarian cancer) and PSA response (in recurrent prostate cancer) have been 
published [JNCI 96:487-488, 2004; J Clin Oncol 17, 3461-3467, 1999; J Clin Oncol 
26:1148-1159, 2008].  In addition, the Gynecologic Cancer Intergroup has developed 
CA-125 progression criteria which are to be integrated with objective tumor assessment 
for use in first-line trials in ovarian cancer [JNCI 92:1534-1535, 2000].
Cytology, Histology. These techniques can be used to differentiate between partial 
responses (PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor 
types, such as germ cell tumors, where known residual benign tumors can remain).
The cytological confirmation of the neoplastic origin of any effusion that appears or 
worsens during treatment when the measurable tumor has met criteria for response or 
stable disease is mandatory to differentiate between response or stable disease (an 
effusion may be a side effect of the treatment) and progressive disease.
11.1.4 Response Criteria
11.1.4.1 Evaluation of Target Lesions
Complete Response (CR):  Disappearance of all target lesions.  Any pathological 
lymph nodes (whether target or non-target) must have reduction in short axis to <10 
mm.
Partial Response (PR):  At least a 30% decrease in the sum of the diameters of target 
lesions, taking as reference the baseline sum diameters.
Progressive Disease (PD):  At least a 20% increase in the sum of the diameters of 
target lesions, taking as reference the smallest sum on study (this includes the 
baseline sum if that is the smallest on study).  In addition to the relative increase of 
20%, the sum must also demonstrate an absolute increase of at least 5 mm.  (Note:  
the appearance of one or more new lesions is also considered progressions).
Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum diameters while on 
study.
11.1.4.2 Evaluation of Non-Target Lesions
Complete Response (CR):  Disappearance of all non-target lesions and normalization 
of tumor marker level.  All lymph nodes must be non-pathological in size (<10 mm 
short axis).
Note:  If tumor markers are initially above the upper normal limit, they must 


DF/HCC Protocol #: 19-403
Protocol Version Date: 20-May-2022
66
normalize for a patient to be considered in complete clinical response.
Non-CR/Non-PD:  Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal limits.
Progressive Disease (PD):  Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target lesions.  Unequivocal progression 
should not normally trump target lesion status.  It must be representative of overall 
disease status change, not a single lesion increase.    
Although a clear progression of “non-target” lesions only is exceptional, the opinion 
of the treating physician should prevail in such circumstances, and the progression 
status should be confirmed at a later time by the review panel (or Principal 
Investigator).
11.1.4.3 Evaluation of New Lesions
The finding of a new lesion should be unequivocal (i.e. not due to difference in 
scanning technique, imaging modality, or findings thought to represent something 
other than tumor (for example, some ‘new’ bone lesions may be simply healing or 
flare of pre-existing lesions). However, a lesion identified on a follow-up scan in an 
anatomical location that was not scanned at baseline is considered new and will 
indicate PD. If a new lesion is equivocal (because of small size etc.), follow-up 
evaluation will clarify if it truly represents new disease and if PD is confirmed, 
progression should be declared using the date of the initial scan on which the lesion 
was discovered.
11.1.4.4 Evaluation of Best Overall Response
The best overall response is the best response recorded from the start of the treatment 
until disease progression/recurrence (taking as reference for progressive disease the 
smallest measurements recorded since the treatment started).  The patient's best 
response assignment will depend on the achievement of both measurement and 
confirmation criteria.
For Participants with Measurable Disease (i.e., Target Disease)
Target 
Lesions
Non-Target 
Lesions
New 
Lesions
Overall 
Response
Best Overall Response when 
Confirmation is Required*
CR
CR
No
CR
>4 wks Confirmation**
CR
Non-CR/Non-
PD
No
PR
CR
Not evaluated
No
PR
PR
Non-CR/Non-
PD/not 
evaluated
No
PR
>4 wks Confirmation**


DF/HCC Protocol #: 19-403
Protocol Version Date: 20-May-2022
67
SD
Non-CR/Non-
PD/not 
evaluated
No
SD
Documented at least once >4 
wks from baseline**
PD
Any
Yes or No
PD
Any
PD***
Yes or No
PD
Any
Any
Yes
PD
no prior SD, PR or CR

See RECIST 1.1 manuscript for further details on what is evidence of a new lesion.
**        Only for non-randomized trials with response as primary endpoint.
***      In exceptional circumstances, unequivocal progression in non-target lesions may be
            accepted as disease progression.
Note:  Participants with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be 
reported as “symptomatic deterioration.”  Every effort should be made to document the 
objective progression even after discontinuation of treatment.
For Participants with Non-Measurable Disease (i.e., Non-Target Disease)
Non-Target Lesions
New Lesions
Overall Response
CR
No
CR
Non-CR/non-PD
No
Non-CR/non-PD*
Not all evaluated
No
not evaluated
Unequivocal PD
Yes or No
PD
Any
Yes
PD

‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is 
increasingly used as an endpoint for assessment of efficacy in some trials so to assign 
this category when no lesions can be measured is not advised
11.1.5 Duration of Response
Duration of overall response:  The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first 
date that recurrent or progressive disease is objectively documented (taking as reference 
for progressive disease the smallest measurements recorded since the treatment started, or 
death due to any cause. Participants without events reported are censored at the last 
disease evaluation).
Duration of overall complete response: The duration of overall CR is measured from the 
time measurement criteria are first met for CR until the first date that progressive disease 
is objectively documented, or death due to any cause. Participants without events 
reported are censored at the last disease evaluation.
Duration of stable disease:  Stable disease is measured from the start of the treatment 
until the criteria for progression are met, taking as reference the smallest measurements 
recorded since the treatment started, including the baseline measurements. 


DF/HCC Protocol #: 19-403
Protocol Version Date: 20-May-2022
68
11.1.6 Survival and Time to Progression Definitions
Overall Survival: Overall Survival (OS) is defined as the time from randomization (or 
registration) to death due to any cause, or censored at date last known alive.
Progression-Free Survival: Progression-Free Survival (PFS) is defined as the time from 
randomization (or registration) to the earlier of progression or death due to any cause. 
Participants alive without disease progression are censored at date of last disease 
evaluation.
Time to Progression: Time to Progression (TTP) is defined as the time from 
randomization (or registration) to progression, or censored at date of last disease 
evaluation for those without progression reported.
11.2 Other Response Parameters
11.2.1 Definition of Tumor Response Using Immune-Related Response Criteria (irRC) 
The sum of the longest diameter of lesions (SPD) at tumor assessment using the immune- related 
response criteria (irRC) for progressive disease incorporate the contribution of new measurable 
lesions. Each net Percentage Change in Tumor Burden per assessment using irRC criteria 
accounts for the size and growth kinetics of both old and new lesions as they appear. 
11.2.2 Impact of New Lesions on irRC 
New lesions in and of themselves do not qualify as progressive disease. However, their 
contribution to total tumor burden is included in the SPD which in turn feeds into the irRC 
criteria for tumor response. Therefore, new non-measurable lesions will not discontinue any 
subject from the study. 
11.2.3 Definition of Target Lesions Response Using irRC 
. irComplete Response (irCR): Complete disappearance of all target lesions. This category 
encompasses exactly the same subjects as “CR” by the mWHO criteria.  
. irPartial Response (irPR): Decrease, relative to baseline, or 50% or greater in the sum of the 
products of the two largest perpendicular diameters of all target and all new measurable 
target lesions (i.e., Percentage Change in Tumor Burden). Note: the appearance of new 
measurable lesions is factored into the overall tumor burden, but does not automatically 
qualify as progressive disease until the SBD increases by >25% when compared to SPD 
at nadir.  
. irStable Disease (irSD): Does not meet criteria for irRC or irPR, in the absence of progressive 
disease. 
. irProgressive Disease (irPD): At least 25% increase Percentage Change in Tumor Burden 
(i.e. taking SPD of all target lesions and any new lesions) when compared to SPD at nadir. 


DF/HCC Protocol #: 19-403
Protocol Version Date: 20-May-2022
69
11.2.4 Definition of Non-Target Lesions Response Using irRC 
. irComplete Response (irCR): Complete disappearance of all non-target lesions. This 
category encompasses exactly the same subjects as “CR” by the mWHO criteria.  
. irPartial Response (irPR) or irStable Disease (irSD): Non-target lesion(s) are not 
considered in the definition of PR; these terms do not apply.  
. irProgressive Disease (irPD): Increases in number or size of non-target lesion(s) does not 
constitute progressive disease unless/until the Percentage Change in Tumor Burden 
increases by 25% (i.e. the SPD at nadir of the target lesions increases by the required 
amount).  
11.2.5 Definition of Overall Response Using irRC Overall response using irRC will be based on 
these criteria:  
. Immune-Related Complete Response (irCR): Complete disappearance of all tumor lesions 
(target and non-target) together with no new measurable/unmeasurable lesions for at least 
4 weeks from the date of documentation of complete response.  
. Immune-Related Partial Response (irPR): The sum of the products of the two largest 
perpendicular diameters of all target lesions is measured and captured as the SPD 
baseline. At each subsequent tumor assessment, the SPD of the two largest perpendicular 
diameters of all target lesions and of new measurable lesions are added together to 
provide the Immune Response Sum of Product Diameters (irSPD). A decrease, relative to 
baseline, of the irSPD compared to the previously SPD baseline of 50% or greater is 
considered an irPR.  
. Immune-Related Stable Disease (irSD): irSD is defined as the failure to meet criteria for 
immune complete response or immune partial response, in the absence of progressive 
disease  
. Immune-Related Progressive Disease (irPD): It is recommended in difficult cases to 
confirm PD by serial imaging. Any of the following will constitute PD: 

At least 25% increase in the SPD of all target lesions over baseline SPD 
calculated for  the target lesions.

At least 25% increase in the SPD of all target lesions and new measurable 
lesions  (irSPD) over the baseline SPD calculated for the target lesions. 
Criteria for determining overall response by irRC are summarized as follows:  


DF/HCC Protocol #: 19-403
Protocol Version Date: 20-May-2022
70
 
11.2.6 Immune-Related Best Overall Response Using irRC (irBOR) 
irBOR is the best confirmed overall response over the study as a whole, recorded 
between the date of first dose until the last tumor assessment before subsequent therapy 
(except for local palliative radiotherapy for painful bone lesions) for the individual 
subject in the study. For the assessment of irBOR, all available assessments per subject 
are considered. 
irCR or irPR determinations included in the irBOR assessment must be confirmed by a 
second (confirmatory) evaluation meeting the criteria for response and performed no less 
than 4 weeks after the criteria for response are first met. 
12
DATA REPORTING / REGULATORY REQUIREMENTS
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7.0 
(Adverse Events: List and Reporting Requirements).
12.1 Data Reporting
12.1.1 Method
The Office of Data Quality (ODQ) will collect, manage, and perform quality checks on 
the data for this study.
12.1.2 Responsibility for Data Submission


DF/HCC Protocol #: 19-403
Protocol Version Date: 20-May-2022
71
Investigative sites within DF/HCC or DF/PCC are responsible for submitting data and/or 
data forms to the Office of Data Quality (ODQ) in accordance with DF/HCC policies.
12.2 Data Safety Monitoring
The DF/HCC Data and Safety Monitoring Committee (DSMC) will review and monitor toxicity 
and accrual data from this study. The committee is composed of medical oncologists, research 
nurses, pharmacists and biostatisticians with direct experience in cancer clinical research.  
Information that raises any questions about participant safety will be addressed with the Overall 
PI and study team.
The DSMC will review each protocol up to four times a year with the frequency determined by 
the outcome of previous reviews.  Information to be provided to the committee may include: up-
to-date participant accrual; current dose level information; DLT information; all grade 2 or 
higher unexpected adverse events that have been reported; summary of all deaths occurring 
within 30 days of intervention for Phase I or II protocols; for gene therapy protocols, summary of 
all deaths while being treated and during active follow-up; any response information; audit 
results, and a summary provided by the study team. Other information (e.g. scans, laboratory 
values) will be provided upon request. 
12.3  Multi-Center Guidelines
This protocol will adhere to DF/HCC Policy MULTI-100 and the requirements of the DF/HCC 
Multi-Center Data and Safety Monitoring Plan. The specific responsibilities of the Sponsor-
Investigator, Coordinating Center, and Participating Institutions and the procedures for auditing 
are presented in Appendix D.
13
ETHICAL ASPECTS
13.1 Local Regulations
The study must fully adhere to the principles outlined in “Guideline for Good Clinical Practice” 
(GCP) ICH E6 Tripartite Guideline (January 1997). The investigator will ensure that the conduct 
of the study complies with the basic principles of GCP as outlined in the current version of 
21 Code of Federal Regulations, subpart D, Part 312, “Responsibilities of Sponsors and 
Investigators” Part 50, “Protection of Human Subjects” and Part 56, “Institutional Review 
Boards.”
13.2 Informed Consent
It is the responsibility of the investigator, or a person designated by the investigator, to obtain 
written informed consent from each subject participating in this study after adequate explanation 
of the aims, methods, anticipated benefits, and potential hazards of the study. In the case where 
the subject is unable to read, an impartial witness should be present during the entire informed 
consent discussion. After the subject has orally consented to participation in the trial, the 


DF/HCC Protocol #: 19-403
Protocol Version Date: 20-May-2022
72
witness’s signature on the form will attest that the information in the consent form was 
accurately explained and understood.
If new safety information results in significant changes in the risk/benefit assessment, the 
consent form should be reviewed and updated as necessary. All subjects (including those already 
being treated) should be informed of the new information, should be given a copy of the revised 
form, and should give their consent to continue in the study.
13.3 Institutional Review Board/Ethics Committee 
This study is being conducted under a United States Investigational New Drug application or 
other Clinical Trial Application, as appropriate. This protocol (and any modifications) and 
appropriate consent procedures must be reviewed and approved by an IRB/EC. This board must 
operate in accordance with current local, regional, and federal regulations. The investigator will 
send a letter or certificate of IRB/EC approval to Exelixis (or designee) before subject enrollment 
and whenever subsequent modifications to the protocol are made.
14
CONDITIONS FOR MODIFYING THE PROTOCOL
Protocol modifications (including protocol amendments) may be made and will be prepared, 
reviewed, and approved by representatives of the investigator. Protocol modifications or 
amendments must be reviewed and approved by Exelixis and Bristol Myers Squibb prior to 
implementation.
All protocol modifications must be submitted to the IRB/EC for information and approval in 
accordance with local requirements and to regulatory agencies if required. Approval must be 
obtained before any changes can be implemented, except for changes necessary to eliminate an 
immediate hazard to study subjects or those that involve only logistical or administrative aspects 
of the trial (eg, change in monitor or change of telephone number).
15
CONDITIONS FOR TERMINATING THE STUDY
At any time, the study may be terminated by the study sponsor(s), the sponsoring institution, or 
by Exelixis and/or Bristol Myers Squibb. Should this be necessary, Exelixis and/or Bristol Myers 
Squibb and the investigator will arrange the procedures on an individual study basis after review 
and consultation. In terminating the study, Exelixis and/or Bristol Myers Squibb and the 
investigator will ensure that adequate consideration is given to the protection of the subjects’ 
interests. Upon study termination, the investigator(s) shall cease enrolling subjects into the study, 
and shall discontinue conduct of the study as soon as is medically practicable.
15.1 Collaborative Agreements Language
N/A


DF/HCC Protocol #: 19-403
Protocol Version Date: 20-May-2022
73
16 STATISTICAL CONSIDERATIONS
 
16.1 Study Design/Endpoints
The study intends to examine the clinical efficacy and tolerability of cabozantinib and nivolumab 
in the treatment of patients with advanced carcinoid. The study includes an interim analysis after 
18 patients to assure tolerability and to evaluate response rate of combining cabozantinib and 
nivolumab. This combination is likely to be well tolerated based on prior studies in patients with 
breast cancer and renal cell carcinoma, but these data require confirmation in patients with 
carcinoid tumors. This is a one-arm study without randomization. If objectives of the interim 
analysis are met then enrollment will be expanded to include 17 additional patients. 
16.1.1 Primary endpoint:
The primary efficacy endpoint is the objective response rate (ORR) in patients with advanced 
carcinoid tumors treated with the combination of cabozantinib and nivolumab. ORR is defined 
using the RECIST 1.1 criteria as the proportion of subjects with a confirmed CR or a confirmed 
PR. 
16.1.2 Secondary endpoint: 
The secondary endpoints are safety, response rate according to immune-related response criteria, 
duration of response, progression free survival (PFS), and overall survival (OS) for patients with 
advanced carcinoid tumors treated with the combination of cabozantinib and nivolumab.
 
16.2 Sample Size, Accrual Rate and Study Duration
The primary objective of this study is to investigate the safety and tolerability of the combination 
of cabozantinib and nivolumab. Based on the results of a phase II trial of cabozantinib as 
monotherapy for patients with advanced carcinoid and pancreatic NET and other trials examining 
anti-PD-1 agents in patients with other malignancies not selected by PD-L1 status, a true objective 
response rate (ORR) of 10% or less would not be of clinical interest and represents the null 
hypothesis of this study.  A true rate of 30% would be considered a clinically meaningful level of 
response. The sample size for this study was chosen to have 95% power to declare the 
combination effective at this rate with a one-sided Type 1 error of no more than 5%.
Using a Simon’s two-stage design, 18 patients will be enrolled in the first stage.  If in this first 
stage there are at least 3 patients with an objective response (ORR), accrual will continue to the 
second stage where an additional 17 patients will be enrolled. If there are at least 7 patients with 
an objective response among the total 35 patients, the regimen will be considered worthy of 
further study. 
 
If the true response rate is 10%, the chance the regimen is declared worthy of further study is less 
than 5% (exact alpha = 0.047).  If the true response rate is 30%, the chance that the regimen is 
declared worthy of further study is 95%


DF/HCC Protocol #: 19-403
Protocol Version Date: 20-May-2022
74
16.3 Analysis Plan 
The primary endpoint is the objective response rate (ORR). We will calculate the frequency and 
percentage of responses. The point estimate of the ORR with a 9% confidence interval based on 
the exact binomial distribution will be presented.
With a sample size of 35, if the observed ORR is 30%, we will  estimate the 95% confidence 
interval for the ORR to be 14.8% to 45.2%.


DF/HCC Protocol #: 19-403
Protocol Version Date: 20-May-2022
75
Below is a table for the 95% CIs corresponding to varying observed ORR
  
95% CI
15%
3.2% to 26.8%
20%
6.8% to 33.3%
30%
14.8% to 45.2%
40%
23.8% to 56.2%
 
The secondary endpoints are safety, response rate according to immune-related response criteria, 
duration of response, progression free survival (PFS), and overall survival (OS) for patients with 
advanced carcinoid tumors treated with the combination of cabozantinib and nivolumab. 
Safety will be assessed by analysis of adverse event (AE) and toxicity data. AE and toxicity data, 
including laboratory values, will be graded using CTCAE version 5.0. Tabulations of toxicities 
will be provided by organ system and attribution. 
Response rate according to immune-related response criteria will be analyzed using the same 
method for ORR. Duration of response will be summarized using mean, standard deviation, 
median, and inter-quartile range.
Progression free survival and overall survival will be defined from time of randomization to time 
of progression or date of death, respectively. Any patients who have not died by the analysis cut-
off date or are lost to follow up will be censored at their last date of contact. Any patient that 
withdraws consent for follow up will be censored on the date of withdrawal of consent. Kaplan-
Meier method will be employed to obtain survival estimates and median survival times will be 
provided. Greenwood’s formula will be used to construct 95% confidence intervals around these 
estimates.
16.4 Interim Monitoring Plan
If in the first stage there are at least 3 patients with an objective response (ORR), accrual will 
continue to the second stage where an additional 17 patients will be enrolled.  
16.5 Evaluation of Toxicity
For the safety analysis, all enrolled patients who receive at least one dose of cabozantinib and 
nivolumab will have information collected on adverse events, which will be summarized by 
severity as assessed by the Common Toxicity Criteria for Adverse Events (CTCAE), v. 5.0 and 
relationship to study drugs. 
17 PUBLICATION PLAN
A final study report will be provided within 12 months of the first visit of the last patient 
enrollled.  The results should be made public within 12 months of reaching the end of the study. 


DF/HCC Protocol #: 19-403
Protocol Version Date: 20-May-2022
76
The end of the study is the time point at which the last data items are to be reported, or after the 
outcome data are sufficiently mature for analysis, as defined in the section on Sample Size, 
Accrual Rate and Study Duration. If a report is planned to be published in a peer-reviewed 
journal, then that initial release may be an abstract that meets the requirements of the 
International Committee of Medical Journal Editors. A full report of the outcomes should be 
made public no later than three (3) years after the end of the study. 


DF/HCC Protocol #: 19-403
Protocol Version Date: 20-May-2022
77
REFERENCES
Restifo N, Dudley M, Rosenberg S. Adoptive immunotherapy for cancer: harnessing the T cell 
response. Nature Reviews Immunology. 2012; 12:269.
Mlecnik, B., Bindea, G., Angell, H.K., et al. Integrative analyses of colorectal cancer show 
immunoscore is a stronger predictor of patient survival than microsatellite instability.Immunity. 
2016: 44(3): 698. 
Intlekofer, A.M. and Thompson, C.B. AT the Bench: Preclinical Rationale for Ctla-4 and Pd-1 
Blockade as Cancer Immunotherapy. Jounal of Leukocyte Biology. 2013; 94: 25-39. 
Oberg K. Interferon int eh Management of Neuroendocrine GEP-Tumors. Digestion 2000; 
62(suppl 1):92-97
Lamarca A, Nonanka D, Breitwiese W, et al. PD-L1 expression and presence of TILs in small 
intestinal neuroendocrine tumours. Oncotarget, 2018; 9(19): 14922. 
Cavalcanti E, Armentano R, Valentini A, et al. Role of PD-L1 express as a biomarker for GEP 
neuroendocrine neoplasm grading. Cell Death and Disease. 2017; 8: e3004. 
da Silva A, Qian Z, Zhang S, et al. Well Differentiated Neuroendocrine Tumors (NET) of the 
Small Intestine and Pancreas. NANET 2016.
Mehnert JM, Rugo HS, O'Neil BH, Santoro A, Schellens JH, Cohen RB, Doi T, Ott PA, 
Pishvaian MJ, Puzanov I, Aung KL, Hsu C, Le Tourneau C, et al. Pembrolizumab for patients 
with PD-L1–positive advanced carcinoid or pancreatic neuroendocrine tumors: results from the 
KEYNOTE-028 study. Ann Oncol. 2017; 28: v142-v157. 
Phase Ib Study of Safety and Efficacy of Recombinant Humanized Anti-PD-1 Monoclonal 
Antibody for Patients With Advanced Neuroendocrine Tumors Following Failure of First-Line. 
NCT03167853.Taken on August 19, 2018 from https://clinicaltrials.gov/ct2/show/NCT03167853
An Open Label Phase II Study to Evaluate the Efficacy and Safety of PDR001 in Patients With 
Advanced or Metastatic, Well-differentiated, Non-functional Neuroendocrine Tumors of 
Pancreatic, Gastrointestinal (GI), or Thoracic Origin or Poorly-differentiated 
Gastroenteropancreatic Neuroendocrine Carcinoma (GEP-NEC), That Have Progressed on Prior 
Treatment EUDRACT 2016-002522-36. NCT02955069. Taken on August 19, 2018 from 
https://clinicaltrials.gov/ct2/show/NCT02955069
A Phase II Study of Durvalumab (MEDI4736) Plus Tremelimumab for the Treatment of Patients 
With Advanced Neuroendocrine Neoplasms of Gastroenteropancreatic or Lung Origin (the 
DUNE Trial). NCT03095274. Taken on August 19, 2018 from 
https://clinicaltrials.gov/ct2/show/NCT03095274
Grullich C. (2014) Cabozantinib: a MET, RET, and VEGFR2 tyrosine kinase inhibitor. Recent 
Results Cancer Res 201: 207–214.


DF/HCC Protocol #: 19-403
Protocol Version Date: 20-May-2022
78
Choueri T, Halabi S, Sanford B, et al. Cabozantinib versus sunitinib as initial targeted therapy 
for patients with metastatic renal cell carcinoma of poor or intermediate risk: The Alliance 
A031203 CABOSUN trial. JCO 2017 Feb; 35(6): 591. 
Brose, MS Shenoy,S, Bhat, N, et al. A Phase II Trial of Cabozantinib for the Treatment of 
Radioiodine (RAI)-refractory Differentiated Thyroid Carcinoma (DTC) in the First-line Setting 
(Oral Presentation/Press Program). ASCO/ASTRO Head and Neck Multidiciplinary Meeting 
2018 February 2018 Notes: Oral Abstract/Top 4 abstracts/Press Program.
Chan J, Faris J, Murphy J, et al. Phase II trial of cabozantinib in patients with carcinoid and 
pancreatic neuroendocrine (pNET). Journal of Clinical Oncology 2017 35:4_suppl, 228-228 
Tolaney SM, Ziehr DR, Guo H, Ng MR, Barry WT, Higgins MJ, et al. Phase II and Biomarker 
Study of Cabozantinib in Metastatic Triple Negative Breast Cancer Patients. Oncologist 2016; 
21:1-8.  
Nivolumab Investigator Brochure. Version 15. Bristol-Myer Squibb Research and Development. 
Princeton, NJ. June 2016. Document Control No. 930038243.  
Cabozantinib Investigator Brochure. Version  13.0. Exelixis. San Francisco, CA. July 10 2017. 
Gao, J., Shi, L.Z., Zhao, H., Chen, J., Xiong, L., He, Q. et al. (2016) Loss of Ifn-Gamma 
Pathway Genes in Tumor Cells as a Mechanism of Resistance to Anti-Ctla-4 Therapy. Cell 167: 
397-404.e399. 
Zaretsky, J.M., Garcia-Diaz, A., Shin, D.S., Escuin-Ordinas, H., Hugo, W., Hu-Lieskovan, S. et 
al. (2016) Mutations Associated with Acquired Resistance to Pd-1 Blockade in Melanoma. N 
Engl J Med. 2016; 275: 819.
Ribas A, Wolchok J. Cancer immunotherapy using checkpoint blockade. Science  23 Mar 2018:
Vol. 359, Issue 6382, pp. 1350-1355
Snyder, A., Makarov, V., Merghoub, T., Yuan, J., Zaretsky, J.M., Desrichard, A. et al. (2014) 
Genetic Basis for Clinical Response to Ctla-4 Blockade in Melanoma. NEJM: 2189-2199. 
Rizvi, N.A., Hellmann, M.D., Snyder, A., Kvistborg, P., Makarov, V., Havel, J.J. et al. (2015) 
Cancer Immunology. Mutational Landscape Determines Sensitivity to Pd-1 Blockade in Non- 
Small Cell Lung Cancer. Science. 348: 124-128. 
Davoli, T., Uno, H., Wooten, E.C., and Elledge, S.J. (2017) Tumor Aneuploidy Correlates with 
Markers of Immune Evasion and with Reduced Response to Immunotherapy. Science. 2017; 
355: 6322.
Le  D, Uram J, Wang H, PD-1 Blockade in Tumors with Mismatch-repair deficiency. NEJM. 
June 2015; 372: 2509-2520. 


DF/HCC Protocol #: 19-403
Protocol Version Date: 20-May-2022
79
Hugo, H.S., Delord, J., Im, S., Ott, P.A., P, S.A., Bedard, P.L. et al. Preliminary Efficacy and 
Safety of Pembrolizumab in Patients with Pd-L1-Positive, Estrogen Receptor-Positive/Her2- 
Negative Advanced Breast Cancer Enrolled in Keynote-028, SABCS 2015. 
Wagle, N., Berger, M.F., Davis, M.J., Blumenstiel, B., Defelice, M., Pochanard, P. et al. High-
Throughput Detection of Actionable Genomic Alterations in Clinical Tumor Samples by 
Targeted, Massively Parallel Sequencing. Cancer Discov. 2012; 2: 82-93. 
Brahmer J, Tykodi S, Chow L, et al. Safety and Activity of Anti–Pd-L1 Antibody in Patients 
with Advanced Cancer.NEJM. 2012; 2455-2465. 


DF/HCC Protocol #: 19-403
Protocol Version Date: 20-May-2022
80
APPENDIX A
PERFORMANCE STATUS CRITERIA
ECOG Performance Status Scale
Karnofsky Performance Scale
Grade
Descriptions
Percent
Description
100
Normal, no complaints, no evidence 
of disease.
0
Normal activity.  Fully active, able 
to carry on all pre-disease 
performance without restriction.
90
Able to carry on normal activity; 
minor signs or symptoms of disease.
80
Normal activity with effort; some 
signs or symptoms of disease.
1
Symptoms, but ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work).
70
Cares for self, unable to carry on 
normal activity or to do active work.
60
Requires occasional assistance, but 
is able to care for most of his/her 
needs.
2
In bed <50% of the time.  
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities.  Up and about 
more than 50% of waking hours.
50
Requires considerable assistance and 
frequent medical care.
40
Disabled, requires special care and 
assistance.
3
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours.
30
Severely disabled, hospitalization 
indicated.  Death not imminent.
20
Very sick, hospitalization indicated. 
Death not imminent.
4
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair.
10
Moribund, fatal processes 
progressing rapidly.
5
Dead.
0
Dead.


DF/HCC Protocol #: 19-403
Protocol Version Date: 20-May-2022
81
APPENDIX B GI ADVERSE EVENT MANAGEMENT ALGORITHM
These general guidelines constitute guidance to the Investigator and may be supplemented by 
discussions with the Medical Monitor representing the Sponsor. The guidance applies to all 
immuno-oncology agents and regimens.
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. 


DF/HCC Protocol #: 19-403
Protocol Version Date: 20-May-2022
82


DF/HCC Protocol #: 19-403
Protocol Version Date: 20-May-2022
83


DF/HCC Protocol #: 19-403
Protocol Version Date: 20-May-2022
84


DF/HCC Protocol #: 19-403
Protocol Version Date: 20-May-2022
85


DF/HCC Protocol #: 19-403
Protocol Version Date: 20-May-2022
86


DF/HCC Protocol #: 19-403
Protocol Version Date: 20-May-2022
87


DF/HCC Protocol #: 19-403
Protocol Version Date: 20-May-2022
88


DF/HCC Protocol #: 19-403
Protocol Version Date: 20-May-2022
89


DF/HCC Protocol #: 19-403
Protocol Version Date: 20-May-2022
90
APPENDIX C BIOSPECIMEN PREPARATION
Processing Guidelines for Tissue Biopsies
1. Five to seven cores will be collected utilizing a 16-18 gauge needle is recommended, a 20 
gauge core needle biopsy is also acceptable at the discretion of the interventionalist 
performing the procedure. Collection of less than the goal amount of tissue will not be 
considered a protocol violation and should be based upon the clinical judgement of the 
clinician performing the biopsy procedure. 
2. Tissue mass is placed on a sterile saline soaked Telpha pad
3. Using forceps or scalpel, tumor tissue is separated into multiple fragments, if necessary
4. Distinct tissue fragments will be allocated for the following, in order of protocol priority: 
a.
Two to three samples placed in room temperature formalin for processing to a 
FFPE block to be set to the DFCI Rodig Lab.
b. One sample placed in room temperature formalin to be set to BWH Pathology per 
BWH CSIR SOP. 
c.
Two to three samples placed in room temperature formalin for processing to 
additional FFPE block(s) to be stored by the DFCI Clinical Trials Team (Dr. 
Perez).
5. Samples will be annotated with only a unique de-identified study subject number, 
protocol number, and the date of collection. Links to identifying information for each 
sample will be stored centrally on a password-protected firewall secured database in 
accordance with institution tissue bank protocols.
Processing Guidelines for Whole Blood and Plasma Samples
1. Samples will be collected as follows:
a.
Green Top 10 ml Sodium Heparin Tubes for PBMCs
2. Samples will be delivered immediately to the CIO Immune Assesment Lab to be 
processed within 1.5 hours of being drawn.
CIO Immune Assessment Lab of Mariano Severgnini:
Center for Immuno-Oncology
Dana-Farber Cancer Institute
1 Jimmy Fund Way, JF0406
Boston, MA 02215
Phone: (617) 632-2421
Pager: 42093
Processing Guidelines for Stool Samples
1. Samples will be collected per kit instructions.
2. Samples will be delivered immediately to the CIO Immune Assesment Lab to be 
processed.


DF/HCC Protocol #: 19-403
Protocol Version Date: 20-May-2022
91
CIO Immune Assessment Lab of Mariano Severgnini:
Center for Immuno-Oncology
Dana-Farber Cancer Institute
1 Jimmy Fund Way, JF0406
Boston, MA 02215
Phone: (617) 632-2421
Pager: 42093


DF/HCC Protocol #: 19-403
Protocol Version Date: 20-May-2022
92
APPENDIX D MULTI-CENTER GUIDELINES
APPENDIX D
Dana-Farber/Harvard Cancer Center
Multi-Center Data and Safety Monitoring Plan
 


DF/HCC Protocol #: 19-403
Protocol Version Date: 20-May-2022
93
1
INTRODUCTION
The Dana-Farber/Harvard Cancer Center Multi-Center Data and Safety Monitoring Plan (DF/HCC DSMP) 
outlines the procedures for conducting a DF/HCC Multi-Center research protocol. The DF/HCC DSMP serves 
as a reference for any sites external to DF/HCC that are participating in a DF/HCC clinical trial. 
1.1
Purpose
To establish standards that will ensure that a Dana-Farber/Harvard Cancer Center Multi-Center protocol 
will comply with Federal Regulations, Health Insurance Portability and Accountability Act (HIPAA) 
requirements and applicable DF/HCC Policies and Operations.       
2
GENERAL ROLES AND RESPONSIBILITIES
For DF/HCC Multi-Center Protocols, the following general responsibilities apply, in addition to those outlined 
in DF/HCC Policies for Sponsor-Investigators: 
2.1
External Site
An External Site is an institution that is outside the DF/HCC and DF/PCC consortium that is collaborating 
with DF/HCC on a protocol where the sponsor is a DF/HCC investigator.  The External Site acknowledges 
the DF/HCC Sponsor as having the ultimate authority and responsibility for the overall conduct of the study. 
Each External Site is expected to comply with all applicable DF/HCC requirements stated within this Data 
and Safety Monitoring Plan and/or the protocol document. 
The general responsibilities for each External Site may include but are not limited to:

Document the delegation of research specific activities to study personnel.

Commit to the accrual of participants to the protocol.

Submit protocol and/or amendments to their IRB of record. 

Maintain regulatory files as per ICH GCP and federal requirements.

Provide the Coordinating Center with regulatory documents or source documents as requested.

Participate in protocol training prior to enrolling participants and throughout the trial as required.

Update Coordinating Center with research staff changes on a timely basis.

Register participants through the Coordinating Center prior to beginning research related activities 
when required by the sponsor. 

Submit Serious Adverse Event (SAE) reports to sponsor, Coordinating Center, and IRB of record as 
applicable, in accordance with DF/HCC requirements. 

Submit protocol deviations and violations to the Sponsor, Coordinating Center, and IRB of record 
as applicable.

Order, store and dispense investigational agents and/or other protocol mandated drugs per federal 
guidelines and protocol requirements.

Participate in any quality assurance activities and meet with monitors or auditors at the conclusion 
of a visit to review findings.

Promptly provide follow-up and/or corrective action plans for any monitoring queries or audit 
findings.

Notify the sponsor immediately of any regulatory authority inspection of this protocol at the External 
Site.
3
DF/HCC REQUIREMENTS FOR MULTI-CENTER PROTOCOLS
Certain DF/HCC Policy requirements apply to External Sites participating in DF/HCC 
research. The following section will clarify DF/HCC requirements and further detail the 
expectations for participating in a DF/HCC Multi-Center protocol. 


DF/HCC Protocol #: 19-403
Protocol Version Date: 20-May-2022
94
3.1
Protocol Revisions and Closures
The External Sites will receive notification of protocol revisions and closures from the 
Coordinating Center.  When under a separate IRB, it is the individual External Site’s 
responsibility to notify its IRB of these revisions.

Protocol revisions: External Sites will receive written notification of protocol revisions from the 
Coordinating Center. All protocol revisions should be IRB approved and implemented within a timely 
manner from receipt of the notification.

Protocol closures and temporary holds: External Sites will receive notification of protocol closures 
and temporary holds from the Coordinating Center. Closures and holds will be effective immediately.  
In addition, the Coordinating Center, will update the External Sites on an ongoing basis about 
protocol accrual data so that they will be aware of imminent protocol closures.
3.2
Informed Consent Requirements
The DF/HCC approved informed consent document will serve as a template for the 
informed consent for External Sites. The External Site consent form must follow the consent 
template as closely as possible and should adhere to specifications outlined in the DF/HCC 
Guidance Document on Model Consent Language for Investigator-Sponsored Multi-Center 
Trials.  This document will be provided separately to each External Site upon request.
External Sites must send their version of the informed consent document to the Coordinating 
Center for sponsor review and approval. If the HIPAA authorization is a separate document, 
please submit to the sponsor for the study record. Once sponsor approval is obtained, the 
External site may submit to their IRB of record, as applicable. In these cases, the approved 
consent form must also be submitted to the Coordinating Center after approval by the local 
IRB for all consent versions.
The Principal Investigator (PI) at each External Site will identify the appropriate members 
of the study team who will be obtaining consent and signing the consent form for protocols. 
External Sites must follow the DF/HCC requirement that for all interventional drug, 
biologic, or device research, only attending physicians may obtain initial informed consent 
and any re-consent that requires a full revised consent form.  
3.3
IRB Re-Approval
Verification of IRB re-approval for the External Sites is required in order to continue 
research activities.  There is no grace period for continuing approvals.
The Coordinating Center will not register participants if a re-approval letter is not received 
for the External Site on or before the anniversary of the previous approval date.  
3.4
DF/HCC Multi-Center Protocol Confidentiality
All documents, investigative reports, or information relating to the participant are strictly confidential. 
Whenever reasonably feasible, any participant specific reports (i.e. Pathology Reports, MRI Reports, 
Operative Reports, etc.) submitted to the Coordinating Center should be de-identified. It is recommended that 


DF/HCC Protocol #: 19-403
Protocol Version Date: 20-May-2022
95
the assigned protocol case number be used for all participant specific documents. Participant initials may be 
included or retained for cross verification of identification. 
3.5
Participant Registration and Randomization 
To register a participant, the following documents should be completed by the External 
Site and faxed or e-mailed to the Coordinating Center.
Email: DanielleE_Stonely@dfci.harvard.edu; Fax: 617-582-7988.

Signed participant consent form

HIPAA authorization form

Eligibility Checklist

Registration Request Coversheet 

External Site Subject Registration form

Screening provider note including medical/ surgical history, ECOG performance 
status, vital signs, and physical exam findings

Pathology report to support inclusion criteria

Laboratory reports including:
o
CBC with differential 
o
Chemistry panel
o
Pregnancy test (if applicable)
o
Thyroid panel
o
Coagulation panel 
o
LDH

Screening radiology reports (CT and/or MRI scans)

Screening EKG
The Coordinating Center will review the submitted documents in order to verify 
eligibility and consent. To complete the registration process, the Coordinating Center 
will:

Register the participant on the study with the DF/HCC Clinical Trial Management System (CTMS).

Upon receiving confirmation of registration, the Coordinating Center will inform the External Site 
and provide the study specific participant case number, and, if applicable, assigned treatment and/or 
dose level. 
At the time of registration, the following identifiers are required for all subjects: initials, 
date of birth, gender, race and ethnicity. Once eligibility has been established and the 
participant successfully registered, the participant is assigned a unique protocol case 
number.  External Sites should submit all de-identified subsequent communication and 
documents to the Coordinating Center, using this case number to identify the subject.  
3.5.1    Initiation of Therapy
Participants must be registered with the DF/HCC CTMS before the initiation of treatment 
or other protocol-specific interventions. Treatment and other protocol-specific interventions 
may not be initiated until the External Site receives confirmation of the participant’s 
registration from the Coordinating Center. The DF/HCC Sponsor and IRB of record must 
be notified of any violations to this policy.


DF/HCC Protocol #: 19-403
Protocol Version Date: 20-May-2022
96
3.5.2    Eligibility Exceptions
No exceptions to the eligibility requirements for a protocol without IRB approval will be 
permitted. All External Sites are required to fully comply with this requirement. The process 
for requesting an eligibility exception is defined below.
3.6 
Data Management
DF/HCC develops case report forms (CRF/eCRFs), for use with the protocol.  These forms 
are designed to collect data for each study. DF/HCC provides a web-based training for all 
eCRF users.
  
3.6.1     Data Forms Review
Data submissions are monitored for timeliness and completeness of submission. If study 
forms are received with missing or questionable data, the submitting institution will receive 
a written or electronic query from the DF/HCC Office of Data Quality, Coordinating Center, 
or designee. 
Responses to all queries should be completed and submitted within 14 calendar days.  
If study forms are not submitted on schedule, the External Sites will periodically receive a 
Missing Form Report from the Coordinating Center noting the missing forms. 
3.7
 Protocol Reporting Requirements
3.7.1 
 Protocol Deviations, Exceptions and Violations
Federal Regulations require an IRB to review proposed changes in a research activity to 
ensure that researchers do not initiate changes in approved research without IRB review 
and approval, except when necessary to eliminate apparent immediate hazards to the 
participant. DF/HCC requires all departures from the defined procedures set forth in the 
IRB approved protocol to be reported to the DF/HCC Sponsor and to the IRB of record.
3.7.2  
Reporting Procedures
Requests to deviate from the protocol require approval from the IRB of record and the 
sponsor. 
All protocol violations must be sent to the Coordinating Center in a timely manner. The 
Coordinating Center will provide training for the requirements for the reporting of 
violations. 


DF/HCC Protocol #: 19-403
Protocol Version Date: 20-May-2022
97
3.7.3  Guidelines for Processing IND Safety Reports 
The DF/HCC Sponsor will review all IND Safety Reports per DF/HCC requirements, and 
ensure that all IND Safety Reports are distributed to the External Sites as required by 
DF/HCC Policy. External Sites will review/submit to the IRB according to their 
institutional policies and procedures.
4
MONITORING: QUALITY CONTROL
The Coordinating Center, with the aid of the DF/HCC Office of Data Quality, provides 
quality control oversight for the protocol.
4.1
Ongoing Monitoring of Protocol Compliance
The External Sites may be required to submit participant source documents to the 
Coordinating Center for monitoring. External Sites may also be subject to on-site 
monitoring conducted by the Coordinating Center. 
The Coordinating Center will implement ongoing monitoring activities to ensure that 
External Sites are complying with regulatory and protocol requirements, data quality, and 
participant safety. Monitoring practices may include but are not limited to source data 
verification, and review and analysis of eligibility requirements, informed consent 
procedures, adverse events and all associated documentation, review of study drug 
administration/treatment, regulatory files, protocol departures reporting, pharmacy records, 
response assessments, and data management. 
External Sites will be required to participate in regular Coordinating Center initiated 
teleconferences. Overall protocol progress and important announcements will be distributed 
regularly as minutes from these teleconferences.
Remote Monitoring will be conducted as agreed upon per the Remote Monitor Plan……. 
External Sites may be required to forward de-identified copies of participants’ medical 
record and source documents to the Coordinating Center to aid in source data verification. 
4.2
Monitoring Reports
The DF/HCC Sponsor will review all monitoring reports to ensure protocol compliance. 
The DF/HCC Sponsor may increase the monitoring activities at External Sites that are 
unable to comply with the protocol, DF/HCC Sponsor requirements or federal and local 
regulations. 
4.3
Accrual Monitoring
Prior to extending a protocol to an external site, the DF/HCC Sponsor will establish 
accrual requirements for each External Site. Accrual will be monitored for each External 
Site by the DF/HCC Sponsor or designee. Sites that are not meeting their accrual 
expectations may be subject to termination.


DF/HCC Protocol #: 19-403
Protocol Version Date: 20-May-2022
98
The following minimum accrual requirements are recommended: 
1) Phase II-III: 3 per site/annually.  
However, given the additional regulatory burden and cost of overseeing each site, a 
consideration of 5 per site annually should be a minimum target for each site.
5
AUDITING: QUALITY ASSURANCE
5.1
DF/HCC Internal Audits
 
All External Sites are subject to audit by the DF/HCC Office of Data Quality (ODQ). 
Typically, approximately 3-4 participants would be audited at the site over a 2-day period. 
If violations which impact participant safety or the integrity of the study are found, more 
participant records may be audited. 
5.2
Audit Notifications
It is the External Site’s responsibility to notify the Coordinating Center of all external audits 
or inspections (e.g., FDA, EMA, NCI) that involve this protocol. All institutions will 
forward a copy of final audit and/or re-audit reports and corrective action plans (if 
applicable) to the Coordinating Center, within 12 weeks after the audit date. 
5.3
Audit Reports 
The DF/HCC Sponsor will review all final audit reports and corrective action plans, if 
applicable. The Coordinating Center, must forward any reports to the DF/HCC ODQ per 
DF/HCC policy for review by the DF/HCC Audit Committee. For unacceptable audits, the 
DF/HCC Audit Committee would forward the final audit report and corrective action plan 
to the IRB as applicable.
5.4
External Site Performance
The DF/HCC Sponsor and the IRB of record are charged with considering the totality of an 
institution’s performance in considering institutional participation in the protocol.
External Sites that fail to meet the performance goals of accrual, submission of timely and 
accurate data, adherence to protocol requirements, and compliance with state and federal 
regulations, may be put on hold or closed. 


DF/HCC Protocol #: 19-403
Protocol Version Date: 20-May-2022
99