Clinical trial NCT04899921
Conditions: Melanoma Metastatic Melanoma
Keywords: Melanoma Metastatic Melanoma Metastatic Melanoma, Brain
Sponsor: Dana-Farber Cancer Institute
Start date: 2021-06-30; Completion date: 2023-05-29
Enrollment: 1 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this research is to test the safety and effectiveness of the investigational combination of Troriluzole, ipilimumab, and nivolumab, and to learn whether this combination works in treating melanoma that has spread to the brain.

Detailed description:
This is a multi-center, double-blind, randomized, phase II signal-detection trial with a non-randomized safety run-in to assess the efficacy and safety of adding troriluzole to ipilimumab/nivolumab induction and nivolumab maintenance in patients with melanoma that has metastasized to the brain. Measuring the shrinking or growth of melanoma in participants will allow researchers to learn about these study drugs and provide information on the safety and effectiveness of this combination in treating melanoma.

The U.S. Food and Drug Administration (FDA) has not approved Troriluzole as a treatment for any disease. The U.S. Food and Drug Administration (FDA) has approved nivolumab, ipilimumab, and the combination of these two drugs as treatment options for melanoma that has metastasized to the brain.

Ipilimumab and nivolumab are drugs that treat cancer by blocking certain molecules in the body. This blocking action prevents other molecules from binding to cells involved in the immune system. With these changes, the immune system is more likely to become active, and will react more intensely when activated. The immune system is able to destroy cancer cells and reduce the size of tumors, so activating the immune system is an important part of cancer treatment. Ipilimumab blocks a molecule called cytotoxic T-lymphocyte-associated protein-4 (CTLA-4), which normally decreases the activation of the immune system by binding to T-Cells, which are important immune system cells that can attack cancer cells. Nivolumab blocks a molecule called programmed death receptor-1 (PD-1), which also normally decreases the activation of the immune system.

Troriluzole is a drug that modulates glutamate, the most abundant excitatory neurotransmitter in the human body. The primary mode of action of Troriluzole is reducing synaptic levels of glutamate. This may change parts of the immune system in the brain, which is could improve treatment outcomes with anti-cancer drugs such as ipilimumab and nivolumab that can work in the brain. This study is testing Troriluzole's ability to increase the effectiveness of ipilimumab and nivolumab treatment in melanoma that has spread to the brain, as well as testing the safety of the combination of these three drugs.

Participation in this research is expected to last up to 4 years: 1 year of treatment and 3 years of follow up.

About 108 subjects will take part in this research.

Arms: arm 1: Phase I dose level 1 participants received nivolumab 1 mg/kg and ipilimumab 3 mg/kg intravenously (IV) on day 1 of each 21-day cycle and the original starting troriluzole dose of 140 mg orally in the morning as well as 280 mg orally in the evening every day of each 21-day cycle. Participants were treated until disease progression or unacceptable toxicity. arm 2: Participants will be randomly assigned and receive:

12 Week Induction Phase: Nivolumab at pre-determined dose followed by ipilimumab at predetermined dose every 3 weeks, with 21 consecutive days defined as a treatment cycle. Troriluzole self-administered at a predetermined dose orally twice a day

36 Week Maintenance Phase: Nivolumab will be administered every 4 weeks, with 28 consecutive days defined as a treatment cycle. Troriluzole self administered at a predetermined dose orally twice a day. No ipilimumab will be given in the maintenance phase. arm 3: Participants will be randomly assigned and receive:

12 Week Induction Phase: Nivolumab at pre-determined dose followed by ipilimumab at predetermined dose every 3 weeks, with 21 consecutive days defined as a treatment cycle. Placebo self-administered at a predetermined dose orally twice a day

36 Week Maintenance Phase: Nivolumab will be administered every 4 weeks, with 28 consecutive days defined as a treatment cycle. Placebo self administered at a predetermined dose orally twice a day. No ipilimumab will be given in the maintenance phase. arm 4: Phase I dose level 2 participants received nivolumab 1 mg/kg and ipilimumab 3 mg/kg intravenously (IV) on day 1 of each 21-day cycle and troriluzole 140 mg twice per day orally. Participants were treated until disease progression or unacceptable toxicity. arm 5: Phase I dose level 3 participants received nivolumab 1 mg/kg and ipilimumab 3 mg/kg intravenously (IV) on day 1 of each 21-day cycle and troriluzole 140 mg/day orally. Participants were treated until disease progression or unacceptable toxicity.
Interventions: intervention 1: Ipilimumab intervention 2: Nivolumab intervention 3: Troriluzole intervention 4: Placebo
Intervention descriptions: intervention 1: Intravenous injection intervention 2: Intravenously (IV) into the vein intervention 3: Taken orally intervention 4: Taken orally

Protocol documents:
Prot_SAP_000.pdf: 
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NCI Protocol #: Not applicable 
DF/HCC Protocol #: 20-675 
 
 
 
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NCI Protocol #: 
Not applicable 
 
DF/HCC Protocol #:  20-675  
 
TITLE:  A Blinded, Randomized Phase 2 Study of Troriluzole in Combination with Ipilimumab 
and Nivolumab in Patients with Melanoma Brain Metastases  
 
Sponsor-Investigator: 
Ann W. Silk, MD, MS 
 
Dana-Farber Cancer Institute  
 
ann_silk@dfci.harvard.edu 
 
Principal Investigator (PI): 
Ann W. Silk, MD, MS 
 
Dana-Farber Cancer Institute  
 
ann_silk@dfci.harvard.edu 
 
Other Investigators:  
Ayal Aizer, MD 
Elizabeth I. Buchbinder, MD 
 
 
 
 
Daniel Cagney, MD 
Rizwan Haq, MD, PhD 
 
 
 
 
F. Stephen Hodi, MD 
 
 
 
 
Megan Insco, MD, PhD 
 
 
 
 
Eudocia Lee, MD 
 
 
 
 
David Liu, MD, MPH, MS 
 
 
 
 
Patrick Ott, MD, PhD 
 
Statistician: 
 
Study Coordinator:   
 
Anita Giobbie-Hurder, MS 
DFCI Melanoma    
      Dana-Farber Cancer Institute 
Group Inbox  
 
agiohur.ds@dfci.harvard.edu 
Dana-Farber Cancer Institute  
 
    DFCIMelanomaCRCs@partnershealthcare.onmicrosoft.com 
 
 
 
 
 
 
 
Fax: 617-582-8216 
 
 
 
 
Responsible Research Nurses: 
Responsible Research Manager:   
Amanda Livengood, RN                                
David Husselbee 
Dana-Farber Cancer Institute  
 
 
Dana-Farber Cancer Institute 
                                                                                  Telephone: 617-632-6704     
Jill Gormley, RN                                                      Fax: 617-582-8216 
Dana-Farber Cancer Institute  
 
 
David_husselbee@dfci.harvard.edu 
 
NCI-Supplied Agents:  None 
Other Agent(s): 
  Troriluzole, Biohaven Pharmaceuticals 
  Ipilimumab (NSC-732442), commercial supply 
  Nivolumab (NSC-748726), commercial supply 
 


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IND #:  153188 
IND Sponsor:  Ann W. Silk, MD 
 
Protocol Type / Version # / Version Date: Revised / Version #5 / Version date 11/15/2021  
 
SCHEMA 
 
Study Flow Diagram 
 
 
 
Treatment Schema for Randomized Blinded Placebo-Controlled Trial 
 
 


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TABLE OF CONTENTS 
 
SCHEMA 
2 
1. 
OBJECTIVES 
1.1 
Study Design ............................................................................................................6 
1.2 
Primary Objectives...................................................................................................6 
1.3 
Secondary Objectives...............................................................................................6 
1.4 
Exploratory Objectives ............................................................................................7 
2. 
BACKGROUND .................................................................................................................7 
2.1 Melanoma brain metastases ...........................................................................................7 
2.2 Glutamate Signaling in Melanoma ................................................................................8 
2.3 Riluzole ..........................................................................................................................8 
2.4 Troriluzole....................................................................................................................11 
2.5 Ipilimumab and Nivolumab .........................................................................................14 
2.6 Radiation Therapy ........................................................................................................15 
2.7 Rationale ......................................................................................................................16 
2.8 Correlative Studies Background ..................................................................................17 
3. 
PARTICIPANT SELECTION ...........................................................................................18 
3.1 Eligibility Criteria ........................................................................................................18 
3.2 Exclusion Criteria ........................................................................................................20 
3.3 Inclusion of Women and Minorities ............................................................................21 
4. 
REGISTRATION And Randomization PROCEDURES ..................................................21 
4.1 General Guidelines for DF/HCC Institutions ..............................................................21 
4.2 Registration Process for DF/HCC Institutions .............................................................22 
4.3 General Guidelines for Other Investigative Sites ........................................................22 
4.4 Registration Process for Other Investigative Sites .......................................................22 
5. 
TREATMENT PLAN ........................................................................................................23 
5.1 
Treatment Regimen ................................................................................................23 
5.2 
Pre-Treatment Criteria ...........................................................................................26 
5.3 
Agent Administration.............................................................................................26 
5.4 
End of Treatment ...................................................................................................28 
5.5 
Concomitant Medication and Supportive Care Guidelines ...................................28 
5.6 Concomitant Brain-Directed Stereotactic Radiation therapy during the study ...........29 
5.7 Concomitant Surgery therapy during the study ...........................................................30 
5.8 Criteria for Taking a Participant Off Protocol Therapy ...............................................30 
5.9 Duration of Follow Up .................................................................................................31 
5.10 Criteria for Taking a Participant Off Study ...............................................................32 
5.11 Requests for Unblinding ............................................................................................32 
6. 
DOSING DELAYS/DOSE MODIFICATIONS ...............................................................34 
6.1 
General considerations ...........................................................................................34 


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6.2 
Dose Limiting Toxicities .......................................................................................34 
6.3 
Troriluzole..............................................................................................................35 
6.4 
Ipilimumab and Nivolumab ...................................................................................37 
6.5 
Treatment of Infusion Reactions Associated with Ipilimumab and/or 
Nivolumab..............................................................................................................43 
6.5  
Treatment of Ipilimumab-Related Isolated Drug Fever .........................................44 
6.6  
Monitoring and Management of Immune-mediated Adverse Reactions ...............45 
6.7 
Overlapping toxicities (“shared AEs”) ..................................................................48 
7. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ............................49 
7.1 
Expected Toxicities ................................................................................................49 
7.2 
Adverse Event Characteristics ...............................................................................53 
7.3 Adverse Event Reporting .............................................................................................53 
7.4 
Reporting to the Food and Drug Administration (FDA) .......................................55 
7.5 Reporting to Hospital Risk Management .....................................................................55 
7.6 Routine Adverse Event Reporting ...............................................................................55 
8. 
PHARMACEUTICAL INFORMATION ..........................................................................55 
8.1 
Troriluzole..............................................................................................................55 
8.2 
Ipilimumab .............................................................................................................58 
8.3 
Nivolumab..............................................................................................................58 
9. 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ........................................58 
9.1 
Biomarker Studies ..................................................................................................58 
9.2 Laboratory Correlative Studies ....................................................................................59 
10. 
STUDY CALENDAR .......................................................................................................59 
10.1 
Scheduling windows ..............................................................................................59 
11. 
MEASUREMENT OF EFFECT........................................................................................65 
11.1 
Antitumor Effect – Intracranial tumors and Extracranial tumors ..........................65 
11.2 
Methods for Evaluation of Disease ........................................................................67 
11.3 
Response Criteria: modified RECIST version 1.1 .................................................69 
11.4 
Duration of Response .............................................................................................71 
11.5 
Progression-Free Survival ......................................................................................72 
11.6 
Response Review ...................................................................................................72 
12. 
DATA REPORTING / REGULATORY REQUIREMENTS ...........................................72 
12.1 
Data Reporting .......................................................................................................72 
12.2 
Data Safety Monitoring..........................................................................................73 
12.3 
Multi-Center Guidelines ........................................................................................73 
12.4 
Collaborative Agreements Language .....................................................................73 
13. 
STATISTICAL CONSIDERATIONS...............................................................................73 
13.1 
Study Design/Endpoints.........................................................................................73 
13.2 
Sample Size, Accrual Rate and Study Duration ....................................................75 
13.3 
Stratification Factors ..............................................................................................76 


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13.4 
Interim Monitoring Plan ........................................................................................76 
13.5 
Analysis of Primary Endpoints ..............................................................................77 
13.6 
Analysis of Secondary Endpoints ..........................................................................77 
13.7 
Reporting and Exclusions ......................................................................................79 
14. 
PUBLICATION PLAN .....................................................................................................79 
15. 
REFERENCES ..................................................................................................................80 
APPENDIX A 
PERFORMANCE STATUS CRITERIA ..................................................83 
APPENDIX B 
MULTI-CENTER GUIDELINES .............................................................84 
1. 
Introduction 
84 
1.1 
Purpose ...................................................................................................................84 
2. 
GENERAL ROLES AND RESPONSIBILITIES .............................................................84 
2.1 
Coordinating Center ...............................................................................................84 
2.1 
External Site ...........................................................................................................85 
3. 
DF/HCC REQUIREMENTS FOR MULTI-CENTER PROTOCOLS..............................86 
3.1 Protocol Revisions and Closures .................................................................................86 
3.2 Informed Consent Requirements .................................................................................86 
3.3 IRB Re-Approval .........................................................................................................87 
3.4 DF/HCC Multi-Center Protocol Confidentiality .........................................................87 
3.5 Participant Registration and Randomization ...............................................................87 
3.6 Initiation of Therapy ....................................................................................................88 
3.7 Eligibility Exceptions...................................................................................................88 
3.8 Data Management ........................................................................................................88 
3.9 Protocol Reporting Requirements ................................................................................88 
3.10 Reporting Procedures .................................................................................................89 
3.11 Guidelines for Processing IND Safety Reports .........................................................89 
4. 
MONITORING: QUALITY CONTROL ..........................................................................89 
4.1 
Ongoing Monitoring of Protocol Compliance .......................................................89 
4.2 
Monitoring Reports ................................................................................................89 
4.3 
Accrual Monitoring ................................................................................................90 
5. 
AUDITING: QUALITY ASSURANCE ...........................................................................90 
5.1 
DF/HCC Internal Audits ........................................................................................90 
5.2 
Audit Notifications.................................................................................................90 
5.3 
Audit Reports .........................................................................................................90 
5.4 
External Site Performance .....................................................................................90 
APPENDIX E External Site Subject Registration Form ...............................................................91 
APPENDIX F. PILL DIARY ........................................................................................................93 
 


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1. OBJECTIVES 
 
1.1 Study Design 
 
We propose a multi-center, blinded, randomized, phase II signal-detection trial with safety run-in 
to assess the efficacy and safety of adding troriluzole to ipilimumab + nivolumab in patients with 
melanoma that has metastasized to the brain.   
 
There will be a Safety Run-in, which will be a single-arm, open-label 3+3 design in which all 
subjects will be treated with ipilimumab + nivolumab + troriluzole (INT).  Following the Safety 
Run-in (Part I), all participants will be enrolled on the double-blind randomized portion of the 
study (Part II). Subjects will be randomly assigned in equal proportions to induction therapy with 
ipilimumab + nivolumab + placebo (INP) or ipilimumab + nivolumab + troriluzole (INT). 
Subjects assigned to the troriluzole vs. placebo arm will continue troriluzole or placebo in the 
maintenance period with nivolumab. The randomization will be stratified by prior therapy with 
BRAF-directed therapy (yes/no) and prior therapy with anti-PD-1 treatment (yes/no). 
 
 
1.2 Primary Objectives 
 
The primary objective is to assess the efficacy and safety of adding troriluzole to ipilimumab + 
nivolumab in patients with melanoma that has metastasized to the brain.   
 
The primary endpoint of the study is global progression-free survival (PFS) in patients with 
melanoma brain metastases who are treated with troriluzole + ipilimumab + nivolumab + (INT) 
vs. ipilimumab + nivolumab (INP).  The proportions at 6 months will be of particular interest. 
 
Herein, the term “PFS” refers to PFS in both the intracranial and extracranial compartments 
(global). 
 
1.3 Secondary Objectives 
 
The secondary objectives are to evaluate other important clinical outcomes, including: 
• overall survival 
• intracranial response rate (RR) and PFS 
• extracranial RR and PFS 
• safety (number of participants experiencing adverse events, particularly serious 
neurologic events such as seizure, MRI-defined intracranial hemorrhage, radiation 
necrosis) 
• tolerability (number of induction cycles administered, number of maintenance cycles 
administered) 
• use of corticosteroids for management of symptomatic cerebral edema (number of 
participants) 
• use of corticosteroids for management of immune related adverse events (number of 
participants who require prednisone ≥1 mg/kg or equivalent) 


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• frequency of clinically-indicated stereotactic radiation therapy to the brain on study 
(number of patients, number of instances and number of lesions irradiated) 
• frequency of clinically-indicated surgical intervention to the brain on study (number of 
participants) 
 
 
1.4 Exploratory Objectives 
 
• Determine associations between BRAF/NRAS mutation status and response endpoints, as 
well as tissue biomarker profiles between paired tissues from extracranial and intracranial 
metastases from individual patients, where available 
• Determine associations between peripheral blood immune cell subpopulations (which 
may include but is not limited to T-cell, NK, B-cell, MDSC, and serum soluble factors) 
with clinical endpoints and/or the occurrence of adverse events 
 
2. BACKGROUND 
 
2.1 Melanoma brain metastases 
 
Brain metastases are a key complication of melanoma because 44% of patients with metastatic 
melanoma will develop symptomatic brain metastases, and intracranial disease accounts for 20% 
to 54% of deaths in patients with melanoma.1 Prognosis is poor, and historical estimates of 
survival range from 3 to 13 months despite radiation therapy (RT), which includes stereotactic 
radiotherapy (SRT; also known as stereotactic radiosurgery or SRS) and whole brain radiation 
therapy (WBRT).  The most common solid tumors to form brain metastases are lung cancer, 
breast cancer, and melanoma. Melanoma is unique in that it is common for there to be multiple 
synchronous brain metastases rather than a single brain metastasis.  
 
Brain metastases have distinct metabolic and immunologic features as compared to extracranial 
metastases.  There is increased dependence on the PI3K pathway and increased dependence on 
glutamine and oxidative phosphorylation.  Recently, Davies and colleagues from M.D. Anderson 
performed RNA sequencing on patient-matched resected melanoma brain metastases and 
extracranial metastases. Compared with patient-matched extracranial metastases, brain 
metastases exhibited substantial immunosuppression and elevated levels of oxidative 
phosphorylation gene expression and metabolites.2 
 
Systemic therapy for melanoma has improved dramatically since 2011 with the availability of 
immunotherapy agents, including the immune checkpoint inhibitor antibodies ipilimumab, 
pembrolizumab and nivolumab. The PD-1 inhibitors pembrolizumab and nivolumab are more 
effective and less toxic than the CTLA-4 inhibitor ipilimumab, and they have a response rate of 
30-40% when given as single agents. Dual CTLA-4 and PD-1 checkpoint inhibition (ipilimumab 
and nivolumab) is approved in combination for melanoma with a response rate of 56%.  Patients 
with untreated, uncontrolled brain metastases were excluded from these early studies. 
 
The importance of systemic therapy for the treatment of melanoma brain metastases has recently 
been demonstrated in a study using dual checkpoint blockade with IPI/NIVO.3 In neurologically 


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asymptomatic patients with small volume brain metastases and no previous systemic therapy, the 
combination was shown to be an active regimen with a response rate of 48%.3 The response rate 
in symptomatic patients was far lower. The vast majority of patients have concordant responses 
in their intracranial and extracranial disease. Brain-directed stereotactic radiation therapy of one 
lesion was allowed on study. However, as the PFS at 12 months was only 57%, there is still an 
unmet clinical need in this population. 
 
The clinical management of a single metastasis with craniotomy and/or brain-directed stereotactic 
radiation is supported by the literature and has been the standard of care for nearly twenty years. 
Prior to the approval of immune checkpoint inhibitors, radiation therapy, in the form of WBRT or 
SRT, was the considered the mainstay of treatment.   In randomized controlled trials, WBRT failed 
to demonstrate benefits in disease control or survival,4,5 and the field has shifted away from using 
WBRT by itself or following SRT.6 Since 2012, a large amount of retrospective data and some 
prospective data has emerged combining immune checkpoint inhibitors with SRT,7-14 and 
concurrent immune checkpoint inhibitors + SRT is now considered standard of care. 
Complications of brain metastases including perilesional edema, intralesional hemorrhage, and 
radiation necrosis have been reported;15 however, there is no clear evidence that the frequency of 
these complications is higher than expected, and the impact of these events must be weighed 
against the complications arising from untreated, progressive brain metastases.  
 
2.2 Glutamate Signaling in Melanoma  
 
Glutamate (the anion of the amino acid called glutamic acid) is the most abundant excitatory 
neurotransmitter in the brain. The glutamatergic system also plays a key role in tumor biology. 
The Metabotropic Glutamate Receptor 1 (GRM1) is expressed in 60-100% of human 
melanomas. GRM1-expressing melanoma cell lines release elevated levels of glutamate, which 
is the natural ligand for GRM1, thus establishing autocrine loops and constitutive activated 
GRM1. Activation of GRM1 leads to a dual signaling cascade that stimulates both MAPK and 
PI3K pathways. Antagonizing glutamate receptors in cell lines from various human tumors 
including melanoma, colon adenocarcinoma, breast, glioma, and lung carcinoma has been 
reported to inhibit their growth. Glutamate signaling may be important in carcinomagenesis, as 
ectopic expression of GRM1 is sufficient for the spontaneous development of a metastatic 
murine-form of melanoma in a transgenic mouse model.16,17  
 
GRM1 signal transduction appears to induce a suppressive tumor microenvironment.  GRM1 
signal transduction in melanoma results in increased tumor-derived exosome production,18 and 
increased expression of the immune suppressing factors M-CSF and CCL2, which promoted 
suppressive tumor-associated M2 macrophages. Over-expression of M-CSF and its receptor, 
CSF-1R, in tumors has been associated with a poor prognosis and M-CSF and CCL4 have also 
been implicated in mobilization of tumor-associated macrophages (TAMs) into the tumor 
microenvironment. In a laboratory model, GRM1 activation leads to inhibition of release of 
exosomes containing MCSF and CCL-2, which create an immunosuppressive tumor 
microenvironment by promoting TAMS.19,20   
 
2.3 Riluzole 
 


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Riluzole is an FDA-approved medication for the debilitating neurologic disease amyotrophic 
lateral sclerosis (ALS), also known as Lou Gehrig’s disease. The standard dose used clinically for 
ALS is 50 mg PO bid. The chemical structures of riluzole is shown below. 
 
 
N
S
NH2
F3CO
Riluzole, 1
 
Figure 2.1. Chemical structure of riluzole.  
 
Preclinical data. Following treatment with riluzole, the Chen lab observed a reduction in the 
number of viable cells in two different GRM1-positive cell lines (C8161 and SKMEL187) while 
two different GRM1-negative human melanoma cell lines (UACC930 and C81-61) or normal 
human melanocytes (HEM) were less sensitive under similar conditions. They demonstrated a 
correlation between a decrease in released glutamate and the number of viable cells in riluzole-
treated C8161 cells, showing that high glutamate release may promote tumor cell growth.17,21 
 
The cystine-glutamate amino acid antiporter (xCT) is an obligate transporter that exchanges 
glutamate for cystine at 1:1 ratio, meaning for every one molecule of cystine that is pumped in, 
one molecule of glutamate is pumped out into the extracellular space. Once transported 
intracellularly, cystine is reduced into 2 molecules of cysteine, the rate-limiting precursor of 
glutathione (GSH) synthesis. In normal melanocytes, transport of cystine by xCT is utilized for 
cell proliferation, glutathione production, and protection of cells from oxidative stress. In 
melanoma cell lines, riluzole stimulates the expression of xCT, inhibiting the release of 
glutamate into the extracellular space.22  
 
In melanoma cell lines, inhibition of GRM1 blocks exosomal release of CCL4 and CSF1 (M-CSF), 
which normally recruit suppressive macrophages and exclude lymphocytes from infiltrating the 
tumor. This results in increased apoptotic death and pleotropic effects on the tumor 
microenvironment, including a decrease in the numbers of M2-type (suppressive) TAMs, myeloid-
derived suppressor cells (MDSCs) and regulatory T cells (T regs), and an increase in the numbers 
of tumor-infiltrating lymphocytes (TILs).  
 
Clinical trials. The group at Rutgers Cancer Institute of New Jersey evaluated riluzole for 
potential anti-cancer activity in Phase 0 and 2 clinical trials for advanced Stage III and IV 
melanoma, treating 25 patients in total. All of the patients (100%) had GRM1-positive tumors 
(100%).   
 
In the Phase 0 trial, riluzole (100 mg PO BID) was given to patients with advanced but resectable 
melanoma for two weeks, followed by surgical resection and tissue collection for 
pharmacodynamic analysis.23 Four out of 12 patients (34%) had a significant decrease in pAKT 
and/or pERK in post-treatment tumor samples as compared with their paired pretreatment 
sample. The same 4 patients had metabolic responses seen on FDG–PET scans despite a short 
duration of treatment (14 days) as seen in Figure 2.2.  
 


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Figure 2.2. A representative FDG-PET scan of one of the four patients that had a radiologic and metabolic response 
to 2 wk of riluzole administration in the Phase O trial. Pretreatment FDG-PET scan (left) and post-treatment scan 
(right) done 2 wk after the start of riluzole. There is a large decrease in the number of FDG-avid lymph nodes seen in 
the post-treatment scan, and the remaining node seen in the right panel has decreased in intensity by >40%. The 
three other patients who had metabolic responses had similar FDG-PET scan results. 
 
In the Phase 2 trial, there were no objective responses observed, but 6/13 patients who initially had 
rapidly progressive disease achieved stable disease and 4 of those patients maintained stable 
disease for 23-56 weeks. Riluzole was well-tolerated. There were no grade 4 or 5 adverse events, 
and grade 3 dizziness was seen in 5 patients (38%) but only one subject had to discontinue therapy 
due to dizziness. Pharmacokinetic analysis showed high inter-patient variability, consistent with 
prior riluzole studies. Markers of angiogenesis (VEGF, IL-8) were suppressed in the post-
treatment samples in 4/8 (50%) and 3 of them had clinical benefit (stable disease).24 Patients who 
had BRAF-mutated and B-RAF wild type tumors benefitted.   
 
Immune effects. Exploratory correlative studies demonstrated a pattern suggesting that the patients 
who had clinical benefit from riluzole treatment displayed multiple downstream markers of GRM1 
signaling inhibition, including suppression of MAPK, PI3K/AKT, and markers of angiogenesis. 
Additionally, two patients (#1 and #11) who derived clinical benefit from riluzole treatment 
displayed an increase in CD45+ leukocytes at the tumor-stromal interface (Figure 2.3a). Two 
patients who did not benefit from treatment did not show suppression of PI3K/AKT, angiogenesis, 
nor an increase in CD45+ cells at the interface (Figure 2.3b). The increase in leukocytes at the 
interface, or “active edge,” of the tumor may be mediated by inhibition of exosomes containing 
MCSF and CCL-2, which normally recruit tumor-associated macrophages (TAMs) and exclude 
tumor infiltrating lymphocytes (TILs).  
 
 
 
 
 
 
 
 
 
 
 
 
 
Therefore, the pattern of the correlate studies outcomes suggests that the patients who had 
clinical benefit from riluzole treatment displayed multiple downstream markers of GRM1 
signaling inhibition, including suppression of MAPK, PI3K/AKT, and markers of angiogenesis, 
Figure 2.3a. CD45 staining on fresh paired 
tumor biopsies from 2 patients with stable 
disease (SD). a) CD45 from patients 1 (a) and 
11 (b), before (left) and after (right) riluzole 
treatment, showing an increase in CD45+ 
cells in the tumor/stroma interface.  
Figure 2.3b. CD45 staining on fresh paired 
tumor biopsies from 2 patients with 
progressive disease (PD). a) CD45 from 
patients 6 (a) and 8 (b), before (left) and 
after (right) riluzole, showing a decrease in 
intratumoral CD45+ cells after treatment. 


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as well as an increase in leukocytes at the tumor-stroma interface. Put together, these factors 
suppress the growth of tumor cells and blood vessels and allow immune infiltrate into the edge of 
the tumor.  
 
These correlative data are consistent with the mounting evidence demonstrating that anti-
angiogenic agents can reprogram the immune milieu of the tumor microenviroment to improve 
the effectiveness of checkpoint blockade.25 Bevacizumab treatment was associated with a post-
treatment increase in T-cell infiltration in the tumor and increased MHC-Class I expression in 
patients with renal cell carcinoma and it improved the efficacy of the immune checkpoint 
inhibitor atezolizumab.26 The strategy of combining an angiogenesis inhibitor with an immune 
checkpoint inhibitor has now been validated in several clinical trials and has led to two 
combinations approvals, pembrolizumab plus lenvatinib for endometrial cancer27 and axitinib 
plus pembrolizumab or avelumab for first-line treatment of renal cell carcinoma.28,29 
 
2.4 Troriluzole 
 
i. Overview 
 
Mechanism of action. Troriluzole (formerly known as FC-4157, BHV-4157, and trigriluzole) is an 
investigational tri-peptide prodrug of riluzole with improved PK/PD properties. Riluzole was 
FDA-approved for ALS in 1995.  The mechanism of action of troriluzole, which is rapidly cleaved 
into riluzole, is not fully understood, is thought to be entirely due to the action of riluzole which 
blocks the release of glutamic acid and up-regulates the excitatory amino acid transporter EAAT2.  
Interruption of GRM1-mediated signaling by limiting the available ligand, glutamate, leads to 
intracellular build-up of glutamate. The build-up decreases the exchange of glutamate and cystine, 
which limits the availability of cysteine, a key component of L-Glutathione (GSH) synthesis. This 
process results in reduced intracellular GSH and enhanced cellular stress, genome instability and 
DNA damage.  
 
Pharmacologic advantages. Blood levels of riluzole are highly variable upon oral administration 
of riluzole due to its metabolism by a particular cytochrome P450 enzyme, Cyp1A2, which is 
variably expressed. We have discovered a novel Type IIb prodrug of riluzole, troriluzole, that 
minimizes this variable metabolism, readily releases the drug riluzole into the blood stream when 
given orally to mice, rats, cynomolgus monkeys and humans and is >20X more potent than riluzole 
itself in a mouse melanoma xenograft model.  
 
Highlights of the prodrug troriluzole include: 
o Troriluzole is stable in simulated gastric fluid (SGF) and simulated intestinal fluid 
with stability half-lives of >60 and 98 min respectively.  
o Troriluzole has adequate solubility (247 ug/mL) in a standard aqueous oral delivery 
vehicle (aqueous 2% Tween 80/0.5% methylcellulose) and high cellular 
permeability with no efflux potential.  
o Troriluzole is highly stable in mouse (MLM) and human (HLM) liver microsomes 
with half-lives greater than 1 h in both species. Riluzole is metabolized to N-
hydroxyriluzole in HLM containing high activity Cyp1A2 with a half-life of <30 
min, but is stable to HLM with low activity of Cyp1A2.  


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o Troriluzole is actively transported by the PepT1 transporter. 
 
Non-oncologic indications under investigation. Troriluzole is currently under investigation in 
phase 3 trials for spinocerebellar ataxia and generalized anxiety disorder. It is also in Phase 2 
studies for Alzheimer's dementia and obsessive-compulsive disorder.  In December 2019, 
Biohaven Pharmaceuticals announced that troriluzole successfully advanced past the interim 
futility analysis in the pivotal phase 2/3 Alzheimer's disease study, “T2 PROTECT AD.” 
 
ii. Supporting Preclinical Data for Troriluzole  
 
Troriluzole is highly effective in reducing melanoma tumor growth in a mouse xenograft 
experiment carried out for 14 days. In this experiment, nude mice were injected with melanoma 
cells (C8161 line) and developed tumors that were visible after one week. A dose of troriluzole 
corresponding to 20X less riluzole being formed, was as active as riluzole itself, showing a >20X 
increase in potency in this in vivo model of melanoma (Figure 2.4). 
 
 
Figure 2.4. Trogriluzole ("FC", 1.7 mg/kg) exhibits an increase in potency when compared to riluzole (7.5 mg/kg) 
in a mouse xenograft model of melanoma.  C8161 human melanoma cells (106) were inoculated in the flanks of nude 
mice and when the tumor volume reached 40 mm3 the mice were divided randomly into groups with similar tumor 
volumes: No treatment (NT), vehicle (Veh, DMSO), riluzole (Ril, 7.5 mg/kg), Troriluzole (FC) at 0.56 mg/kg, 1.7 mg/kg 
and 5 mg/kg.  Mice were treated daily by oral gavage.  Tumor volume (mm3) mean ±SD of 12 mice/group, P <0.001, for 
riluzole or troriluzole groups (regardless of dosage) compared to NT/Veh. 
 
iii. Supporting Preclinical Data for Troriluzole + PD-1 Inhibition 
 
Combination study in mouse model of melanoma. Very few preclinical animal studies have been 
carried out in immunotherapy due to lack of tumor growth in immunocompetent animal models. 
Many investigators have used the syngeneic mouse B16 melanoma model in C57BL/6 mice widely 
over the years. In B16 preclinical studies, combining CTLA-4 and PD1 blockade has been shown 
to increase CD8+cytotoxic and CD4+ helper T cell populations and to promote rejection of B16 
tumor allografts (compared to either one alone). In our studies, we isolated several stable clones 
(MASS) derived from immortalized C57BL/6 murine melanocytes (Melan-A) transfected with 
exogenous murine GRM1 cDNA. MASS clones were very tumorigenic in both immune-deficient 
nude mice and immune-competent syngeneic C57BL/6 mice, while the parental Melan-A cells and 
control clones transfected with empty vector, MelanA-Vec, were not tumorigenic even after 
several months. GRM1 receptors in MASS clones are responsive to agonists/antagonists of GRM1, 


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suggesting a functional receptor. 
 
We found that administering riluzole, troriluzole (FC-4157) or anti-PD-1 alone initially had no 
impact on inhibition of tumor outgrowth in this immunocompetent model. However, by Day 28, 
the combinations with anti-PD-1 demonstrated good tumor control (Figure 2.5).  
 
 
Figure 2.5. Troriluzole is active at Day 28 in combination with anti-PD-1 antibody in a MASS20 GRM-1 allograft 
mouse model, giving a similar response at ~10X less molar concentrations compared to riluzole itself. 105 
MASS20 cells were inoculated into flanks of C57BL/6 mice. When the tumor volumes reached ≈40 mm3, we randomly 
divided the tumor-bearing mice into vehicle 1 (DMSO), vehicle 2 (control rat IgG), riluzole (10 mg/kg) alone, anti-PD-1 
(100 µg/mouse/injection) alone, troriluzole (1.7 mg/kg) alone, combination of riluzole and anti-PD-1, and combination 
of troriluzole and anti-PD-1. The treatment was terminated at 25 days after start of the treatment as day 1. 
 
The role of exosome inhibition in the immunologic mechanism of action of troriluzole. Exosomes 
are naturally occurring small membrane enclosed microvesicles generated constitutively and 
released by fusion with the cell membrane by various cell types and more frequently by tumor 
cells. Hood et al. suggested an “exosomal messenger system” that facilitate communication within 
the local tumor microenvironment and is instrumental in melanoma cell dissemination and early 
events in metastasis. Studies show that melanoma exosomes “educate” bone progenitor cells to 
support tumor cell growth and metastasis, alter macrophage and dendritic cell functions, 
sometimes call “preparing the metastatic niche.” In a laboratory model, GRM1 activation leads to 
inhibition of release of exosomes containing MCSF and CCL-2,20 which create an 
immunosuppressive tumor microenvironment by promoting tumor-associated macrophages. Our 
preliminary results suggest that treatment with riluzole reduces exosome levels in vivo (Chen lab, 
unpublished data).     
 


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iv. Supporting Clinical Data for Troriluzole + PD-1 Inhibition 
 
Given the hypothesis that troriluzole treatment inhibits GRM1 signaling, thereby inhibiting 
release of exosomes, decreasing TAMs, and allowing lymphocytes into the tumor-stromal 
interface, and the compelling preclinical data the troriluzole enhances the antitumor activity of 
PD-1 immune checkpoint inhibitor, a phase Ib trial was conducted at a single site. The 
combination of troriluzole and nivolumab was found to be well tolerated. We enrolled 14 
patients with advanced solid tumors (melanoma = 3, NSCLC = 3, renal cell cancer = 2, NSCLC 
= 2, head and neck cancer = 2). Eleven patients had prior therapy with anti-PD-1 or anti-PD-L1. 
Patients were exposed to troriluzole doses from 140mg to 560mg total daily dose. Dose limiting 
toxicities (DLT) occurred in 3 patients which were characterized as 1) intolerable nausea in a 
patient who was subsequently diagnosed with brain metastases 2) grade 3 fatigue and 3) atrial 
fibrillation. No patient required more than one dose reduction. PK sampling demonstrated that 
the prodrug was cleaved efficiently without regard to food. The most common TEAEs (all 
grades) occurring in > 40% of patients were transaminitis, increased lipase and nausea. DLT 
occurred in 3 patients: 1) grade 3 anorexia, 2) grade 3 fatigue and, 3) atrial fibrillation. The MTD 
was determined to be troriluzole 140 mg QAM + 280 mg PO QPM. The response rate was 7 % 
(1/14); this occurred in a PD-L1 treated patient. The 6-month PFS rate was 21%.30 
 
2.5 Ipilimumab and Nivolumab 
 
Combination dual checkpoint inhibitor therapy with ipilimumab and nivolumab is an FDA 
approved regimen for metastatic melanoma.  As compared to PD-1 monotherapy, this 
combination is associated with a higher response rate.  An analysis of long-term overall survival 
from the Checkmate–067 study demonstrated that there is a 7% survival advantage at the 4-year 
mark (53% for ipilimumab plus nivolumab vs 46% for nivolumab alone).31  Immune therapy is 
used regardless of BRAF mutational status and in BRAF-mutant patients, it is used as a first-line 
regimen or following BRAF-directed therapy. 
 
The schedule of therapy is 4 cycles of induction where both ipilimumab and nivolumab are given 
on the same day in 3-week cycles.  Following this 12-week induction.  Patients are treated with 
nivolumab monotherapy for up to 2-years.  Combination therapy has a higher rate of grade 3 and 
4 toxicities (55%) as compared to single agent therapy, leading to treatment discontinuation in 
36% of patients.32  Patients who experience significant side effects during the induction period 
generally have an interruption in their therapy while they are requiring corticosteroids. Any 
remaining cycles of combination therapy are omitted, and upon recovery and discontinuation of 
steroids, the patient is treated with nivolumab monotherapy. If significant side effects occur on 
monotherapy, therapy is discontinued.  
 
While patients with untreated brain metastases were generally excluded from all of the early 
studies, a study published of dedicated to melanoma brain metastases, the Checkmate 204 study, 
was recently published.3 In neurologically asymptomatic patients with small volume brain 
metastases and no previous systemic therapy, the combination was shown to be an active 
regimen with a response rate of 48%.3 The response rate in symptomatic patients was far lower. 
The vast majority of patients have concordant responses in their intracranial and extracranial 
disease. Stereotactic radiotherapy (SRT) of one brain lesion was allowed on study. The response 


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rate in this study was 48% and the intracranial and the extracranial response rates were largely 
concordant.  The global PFS was 61% at the 6-month mark (Figure 2.6). Notably, the slope of 
the PFS curve began to flatten out and only decreased by 5% at the 12-month mark, after which 
time it remained relatively flat and the median PFS was not reached. This suggests that the 
weeks to months just after the diagnosis of brain metastases is a key period for intervention.   
 
 
Figure 2.6 PFS curve from the asymptomatic cohort of patients (n=94) in Check-Mate-204. 
 
The study did not identify any new safety signals. Treatment-related adverse event leading to 
discontinuation of treatment were observed in 27% of subjects, which is not higher than the rate 
in previous studies.32  Grade 3-4 treatment-related nervous system adverse events were observed 
in 8% of patients.  These and events included headache (4%), brain edema (1%), intracranial 
hemorrhage (1%), peripheral motor neuropathy (1%), and syncope (1%). 
 
2.6 Radiation Therapy 
Preclinical studies in melanoma and breast cancer cell lines and animal models have 
demonstrated that riluzole enhances the effectiveness of radiation therapy. To mimic brain 
metastases observed in melanoma patients, Wall et al developed an intracranial orthotopic 
transplant model of human melanoma.33 They injected C8161-luciferase expressing cells 
intracranially into immunodeficient nude mice and monitored tumor cell establishment using 
luminescent imaging.  Upon initial detection, animals were imaged bi-weekly to determine if 
riluzole could further sensitize orthotopic tumors to the effects of radiation therapy.  The results 
in the intracranial model show that riluzole and irradiation alone resulted in decreased 
luminescence compared to vehicle treated alone (Figure 2.7).  The combination of riluzole and 
irradiation resulted in enhanced reduction in tumor cell growth as suggested by luminescent 
signal detected. Similar outcomes were seen in a glioma model.  


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Figure 2.7. Intracranial transplants of human melanoma cells: Left: Week1: C8161-luc+ human melanoma cells 
were introduced into the brains of nude mice. Once luminescent signal was detected, animals were separated into 
groups and treated with either DMSO (Veh) or riluzole (Ril, 10 mg/kg), localized ionizing radiation (IR, 4 Gy) or a 
combination of the two (Ril+IR). Animals were terminated after 4 weeks of treatment. Images of animals showing 
initials and terminal images (Left: Week 1, Middle: Week 4). Right: The intensities of the emitted signal were 
quantified. The data were expressed as photon flux (photons/s/cm2/steradian, where steradian refers to the photons 
emitted). The background photon flux was subtracted from the signal intensities measured at the same site. Data were 
normalized to peak signal intensity of each time course. 
 
 
2.7 Rationale 
 
A key reason for resistance to immune checkpoint blockade is the lack of immune infiltrate in the 
tumor. In patients with metastatic melanoma, responses to PD-1 inhibitors are more frequent with 
an inflamed tumor microenvironment, distinguished by high numbers of TILs, high PD-L1 
expression, and increased gene expression of the immune-related profile. Thus, adjunct agents that 
can increase immune infiltration in the tumor microenvironment, or convert a “cold” tumor into a 
“hot” tumor, are rational combination strategies. In tumors devoid of infiltrating lymphocytes 
(immune desert), troriluzole treatment may inhibit release of the exosomes and decrease TAMs, 
allowing lymphocytes into the tumor-stromal interface, thereby, enhancing the antitumor activity 
of immune checkpoint inhibitors. This hypothesis is supported by preclinical observations using 
an immunocompetent mouse model of melanoma, which demonstrates that the combination of 


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troriluzole + PD-1 blocking antibody inhibited the outgrowth of tumors better than either agent 
alone (Fig. 2.5).  
 
There is an increasingly recognized intersection between antiangiogenic agents and 
immunotherapy.25 We have shown that riluzole decreases VEGF levels and increase the immune 
infiltrate in tumor specimens from melanoma patients.24 Others have shown that anti-angiogenic 
therapy can increase the efficacy of checkpoint blockade in uterine cancer and kidney cancer.27-29 
There are numerous ongoing clinical studies in various cancers using a similar rationale, 
combining immune checkpoint blockade with either an anti-angiogenesis agent (e.g. bevacizumab, 
ramucurimab), or a macrophage-directed agent (e.g. CSF1 antibody, IPI-549). However, our 
approach is unique in two ways: 1) that troriluzole is a pro-drug of a well-known entity riluzole 
that has been FDA-approved for a non-oncology indication for over two decades, and therefore 
the safety track record is superior, and 2) riluzole crosses the blood-brain barrier and synergizes 
with radiation therapy, making it well-suited for study in brain metastases. 
 
Despite recent advances, the care of patients with brain metastases due to melanoma remains 
very challenging. The FDA has called for inclusion of patients with brain metastases in trials of 
new agents, especially for diseases but commonly involve the CNS, and welcomed applications 
to expand an indication to include brain metastases.34  
 
Taking ipilimumab and nivolumab as the new standard of care for treatment of small 
asymptomatic melanoma brain metastases, the randomized phase 2 study described herein will 
attempt to build on the success of this regimen with the addition of troriluzole.  The starting dose 
of troriluzole was determined in the phase 1b study with nivolumab.  Patients in both arms may 
receive brain-directed stereotactic radiotherapy as needed. The rationale to include stereotactic 
radiosurgery in this trial is that it is standard of care to radiate isolated brain metastases and 
continue systemic therapy if it is otherwise effective, as was done in the Checkmate 2004 study.3  
As there is preclinical synergy with radiation therapy with troriluzole this is something we will to 
investigate further in this trial in a subset analysis. 
 
 
2.8 Correlative Studies Background 
 
The primary goal of the correlative science is to obtain an understanding of the effects of the 
three-drug regimen vs. the two-drug regimen upon anti-cancer immunological activity. To that 
end, this study will include the following correlative studies:  
 
• IHC on archival and fresh tumor samples. Tumors from patients who respond favorably to 
checkpoint blockade therapy showed higher pre-existing numbers of CD8, PD-1, and PD-
L1 expressing cells in the tumors and at the invasive tumor margin (tumor-stroma interface) 
compared to non-responders.35,36 Response rate are often observed to be approximately 3 
times higher in patients with tumors expressing high levels of PD-L1. IHC will be used to 
determine GRM1 expression, PD-L1 expression, the degree of TILs, and other immune 
effector cells, and on-treatment biopsies will be examined for change in TILS and decrease 
in signal transduction in key pathways (e.g. MAPK, Pi3K/AKT) and evidence of apoptosis 
(cleaved caspases). We hypothesize that nearly 100% of melanomas will have GRM1 


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overexpression.   
 
• Flow cytometry on PBMCs. Immunophenotypic analysis of immune cells and markers 
will be assessed by multiparameter flow cytometry.  We hypothesize that responders will 
display more favorable T cell population ratios, markers of activation, and differentiation, 
and fewer MDSCs. 
 
• Multiplex cytokine analysis on serum and CSF.  We hypothesize that responders will 
demonstrate a decrease in the expression of VEGF, IL-8, CD34, CCL2, and M-CSF. 
 
• Gene expression analysis by Nanostring on blood and tumor samples.  We hypothesize 
that responders will have a higher immune-related gene expression profile. We 
hypothesize there will be a decrease in oxidative phosphorylation genes post-treatment.  
 
• Tumor genomic profiling. We will determine if activating mutations in B-RAF or N-
RAS, or PTEN inactivation (or activating B-RAF mutations and PTEN inactivation 
together) in the pre-treatment tumor samples correlates with response to therapy.   
 
• Exosome analysis. We will examine exosome contents and hypothesize that post-
treatment serum samples will contain fewer suppressive cytokines than pre-treatment 
samples.  
 
 
 
3. PARTICIPANT SELECTION 
 
3.1 Eligibility Criteria  
 
3.101 Participants must have histologically or cytologically confirmed 
melanoma. All melanoma subtypes are included, except for ocular 
melanoma.  
 
3.102 Participants must have measurable disease in the brain (intraparenchymal 
brain metastases), defined as at least one lesion that can be accurately 
measured by MRI in at least one dimension as ≥5 mm and ≤ 3 cm in 
longest diameter. See Section 11 (Measurement of Effect) for the 
evaluation of measurable disease. Measurable disease in the extracranial 
compartment (body) is not required. Measurable lesions may not have 
received previous treatment with radiation therapy. Prior stereotactic 
radiation therapy or SRT (e.g. GammaKnife, CyberKnife) is allowed for 
lesions other than the lesions selected as measurable target lesions. Prior 
craniotomy with resection of brain metastases is allowed. 
 
3.103 Participants are allowed, but not required to have received prior systemic 
treatment with anti-PD-1 therapy (e.g. pembrolizumab, or nivolumab) in 
any setting (neoadjuvant, adjuvant or metastatic). Prior anti-CTLA-4 
monotherapy is allowed (e.g. ipilimumab). Prior targeted therapy (e.g. 


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BRAF inhibitors, MEK inhibitors) is allowed.  
 
3.104 Age ≥18 years.  Because no dosing or adverse event data are currently 
available on the use of troriluzole in participants <18 years of age, 
children are excluded from this study, but will be eligible for future 
pediatric trials.   
 
3.105 ECOG performance status 0 or 1 (see Appendix A). 
 
3.106 Participants must have adequate organ and marrow function as defined 
below: 
 
− 
absolute neutrophil count ≥1,000/mcL 
− 
total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN), or                                      
in the case of Gilbert’s disease ≤ 3x ULN 
− 
AST(SGOT)/ALT(SGPT) ≤3 × institutional ULN 
 
3.107 Human immunodeficiency virus (HIV)-infected participants on effective 
anti-retroviral therapy with undetectable viral load within 6 months are 
eligible for this trial. 
 
3.108 For participants with evidence of chronic hepatitis B virus (HBV) 
infection, the HBV viral load must be undetectable on suppressive 
therapy, if indicated. 
 
3.109 Participants with a history of hepatitis C virus (HCV) infection must have 
been treated and cured.  For participants with HCV infection who are 
currently on treatment, they are eligible if they have an undetectable HCV 
viral load. 
 
3.110 Participants with known history or current symptoms of cardiac disease, or 
history of treatment with cardiotoxic agents, should have a clinical risk 
assessment of cardiac function using the New York Heart Association 
Functional Classification.  To be eligible for this trial, participants should 
be class 2B or better. 
 
3.111 The effects of troriluzole on the developing human fetus are unknown.  
For this reason and because ipilimumab is a pregnancy category C, women 
of child-bearing potential and men must agree to use adequate 
contraception (hormonal or barrier method of birth control; abstinence 
from heterosexual intercourse) prior to study entry, for the duration of 
study participation, and 4 months after completion of all study drugs.  
Should a woman become pregnant or suspect she is pregnant while she or 
her partner is participating in this study, she should inform her treating 
physician immediately.  Men treated or enrolled on this protocol must also 
agree to use adequate contraception prior to the study, for the duration of 


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study participation, and 4 months after completion of all study drugs. 
 
3.112 Ability to swallow pills. 
 
3.113 Ability to understand and the willingness to sign a written informed 
consent document. 
 
3.2 Exclusion Criteria 
 
3.201 Ocular subtype of melanoma. 
 
3.202 Cytologically confirmed leptomeningeal metastases, or convincing 
imaging evidence of leptomeningeal spread.  
 
3.203 Prior whole brain radiation therapy (WBRT). 
 
3.204 Prior combination therapy with concurrent ipilimumab (3 mg/kg IV) + 
nivolumab (1 mg/kg IV) in the 24 months prior to the date of registration. 
 
3.205 Participants who have had systemic therapy (immunotherapy, 
chemotherapy, or targeted therapy), or major surgery within 3 weeks prior 
to the date of registration.  Participants who have had radiotherapy within 
10 days prior to the date of registration.  
 
3.206 Participants who require immediate local treatment (surgical resection or 
radiosurgery) of brain metastases due to neurological symptoms, or brain 
metastases located in sensitive areas of the brain requiring immediate local 
treatment.   
 
3.207 Participants who have required systemic steroids to manage neurologic 
symptoms (seizures, cerebral edema, severe headache, nausea/vomiting, 
etc.) within 1 week prior to the date of registration.   
 
3.208 Participants who are receiving any other investigational agents for cancer 
or neurologic disease.  
 
3.209 Extreme claustrophobia that would interfere with performing brain MRIs 
or severe allergy to gadolinium contrast.  
 
3.210 History of severe or life-threatening allergic reactions attributed to 
compounds of similar chemical or biologic composition to troriluzole, 
riluzuole, ipilimumab, or nivolumab.    
 
3.211 Second primary malignancy that is a competing cause of death in the 
opinion of the treating investigator (prognosis < 6 months).  
 


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3.212 Patients with a history of solid organ transplant, or allogeneic bone 
marrow transplant. 
 
3.213 Active autoimmune disease or any other condition requiring systemic 
treatment with either corticosteroids (>10 mg daily prednisone 
equivalents) or other systemic immunosuppressive medications within 3 
weeks of registration.  
 
3.214 History of grade 4 immune related adverse event from prior cancer 
treatment, (with the exception of asymptomatic elevation of serum 
amylase or lipase). 
 
3.215 History of immune-related adverse event from prior cancer 
immunotherapy treatment that has not improved to grade 0-1 (with the 
exception of patients with ongoing thyroid, adrenal or gonadal 
insufficiency requiring continued medical treatment, vitiligo, or 
asymptomatic elevation of serum amylase or lipase).  
 
3.216 Participants receiving any medications or substances that are inhibitors or 
inducers of the liver enzyme Cytochrome P-450 CYP1A2, including 
fluvoxamine, cimetidine, amiodarone, efavirenz, fluoroquinolones 
(including ciprofloxacin and levofloxacin), fluvoxamine, furafylline, 
interferon, methoxsalen, mibefradil, or ticlopidine. These medications 
must be discontinued at least 7 days prior to registration. 
 
3.217 Participants with uncontrolled intercurrent illness. 
 
3.218 Participants with psychiatric illness/social situations that would limit 
compliance with study requirements. 
 
3.219 Pregnant and nursing (breastfeeding) women are excluded from this study 
because the effects of troriluzole on the developing human fetus are 
unknown, and because ipilimumab is pregnancy category C. 
 
3.3 Inclusion of Women and Minorities 
 
Both men and women of all races and ethnic groups are eligible for this trial. 
 
 
4. REGISTRATION AND RANDOMIZATION PROCEDURES  
 
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 


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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. 
 
The eligibility checklist and all pages of the consent form will be faxed to the DF/HCC Office of 
Data Quality (ODQ) at 617-632-2295. The ODQ will (a) review the eligibility checklist, (b) 
register the participant on the protocol, and (c) when applicable, randomize the participant. 
 
Randomization can only occur during ODQ business hours (8:30am – 5pm Eastern Time, 
Monday through Friday excluding holidays).  
 
An email confirmation of the registration and/or randomization will be sent to the PI, study 
coordinator(s) from the registering site, treating investigator and registering person immediately 
following the registration and/or randomization. 
 
As this is a double-blinded study in the randomized portion (Part II), an email confirmation of 
the treatment assignment (troriluzole vs. placebo) will be sent to the investigational pharmacy 
team.  
 
Following registration, participants may begin protocol-specific therapy and/or intervention. 
Issues that would cause treatment delays should be discussed with the Principal Investigator (PI) 
of the registering site. 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 at DF/HCC by the Study Coordinator.  All 
sites should contact the Study Coordinator at DFC to verify slot availability: 
DFCIMelanomaCRCs@partnershealthcare.onmicrosoft.com 
 
The required form, the External Site Subject Registration Form, can be found in Appendix E. 
 
Following registration, participants should begin protocol therapy within 10 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 
 


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To register a participant, the following documents should be completed by the participating site 
and faxed (Fax # 617-582-8216) or e-mailed 
(DFCIMelanomaCRCs@partnershealthcare.onmicrosoft.com) to the Study Coordinator at DFCI: 
• Copy of brain MRI    
• Signed participant consent form 
• HIPAA authorization form (if not included in consent form) 
• Eligibility Checklist 
• External Site Subject Registration Form (Appendix E) 
 
The participating site will then contact the Study Coordinator at DFCI 
(DFCIMelanomaCRCs@partnershealthcare.onmicrosoft.com) to verify eligibility.  The Study 
Coordinator will follow DF/HCC policy (REGIST-101) and register the participant on the 
protocol.  The Study Coordinator will fax or e-mail the participant study number to the 
participating site.  The Study Coordinator will also contact the participating site and confirm 
registration. 
 
 
 
5. TREATMENT PLAN 
 
5.1 
Treatment Regimen 
 
Cycle length is variable during this protocol.  During the induction phase, cycles are 3 weeks.  
During the maintenance phase, cycles are 4 weeks. 
 
5.1.1 Safety Run-In:  
 
The starting dose of the Safety Run-In is outlined below.  Up to three cohorts of participants will 
be treated in a 3+3 design.  At the end of each cohort accrual of 3 participants, enrollment will 
pause for a comprehensive review of the safety data including dose-limiting toxicity (DLT).  A 
starting dose of Troriluzole at 140 mg/280 mg will be used.  If there are ≥2 DLTs as defined in 
Section 6.2, the fallback dose in cohort -1 will be used for three new participants accrued to 
Cohort -1.  If there are < 2 DLTs in the first three participants, an additional three participants 
will be added to the starting cohort.   From this point, if fewer than two patients within a cohort 
have DLTs then that dose level will be considered the MTD and enrollment to the randomized 
trial will begin. If two or more patients within a safety cohort have DLTs, then the dose will 
either be de-escalated, or the trial will stop.   A participant will be considered to have completed 
the DLT period with no dose limiting toxicities only if they have taken ≥ 80% of their assigned 
Troriluzole doses in the DLT period, which is the first 6 weeks of treatment.      
 
Table 5.11 Cohort de-escalation table during safety run-in: 
 
Dose Level 
Troriluzole Dose 
Starting cohort  
140 mg PO QAM and  
280 mg PO QPM 
Cohort -1 
140 mg PO BID 


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Cohort -2 
140 mg PO daily 
If ≥2 DLTs on Cohort -2 
Permanently stop the trial 
 
 
During the induction phase:  
Nivolumab (1 mg/kg) followed by ipilimumab (3 mg/kg) will be administered every 3 weeks, 
with 21 consecutive days defined as a treatment cycle. Troriluzole will be continuously self-
administered orally twice a day (at the dose level indicated by participant’s cohort).  
 
During the maintenance phase: 
Nivolumab (480 mg IV) will be administered every 4 weeks, with 28 consecutive days defined 
as a treatment cycle. Troriluzole will be continuously self-administered orally twice a day (at the 
dose level indicated by participant’s cohort). 
 
Treatment will be administered on an outpatient basis.  Reported adverse events and potential 
risks are described in Section 7.  Appropriate dose modifications are described in Section 6.  No 
investigational or commercial agents or therapies other than those described below may be 
administered with the intent to treat the participant’s malignancy. 
 
Table 5.12 
 
Regimen Description – Induction 
Agent 
Premedications; 
Precautions 
Dose 
Route 
Schedule 
Cycle 
Length 
Troriluzole  
Take with or 
without food.  
 
Twice 
daily per 
cohort 
assigned 
dose 
Oral, 140 mg 
capsules 
Days 1-21* 
3 weeks 
 
 
 
Nivolumab  
 
1 mg/kg 
over 30 
minutes** 
IV 
Day 1 
Ipilimumab 
 
3 mg/kg 
over 30 
minutes** 
IV 0-60 min 
after completion 
of nivolumab 
through 
separate IV line 
Day 1 
*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 
** Infusion time windows of -5 min/+ 10 min are allowed 
 
Regimen Description – Maintenance 
Agent 
Premedications; 
Precautions 
Dose 
Route 
Schedule 
Cycle 
Length 


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Troriluzole or 
placebo 
Take with or 
without food.  
 
Twice 
daily per 
cohort 
assigned 
dose 
Oral, 140 mg 
capsules 
Days 1-28* 
4 weeks 
 
 
 
Nivolumab 
 
 
 
480 mg 
over 30 
minutes** 
IV  
Day 1 
*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 
** Infusion time windows of -5 min/+ 10 min are allowed  
 
 
5.1.2 Randomized Treatment 
 
 
During the induction phase:  
Nivolumab (1 mg/kg) followed by ipilimumab (3 mg/kg) will be administered every 3 weeks, 
with 21 consecutive days defined as a treatment cycle. Troriluzole vs. placebo will be 
continuously self-administered orally twice a day (140 mg PO QAM and 280mg PO QPM**).  
 
During the maintenance phase: 
Nivolumab (480 mg IV) will be administered every 4 weeks, with 28 consecutive days defined 
as a treatment cycle. Troriluzole vs. placebo will be continuously self-administered orally twice a 
day (140 mg PO QAM and 280mg PO QPM**). 
 
**This is the anticipated MTD from the Safety Run-In.  If the Safety Run-In fallback cohorts are 
needed and the MTD is lowered, this will be amended. 
 
Treatment will be administered on an outpatient basis.  Reported adverse events and potential 
risks are described in Section 7.  Appropriate dose modifications are described in Section 6.  No 
investigational or commercial agents or therapies other than those described below may be 
administered with the intent to treat the participant’s malignancy. 
 
Table 5.13 
Regimen Description – Induction 
Agent 
Premedications; 
Precautions 
Dose 
Route 
Schedule 
Cycle 
Length 
Troriluzole or 
placebo 
Take with or 
without food.  
 
1 cap oral 
Q AM; 2 
caps oral 
QPM 
Oral, 140 mg 
capsules 
Days 1-21* 
3 weeks 
 
 
 
Nivolumab  
 
1 mg/kg 
over 30 
minutes** 
IV 
Day 1 


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Ipilimumab 
 
3 mg/kg 
over 30 
minutes** 
IV 0-60 min 
after completion 
of nivolumab 
through 
separate IV line 
Day 1 
*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 
** Infusion time windows of -5 min/+ 10 min are allowed 
 
 
Regimen Description – Maintenance 
Agent 
Premedications; 
Precautions 
Dose 
Route 
Schedule 
Cycle 
Length 
Troriluzole or 
placebo 
Take with or 
without food.  
 
1 cap oral 
Q AM; 2 
caps oral 
QPM 
Oral, 140 mg 
capsules 
Days 1-28* 
4 weeks 
 
 
 
Nivolumab 
 
 
 
480 mg 
over 30 
min** 
IV  
Day 1 
*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 
** Infusion time windows of -5 min/+ 10 min are allowed 
 
 
5.2 
Pre-Treatment Criteria 
 
Safety Run-In and Randomized Treatment:  
 
Cycle 1, Day 1. The subject must meet all eligibility criteria on Day 1. Baseline laboratory and 
clinical evaluations are to be conducted within 1 week prior to start of protocol therapy. If the 
participant’s condition is deteriorating, evaluations should be repeated within 48 hours prior to 
initiation of therapy. Complete blood count with differential and comprehensive metabolic panel 
results should be reviewed prior to treatment.  It is recommended that participants receive all 
indicated routine immunizations prior to the start of treatment (due to possible effect on 
immunologic correlative science and desire to minimize toxicity during the induction phase). 
 
Subsequent Cycles. Safety assessments, including complete blood count with differential and 
comprehensive metabolic panel results must be performed prior to administration of any study 
agent, excluding oral therapy, which is continuous. Study assessments and agents should be 
administered within + 7 days of the protocol-specified date for Days 1-309, and within + 14 days 
of the protocol-specified date for Days 337-673. 
 
5.3 
Agent Administration 
 


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Safety Run-In and Randomized Treatment: 
 
Administration and Dosing. As nivolumab and ipilimumab are FDA approved for metastatic 
melanoma, administration will follow institutional standard/package insert. The IV agents are not 
vesicants or irritants. No observation period is necessary. Doses of nivolumab and ipilimumab 
are weight-based during the induction phase. It is acceptable to use baseline weight for all 
induction cycles. In the instance that the institutional policy is more strict, institutional policy 
should be followed. Refer to table in Section 5.1. Details are provided below for reference.  
 
During the induction phase:  
Nivolumab (1 mg/kg) followed by ipilimumab (3 mg/kg) 0-60 minutes later will be 
administered every 3 weeks, with 21 consecutive days defined as a treatment cycle. 
Troriluzole vs. placebo will be continuously self-administered orally twice a day (140 mg 
PO QAM and 280mg PO QPM; or twice daily per cohort assigned dose if in Safety Run-
In). Due to toxicity, not all patients are expected to complete all 4 cycles of the induction. 
See section 6 for dosing modifications/omissions.  
 
During the maintenance phase: 
Nivolumab (480 mg IV) will be administered every 4 weeks, with 28 consecutive days 
defined as a treatment cycle. Troriluzole vs. placebo will be continuously self-
administered orally twice a day (140 mg PO QAM and 280mg PO QPM; or twice daily 
per cohort assigned dose if in Safety Run-In). 
 
Oral agents, troriluzole vs. placebo. Troriluzole or placebo in a blinded fashion will be 
self-administered orally with BID dosing Q 12 hours (± 2 hours).  On a continuous basis 
throughout the protocol. Capsules can be taken with or without food; if a patient 
experiences nausea, taking the capsule with food is recommended. Capsules cannot be 
crushed, chewed, or dissolved. If a dose has been missed or it is vomited up, it should be 
skipped. Patients may choose to use an antiemetic prior to taking troriluzole if needed.  
 
Order of administration: On Cycle 1 Day 1, the nivolumab will be administered first, followed 
by the ipilimumab, and in the evening, the first dose of troriluzole or placebo will be self-
administered at home. For subsequent cycles, troriluzole or placebo will be self-administered in 
the morning before coming to the outpatient infusion center, followed by the infusion(s), and 
then troriluzole will be self-administered in the evening.  
 
Management of infusion reactions: refer to institutional policy; see section 6.4 for additional 
guidance.  Steroids should be avoided as a routine premedication due to possible interference 
with the efficacy of the study agents. Pre-medications are not required but are allowed for 
patients with previous infusion reaction.   
 
Treatment Period.  
 
The treatment period of the induction phase is Day 1-84 (12 weeks).  
 
The treatment period of the maintenance phase is from Day 85 to 337 (36 weeks). Day 


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337 is the last protocol-directed infusion of nivolumab (see below) and the last dose of 
troriluzole.   
 
Adherence/Compliance. At the visit, each subject will be given a bottle containing capsules of 
study drug.  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. 
Unused study medication will be returned to the research pharmacy. At the end of each cycle of 
treatment, the actual amount of unused drug will be compared to the amount taken as recorded 
on the subject’s medication diary. The desired level of compliance is >75%. If a subject is below 
that threshold, the treating investigator should assess barriers to compliance and address any 
correctable barriers (e.g. antiemetic therapy). Patients who cannot maintain this level of 
compliance may be removed from the study at the discretion of the treating investigator.  
 
5.4 
End of Treatment 
 
Safety Run-In and Randomized Treatment: 
 
The End of Treatment (EOT) visit, Day 337 (or sooner if the patient discontinues active 
treatment) is the last dose of nivolumab and the last dose of Troriluzole vs. placebo.  EOT 
assessments are listed in Section 10 (Study Calendar).  
 
Participants removed from active protocol therapy for unacceptable adverse event(s) will receive 
management and supportive care for the adverse event until resolution or stabilization of the 
adverse event, per the treating investigator. During this time, participants must present for in-
person visits at least every 12 weeks ± 1 week. 
 
Following EOT, participants may continue on nivolumab therapy indefinitely, as it is FDA 
approved without a maximum duration. Continuation of nivolumab is not required for this 
protocol.  Patients who have completed the last dose of study medication (Day 337) should 
discuss their individual treatment plans with their treating physician.  See Section 5.9 for 
protocol-required follow up.  
 
 
5.5 
Concomitant Medication and Supportive Care Guidelines 
 
Safety Run-In and Randomized Treatment: 
 
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.  All concomitant medication will be recorded on the 
case report form (CRF) including all prescription, over-the-counter (OTC), herbal supplements, 
and IV medications and fluids.   
 
Selected acceptable medications include: 
• Antiepileptic (anti-seizure, anticonvulsant) medications. Exception: Carbamazepine, 
which is a CYP1A2 inducer, is prohibited.  


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• Erythropoietin 
• Hormone replacement therapy  
• Immunizations. Routine vaccinations are permitted but discouraged during Days 1-84 
when the most toxicity is expected. If the treating investigator feels that a vaccination is 
unsafe to delay (e.g. seasonal influenza immunization), the patient may receive the 
vaccination during Days 1-84. Vaccinations received during the study period should be 
documented as a concomitant medication. 
• Anticoagulation. Prophylactic or treatment-dose anticoagulation is permitted when 
indicated. ASCO has recently published new a guideline on venous thromboembolism 
prophylaxis and treatment in patients with cancer. Intracranial or CNS bleeding within 
the past 4 weeks is considered a relative contraindication to therapeutic anticoagulation.37 
• Steroids (dexamethasone, prednisone, etc.) – allowable indications 
o During study participation, neurologic symptoms may arise or worsen.  Steroids 
may be used to control neurologic symptoms. Steroid treatment ≤ 16 mg 
dexamethasone PO daily tapered in ≤ 4 weeks is allowed for the treatment of 
brain edema (single episode). If a second episode of brain edema requires steroid 
treatment, the Sponsor-Investigator must be consulted. 
o Systemic steroids may be used for treatment of irAEs. 
o A brief course (< 7 days) of corticosteroids for prophylaxis of side effects from 
SRT is permitted. 
o A brief course (< 7 days) of corticosteroids for prophylaxis (e.g., contrast dye 
allergy) or for treatment of non-autoimmune conditions (e.g., delayed-type 
hypersensitivity reaction caused by contact allergen) is permitted. 
o Intranasal, intra-articular, and inhaled steroids are acceptable for any indication. 
o NOTE: Patients who receive systemic corticosteroids for any reason (including 
toxicity or management of symptoms brain metastases) must be off 
corticosteroids or have tapered down to an equivalent dose of prednisone 10 
mg/day (dexamethasone ≤1.5 mg PO daily) or less to continue immune 
checkpoint therapy.   
 
Prohibited Medications  
• Systemic steroids for indications other than the indications above 
• No investigational or commercial agents or therapies other than those described below 
may be administered with the intent to treat the patient’s malignancy.   
• Prophylactic use of colony stimulating factors (CSFs) are not permitted. They may be 
needed for supportive care and should be discontinued when the event resolves/improves. 
If needed longer than 4 weeks, the subject must discontinue study treatment. 
• IVIG 
 
5.6 Concomitant Brain-Directed Stereotactic Radiation therapy during the study 
 
Safety Run-In and Randomized Treatment: 
 
Permitted Therapy: Brain-directed Stereotactic Radiotherapy (SRT), also called stereotactic 
radiosurgery (SRS). If a subject demonstrates clinical benefit, but disease progression in ≤ 4 
intracranial metastases occurs, the investigators may prescribe SRT (single episode), and 2 


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scenarios are permitted as detailed below.  
• 
If the patient is clinically stable, progression should be confirmed by follow-up 
imaging after 4 weeks. If progression is confirmed, the patient may undergo SRT 
treatment (single episode in 1 – 5* fractions) for ≤ 4 lesions and may receive ≤ 16 mg 
dexamethasone PO daily tapered in ≤ 4 weeks. Treatment with the study drugs can be 
resumed after taper completion as long as the patient does not demonstrate criteria for 
discontinuation.  
Note: Treatment in 5 fractions is generally indicated for lesions in critical 
anatomical locations, such as in the brainstem or abutting the optic chiasm.  
• 
If the patient is symptomatic as a result of the disease progression, and clinical 
assessment indicates a requirement for SRT without the delay imposed by the 4 week 
confirmatory scan, the patient may undergo SRT and may receive ≤ 16 mg 
dexamethasone PO daily tapered in ≤ 4 weeks. Treatment with the study drugs can be 
resumed after the completion of the taper as long as the patient does not demonstrate 
criteria for discontinuation. 
 
As a general guide, efforts should be made to avoid radiotherapy within 2 weeks after a 
treatment of either nivolumab + ipilimumab combination therapy or nivolumab monotherapy and 
avoid treatment resumption until at least 1 treatment-cycle length after radiotherapy. 
 
These guidelines are adapted from a previous protocol (Tawbi, et al) that allowed SRT for ≤ 3 
lesions,3 and adapted as per Aoyama, et al to allow SRT to up to 4 lesions.6 The ability to use 5 
fractions for lesions in anatomically critical areas as described above is a second adaptation.   
 
Administration of SRT and size of irradiated target lesions will be recorded on case report forms. 
The data from subjects who receive on-study SRT will be analyzed as a “radiation salvage” 
subgroup.  
  
Permitted Therapy: Palliative Radiotherapy to a non-target lesion. Radiation therapy may be 
performed to palliate an extracranial tumor as long as it is not a target lesion for tumor assessment. 
 
5.7 Concomitant Surgery therapy during the study 
 
Safety Run-In and Randomized Treatment: 
 
If a subject has disease progression in the brain and craniotomy or other skull surgery is 
recommended per standard of care, a single surgical intervention is permitted with the approval 
of the Sponsor-Investigator. To remain on-study, the subject must have remaining measurable 
disease in the brain. 
 
Surgery for non-cancer indications may be allowed. The case should be discussed with the 
Sponsor-Investigator. 
 
5.8 Criteria for Taking a Participant Off Protocol Therapy 
 
Safety Run-In and Randomized Treatment: 


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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 
until Day 337 or until one of the following criteria applies: 
 
• 
Disease progression, with the following exceptions: 
• 
To allow for the possibility of pseudoprogression, investigators may continue to 
treat a patient beyond progression until the next assessment if the investigator 
believes the patient is clinically benefitting (must document in progress note). If 
PD is confirmed on a subsequent scan, therapy must be discontinued. 
• 
Investigators may continue to treat a patient beyond progression if the progressing 
lesion(s) can be addressed with brain-directed SRT (See Section 5.6).  NOTE: To 
continue on study after SRT, the subject must have at least 1 non-irradiated target 
lesion and/or non-target lesion in the brain or body. 
 
• 
Intercurrent illness that prevents further administration of treatment 
 
• 
Unacceptable adverse event(s) 
 
• 
Participant demonstrates an inability or unwillingness to comply with the oral 
medication regimen and/or documentation requirements 
 
• 
Participant decides to withdraw from the protocol therapy 
 
• 
General or specific changes in the participant's condition render the participant 
unacceptable for further treatment in the judgment of the treating investigator 
 
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 participant’s 
status must be updated in OnCore in accordance with REGIST-OP-1. 
 
 
5.9 Duration of Follow Up 
 
Safety Run-In and Randomized Treatment: 
 
Participants will be followed with in-person visits on Days 421, 505, and 589, or until death, 
whichever occurs first. If they are receiving additional nivolumab, this should be documented in 
the progress notes and reported in the case report forms.  Treatment-emergent AEs should 
continue to be monitored during the follow-up period (until resolution).  New AEs during follow 
up that are not related to treatment should not be recorded. 
 


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Tumor assessments will be performed as per standard of care during Days 421-589 and will be 
captured on CRFs.  
 
Day 673 is the last required in-person visit. Subjects will continue to be contacted (or their charts 
will be accessed) for information on subsequent therapy and vital status for a total of 3 years.  
The study team will contact participants by phone every 12 weeks (+/- 14 days) to assess 
survival.  
 
 
 
5.10 Criteria for Taking a Participant Off Study 
 
Safety Run-In and Randomized Treatment: 
 
Participants will be removed from study (including study follow-up) 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 the 
participant’s status is updated in OnCore in accordance with REGIST-OP-1. 
 
5.11 Requests for Unblinding 
 
Only applicable for Randomized Treatment: 
 
Requests for unblinding may be granted under the following circumstances 
 
1. Emergency unblinding- If there is a serious adverse event or other severe illness and the 
study drug is suspected to be a factor, a request for unblinding may be submitted to the 
study team/pharmacy.  It is preferable that the decision to unblind is discussed with the 
Principal Investigator, but the treating investigator holds the final authority to request 
emergency unblinding to protect the safety of participants.  The study team will contact 
the pharmacy to facilitate unblinding.   
a. Contact #1 for Emergency Unblinding: 
David Husselbee – Research Manager  
Telephone: 617-632-6704    //     Fax: 617-582-8216 
David_Husselbee@DFCI.HARVARD.EDU 
b. Contact #3 for Emergency Unblinding: 
DFCI CRC General Inbox 
DFCIMelanomaCRCs@partnershealthcare.onmicrosoft.com 
  
 


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24-hour contact for emergency unblinding: 
 
 
Ann W. Silk, MD 
 
 
Pager: Call (617) 632-3352 for beeper # 41109 
 
2. Elective unblinding – Patients or their treating investigators who would like to know if 
they have received troriluzole or not may request unblinding from the study team on Day 
365.  Unblinding will be facilitated by the study team members: 
a. John Collantes – Study Coordinator 
Telephone: 617-632-3469    //     Fax: 617-582-8216 
JohnV_Collantes@dfci.harvard.edu 
b. David Husselbee – Research Manager  
Telephone: 617-632-6704    //     Fax: 617-582-8216 
David_Husselbee@DFCI.HARVARD.EDU 
 
 
3. Final Unblinding 
  
The official, final database will not be unblinded until medical/scientific review has been 
performed, protocol deviations have been identified, and data have been declared final and 
complete.  
  
The final unblinding will include distribution of a subject letter to participants and subject 
treatment information to study investigators.  Final unblinding will occur after enrollment has 
been completed and the Sponsor-Investigator has determined that study data are final and 
complete.    
  
A planned futility interim analysis will be conducted during the randomized trial. 
Blinding to treatment assignment will be maintained at all investigational sites at the time 
of the futility analysis. The unblinded results of interim analyses will not be shared with the 
investigators prior to the completion of the study. Subject-level unblinding will be restricted 
to an unblinded statistician and scientific programmer performing the futility analysis. 
  
The Sponsor-Investigator will serve as the primary reviewer of the results of the 
interim analysis and will follow the protocol-defined guidance in making a decision on 
discontinuation of the study or modification.   
  
Subject Letter. 
At the close of the trial after unblinding, a letter is to be sent by the investigator to those 
subjects who received placebos or investigational product to provide information on the 
trial and include the following advice: 
  
“You have participated in a trial conducted by Dana-Farber Cancer Institute under the 
sponsorship of Biohaven Pharmaceuticals. This is to advise you that you were among 
those who received a look-alike capsule created by the Sponsor to resemble the study 
drug troriluzole as much as possible. You did not receive the active drug troriluzole as 
manufactured by Biohaven Pharmaceuticals.” 


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Or 
  
“You have participated in a trial conducted by Dana-Farber Cancer Institute under the 
sponsorship of Biohaven Pharmaceuticals.  This trial included participants that received 
active drug and participants that received a look-alike capsule created by the Sponsor to 
resemble the study drug and act as a placebo.  This is to advise you that you were among 
those who received the active drug troriluzole as manufactured by Biohaven 
Pharmaceuticals.” 
 
 
 
6. DOSING DELAYS/DOSE MODIFICATIONS 
 
6.1 
General considerations  
 
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. A 
copy of the CTCAE version 5.0 can be downloaded from the CTEP website 
 http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.  
 
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) and do not constitute a protocol violation. Subjects should be placed back on study 
therapy within 4 weeks of the missed dose, unless otherwise discussed with the study PI. The 
reason for interruption should be documented in the patient's study record. The maximum dose 
interruption of the checkpoint inhibitors (no administrations) for any reason is 84 calendar days 
(12 weeks). The maximum dose interruption of the Troriluzole for any reason is 42 calendar days 
(6 weeks). Missed doses are not to be made up; efforts will be made to get the patient back on the 
original schedule so that assessments are uniform across subjects. 
 
For AEs unrelated to study drug(s), therapy may be held/resumed at the discretion of the treating 
investigator.  Treatment-emergent AEs should continue to be monitored during the follow-up 
period (until resolution).  New AEs during follow up that are not related to treatment should not 
be recorded 
 
6.2 
Dose Limiting Toxicities 
 
For patients participating in the safety run-in, the following definition of dose-limiting toxicities 
(DLT) will be used:  
 
The occurrence of any AE that meets all three of the following criteria: 
1. Grade ≥3 toxicity or select grade 2 neurologic toxicity lasting 4 days or more, with or 
without medical intervention:  
• Ataxia 
• Central nervous system necrosis (use this term for radiation necrosis) 


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• Cognitive disturbance  
• Concentration impairment  
• Depressed level of consciousness 
• Dizziness 
• Encephalopathy  
• Guillain-Barre syndrome  
• Headache 
• Intracranial hemorrhage 
• Ischemia cerebrovascular  
• Leukoencephalopathy 
• Memory impairment 
• Presyncope 
• Reversible posterior leukoencephalopathy syndrome (PRES) 
• Stroke 
• Somnolence 
Confusion (categorized under Psychiatric disorders) 
2. Occurred during the DLT evaluation period (i.e., occurred during the first 6 weeks of 
therapy), and  
3. Judged by the treating investigator to be possibly, probably or definitely related to 
troriluzole. Grade ≥3 toxicities that are related to ipilimumab and/or nivolumab but are 
unlikely related or not related to troriluzole are not considered DLTs. See Section 6.7 for 
list of Overlapping toxicities (“shared AEs”). Troriluzole therapy will be continued if 
there is an interruption in checkpoint therapy due to AE, and the AE is unlikely related or 
unrelated to troriluzole. Troriluzole and corticosteroids can be taken concurrently.   
 
 
6.3 
Troriluzole 
 
General 
 
Troriluzole therapy will be continued if there is an interruption in checkpoint therapy due to AE, 
and the AE is unlikely related or unrelated to troriluzole. Troriluzole and corticosteroids can be 
taken concurrently.  Nivolumab and/or ipilimumab may still be given if Troriluzole is held or 
discontinued, if AE is unlikely related or unrelated to the checkpoint inhibitor treatments. 
 
The maximum amount of time that troriluzole can be held continuously is 6 weeks. If the patient 
cannot resume troriluzole within 6 weeks, the patient will be removed from the study.  
 
If a participant experiences multiple adverse events and there are conflicting recommendations, 
the investigator should use the recommended dose adjustment that reduces the dose to the lowest 
level. 
 
Holding criteria 
 
Troriluzole vs. placebo will be omitted and dose reduced for related AEs as follows.  
 


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36 
Grade 1 
For grade 1 events, dose holding is not required.  If the grade 1 toxicity is intolerable to the patient, 
the drug may be held for 1 week at a time without lowering the dose. If drug is held for >1 week 
at a time, drug will be dose-reduced one level upon resumption. The intolerable nature of the AE 
must be documented as the reason for holding drug.  
 
Grade 2 
For grade 2 events, dose holding is required. When troriluzole is interrupted for an AE, the toxicity 
should be continually reassessed until it improves to Grade ≤1, on approximately a weekly basis, 
which can be done remotely by telephone and/or lab assessment. If patient is able to resume drug 
≤1 week, drug will be continued at the same dose, or, at the discretion of the treating investigator, 
it may be dose-reduced.  If drug is held for >1 week at a time, it should be dose-reduced one level 
upon resumption. If grade 2 AE meets criteria for DLT (see section 6.2), troriluzole should be 
dose-reduced one level upon resumption. 
 
Grade 3 
For grade 3 events, dose holding is required. When troriluzole is interrupted for an AE, the toxicity 
should be continually reassessed until it improves to Grade ≤1, on approximately a weekly basis, 
which can be done remotely by telephone and/or lab assessment. If the treating investigator 
believes permanent discontinuation is in the best interest of the patient (e.g. anaphylaxis), 
Troriluzole may be permanently discontinued after a discussion between the treating investigator 
and principal investigator.  If the patient is able to resume drug, drug will be dose-reduced one 
level.  
 
Grade 4 
For grade 4 events, dose holding is required. When troriluzole is interrupted for an AE, the toxicity 
should be continually reassessed until it improves to Grade ≤1, on approximately a weekly basis, 
which can be done remotely by telephone and/or lab assessment. If the treating investigator 
believes permanent discontinuation is in the best interest of the patient (e.g. anaphylaxis), 
troriluzole may be permanently discontinued after a discussion between the treating investigator 
and principal investigator.  If the patient is able to resume drug, drug will be dose-reduced two 
levels.  
 
Troriluzole vs. Placebo Dose Reductions 
 
No specific management is indicated when troriluzole vs. placebo is held, other than supportive 
care. When therapy resumes, the dose must be reduced by one level per the table below. The 
maximum number of dose reductions is 2 as shown in the following de-escalation table. 
 
Dose reductions for troriluzole 
 
Dose Level 
 
Troriluzole vs. Placebo Dose 
 
0 
140 mg PO QAM and 280 mg PO QPM 
-1 
140 mg PO BID 
-2 
140 mg PO daily 


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Intra-participant dose reescalation. Intra-participant dose reescalation is allowed.  At the 
discretion of the treating physician, a patient who has previously been dose-reduced may re-
escalate up to the starting dose.  No patient should take more than the starting dose (Cohort 0).  
For example, if a AE improves with additional supportive measures (antiemetics, etc), or an 
alternate cause of the AE is identified, the physician and patient may opt to re-escalate. 
 
6.4 
Ipilimumab and Nivolumab 
 
Dose modifications for nivolumab in combination with ipilimumab by adverse event type are 
detailed in Table 6.1.  No dose reductions are allowed.  General considerations for holding the 
dose(s) are as follows.  
 
For the initial induction period, patients with Grade 2 or 3 events requiring 
discontinuation of treatment with the combination may consider continuing treatment with 
single agent nivolumab when the event resolves to grade 0-1 (or baseline, when baseline 
grade is >1). If induction cycles (Ipilimumab + Nivolumab) are held, they will be omitted, not 
delayed.   
 
 
Nivolumab monotherapy may be continued at treating investigator discretion if there is evidence 
of clinical benefit. In this event, patient will continue nivolumab until AE is resolved and 
ipilimumab may be re-started or if ipilimumab is permanently discontinued (in congruence with 
guidelines in table below), then patient will continue nivolumab alone until cycles are completed.  
At completion of 4 dose of combination IPI + NIVO, patient may continue on nivolumab alone, 
as per protocol. If ipilimumab is permanently discontinued prior to receipt of 4 doses, nivolumab 
dosing should remain at the induction dosing (refer to Section 5) until completion of induction, 
and should then switch to maintenance dosing (refer to Section 5). 
 
Example: Following IPI + NIVO treatment on Day 22, there is a grade 3 AE and Day 43 
is held. The patient is treated with steroids and the grade 3 AE resolves quickly. The 
patient has been tapered down to a steroid dose of prednisone 5 mg po daily by Day 64 
and the investigator wishes to continue protocol therapy with nivolumab monotherapy. 
The patient will receive nivolumab (induction dosing) on Day 64, and then continue as 
per the Study Calendar. 
 
In addition to the AEs identified in the table below, ipilimumab and nivolumab dose should be 
delayed for any AE, laboratory abnormality or inter-current illness which, in the judgment of the 
treating investigator, warrants delaying the dose of study medication. 
 
NOTE: Patients who receive systemic corticosteroids for any reason (including toxicity or 
management of symptoms brain metastases) must be off corticosteroids or have tapered down to 
an equivalent dose of prednisone 10 mg/day (dexamethasone ≤1.5 mg PO daily) or less to 
continue immune checkpoint therapy.   
 
Maximum delay: The maximum amount of time that checkpoint inhibitor(s) can be held 
continuously is 12 weeks. If the patient cannot resume therapy within 12 weeks, the patient will 


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be removed from treatment with checkpoint inhibitor.  
 
Patients requiring a delay of > 12 weeks due to ongoing immune-related toxicity or inability to 
taper prednisone to ≤10 mg PO daily (dexamethasone ≤1.5 mg PO daily) must go off checkpoint 
inhibitor therapy entirely. 
 
 
Table 6.1 Dose Modification for Related Adverse Events 
Treatment-
related Adverse 
Event 
Grade of 
Event 
Nivolumab or Nivolumab/Ipilimumab 
Nausea 
≤ Grade 1 
No dose modification  
Grade 2 
Hold until ≤ Grade 1 OR baseline 
(exceptions as noted below) 1      
Grade 3 
Off nivolumab and/or ipilimumab treatment 
(exceptions as noted below) 1  
Grade 4 
Off nivolumab and/or ipilimumab treatment 
 Recommended management:  antiemetics. 
 
Diarrhea 
(immune-related 
enterocolitis) 
≤ Grade 1 
No dose modification  
Grade 2 
Hold until ≤ Grade 1 OR baseline   
Grade 3 
Off nivolumab and/or ipilimumab treatment 
(exceptions as noted below) 1  
Grade 4 
Off nivolumab and/or ipilimumab treatment 
 Recommended management:  Loperamide antidiarrheal therapy 
Dosage schedule:  4 mg at first onset, followed by 2 mg with each loose 
motion until diarrhea-free for 12 hours (maximum dosage:  16 mg/24 hours) 
Adjunct anti-diarrheal therapy is permitted and should be recorded when used. 
Please evaluate pituitary function prior to starting steroids if possible without 
compromising acute care.   
Evaluation for all patients for additional causes includes C. diff, acute and self-
limited infectious and foodborne illness, ischemic bowel, diverticulitis, and IBD. 
 
Vomiting 
≤ Grade 1 
No dose modification  
Grade 2 
Hold until ≤ Grade 1 OR baseline 
(exceptions as noted below) 1      
Grade 3 
Off nivolumab and/or ipilimumab treatment 
(exceptions as noted below) 1  
 
Grade 4 
Off nivolumab and/or ipilimumab treatment 
 Recommended management:  antiemetics. 
 
Other GI  
≤ Grade 1 
No dose modification  
Grade 2 
Hold until ≤ Grade 1 OR baseline 
(exceptions as noted below) 1    
Grade 3 
Off nivolumab and/or ipilimumab treatment 
(exceptions as noted below1)   
 
Grade 4 
Off nivolumab and/or ipilimumab treatment 
Patients with Grade 2 or 3 N-V should be evaluated for upper GI inflammation 
and other immune related events.   
 
Neurologic 
≤ Grade 1 
No dose modification  


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39 
Treatment-
related Adverse 
Event 
Grade of 
Event 
Nivolumab or Nivolumab/Ipilimumab 
events (new, 
motor, sensory, 
encephalitis, or 
intracranial 
hemorrhage)* 
Grade 2 
Hold until ≤ Grade 1 OR baseline 
(exceptions as noted below) 1      
Grade 3 
Off nivolumab and/or ipilimumab treatment 
(exceptions as noted below) 1  
Grade 4 
Off nivolumab and/or ipilimumab treatment 
 
* Intralesional bleeding events are common in melanoma. Patients with grade 
2 intracranial hemorrhage (“moderate symptoms; intervention indicated”) may 
be treated with antiepileptic medication and/or corticosteroids as indicated. 
Treatment may be held until symptoms improve to grade 1 (asymptomatic).  
For extralesional bleeding events, a repeat brain MRI may be indicated prior to 
resuming treatment, at the discretion of the treating investigator.  
 
Fatigue 
≤ Grade 1 
No dose modification  
Grade 2 
No dose modification 
≥Grade 3 
Off nivolumab and/or ipilimumab treatment 
(exceptions as noted below) 1 – if fatigue is 
found related to endocrinopathy and 
clinical symptoms are managed with 
hormone replacement, patient resume 
therapy 
Grade 4 
Off nivolumab and/or ipilimumab treatment 
Fatigue is the most common adverse event associated with immune 
checkpoint therapy.  Grade 2 or greater fatigue should be evaluated for 
associated or underlying organ involvement including pituitary, thyroid, and 
hepatic, or muscle (CPK) inflammation 
 
Fever 
≤ Grade 1 
Evaluate and continue  
Grade 2 
Hold until ≤ Grade 1  
Grade 3 
Hold until ≤ Grade 1 
Grade 4 
Off nivolumab and/or ipilimumab treatment 
Patients with fever should be evaluated as clinically appropriate.  Patients may 
experience isolated fever during infusion reactions or up to several calendar 
days after infusion.  Evaluation over the course of 1-2 weeks should be done 
for other autoimmune events that may present as fever 
 
Skin drug-
related AE 
≤ Grade 1 
No dose modification  
Grade 2 
Hold until ≤ Grade 1 OR baseline 
(exceptions as noted below) 1      
Grade 3 
Off nivolumab and/or ipilimumab 
treatment (exceptions as noted below) 1  
Grade 4 
Off nivolumab and/or ipilimumab 
treatment 
Patients with purpuric or bullous lesions must be evaluated for vasculitis, 
Steven-Johnson syndrome, TEN, and autoimmune bullous disease including 
oral lesions of bullous pemphigus/pemphagoid.  Pruritus may occur with or 
without skin rash and should be treated symptomatically if there is no 
associated liver or GI toxicity.  Note skin rash typically occurs early and may 
be followed by additional events particularly during steroids tapering.   
 


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Treatment-
related Adverse 
Event 
Grade of 
Event 
Nivolumab or Nivolumab/Ipilimumab 
Pneumonitis, 
broncho-spasm, 
pulmonary 
toxicity or 
interstitial lung 
disease 
≤ Grade 1 
No dose modification.  
Grade 2 
Hold dose pending evaluation. Consider 
pulmonary and/or ID consultation. Resume 
if an alternative diagnosis is rendered.  
Grade 3 
Off nivolumab and/or ipilimumab treatment 
Grade 4 
Off nivolumab and/or ipilimumab treatment 
Above does not include infusion reactions.  
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 killed vaccine for all patients. 
 
Thrombocyto-
penia 
≤ Grade 1 
No dose modification  
Grade 2 
Hold until ≤ Grade 1 OR baseline 
(exceptions as noted below) 1      
Grade 3 
 Off nivolumab and/or ipilimumab treatment  
Grade 4 
 
Off nivolumab and/or ipilimumab treatment 
 
Neutropenia 
≤ Grade 1 
No dose modification  
 
 
Grade 2 
Hold until ≤ Grade 1 OR baseline 
(exceptions as noted below) 1      
Grade 3 
 Off nivolumab and/or ipilimumab treatment  
Grade 4 
 
Off nivolumab and/or ipilimumab treatment 
  
Renal 
≤ Grade 1 
No dose modification 
Grade 2 
Hold until ≤ Grade 1 (or baseline) 
Grade 3 
Off nivolumab and/or ipilimumab treatment   
Grade 4 
 
Off nivolumab and/or ipilimumab treatment 
  
Endocrine 
Hypophysitis 
Adrenal 
Insufficiency 
≤ Grade 1 
No dose modification  
Grade 2 
Hold until patients are on a stable 
replacement hormone regimen. If treated 
with steroids patients must be stable off 
steroids for two weeks.      
Grade 3 
Hold until patients are on a stable 
replacement hormone regimen.  If treated 
with steroids patients must be stable off 
steroids for two weeks. 
Grade 4 
Off nivolumab and/or ipilimumab treatment 


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Treatment-
related Adverse 
Event 
Grade of 
Event 
Nivolumab or Nivolumab/Ipilimumab 
Note all patients with symptomatic pituitary enlargement, exclusive of hormone 
deficiency, but including severe headache or enlarged pituitary on MRI 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.  
Please evaluate pituitary function before beginning steroid therapy or 
replacement therapy of any kind.  
Note patients with thyroiditis may be retreated on replacement therapy.  
Patients must be evaluated to rule out pituitary disease prior to initiating thyroid 
replacement. 
 
Abnormal liver 
function 
(AST/ALT, Total 
bilirubin, 
immune-related 
hepatitis) 
≤ Grade 1 
No dose modification  
Grade 2 
Hold until ≤ Grade 1 OR baseline 
(exceptions as noted below) 1      
Grade 3 
Off nivolumab and/or ipilimumab treatment  
Grade 4 
Off nivolumab and/or ipilimumab treatment 
Continued treatment of active immune mediated hepatitis may exacerbate 
ongoing inflammation.  Holding drug to evaluate LFT changes and early 
treatment are recommended.   
LFT changes may occur during steroid tapers from other events and may 
occur together with other GI events including cholecystitis/pancreatitis. 
 
Amylase or 
lipase, 
associated with 
GI symptoms 
≤ Grade 1 
No dose modification  
Grade 2 
Hold until ≤ Grade 1 OR baseline 
(exceptions as noted below) 1      
Grade 3 
Hold until baseline and asymptomatic. 
Patients who develop symptomatic 
pancreatitis or DM must be taken off 
treatment 
Grade 4 
Off nivolumab and/or ipilimumab treatment 
Patients may develop symptomatic and radiologic evidence of pancreatitis as 
well as DM and DKA.  Lipase elevation may occur during the period of steroid 
withdrawal and with other immune mediated events or associated with colitis, 
hepatitis, and patients who have asymptomatic lipase elevation typically have 
self-limited course and may be retreated.  
Any other 
laboratory 
abnormality 
(except 
AST/ALT, Total 
bilirubin, 
thrombocytope
nia, 
neutropenia, 
lymphopenia)  
≤ Grade 1 
No change. 
Grade 2 
No change. 
Grade 3 
Off nivolumab and/or ipilimumab treatment 
unless is unrelated to underlying organ 
pathology and can be managed with 
electrolyte replacement, hormone 
replacement, insulin, or no therapy   
Grade 4* 
 Off nivolumab and/or ipilimumab treatment 
unless is unrelated to underlying organ 
pathology and can be managed with 
electrolyte replacement, hormone 
replacement, insulin, or no therapy   


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Treatment-
related Adverse 
Event 
Grade of 
Event 
Nivolumab or Nivolumab/Ipilimumab 
*  Grade 4 lymphopenia or leukopenia or does not 
require drug discontinuation. 
*  Isolated Grade 4 electrolyte 
imbalances/abnormalities that are not associated with 
clinical sequelae and are corrected with 
supplementation/appropriate management within 72 
hours of their onset do not require drug 
discontinuation. 
*  Resolved, well-controlled, or asymptomatic 
hypothyroidism does not require approval by the 
Sponsor-Investigator prior to restarting therapy. 
 
Cardiac* 
≤ Grade 1  
Hold dose pending evaluation and 
observation.**  Evaluate for signs and 
symptoms of CHF, ischemia, arrhythmia 
or myositis.  Obtain history EKG, CK (for 
concomitant myositis), CK-MB.  Repeat 
troponin, CK and EKG 2-3 calendar days.  
If troponin and labs normalize may 
resume therapy.  If labs worsen or 
symptoms develop then treat as below.  
Hold pending evaluation.  
Grade >2  
with 
suspected 
myocarditis 
Hold dose.**  Admit to hospital.  
Cardiology consult.  Rule out MI and 
other causes of cardiac disease.  Cardiac 
Monitoring.  Cardiac Echo.  Consider 
cardiac MRI and cardiac biopsy.  Initiate 
high dose methylprednisolone.  If no 
improvement within 24 hours, add either 
infliximab, ATG or tacrolimus. Resume 
therapy if there is a return to baseline and 
myocarditis is excluded or considered 
unlikely. 
Grade >2 with 
confirmed 
myocarditis   
Off nivolumab and/or ipilimumab 
treatment.  Admit to CCU (consider 
transfer to nearest Cardiac Transplant 
Unit).  Treat as above.  Consider high 
dose methylprednisolone.   
Add ATG or tacrolimus if no improvement.  
Off treatment. 
*Including CHF, LV systolic dysfunction, Myocarditis, CPK, and troponin  
**Patients with evidence of myositis without myocarditis may be treated 
according as “other event”   
Note:  The optimal treatment regimen for immune mediated myocarditis has 
not been established.   
Since this toxicity has caused patient deaths, an aggressive approach is 
recommended.   
Infusion 
≤ Grade 1 
No dose modification 


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Treatment-
related Adverse 
Event 
Grade of 
Event 
Nivolumab or Nivolumab/Ipilimumab 
Reaction 
Grade 2 
Interrupt study drug. Upon recovery from 
symptoms, resume study drug at one half 
the initial infusion rate, then increase 
incrementally to the initial infusion rate   
Grade 3 
Off nivolumab and/or ipilimumab treatment   
Grade 4 
Off nivolumab and/or ipilimumab treatment 
Patients with fever should be evaluated as clinically appropriate.  Patients may 
experience isolated fever during infusion reactions or up to several calendar 
days after infusion.  Evaluation over the course of 1-2 weeks should be done 
for other autoimmune events that may present as fever 
All other events  
≤ Grade 1 
No dose modification  
Grade 2 
Hold until ≤ Grade 1 OR baseline 
(exceptions as noted below) 1      
Grade 3 
Off nivolumab and/or ipilimumab treatment  
Grade 4 
Off nivolumab and/or ipilimumab treatment 
 
Table 6.1 Footnotes 
1Recommended management:  As clinically indicated 
Exceptions:  
o 
Any Grade 2 drug-related uveitis or eye pain or blurred vision 
that does not respond to topical therapy and does not 
improve to Grade 1 severity within the re-treatment period 
OR requires systemic treatment must go off protocol 
treatment  
o 
Any adverse event, laboratory abnormality, or intercurrent 
illness which, in the judgment of the treating investigator, 
presents a substantial clinical risk to the patient with 
continued study drug dosing must go off protocol treatment.  
o 
Any Grade 3 or 4 drug-related laboratory abnormality or 
electrolyte abnormality, that can be managed independently 
from underlying organ pathology with electrolyte 
replacement, hormone replacement, insulin or that does not 
require treatment does not require discontinuation.  
o 
See Section 6.6 for treatment management 
 
 
 
For additional management recommendations and considerations, see the ASCO Clinical 
Practice Guideline Management of Immune-Related Adverse Events in Patients Treated With 
Immune Checkpoint Inhibitor Therapy.38  
 
6.5 
Treatment of Infusion Reactions Associated with Ipilimumab and/or Nivolumab 
Since ipilimumab contains only human protein sequences, and since nivolumab is a fully human 
monoclonal antibody, it is less likely that any allergic reaction will be seen in patients receiving 
these agents.  However, it is possible that infusion of ipilimumab or nivolumab will induce a 
cytokine release syndrome that could be evidenced by fever, chills, rigors, rash, pruritus, 
hypotension, hypertension, bronchospasm, or other symptoms.  No prophylactic pre-medication 


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should be given unless indicated by previous experience in an individual patient. Reactions 
should be treated based upon the following recommendations.  
 
• For mild symptoms (e.g., localized cutaneous reactions such as mild pruritus, flushing, 
rash): 
o Decrease the rate of infusion until recovery from symptoms, remain at bedside 
and monitor patient. 
o Complete the infusion at the initial planned rate. 
o Diphenhydramine 50 mg IV may be administered at the discretion of the treating 
physician and patients may receive additional doses with close monitoring. 
o Premedication with diphenhydramine may be given at the discretion of the 
investigator for subsequent doses. 
  
• For moderate symptoms (any symptom not listed above [mild symptoms] or below 
[severe symptoms] such as generalized pruritus, flushing, rash, dyspnea, hypotension 
with systolic BP >80 mmHg):  
o Interrupt infusion of offending agent. 
o Administer diphenhydramine 50 mg IV. 
o Monitor patient closely until resolution of symptoms. 
o Corticosteroids may abrogate any beneficial immunologic effect, but may be 
administered at the discretion of the treating physician. 
o Resume infusion after recovery of symptoms. 
o At the discretion of the treating physician, infusion may be resumed at one half 
the initial infusion rate, then increased incrementally to the initial infusion rate. 
o If symptoms develop after resumption of the infusion, the infusion should be 
discontinued and no additional ipilimumab or nivolumab should be administered 
that day. 
o The next dose will be administered at its next scheduled time and may be given 
with pre-medication (diphenhydramine and acetaminophen) and careful 
monitoring, following the same treatment guidelines outlined above. 
o At the discretion of the treating physician additional oral or IV antihistamine may 
be administered prior to dosing. 
 
• For severe symptoms (e.g., any reaction such as bronchospasm, generalized urticaria, 
systolic blood pressure < 80 mm Hg, or angioedema): 
o Immediately discontinue infusion and disconnect infusion tubing from the patient. 
o Consider bronchodilators, epinephrine 1 mg IV or subcutaneously, and/or 
diphenhydramine 50 mg IV, with solumedrol 100 mg IV, as needed. 
o Patients should be monitored until the investigator is comfortable that the 
symptoms will not recur. 
o No further ipilimumab (if related to ipilimumab) or nivolumab (if related to 
nivolumab) will be administered. 
 
6.5  
Treatment of Ipilimumab-Related Isolated Drug Fever 
 
In the event of isolated drug fever, the investigator must use clinical judgment to determine if the 


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fever is related to the ipilimumab or to an infectious etiology.  If a patient experiences isolated 
drug fever, for the next dose, pre-treatment with acetaminophen or non-steroidal anti-
inflammatory agent (investigator discretion) should be instituted and a repeated antipyretic dose 
at 6 and 12 hours after ipilimumab infusion, should be administered.  The infusion rate will 
remain unchanged for future doses.  If a patient experiences recurrent isolated drug fever 
following premedication and post dosing with an appropriate antipyretic, the infusion rate for 
subsequent dosing should be decreased to 50% of the previous rate.  If fever recurs following 
infusion rate change, the investigator should assess the patient’s level of discomfort with the 
event and use clinical judgment to determine if the patient should receive further ipilimumab. 
 
6.6  
Monitoring and Management of Immune-mediated Adverse Reactions 
 
Immune-mediated Enterocolitis 
The clinical presentation of GI immune-related AEs included diarrhea, increase in the frequency 
of bowel movements, abdominal pain, or hematochezia, with or without fever. However, 
inflammation may occur in any part of the GI tract including esophagitis and gastritis.  Fatalities 
due to GI perforation have been reported in clinical trials of ipilimumab. Patients should be 
carefully monitored for GI symptoms that may be indicative of immune-related colitis, diarrhea, 
or GI perforation.  Diarrhea or colitis occurring after initiation of ipilimumab therapy should be 
evaluated to exclude infectious or alternate etiologies. In clinical trials, immune-related colitis 
was associated with evidence of mucosal inflammation, with or without ulcerations, and 
lymphocytic infiltration. 
 
Monitor patients for signs and symptoms of enterocolitis (such as diarrhea, abdominal pain, 
mucus or blood in stool, with or without fever) and bowel perforation (such as peritoneal signs 
and ileus).  In symptomatic patients, rule out infectious etiologies and consider endoscopic 
evaluation to establish etiology and for persistent or severe symptoms.  C.difficile toxin has been 
detected in several patients with colitis and may be an independent entity or may co-exist with 
ipilimumab induced inflammatory colitis.   
 
Withhold ipilimumab and/or nivolumab dosing for any patients with enterocolitis pending 
evaluation; administer anti-diarrheal treatment and, if persistent evaluate with colonoscopy and 
initiate systemic corticosteroids at a dose of 0.5 mg/kg/day prednisone or equivalent. 
 
Permanently discontinue ipilimumab and nivolumab in patients with severe enterocolitis and 
initiate systemic corticosteroids at a dose of 1 to 2 mg/kg/day of prednisone or equivalent. Upon 
improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 
one month. In clinical trials, rapid corticosteroid tapering has resulted in recurrence or worsening 
symptoms of enterocolitis in some patients.  
 
Patients have been treated with anti-TNF agents for persistent colitis not responding to steroids. 
 
Please note autoimmune pancreatitis may cause abdominal pain and should be included in all 
evaluations. Enteritis may occur occasionally with other autoimmune events including hepatitis, 
pancreatitis, and endocrine insufficiency, which should be evaluated as clinically indicated.  
 


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Immune-mediated Hepatitis and Pancreatitis  
Hepatic immune-related AEs were mostly clinically silent and manifested as transaminase or 
bilirubin laboratory abnormalities.  Fatal hepatic failure has been reported in clinical trials of 
ipilimumab.  Serum transaminase and bilirubin must be evaluated before each dose of 
ipilimumab and nivolumab as early laboratory changes may be indicative of emerging immune-
related hepatitis/ pancreatitis and elevations in liver function tests (LFTs) may develop in the 
absence of clinical symptoms.  Increase in LFT or total bilirubin should be evaluated to exclude 
other causes of hepatic injury, including infections, disease progression, or other medications, 
and monitored until resolution.  Liver biopsies from patients who had immune-related 
hepatotoxicity showed evidence of acute inflammation (neutrophils, lymphocytes, and 
macrophages). 
 
Monitor liver function tests (hepatic transaminase and bilirubin levels) and assess patients for 
signs and symptoms of hepatotoxicity/ pancreatitis before each dose of ipilimumab and 
nivolumab.  In patients with hepatotoxicity, rule out infectious or malignant causes and increase 
frequency of liver function test monitoring until resolution.  Withhold ipilimumab and 
nivolumab in patients with Grade 2 hepatotoxicity.  
 
Permanently discontinue ipilimumab and nivolumab in patients with Grade 3–5 
hepatotoxicity/pancreatitis and administer systemic corticosteroids at a dose of 1 to 2 mg/kg/day 
of prednisone or equivalent.  When liver function tests show sustained improvement or return to 
baseline, initiate corticosteroid tapering and continue to taper over 1 month.  Across the clinical 
development program for ipilimumab, mycophenolate treatment has been administered in 
patients who have persistent severe hepatitis despite high-dose corticosteroids.  
 
Immune-mediated Dermatitis 
Skin immune-related AEs presented mostly frequently as a rash and/or pruritus.  Some patients 
reported vitiligo associated with ipilimumab administration.  Fatal toxic epidermal necrolysis has 
been reported in clinical trials of ipilimumab.  
 
Monitor patients for signs and symptoms of dermatitis such as rash and pruritus.  Unless an 
alternate etiology has been identified, signs or symptoms of dermatitis should be considered 
immune-mediated.   
 
Permanently discontinue ipilimumab and nivolumab in patients with Stevens-Johnson syndrome, 
toxic epidermal necrolysis, or rash complicated by full thickness dermal ulceration, or necrotic, 
bullous, or hemorrhagic manifestations.  Administer systemic corticosteroids at a dose of 1 to 2 
mg/kg/day of prednisone or equivalent.  When dermatitis is controlled, corticosteroid tapering 
should occur over a period of at least 1 month.  Withhold ipilimumab and nivolumab dosing in 
patients with moderate to severe signs and symptoms.  
 
For mild to moderate dermatitis, such as Grade 2 localized rash and pruritus, treat 
symptomatically. For persistent Grade 2, Grade 3, or greater, topical steroids may be 
administered.  Administer topical or systemic corticosteroids as indicated if there is no 
improvement of symptoms within 1 week. 
 


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Immune-related Neurological Events  
Fatal Guillain-Barré syndrome has been reported in clinical trials of ipilimumab. Patients may 
present with muscle weakness and myasthenia gravis, cranial nerve palsy (n VII Bell’s palsy), 
and aseptic meningitis, encephalopathy.  Unexplained motor neuropathy, muscle weakness, or 
sensory neuropathy lasting more than 4 calendar days should be evaluated and non-inflammatory 
causes such as disease progression, infections, metabolic syndromes, nerve entrapment, and 
medications should be excluded as causes.  
 
Withhold ipilimumab and nivolumab dosing in patients with any evidence of neuropathy pending 
evaluation.   
 
Monitor for symptoms of motor or sensory neuropathy such as unilateral or bilateral weakness, 
sensory alterations, or paresthesia.  Permanently discontinue ipilimumab and nivolumab in 
patients with severe neuropathy (interfering with daily activities) such as Guillain-Barré-like 
syndromes.  Institute medical intervention as appropriate for management of neuropathy and 
other neurologic events.  Consider initiation of systemic corticosteroids at a dose of 1 to 2 
mg/kg/day prednisone or equivalent for severe neuropathies.  
 
Immune-mediated Endocrinopathies 
Ipilimumab and/or nivolumab can cause inflammation of endocrine organs including thyroid 
(Hashimoto’s thyroiditis with positive antibodies) and adrenal glands, hypophysitis, 
hypopituitarism, and resulting thyroid and adrenal insufficiency, low ADH, prolactin, FSH, LH.  
Hyperthyroid with Graves’ disease and positive antibody has been reported.  Patients may 
present with subtle and nonspecific symptoms.  The most common clinical presentation includes 
headache and fatigue.  Symptoms may also include visual field defects, behavioral changes, and 
electrolyte disturbances including hyponatremia and hypotension.  Adrenal crisis as a cause of 
the patient’s symptoms should be excluded.  Based on the available data with known outcome, 
most of the patients symptomatically improved with hormone replacement therapy.  Long term 
hormone replacement therapy with HC and Synthroid will typically be required for patients 
developing hypophysitis/hypopituitarism after treatment with ipilimumab alone or with 
nivolumab.  Some patients have regained partial function following steroid treatment.  
 
Monitor patients for clinical signs and symptoms of hypophysitis, adrenal insufficiency 
(including adrenal crisis), and hyper- or hypothyroidism.  Headache is often the first symptoms 
of hypophysitis.  Patients may present with fatigue, headache, mental status changes, loss of 
libido, abdominal pain, unusual bowel habits, and hypotension, or nonspecific symptoms which 
may resemble other causes such as brain metastasis or underlying disease.  Unless an alternate 
etiology has been identified, signs or symptoms of endocrinopathies should be considered 
immune-mediated and drugs withheld pending evaluation.  Patients may demonstrate both 
central (hypophysitis) and peripheral adrenal and thyroid insufficiency.  Evaluation of 
hypophysitis should include pituitary MRI.  
 
Endocrine evaluation, including TSH, should be performed at baseline prior to initial treatment.  
Monitor thyroid function tests and clinical chemistries at the start of treatment and hold blood for 
possible evaluation should clinical events require determining baseline function and anti-thyroid 
antibodies.  In a limited number of patients, hypophysitis was diagnosed by imaging studies 


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48 
through enlargement of the pituitary gland.   
 
Withhold ipilimumab and nivolumab dosing in patients symptomatic for hypophysitis.  Initiate 
systemic corticosteroids at a dose of 1 to 2 mg/kg/day of prednisone or equivalent and initiate 
appropriate hormone replacement therapy.  
 
Other Immune-mediated Adverse Reactions, Including Ocular Manifestations  
Ocular inflammation, manifested as Grade 2 or Grade 3 episcleritis or uveitis, was associated 
with concomitant diarrhea in a few patients (< 1%) and occasionally occurred in the absence of 
clinically apparent GI symptoms.  Other presumed immune-related AEs reported include, but 
were not limited to, arthritis/arthralgias, pneumonitis, pancreatitis, autoimmune (aseptic) 
meningitis, autoimmune nephritis, pure red cell aplasia, noninfective myocarditis, polymyositis, 
and myasthenia gravis, of which were individually reported for < 1% of patients.  
 
The following clinically significant immune-mediated adverse reactions were seen in less than 
1% of ipilimumab-treated patients in Study 1: nephritis, pneumonitis, pulmonary granuloma 
resembling sarcoidosis, meningitis, pericarditis, uveitis, iritis, ITP, neutropenia and hemolytic 
anemia. 
 
Across the clinical development program for ipilimumab, the following likely immune-mediated 
adverse reactions were also reported with less than 1% incidence: myocarditis, angiopathy, 
temporal arteritis, vasculitis, polymyalgia rheumatica, conjunctivitis, blepharitis, episcleritis, 
scleritis, leukocytoclastic vasculitis, erythema multiforme, psoriasis, pancreatitis, arthritis, and 
autoimmune thyroiditis.   
 
Permanently discontinue ipilimumab and nivolumab for clinically significant or severe immune-
mediated adverse reactions.  Initiate systemic corticosteroids at a dose of 1 to 2 mg/kg/day 
prednisone or equivalent for severe immune-mediated adverse reactions. 
 
Administer corticosteroid eye drops to patients who develop uveitis, iritis, or episcleritis.  
Permanently discontinue ipilimumab for immune-mediated ocular disease that is unresponsive to 
local immunosuppressive therapy. 
 
Overall, immune-related AEs commonly started within 3 to 10 weeks from first dose, were 
successfully managed in most instances by omitting doses, discontinuing dosing, and/or through 
administering symptomatic or immunosuppressive therapy, including corticosteroids, as 
mentioned above.  Immune-related AEs generally resolved within days to weeks in most 
patients. 
 
6.7 
Overlapping toxicities (“shared AEs”) 
 
Although the safety profiles of troriluzole and nivolumab/ipilimumab are different, there are 
several overlapping side effects. The treating investigator must use judgement to attribute the 
AEs. The treating investigator may elect to hold all study therapy if they believe the AE is at 
least possibly related to all of the study drugs, particularly for high grade events.  
 


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49 
Shared AEs:  The following AEs and laboratory abnormalities are examples of “shared AEs” that 
are associated with all 3 study agents and, in most cases, should be attributed to all three drugs 
(possible, probably, or definitely related): 
• asthenia  
• nausea  
• dizziness  
• decreased lung function 
• diarrhea  
• abdominal pain  
• pneumonia  
• vomiting  
• vertigo  
• circumoral paresthesia (numbness around the mouth) 
• anorexia  
• somnolence  
• Elevated LFTs 
• Neutropenia (rare) 
 
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 
Expected Toxicities 
 
Adverse Events Lists 
 
Adverse Event List(s) for troriluzole  
 
The clinical experience of riluzole is relevant given the intention of dosing troriluzole 
to yield riluzole exposures within the range already well described for riluzole. 
Riluzole was approved for treatment of ALS in 1995 and US Prescribing Information 
reflects data from placebo-controlled trials and long-term follow-up. Riluzole is not 
associated with immune-related adverse events.   
 
Troriluzole is anticipated to have lesser effects on LFTs, as lower molar doses of 
troriluzole will be expected to yield the riluzole exposures achieved with oral 
RILUTEK – by virtue of bypassing first-pass metabolism. In addition, peak liver 
concentrations are expected to be reduced via use of troriluzole as compared to 
riluzole, which may reduce propensity for LFT changes. 
 
Safety data for riluzole (RILUTEK) 
Riluzole doses of up to 200 mg per day were considered well-tolerated and studied in 


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50 
randomized controlled trials. Among all chronic randomized controlled trials the 
discontinuation rate due to AEs was approximately 14%.  
 
No AEs occurred greater than 5% in the riluzole group and twice that of placebo. The 
AEs occurring greater than 5% and at least 2% more than placebo included asthenia 
(18% vs. 12% placebo) and nausea (14% vs. 9%). 
 
Most common AEs 
The most commonly observed AEs associated with the use of RILUTEK more 
frequently than placebo treated patients were: asthenia, nausea, dizziness, decreased 
lung function, diarrhea, abdominal pain, pneumonia, vomiting, vertigo, circumoral 
paresthesia, anorexia, and somnolence. Asthenia, nausea, dizziness, diarrhea, 
anorexia, vertigo, somnolence, and circumoral paresthesia were dose related. 
 
Approximately 14% (n = 141) of the 982 individuals with ALS who received 
RILUTEK in premarketing clinical trials discontinued treatment because of an 
adverse experience. Of those patients who discontinued due to adverse events, the 
most commonly reported were: nausea, abdominal pain, constipation, and ALT 
elevations. In a dose response study in ALS patients, the rates of discontinuation of 
RILUTEK for asthenia, nausea, abdominal pain, and ALT elevation were dose 
related. 
 
Incidence in Controlled ALS Clinical Studies 
Table 1 lists treatment-emergent signs and symptoms that occurred in at least 2% of 
patients with ALS treated with RILUTEK (n=794) participating in placebo-controlled 
trials and were numerically greater in the patients treated with RILUTEK 100 mg/day 
than with placebo or for which a dose response relationship is suggested. 
 


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51 
 
 


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52 
 
 
Less Common AEs 
• Neutropenia. Rare cases of neutropenia (3 out of 4000 subjects in USPI) have 
been reported  
• Interstitial lung disease, including hypersensitivity pneumonitis, has occurred.  
• Liver Injury. Lab abnormalities associated with riluzole consist of elevated 
transaminases that typically are below 5x upper limit of normal (ULN) and 
often resolve while on treatment. Experience with incidents of alanine 
aminotransferase (ALT) increasing >5xULN are limited, insofar as the USPI 
recommends immediate drug discontinuation. Effects on transaminases show 
a dose response. Importantly, total daily doses of 50 mg were not associated 
with increased rates of marked ALT elevations (>5xULN) compared to 
placebo (1.3% vs. 2.1%, respectively) and such occurrences had a later onset 
than placebo (median 254 vs. 219 days). Total daily doses of 100 mg and 200 
mg had greater rates of marked ALT elevations than placebo, and the median 
occurrence was within 60 days.  
 
Higher dose studies in ALS 
Phase 1 studies of riluzole safety explored much higher doses. Twelve subjects each 
were administered single oral doses of 150mg, 200 mg, 250 mg and/or 300 mg. At 
doses of 250 mg and 300 mg, riluzole administration was associated with dose-
dependent dizziness/vertigo and buccofacial or manual paresthesia.  
 
Troriluzole Phase Ib study with nivolumab  
Fourteen patients with advanced solid tumors (melanoma=3, NSCLC=3, renal cell 
cancer=2, NSCLC=2, head and neck cancer=2) were treated with escalating doses of 
troriluzole.30 Patients were exposed to troriluzole doses from 140mg to 560mg total 
daily dose. The most common TEAEs (all grades) occurring in >40% of patients were 
transaminitis, increased lipase and nausea.  DLT occurred in 3 patients: 1) grade 3 
anorexia, 2) grade 3 fatigue and, 3) atrial fibrillation. The MTD was determined to be 
troriluzole 140 mg QAM + 280 mg PO QPM. 
 


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53 
Adverse Event List for Ipilimumab and Nivolumab 
 
Ipilimumab and Nivolumab are known to have adverse events and immune-related 
adverse events, commonly involving the skin, liver, gut, and less commonly the 
pancreas, nervous system, heart, lungs, and kidneys. Please refer to the Investigators 
Brochures and package inserts for the comprehensive list of adverse events. 
 
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. 
 
• 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  
 
In the event of an unanticipated problem or life-threatening complications treating investigators 
must immediately notify the PI. 
 
Investigators must report to the 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.  
 
Adverse Event Reporting Guidelines 
 
All participating sites will report AEs to the Sponsor-Investigator per DF/HCC 
requirements, and the IRB of record for each site as applicable per IRB policies. The 
table below indicates which events must be reported to the DF/HCC Sponsor-
Investigator. 


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54 
 
 
 
 
 
Attribution 
DF/HCC Reportable Adverse Events (AEs) 
Gr. 2 & 3 AE 
Expected 
Gr. 2 & 3 AE 
Unexpected 
Gr. 4 AE Expected 
Gr. 4 AE 
Unexpected 
Gr. 5 AE 
Expected or 
Unexpected 
Unrelated 
Unlikely 
Not required 
Not required 
5 calendar days# 
5 calendar days 
24 hours* 
Possible 
Probable 
Definite 
 
Not required∞ 
 
5 calendar days 
 
5 calendar days# 
 
5 calendar days 
 
24 hours* 
# If listed in protocol as expected and not requiring expedited reporting, event does not need to be reported. 
 
* For participants enrolled and actively participating in the study or for AEs occurring within 30 days of the last 
intervention, events must be reported within 1 business day of learning of the event. 
 
∞Additional Protocol-Specific Reporting for Select Neurotoxicities 
 
For this protocol only, select grade 2 neurologic toxicity lasting 4 days or more, with or without medical 
intervention (listed below) that are at least possibly related to study require expedited reporting within 5 calendar 
days 
• 
Ataxia 
• 
Central nervous system necrosis (use this term for radiation necrosis) 
• 
Cognitive disturbance  
• 
Concentration impairment  
• 
Depressed level of consciousness 
• 
Dizziness 
• 
Encephalopathy  
• 
Guillain-Barre syndrome  
• 
Headache 
• 
Intracranial hemorrhage 
• 
Ischemia cerebrovascular  
• 
Leukoencephalopathy 
• 
Memory impairment 
• 
Presyncope 
• 
Reversible posterior leukoencephalopathy syndrome (PRES) 
• 
Stroke 
• 
Somnolence 
• 
Confusion (categorized under Psychiatric disorders) 
 
Note: the select neurotoxicities above also meet the definition of a DLT in the Phase Ib portion. 
 
 
 
Protocol-Specific Adverse Event Reporting Exclusions 
 
For this protocol only, the AEs/grades listed below do not require expedited reporting to 
the DF/HCC Sponsor-Investigator.  However, they still must be recorded through the 
routine reporting mechanism (i.e. case report forms). 
 
CTCAE 
System 
Organ 
Class 
Adverse 
Event 
Grade 
Hospitalization/ 
Prolongation of 
Hospitalization 
Attribution 
Comments 


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55 
Investigations Laboratory 
abnormality  
1-4 
See comment 
any 
Laboratory abnormality 
without any clinical 
symptomatology (e.g. 
asymptomatic elevation 
of lipase). If the event 
results in 
hospitalization or 
prolongs 
hospitalization, the 
exclusion does not 
apply. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
7.4 
Reporting to the Food and Drug Administration (FDA) 
 
The Sponsor-Investigator will be responsible for all communications with the FDA. The 
Sponsor-Investigator 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. 
 
7.5 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.  
 
7.6 Routine Adverse Event Reporting 
 
All Adverse Events must be reported in routine study data submissions to the PI on the 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.   
 
Treatment-emergent AEs should continue to be monitored during the follow-up period (until 
resolution).  New AEs during follow up that are not related to treatment should not be recorded 
 
8. PHARMACEUTICAL INFORMATION 
 
A list of the adverse events and potential risks associated with the investigational or other agents 
administered in this study can be found in Section 7.1. 
 
8.1 
Troriluzole  
 


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56 
Description 
 
Troriluzole is also known as FC-4157, BHV-4157, and trigriluzole. Refer to the Investigational 
Drug Brochure (IDB). 
 
The active ingredient of troriluzole is a member of the benzothiazole chemical class. The 
chemical name is 2-Amino-N-((methyl-[(6-trifluoromethoxy-benzothiazol-2-ylcarbamoyl)-
methyl]-carbamoyl)-methyl)-acetamide monohydrate monohydrochloride. The molecular 
formula is C15H16F3N5O4S.HCl.H2O. The chemical structure is seen in the figure below: 
 
N
S
N
H
N
O
Me
O
N
H
O
NH3ClH2O
F3CO
Troriluzole, 2
  
 
Drug Interactions: Clinical drug interaction studies for troriluzole have not been conducted yet. 
Troriluzole, itself, is not expected to interfere with drug metabolism and its cleavage via proteases 
render it unlikely to be affected significantly by liver cytochrome P450 inhibitors. It is not an 
inhibitor or CYP3A4, CYP1A2, or CYP2D6. 
 
Half-life in blood is <0.5 hours (in vitro).  
 
Form 
 
The formulation for clinical development is a common blend capsule of 140 mg of troriluzole 
(dose based on study design) administered orally. The capsule is a formulated common blend of 
troriluzole with standard excipients from a dry granulation, roller compaction process is filled in 
white opaque hard gelatin Size 1 capsules containing 140 mg of troriluzole. This formulation is 
intended for both clinical studies and commercial use. The excipients are mannitol, 
microcrystalline cellulose, hydroxypropyl cellulose, crospovidone, colloidal silicon dioxide, and 
magnesium stearate. The capsules are supplied in 35-count, 75 cc, wide mouth round white high 
density polyethylene bottles with a polyester coil and induction sealed 38 mm white 
child-proof screw cap closures for clinical use.  
 
Visually matching placebos containing microcrystalline cellulose are used throughout the 
clinical trials. 
 
Storage and Stability 
 
Investigational drug will be stored in the Research Pharmacy at each site. The investigational 
pharmacists will be responsible for preparation, dispensing, disposal, and drug accountability. 
 
Formulated blend capsules are stored at room temperature between 20°C and 25°C (68°F to 
77°F) with temporary excursions permitted between 15°C and 30°C (59°F to 86°F).  
 


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57 
Stability of formulated blend capsules and placebo capsules at 18 months also show no 
significant change. Stability studies are ongoing and are expected to extend the retest period of 
clinical supplies. 
 
Compatibility 
 
N/A 
 
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.  
 
Availability 
 
The investigational drug and placebo will be supplied by Biohaven Pharmaceuticals. The drug 
substance is manufactured and purchased commercially from Anthem Biosciences. 
 
Preparation 
 
N/A 
 
Administration 
 
Troriluzole or placebo will be self-administered by the patient orally with continuous BID 
dosing.  Ideally, BID dosing will be as close to Q 12 hours (± 2 hours) apart as possible 
(minimum 10 hours apart). Troriluzole may be taken either with food or on an empty stomach. 
 
Ordering 
 
Each site will order drug from Biohaven Pharmaceuticals using the form provided. Drug should 
be ordered at least 7 days in advance of anticipated dispensing.  
 
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.) 
 
Destruction  
 
Expired, empty and partially empty containers of study drug will be disposed of/destroyed in 
accordance with institutional policies and procedures.  Unused containers of study drug will not 
be returned to the study sponsor. 


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58 
 
8.2 
Ipilimumab 
 
Ipilimumab (YERVOY), commercial supply. 
Refer to the package insert for agent information.  
http://packageinserts.bms.com/pi/pi_yervoy.pdf 
 
8.3 
Nivolumab 
 
Nivolumab (OPDIVO), commercial supply. 
Refer to the package insert for agent information.  
http://packageinserts.bms.com/pi/pi_opdivo.pdf 
 
9. BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 
 
9.1 
Biomarker Studies 
 
The following samples will be collected as per the Study Calendar (mandatory unless specified 
as optional): 
a) Archival tissue at baseline (mandatory) 
b) Serial blood samples for PBMCs and serum on Days 1, 43, 85, 169, and 253 
(mandatory) 
c) Fresh biopsy of extracranial disease (optional, Day 0 and 43) 
d) Intracranial tissue and CSF (optional, at time of clinically indicated brain 
surgery in a subset of patients) 
 
All biomarker studies are ancillary/exploratory. We will compare samples from responders and 
non-responders to test for differences in correlatives. When available, we will compare pre/post 
paired treatment biopsies of extracranial tumors and brain/body paired biopsies from the same 
patient. When CSF is available, we will compare paired CSF/serum from the same patient.   
 
The following studies will be performed: 
 
IHC on archival tumor samples. We hypothesize that nearly 100% of melanomas will have 
GRM1 expression, providing rationale for exploring glutamate modulation as a target in 
melanoma.  IHC will also be used to determine PD-L1 expression, the degree of TILs, and other 
immune effector cells, and on-treatment biopsies will be examined for change in TILS and 
decrease in signal transduction in key pathways (e.g. MAPK, Pi3K/AKT).  
 
Flow cytometry on PBMCs. Immunophenotypic analysis of immune cells and markers will be 
assessed by multiparameter flow cytometry.  We hypothesize that responders will display more 
favorable T cell population ratios, markers of activation, and differentiation, and fewer MDSCs. 
 
Multiplex cytokine analysis on serum and CSF.  We hypothesize that responders will 
demonstrate a decrease in the expression of VEGF, IL-8, CD34, CCL2, and M-CSF. 
 


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59 
Gene expression analysis by Nanostring.  We hypothesize that responders will have a higher 
immune-related gene expression profile. 
 
Tumor genomic profiling. We will determine if activating mutations in B-RAF or N-RAS, or 
PTEN inactivation (or activating B-RAF mutations and PTEN inactivation together) in the pre-
treatment tumor samples correlates with response to therapy.   
 
Exosome analysis. We will examine exosome contents and hypothesize that post-treatment 
serum samples will contain fewer suppressive cytokines than pre-treatment samples.  
 
9.2 Laboratory Correlative Studies 
 
Please refer to the Sample Collection Laboratory Manual for handling and shipping instructions. 
Samples will be collected and shipped to:   
 
Andrew Zloza 
1735 West Harrison Street 
Cohn Research Building - Room 447 
Rush University 
Chicago, Illinois 60612 
Phone: (312) 942-2321 
Fax: (312) 942-3602 
Email: andrew_zloza@rush.edu 
 
The samples will be partitioned for analysis in two labs. Some samples will remain in the Zloza 
lab for analysis. A portion of the samples will be performed shipped to the Chen lab for analysis 
at Rutgers University.   
 
10. STUDY CALENDAR 
 
10.1 Scheduling windows    
 
Baseline evaluations are to be conducted within 1 week prior to start of protocol therapy.  Scans 
and x-rays must be done <4 weeks prior to the start of therapy. If 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 + 7 days of the protocol-specified 
date for Days 1-309, and within + 14 days of the protocol-specified date for Days 337-673. 
 


 
60 
 
Baseline Cycles 1-4: Induction 
Cycles 5-13 
End of 
Treatment 
(EOT)     
Cycle 14 
Follow-
Up Visit 
#1  
Follow-
Up 
Visits 
#2-4i 
Final 
Follow-Up 
Visitj 
EDC Timepoints 
 
Day 
1 
Day 
22 
Day 
43 
Day 
64 
Day:  
85 
169 
253 
Day:  
113 
197 
281 
Day: 
141 
225 
309 
Day 337  
or sooner 
Within 30 
days days 
post EOT 
Day:  
421 
505 
589 
Day 673 or 
sooner 
 
Troriluzole or placeboT 
(continuous oral twice 
daily dosing) 
 
T-------------------------------------------------------------------------T  
 
 
 
 
Medication Diary 
Documentation Day 43, 85, 
169, 253, EOT  
Ipilimumab and 
Nivolumab  
 
I+N 
I+N 
I+N 
I+N 
 
 
 
 
 
 
 
Day 1, 22, 43, 64 
Nivolumab  
 
 
 
 
 
N 
N 
N 
N 
 
 
 
Day 85, 113, 141, 169, 197, 
225, 253, 281, 309 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
N/A 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
Baseline 
Medical history, 
including BRAF 
mutational status 
X 
 
 
 
 
 
 
 
 
 
 
 
Baseline 
Physical exam 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Baseline 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Baseline 
Height  
X 
 
 
 
 
 
 
 
 
 
 
 
Baseline 


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61 
 
Baseline Cycles 1-4: Induction 
Cycles 5-13 
End of 
Treatment 
(EOT)     
Cycle 14 
Follow-
Up Visit 
#1  
Follow-
Up 
Visits 
#2-4i 
Final 
Follow-Up 
Visitj 
EDC Timepoints 
 
Day 
1 
Day 
22 
Day 
43 
Day 
64 
Day:  
85 
169 
253 
Day:  
113 
197 
281 
Day: 
141 
225 
309 
Day 337  
or sooner 
Within 30 
days days 
post EOT 
Day:  
421 
505 
589 
Day 673 or 
sooner 
 
Weight 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
Baseline 
Performance status 
X 
X 
 
 
 
X 
 
 
X 
X 
 
 
Baseline, EOT 
CBC w/diff, plts and 
CMPa 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
N/A 
Gamma-glutamyl 
transferase (GGT), LDH, 
amylase, lipase, TSH, 
free T4b  
 
X 
 
 
 
 
X 
 
 
X 
X 
 
 
GGT only:  Baseline, Day 85, 
169, 253, 337 
B-HCGc, pro-BNP, 
troponin-T  
X 
 
 
 
 
 
 
 
 
 
 
 
N/A 
EKG 
X 
 
 
 
 
X 
 
 
 
 
 
 
Baseline, Day 85, 169, 253. If 
EKG is performed during any 
other Cycle, it must be 
captured in EDC. 
MRI Brain (with and 
without gadolinium 
contrast) for intra-
X 
 
 
X 
 
X 
 
 
X 
 
 
 
Baseline, Day 43, 85, 169, 253. 
If Intracranial Tumor 
Measurements are performed 


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62 
 
Baseline Cycles 1-4: Induction 
Cycles 5-13 
End of 
Treatment 
(EOT)     
Cycle 14 
Follow-
Up Visit 
#1  
Follow-
Up 
Visits 
#2-4i 
Final 
Follow-Up 
Visitj 
EDC Timepoints 
 
Day 
1 
Day 
22 
Day 
43 
Day 
64 
Day:  
85 
169 
253 
Day:  
113 
197 
281 
Day: 
141 
225 
309 
Day 337  
or sooner 
Within 30 
days days 
post EOT 
Day:  
421 
505 
589 
Day 673 or 
sooner 
 
cranial tumor 
measurements d  
 
during any other Cycle, it must 
be captured in EDC. 
CT CAP (or PET/CT) for 
extra-cranial tumor 
measurements e 
X 
 
 
 
 
X 
 
 
X 
 
 
 
Baseline, Day 85, 169, 253. If 
Extracranial Tumor 
Measurements are performed 
during any other Cycle, it must 
be captured in EDC. 
Research blood samplesf 
X 
 
 
X 
 
X 
 
 
X 
 
 
 
N/A 
Archival tumor specimen 
(6-10 unstained slides) 
X 
 
 
 
 
 
 
 
 
 
 
 
N/A 
Research fresh tumor 
biopsy and additional 
blood draw (optional) g 
X 
 
 
X 
 
 
 
 
 
 
 
 
N/A 
Concurrent Medications 
 
X-----------------------------------------------------------------------------------------------------------------------------------------X 
Final Follow-Up Visit (Steroid 
use only) 
Adverse Event 
Evaluation 
 
X-----------------------------------------------------------------------------------------------------------------------------------------X 
All visits. 


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63 
 
Baseline Cycles 1-4: Induction 
Cycles 5-13 
End of 
Treatment 
(EOT)     
Cycle 14 
Follow-
Up Visit 
#1  
Follow-
Up 
Visits 
#2-4i 
Final 
Follow-Up 
Visitj 
EDC Timepoints 
 
Day 
1 
Day 
22 
Day 
43 
Day 
64 
Day:  
85 
169 
253 
Day:  
113 
197 
281 
Day: 
141 
225 
309 
Day 337  
or sooner 
Within 30 
days days 
post EOT 
Day:  
421 
505 
589 
Day 673 or 
sooner 
 
Other correlative studies 
on tumor tissue – if 
brain surgery occurs 
during the study periodh 
 
X-----------------------------------------------------------------------------------------------------------------------------------------X 
If brain surgery is performed, 
EDC should capture date, and 
which tumor was removed. 
Concurrent radiation 
therapy 
 
X-----------------------------------------------------------------------------------------------------------------------------------------X 
If brain or body RT is 
performed, EDC should capture 
start/end dates, # fractions, 
and total dose (cGy) to each 
tumor that was irradiated. 
Survival 
 
X-----------------------------------------------------------------------------------------------------------------------------------------X 
N/A 
Study Drug Dose and administration schedule:  
T: 
Troriluzole [FC-4157, BHV-4157] or placebo.  Safety Run-In cohort will start at 140mg PO Q AM and 280mg PO QPM only open label Troriluzole.   
                  This dose level may change based on participant cohort and MTD determined in Safety Run-In (Section 5). 
I+N: 
Ipilimumab + nivolumab induction: ipilimumab 3 mg/kg IV Q3 weeks and nivolumab 1 mg/kg IV Q3 weeks. 
N: 
Nivolumab: nivolumab 480mg IV Q4 weeks. 
Footnotes: 
a: 
Comprehensive metabolic panel (CMP): Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, potassium, total 
protein, SGOT [AST], SGPT [ALT], sodium. 
b: 
TSH with reflex to free T4 is acceptable replacement for TSH and free T4. 
c:  
Serum pregnancy test (women of childbearing potential). 
d: 
MRI Brain (with and without gadolinium contrast) for intra-cranial tumor measurements with thin cuts. Slice thickness must be 2 mm or less—specify when ordering.  
e: 
PET/CT scan is an allowable alternative to CT scan if approved by Sponsor-Investigator. Tumor assessments will be performed as per standard of care during Days 
421-589 and will be captured on CRFs. 
f:  
Research blood samples. At each time point indicated, 2 green top (heparin) tubes (10 ml each) will be collected for biomarker/correlative studies listed in Section 9.  


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64 
 
Baseline Cycles 1-4: Induction 
Cycles 5-13 
End of 
Treatment 
(EOT)     
Cycle 14 
Follow-
Up Visit 
#1  
Follow-
Up 
Visits 
#2-4i 
Final 
Follow-Up 
Visitj 
EDC Timepoints 
 
Day 
1 
Day 
22 
Day 
43 
Day 
64 
Day:  
85 
169 
253 
Day:  
113 
197 
281 
Day: 
141 
225 
309 
Day 337  
or sooner 
Within 30 
days days 
post EOT 
Day:  
421 
505 
589 
Day 673 or 
sooner 
 
g:  
Fresh biopsy of extracranial disease (optional). The second biopsy may occur at any time between Days 43 and 64 to facilitate scheduling. Patients will also have 2 
CPT top tubes (10 mL tubes) drawn on the day of the fresh tumor biopsies.  Biopsy and shipping must occur Monday – Thursday. 
h:  
If patient is having a craniotomy per standard of care, tumor sample from brain metastasis and 1-2 green top vials of CSF will be collected when feasible. 
i:  
Follow-up visits #2-4. If patients discontinue treatment early, they should be evaluated in-person every 84 days (or more frequently as indicated) until 5 Follow-Up  
visits have been completed.  
j:                Final In-Person visit. Survival data will continue to be collected for 3 years, unless patient dies or withdraws consent to be followed.   
                  The study team will contact participants by phone every 12 weeks (+/- 14 days) to assess survival.      
 


 
65 
11. MEASUREMENT OF EFFECT 
 
11.1 Antitumor Effect – Intracranial tumors and Extracranial tumors 
 
Assessment of extracranial disease (by CT scan or other approved modalities) and intracranial 
disease (by MRI scan with a minimum of 3 mm cuts) will be performed per the schedule in 
Section 10, Study Calendar.     
Investigators may obtain more frequent scans as medically indicated.   
 
Response and progression will be evaluated in this study using the international criteria proposed 
by the Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1)39 for all 
extracranial lesions and modified RECIST 1.1 for all brain lesions (see Section 11.3).  
 
Changes in the largest diameter (unidimensional measurement) of the tumor lesions and the 
shortest diameter in the case of malignant lymph nodes are used in the RECIST criteria. 
 
Definitions 
 
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 
baseline that are evaluable but do not meet the definitions of measurable disease, have 
received at least one cycle (3 weeks) 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.  
 
Disease Parameters 
 
Measurable disease, intracranial (brain lesions).  Measurable brain lesions are defined 
in this study as those that can be accurately measured in at least one dimension 
(longest diameter to be recorded) as ≥5 mm with MRI.  All tumor measurements must 
be recorded in millimeters (or decimal fractions of centimeters). 
 
Note: Brain metastases that have previously been treated with radiation therapy are not 
considered measurable, unless they have grown and the treating investigator considers 
them to be refractory to radiation. 
 
Measurable disease, extracranial lesions (including skull, neck, chest abdomen, pelvis, 
and extremities).  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 


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66 
measurements must be recorded in millimeters (or decimal fractions of centimeters). 
 
Note: Tumor lesions that that have previously been treated with radiation therapy are not 
considered measurable, unless they have grown and the treating investigator considers 
them to be refractory to radiation. 
 
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 <5 mm in the brain or <10 mm in the body, 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).  
 
‘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 
(modification to allow up to 5 lesions in brain) and 8 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.  
 
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.  
 


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67 
11.2 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.  
 
CT scans. 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 scans with “thin cuts.” MRI is required for assessment of brain metastases with 
slices of 2mm or less. Because this study allows a minimum lesion size of 5mm in the 
brain, all brain MRIs must be performed with “thin cuts” (slice thickness required 
to be no greater than 2 mm).  MRI also appropriate in certain additional situations (e.g. 
for extremities).  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 
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 


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68 
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.   
MIBG (meta-iodobenzylguanidine). The following is recommended, to assure high 
quality images are obtained.  
Patient preparation: Iodides, usually SSKI (saturated solution of potassium iodide), 
are administered to reduce thyroidal accumulation of free radioiodine, preferably 
beginning the day prior to injection and continuing for 3 additional days (4 days 
total). For infants and children, one drop t.i.d. is sufficient, for adolescents 2 drops 
t.i.d., and for adults 3 drops t.i.d. Participants and/or parents are asked about exposure 
to potential interfering agents. If none is noted, an indwelling intravenous line is 
established. The dose of MIBG is administered by slow intravenous injection over 90 
seconds.  
Images from the head to the distal lower extremities should be obtained.  
I-123MIBG scintigraphy is performed to obtain both planar and tomographic images.  
Planar: Anterior and posterior views from the top of the head to the proximal lower 
extremities are obtained for 10 minutes at 24 hours and occasionally at 48 hours 
following injection of 10 mCi/1.7 square meters of body surface area (~150 μCi/kg, 
maximum 10 mCi). Anterior views of the distal lower extremities are adequate. A 


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69 
large field of view dual head gamma camera with low energy collimators is preferred.  
 
SPECT: Most participants receiving I-123 MIBG also undergo SPECT at 24 hours, 
using a single or multi-headed camera with a low energy collimator. The camera is 
rotated through 360 degrees, 120 projections at 25 seconds per stop. Data are 
reconstructed using filtered back projections with a Butterworth filter and a cut off 
frequency of 0.2-0.5. SPECT/CT may be performed at institutions with this capacity. 
 
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. 
 
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.     
 
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. 
 
11.3 Response Criteria: modified RECIST version 1.1 
 
Response and progression will be evaluated in this study using the international criteria proposed 
by the Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1);39 
however there will be two modifications for assessment of brain lesions on this protocol:  
 
1) modification to allow up to five target lesions in the brain (all other organs continue 
to have a maximum of 2 target lesions), and the maximum number of target lesions 
globally may be up to 10 lesions.  
 
2) to include target lesions in the brain measuring ≥5 mm in their longest diameter as 
seen on thin cut MRI (slice thickness ≤2 mm), as described previously in other brain 


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70 
metastases trials.3,40,41   
 
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. 
 
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 progression). 
 
Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum diameters while on 
study. 
 
Evaluation of Non-Target Lesions 
 
Complete Response (CR):  Disappearance of all non-target lesions.  All lymph nodes 
must be non-pathological in size (<10 mm short axis). 
 
Non-CR/Non-PD:  Persistence of one or more non-target lesion(s). 
 
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). 
 
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 


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71 
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. 
 
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. 
 
Evaluation of BOR 
 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions* 
Overall 
Response 
CR 
CR 
No 
CR 
CR 
Non-CR/Non-
PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-
PD/not 
evaluated 
No 
PR 
SD 
Non-CR/Non-
PD/not 
evaluated 
No 
SD 
PD 
Any 
Yes or No 
PD 
Any 
PD** 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
  * See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
** 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. 
 
 
11.4 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 


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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.  
 
11.5 Progression-Free Survival 
 
Progression-Free Survival: Progression-Free Survival (PFS) is defined as the time from 
randomization (or registration) to the earlier of progression in the intracranial or 
extracranial sites or death due to any cause. Herein, the term “PFS” refers to PFS in both 
the intracranial and extracranial compartments (global). The follow-up of participants 
alive without disease progression is 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. 
 
11.6 Response Review 
 
Central review is not required. 
 
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 
 
Method 
 
The DF/HCC Office of Data Quality (ODQ) will collect, manage, and perform quality 
checks on the data for this study. 
 
Responsibility for Data Submission 
 
Investigative sites are responsible for submitting data and/or data forms to the Office of 
Data Quality (ODQ) in accordance with DF/HCC policies. 


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73 
 
12.2 Data Safety Monitoring 
 
12.2.1 The DF/HCC Data and Safety Monitoring Board (DSMB) will review and monitor study 
progress, toxicity, safety and other data from the randomized portion of this study. The Board is 
chaired by a medical oncologist from outside of DF/HCC and its membership composed of 
internal and external institutional representation. Information that raises any questions about 
participant safety or protocol performance will be addressed by the Sponsor-Investigator, 
statistician and study team. Should any major concerns arise, the DSMB will offer 
recommendations regarding whether or not to suspend the study. 
 
The DSMB will meet twice a year to review accrual, toxicity, response and reporting 
information. Information to be provided to the DSMB may include: participant accrual; 
treatment regimen information; all adverse events and serious adverse events reported across all 
sites by category; summary of any deaths on study; audit results; and a summary provided by the 
study team. Other information (e.g. scans, laboratory values) will be provided upon request.  
 
12.2.2 The DF/HCC Data Safety Monitoring Committee (DSMC) will review and monitor study 
progress, toxicity, safety and other data from the safety run-in phase of this study.  The DSMC 
meets monthly to review protocols and is chaired by a medical oncologist appointed by the 
Senior VP for Research.  The DSMC will typically review a protocol every 3, 6, or 9 months 
based on protocol specifics.  Information that raises any questions about participant safety or 
protocol performance will be addressed by the Sponsor-Investigator, statistician and study team. 
Should any major safety concerns or issues with data compliance arise, the DSMC will offer 
recommendations regarding whether or not to suspend the study. 
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 B. 
 
12.4 Collaborative Agreements Language 
 
N/A 
 
13. STATISTICAL CONSIDERATIONS 
 
13.1 Study Design/Endpoints 
 
It was recently shown that patients with small asymptomatic brain metastases can be treated with 
medical therapy rather than upfront radiation therapy.3  The response rate in this study was 48% 
and the intracranial and the extracranial response rates were largely concordant.  Progression-
free survival at 6 months (PFS6) was 61%. However, many patients progressed within the first 6 
months. Therefore, freedom from progression at the 6-month mark is a clinically important and 


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74 
measurable outcome.  
 
We propose a multi-center, double-blind, randomized, phase II signal-detection trial with a non-
randomized safety run-in to assess the efficacy and safety of adding troriluzole to 
ipilimumab/nivolumab induction and nivolumab maintenance in patients with melanoma that has 
metastasized to the brain.  Patients will be randomly assigned in equal proportions to 
ipilimumab/nivolumab/placebo induction followed by nivolumab/placebo maintenance (INP) or 
ipilimumab/nivolumab/troriluzole induction followed by nivolumab/troriluzole maintenance 
(INT).  The randomization will be stratified by prior BRAF-directed therapy (yes/no) and prior 
therapy with anti-PD-1 treatments (yes/no). 
 
Safety Run-in:  Up to three cohorts of patients will be treated in a 3+3 design with the triple drug 
combination to provide dosing information and an early assessment of safety.  A starting dose of 
troriluzole at 140 mg/280 mg will be used; two fallback doses will also be investigated if the 
starting dose proves too toxic. 
 
Cohort de-escalation table during safety run-in: 
 
Dose Level 
Troriluzole Dose 
Starting cohort  
140 mg PO QAM and  
280 mg PO QPM 
Cohort -1 
140 mg PO BID 
Cohort -2 
140 mg PO daily 
If ≥2 DLTs on Cohort -2 
Permanently stop the trial 
 
At the end of each cohort of the safety run-in, enrollment will pause for a comprehensive review 
of the safety data including dose-limiting toxicity (DLT).   If fewer than two patients within a 
cohort have DLTs then that dose level will be considered the MTD and enrollment to the 
randomized trial will begin. If two or more patients within a safety cohort have DLTs, then the 
dose will either be de-escalated, or the trial will stop.  A participant will be considered to have 
completed the DLT period with no dose limiting toxicities only if they have taken ≥ 80% of their 
assigned Troriluzole doses in the DLT period, which is the first 6 weeks of treatment.      
 
Following the Safety Run-in, all participants will be enrolled on the randomized portion of the 
study.  
 
Primary Endpoint. The primary endpoint of the study is global progression-free survival in 
patients with melanoma brain metastases who are treated with INT vs. INP.  Of particular 
interest will be PFS at 6 months. 
 
PFS is defined as the time from random assignment to the earlier of death or documented disease 
progression in the intracranial or extracranial compartments.  The follow-up of patients who have 
neither died nor progressed will be censored at the date of the last follow-up visit. 
 
Secondary Endpoints. The secondary objectives and their associated endpoints evaluate other 
important clinical outcomes, including overall survival (OS), intracranial response rate (RR) and 


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75 
PFS, extracranial RR and PFS, and safety (number of participants experiencing adverse events, 
particularly neurologic events).  We will also investigate: 
• tolerability (number of induction cycles administered, number of maintenance cycles 
administered) 
• use of corticosteroids for management of symptomatic cerebral edema (number of 
participants) 
• use of corticosteroids for management of immune related adverse events (number of 
participants who require prednisone ≥1 mg/kg or equivalent) 
• frequency of clinically-indicated stereotactic radiation therapy to the brain on study 
(number of patients, number of instances and number of lesions irradiated) 
• frequency of clinically-indicated surgical intervention to the brain on study (number of 
participants) 
 
Planned subgroup analyses according to baseline characteristics: 
• Prior anti-PD-1 exposure (yes vs. no – if yes then adjuvant vs. metastatic setting) 
• Prior ipilimumab exposure (yes vs. no) 
• Age (<65 years vs 65 years or older) 
• ECOG (0 vs 1) 
• LDH at baseline (normal vs. elevated) 
• Number of brain metastases (<3 vs 3 or more) 
• Brain-directed stereotactic radiation therapy prior to study entry (yes vs. no) 
• Craniotomy prior to study entry (yes vs. no) 
 
Planned subgroup analyses according to on-study events: 
• On-study brain-directed stereotactic radiation therapy (yes vs. no) 
 
Exploratory Endpoints: 
• associations between BRAF/NRAS mutation status and response endpoints, as well as 
tissue biomarker profiles between paired tissues from extracranial and intracranial 
metastases from individual patients, where available 
• associations between peripheral blood immune cell subpopulations (which may include 
but is not limited to T-cell, NK, B-cell, MDSC, and serum soluble factors with clinical 
endpoints and/or the occurrence of adverse events 
 
13.2 Sample Size, Accrual Rate and Study Duration 
 
Accrual Targets 
Ethnic Category 
Sex/Gender 
Females 
 
Males 
 
Total 
Hispanic or Latino 
1 + 
2 = 
3 
Not Hispanic or Latino 
39 + 
66 = 
105 
Ethnic Category: Total of all subjects 
 
40 + 
 
 68 = 
108 
Racial Category 
 


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American Indian or Alaskan Native 
0 + 
0 = 
0 
Asian 
1 + 
2 = 
3 
Black or African American 
0 + 
0 = 
0 
Native Hawaiian or other Pacific 
Islander 
0 + 
0 = 
0 
White 
39 + 
66 = 
105 
Racial Category: Total of all subjects 
 
40 + 
 
68 = 
 
108 
 
  
 
  
 
  
Sample Size.  The total sample size for this investigation is between 6 and 108 patients, which 
includes 6 - 18 patients in the safety run-in, and up to 90 patients in the randomized portion.   
 
Sample size estimates for the randomized trial are based on a proportional hazards mixture cure 
model with type-I error of 0.1, uniform accrual over 24 months, and 12 additional months of 
follow-up.  The six-month global PFS proportion in the INP arm is assumed to be 0.63 and 
follows an exponential distribution; it is also assumed that approximately 30% of patients in the 
INP arm and 50% of patients in the INT arm are cured (odds ratio = 2.33).  Under these 
assumptions, there would be 80% power to detect a 6-month PFS rate of approximately 0.8 in the 
INT arm (hazard ratio = 0.557).42  
 
Accrual rate. Assuming accrual of about 3 patients per month across 6 sites and an equal 
allocation between experimental and control arms, 36 patients will be accrued within one year.  
 
Study duration.  Assuming unequal protocol activation times and holding accrual for analysis of 
safety run-in, study duration will be 4-5 years.  
 
13.3 Stratification Factors 
 
The randomization will be stratified by prior BRAF-directed therapy (yes/no) and prior therapy 
with anti-PD-1 treatments (yes/no).  
 
13.4 Interim Monitoring Plan 
 
Safety Run-in:  The DLT observation period is 6 weeks. After all patients in a dose cohort have 
been followed for 6 weeks or had dose-limiting toxicity (DLT), enrollment will pause for review 
of the safety data.  The safety reviews will decide whether to declare an MTD and proceed with 
the randomized trial, adjust the dose, or stop enrollment. 
 
Early stopping rule for futility:  An interim look for futility will take place when approximately 
45 patients have been enrolled and treated on the Phase II portion of the trial (a total of 15 PFS 
events have occurred).  A proportional hazards mixture cure model (Section 13.5) will be fit to 
the data at the time of the interim analysis and will be stratified by the randomization factors; 
randomized treatment will be the only predictor in this model.  If the observed hazard ratio (INT 
vs. INP) from the latency portion of the model is 0.96 or larger then study enrollment will stop 
and the trial will cease due to futility. 
 


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Early stopping rule for neurotoxicity: Sequential boundaries will be used to monitor the rate of 
neurotoxicity (Section 7.3 Adverse Event Reporting) in the first 45 patients enrolled and treated 
in the Phase II portion of the trial. Accrual will be halted if excessive numbers of neurotoxicities 
are seen, that is, if the number of neurotoxicities is equal to or exceeds bn out of n patients (see 
table). This is a Pocock-type stopping boundary that yields the probability of crossing the 
boundary = 0.1 when the rate of neurotoxicity is equal to 0.20.43 Accrual will be halted if the 
number of neurotoxicities is equal to or exceeds bn out of n patients, and the DSMB or DSMC 
may permanently stop the trial. 
 
Table for neurotoxicity stopping rule: 
 
 
Number of Patients, n 1 2 3 4 5 
6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 
Boundary, bn 
- - 3 3 4 
4 5 5 5 6 6 6 7 7 7 7 8 8 8 9 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Number of Patients, n 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 
Boundary, bn 
9 9 9 10 10 10 11 11 11 11 12 12 12 12 13 13 13 13 14 14 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Number of Patients, n 41 42 43 44 45  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Boundary, bn 
14 14 15 15 15 
 
 
13.5 Analysis of Primary Endpoints 
 
Primary Endpoint: The primary endpoint of the study is global progression-free survival in 
patients with melanoma brain metastases who are treated with troriluzole/ipilimumab/nivolumab 
(INT) vs. ipilimumab/nivolumab (INP).   
 
Analysis of the primary endpoint will be based on the proportional hazards mixture cure model 
(PHMC) with treatment (INT/INP) as the only predictor.  Modeling of parameter estimates of 
survival and cure will be semiparametric with bootstrapped standard errors and stratified by the 
randomization factors. Analyses will be conducted using the smcure package from R, the 
PSPMCM macro from SAS, or any modification to these packages available at the time of 
analysis.  Inference will be based on Z-values and associated p-values.  Cure proportions will be 
based on estimation from the incidence portion of the model and metrics of PFS from patients 
who are not cured will be based on the latency portion of the model.  Comparisons of cure rates 
will be expressed as odds ratios with confidence intervals, and comparisons of PFS will be 
expressed as hazard ratios with confidence intervals.  The distributions of events for INT and 
INP will be summarized using marginal survival function curves.  Point estimates at 6 months 
will be presented with confidence intervals. 
 
13.6 Analysis of Secondary Endpoints 
 
Overall Survival  
Overall Survival (OS) is defined as the time from randomization (or registration) to death due to 


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any cause, or censored at date last known alive. Estimates of overall survival will also be from a 
PHMC model (Section 13.5).  Long-term survival estimates and comparisons will be based on 
the incidence portion of the model; hazards of death will be based on the latency portion of the 
model.  The distribution of deaths will be summarized using marginal survival function curves. 
 
Intracranial or Extracranial Response 
The proportion of patients in each treatment arm with intracranial response (RECIST) will be 
presented with exact, 90% binomial confidence intervals. The randomized treatment arms will be 
compared using Fisher’s exact test.  Comparable comparisons will be conducted for extracranial 
response (RECIST). 
 
Intracranial or Extracranial PFS 
Extracranial PFS is defined as the time from first dose of study therapy to documented 
extracranial progression (per RECIST) or death, whichever occurs first. Intracranial PFS is 
defined as the time from first dose of study therapy to documented intracranial progression or 
death, whichever occurs first. For both endpoints, the follow-up of patients who have neither 
died nor progressed at the time of analysis will be censored at the date of last adequate disease 
assessment. Treatment comparisons of intracranial or extracranial PFS will be based on PHMC 
methods outlined in Section 13.5.  Point estimates at 6 months will be presented with confidence 
intervals. 
 
Safety Data 
Adverse events will be summarized for all patients having received one or more doses of study 
therapy and reported according to CTCAE (Version 5.0).  The data for each dose cohort in the 
dose escalation will be summarized separately as will the safety data from the randomized 
portion of the trial. The proportions of patients in the randomized trial with grade-3 or higher 
toxicities will be presented with 90% exact binomial confidence intervals. The incidence of 
events that are new or worsening from the time of first dose of therapy will be summarized 
according to system organ class and/or preferred term, severity (based on CTCAE grade), type of 
adverse event, and relation to study treatment. Deaths reportable as SAEs and non-fatal serious 
adverse events will be listed by patient and tabulated by primary system organ class, and type of 
adverse event. Of particular interest are serious neurologic events such as seizure, intracranial 
hemorrhage, and radiation necrosis. 
 
Tolerability 
Drug administration will be summarized for all patients having received one or more doses of 
study therapy. Tolerability will be described by the number of induction cycles administered, the 
number of maintenance cycles administered, and the frequency of discontinuation of therapy due 
to toxicity.  
 
Planned Subgroup Analyses 
Pre-specified subgroup analyses according to baseline characteristics will be conducted using 
PHMC methods and will be based on the statistical interaction of treatment assignment and the 
characteristic.  Statistical inference will be based on the interaction p-value.  Forest plots will be 
used to show the results graphically.  
 


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Preplanned sub-analyses will be conducted on patients who received on-study brain-directed 
stereotactic radiation (“radiation salvage subgroup”). Tumor response in the non-irradiated brain 
lesions and overall survival will be described.  
 
Preplanned sub-analyses will be conducted on patients who required corticosteroids to treat 
either cerebral edema or immune-related adverse events (“steroid-treated subgroups”).   
 
Due to the potential for guarantee-time bias in these analyses, a conditional landmark approach 
will be used to evaluate these data. 
 
Exploratory Analyses 
Biomarkers of blood and tissue: Analyses of blood and tissue biomarkers will be based on 
descriptive statistics, as appropriate for the biomarker.  To examine response according to pre-
treatment levels of biomarkers, the study sample will be divided retrospectively according to 
response and summarized descriptively for the resulting groups.  These will be compared using 
Wilcoxon rank-sum tests for markers measured on a continuous scale, or Fisher’s exact tests for 
those measured on a categorical scale. Where appropriate, visualization of the relationship 
between baseline marker levels and the distributions of PFS or OS will employ marginal survival 
function estimates stratified by biomarker levels.  
 
13.7 Reporting and Exclusions 
 
Evaluation of Toxicity 
All participants will be evaluable for toxicity from the time of their first treatment. 
 
Evaluation of the Primary Efficacy Endpoint 
The analysis of the primary endpoint will be conducted using the intention-to-treat principal, 
meaning all randomized patients will be evaluated according to the treatment assigned at the time 
of enrollment.   
 
14. PUBLICATION PLAN 
 
The results should be made public within 24 months of reaching the end of the study. 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. 
 
 


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15. REFERENCES 
 
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Chen L, Douglass J, Kleinberg L, et al. Concurrent Immune Checkpoint Inhibitors and 
Stereotactic Radiosurgery for Brain Metastases in Non-Small Cell Lung Cancer, 
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Knisely JPS, Yu JB, Flanigan J, Sznol M, Kluger HM, Chiang VLS. Radiosurgery for 
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Liniker E, Menzies AM, Kong BY, et al. Activity and safety of radiotherapy with anti-
PD-1 drug therapy in patients with metastatic melanoma. OncoImmunology. 
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Murphy B, Walker J, Bassale S, et al. Concurrent Radiosurgery and Immune Checkpoint 
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13. 
Nardin C, Mateus C, Texier M, et al. Tolerance and outcomes of stereotactic radiosurgery 
combined with anti-programmed cell death-1 (pembrolizumab) for melanoma brain 
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14. 
Silk AW, Bassetti MF, West BT, Tsien CI, Lao CD. Ipilimumab and radiation therapy for 
melanoma brain metastases. Cancer Med. 2013;2(6):899-906. 


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15. 
Tran TT, Mahajan A, Chiang VL, et al. Perilesional edema in brain metastases: potential 
causes and implications for treatment with immune therapy. Journal for ImmunoTherapy 
of Cancer. 2019;7(1). 
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Pollock PM, Cohen-Solal K, Sood R, et al. Melanoma mouse model implicates 
metabotropic glutamate signaling in melanocytic neoplasia. Nature Genetics. 
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Wangari-Talbot J, Wall BA, Goydos JS, Chen S. Functional Effects of GRM1 
Suppression in Human Melanoma Cells. Molecular Cancer Research. 2012;10(11):1440. 
18. 
Isola AL, Eddy K, Zembrzuski K, Goydos JS, Chen S. Exosomes released by 
metabotropic glutamate receptor 1 (GRM1) expressing melanoma cells increase cell 
migration and invasiveness. Oncotarget. 2017;9(1). 
19. 
Wen Y, Li J, Koo J, et al. Activation of the Glutamate Receptor GRM1 Enhances 
Angiogenic Signaling to Drive Melanoma Progression. Cancer Research. 
2014;74(9):2499. 
20. 
Li J, Wen Y, Jeong B-S, et al. GRM1 to induce M-CSF and CCL2 expression to lead to 
an upregulation of M2 macrophages in melanoma. Journal of Clinical Oncology. 
2017;35(7_suppl):122-122. 
21. 
Namkoong J, Shin S-S, Lee HJ, et al. Metabotropic Glutamate Receptor 1 and Glutamate 
Signaling in Human Melanoma. Cancer Research. 2007;67(5):2298. 
22. 
Shin S-S, Jeong B-S, Wall BA, et al. Participation of xCT in melanoma cell proliferation 
in vitro and tumorigenesis in vivo. Oncogenesis. 2018;7(11). 
23. 
Yip D, Le MN, Chan JLK, et al. A Phase 0 Trial of Riluzole in Patients with Resectable 
Stage III and IV Melanoma. Clinical Cancer Research. 2009;15(11):3896. 
24. 
Mehnert JM, Silk AW, Lee JH, et al. A phase II trial of riluzole, an antagonist of 
metabotropic glutamate receptor 1 (GRM1) signaling, in patients with advanced 
melanoma. Pigment Cell & Melanoma Research. 2018;31(4):534-540. 
25. 
Rahma OE, Hodi FS. The Intersection between Tumor Angiogenesis and Immune 
Suppression. Clinical Cancer Research. 2019;25(18):5449-5457. 
26. 
Wallin JJ, Bendell JC, Funke R, et al. Atezolizumab in combination with bevacizumab 
enhances antigen-specific T-cell migration in metastatic renal cell carcinoma. Nature 
Communications. 2016;7(1):12624. 
27. 
Makker V, Rasco D, Vogelzang NJ, et al. Lenvatinib plus pembrolizumab in patients 
with advanced endometrial cancer: an interim analysis of a multicentre, open-label, 
single-arm, phase 2 trial. The Lancet Oncology. 2019;20(5):711-718. 
28. 
Rini BI, Plimack ER, Stus V, et al. Pembrolizumab plus Axitinib versus Sunitinib for 
Advanced Renal-Cell Carcinoma. New England Journal of Medicine. 
2019;380(12):1116-1127. 
29. 
Motzer RJ, Penkov K, Haanen J, et al. Avelumab plus Axitinib versus Sunitinib for 
Advanced Renal-Cell Carcinoma. New England Journal of Medicine. 
2019;380(12):1103-1115. 
30. 
Silk AW, Saraiya B, Groisberg R, et al. A phase Ib study of troriluzole (BHV-4157) in 
combination with nivolumab. J Clin Oncol. 2020;38:suppl 5; abstr 79. 
31. 
Hodi FS, Chiarion-Sileni V, Gonzalez R, et al. Nivolumab plus ipilimumab or nivolumab 
alone versus ipilimumab alone in advanced melanoma (CheckMate 067): 4-year 
outcomes of a multicentre, randomised, phase 3 trial. Lancet Oncol. 2018;19(11):1480-
1492. 


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32. 
Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Combined Nivolumab and Ipilimumab or 
Monotherapy in Untreated Melanoma. New England Journal of Medicine. 
2015;373(1):23-34. 
33. 
Wall BA, Yu LJ, Khan A, Haffty B, Goydos JS, Chen S. Riluzole is a radio-sensitizing 
agent in an in vivo model of brain metastasis derived from GRM1 expressing human 
melanoma cells. Pigment Cell & Melanoma Research. 2015;28(1):105-109. 
34. 
Beaver JA, Ison G, Pazdur R. Reevaluating Eligibility Criteria — Balancing Patient 
Protection and Participation in Oncology Trials. New England Journal of Medicine. 
2017;376(16):1504-1505. 
35. 
Herbst RS, Soria J-C, Kowanetz M, et al. Predictive correlates of response to the anti-PD-
L1 antibody MPDL3280A in cancer patients. Nature. 2014;515(7528):563-567. 
36. 
Tumeh PC, Harview CL, Yearley JH, et al. PD-1 blockade induces responses by 
inhibiting adaptive immune resistance. Nature. 2014;515(7528):568-571. 
37. 
Key NS, Khorana AA, Kuderer NM, et al. Venous Thromboembolism Prophylaxis and 
Treatment in Patients With Cancer: ASCO Clinical Practice Guideline Update. Journal of 
Clinical Oncology. 2019;38(5):496-520. 
38. 
Brahmer JR, Lacchetti C, Schneider BJ, et al. Management of Immune-Related Adverse 
Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: American 
Society of Clinical Oncology Clinical Practice Guideline. Journal of Clinical Oncology. 
2018;36(17):1714-1768. 
39. 
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid 
tumours: Revised RECIST guideline (version 1.1). European Journal of Cancer. 
2009;45(2):228-247. 
40. 
Davies MA, Saiag P, Robert C, et al. Dabrafenib plus trametinib in patients with 
BRAFV600-mutant melanoma brain metastases (COMBI-MB): a multicentre, 
multicohort, open-label, phase 2 trial. The Lancet Oncology. 2017;18(7):863-873. 
41. 
Qian JM, Mahajan A, Yu JB, et al. Comparing available criteria for measuring brain 
metastasis response to immunotherapy. Journal of Neuro-Oncology. 2017;132(3):479-
485. 
42. 
Cai C, Wang S, Lu W, Zhang J. NPHMC: An R-package for estimating sample size of 
proportional hazards mixture cure model. Computer Methods and Programs in 
Biomedicine. 2014;113(1):290-300. 
43. 
Ivanova A, Qaqish BF, Schell MJ. Continuous Toxicity Monitoring in Phase II Trials in 
Oncology. Biometrics. 2005;61(2):540-545. 
 
 
 
 
 
 
 


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APPENDIX A 
PERFORMANCE STATUS CRITERIA 
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor 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). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
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. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 
 
 
 
 
 
 
 
 
 
 
 


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APPENDIX B 
MULTI-CENTER GUIDELINES 
 
DF/HCC Protocol #: Pending 
 
Dana-Farber/Harvard Cancer Center 
Multi-Center Data and Safety Monitoring Plan 
 
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 Coordinating Center  
The Coordinating Center is the entity that provides administrative support to the DF/HCC 
Sponsor in order that he/she may fulfill the responsibilities outlined in the protocol 
document and DSMP, and as specified in applicable regulatory guidelines (i.e. CTEP Multi-
Center Guidelines).  
 
The general responsibilities of the Coordinating Center may include but are not limited to: 
• Assist in protocol development.  
• Maintain FDA and other correspondence, as applicable. 
• Review registration materials for eligibility and register participants from 
Participating Institutions in the DF/HCC clinical trial management system (CTMS). 
• Distribute protocol and informed consent document updates to External Sites as 
needed. 
• Oversee the data collection process from External Sites. 
• Maintain documentation of Serious Adverse Event (SAE) reports and 
deviations/violation submitted by External Sites and provide to the DF/HCC 
Sponsor for timely review and submission to the IRB of record, as necessary.  
• Distribute serious adverse events reported to the DF/HCC Sponsor that fall under 
the reporting requirements for the IRB of record to all External Sites. 


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• Provide External Sites with information regarding DF/HCC requirements that they 
will be expected to comply with. 
 
• Carry out plan to monitor External Sites either by on-site or remote monitoring.  
• Maintain Regulatory documents of all External Sites which includes but is not 
limited to the following: local IRB approvals/notifications from all External Sites, 
confirmation of Federalwide Assurances (FWAs) for all sites, all SAE submissions, 
Screening Logs for all sites, IRB approved consents for all sites 
• Conduct regular communications with all External Sites (conference calls, emails, 
etc) and maintain documentation all relevant communications. 
 
 
 
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. For studies under a 
single IRB, the Coordinating Center will facilitate any study-wide submissions.. 
• 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. 


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• 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.  
 
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, 


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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 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 participating 
External Site and faxed (Fax # 617-582-8216) or e-mailed 
(JohnV_Collantes@dfci.harvard.edu) to the Study Coordinator: 
• Copy of brain MRI    
• Signed participant consent form 
• HIPAA authorization form (if not included in consent form) 
• Eligibility Checklist 
• External Site Subject Registration Form (Appendix E) 
 
The participating site will then contact the Study Coordinator (617-632-3469 or email 
JohnV_Collantes@dfci.harvard.edu) to verify eligibility.  The Study Coordinator will 
follow DF/HCC policy (REGIST-101) and register the participant on the protocol.  The 
Study Coordinator will fax or e-mail the participant study number to the participating site.  
The Study Coordinator will also contact the participating site and confirm registration. 
 
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.  
 


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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.   
 
Randomization can only occur during normal business hours, Monday through Friday 
from 8:00 AM to 5:00 PM Eastern Standard Time. 
 
3.6 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. 
 
 3.7 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 in DF/HCC policies and 
institutional policies of other IRBs. 
 
 
3.8 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. 
   
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.  
 
3.9 Protocol Reporting Requirements 
 
Protocol Deviations, Exceptions and Violations 
 


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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. 
 
3.10 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.  
 
3.11 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.  
 
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.  
 


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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. 
 
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.  
 
 
        
 
 
 
 
 


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APPENDIX E EXTERNAL SITE SUBJECT REGISTRATION FORM 
 
See next page. 
 
 


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* Subject initials are a minimum requirement for registration by DF/HCC. 
† Required by NCI’s Clinical Trials Reporting Program. See https://www.cancer.gov/about-nci/organization/ccct/ctrp/accrual 


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APPENDIX F. PILL DIARY 
 
See separate document.