Conditions: Uveal Melanoma
Keywords: uveal melanoma
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 6
Healthy volunteers: no

Brief summary:
Single arm study with dose escalation Phase Ib cohort followed by a Phase II cohort. PAC-1 (PO) will be given daily on Days 1 through 21 of each cycle (28-day cycle). Entrectinib (PO) will be given daily on Days 1 through 28 of each cycle. Response will be evaluated after every 2 cycles. Treatment will continue until disease progression based on RECIST criteria or intolerable toxicity.

Detailed description:

Arms:
arm 1: Phase 1b will determine the MTD of PAC-1 in combination with entrectinib. Study treatment will include: PAC-1 will be taken orally on Days 1-21 and Entrectinib will be taken orally on Days 1-28 of each 28-day cycle. Treatment will continue until disease progression (based on RECIST 1.1 criteria), unacceptable toxicity, subject withdrawal of informed consent, or subject death either from progression of disease, the therapy itself, or from other causes.

Interventions: intervention 1: PAC-1 intervention 2: Entrectinib
Intervention descriptions: intervention 1: Pharmacokinetic (PK) and pharmacodynamic (PD) assay for PAC-1 will be performed during Days 1 and 21 of Cycle 1. PAC-1 will be given on Day 1 of Cycle 1, withheld on Day 2 and Day 3 of Cycle 1 then reinitiated on Day 4 of Cycle 1 to continue for 21 days of the 28-day cycle. For each successive cycle, PAC-1 therapy will be initiated on Day 1 and continue for 21 days of the 28-day cycle. intervention 2: Pharmacokinetic and pharmacodynamic assay for entrectinib will be performed during Days 3 and 21 of Cycle 1. Entrectinib therapy will be withheld on Day 1 and Day 2 of Cycle 1, initiated on Day 3 of Cycle 1 and continue for the remainder of the 28 day cycle. For each successive cycle, entrectinib will be intiated on Day 1 and continue for 28 days of the 28-day cycle.

Protocol document:
Prot_SAP_000.pdf: 
PAC-1 and Entrectinib for Patients with Metastatic Uveal Melanoma 
Clinical Study Protocol 
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Version Date: 04DEC2020 
Confidential 
Page 1 of 58 
Phase 1B/2 Study of PAC-1 and Entrectinib for Patients with Metastatic Uveal Melanoma 
 
 
Sponsor-Investigator 
Arkadiusz Z. Dudek, MD, PhD 
HealthPartners and Regions Cancer Care Centers 
St. Paul, Minnesota  
 
 
Principal Investigator 
Yan Ji, MD 
HealthPartners Regions Cancer Care and 
Frauenshuh Cancer Care Centers 
Suite 1161 Mail Stop 11101G 
640 Jackson Street, St. Paul, MN 55101 
Tel: 651 254-3321 
Fax: 651 254-3102 
 
Co-Investigator 
Bryan Trottier, MD 
HealthPartners Regions Cancer Care and 
Frauenshuh Cancer Care Centers 
Suite 1161 Mail Stop 11101G 
640 Jackson Street, St. Paul, MN 55101 
Tel: 651 254-3321 
Fax: 651 254-3102 
 
Statistician 
Lauren Erickson, PhD 
HealthPartners Institute 
Bloomington, Minnesota 
 
 
Trial Management Provided by  
Hoosier Cancer Research Network, Inc. 
500 N. Meridian, Suite 100 
Indianapolis, IN 46204 
Trial Supported by  
Vanquish Oncology, Inc.  
Genentech 
 
 
Investigational New Drug (IND) # 149254 
 
 
 
Initial Protocol Version Date: 21APR2020 (For lead site ONLY) 
Protocol Amendment Version Date:  
04DEC2020 (Amendment for Lead Institution ONLY; Initial version for participating sites) 
 
 


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PROTOCOL SIGNATURE PAGE 
 
Phase 1B/2 Study of PAC-1 and Entrectinib for Patients with Metastatic Uveal Melanoma 
 
VERSION DATE: 04DEC2020 
I confirm I have read this protocol, I understand it, and I will work according to this protocol and 
to the ethical principles stated in the latest version of the Declaration of Helsinki, the applicable 
guidelines for good clinical practices, whichever provides the greater protection of the 
individual. I will accept the monitor’s overseeing of the study. I will promptly submit the 
protocol to applicable institutional review board(s). 
 
 
 
 
____________________________________ 
 ________________________ 
Signature of Site Investigator 
 
Date 
 
 
  
 
 
 
____________________________________ 
Site Investigator Name (printed) 
 
 
____________________________________ 
Site Investigator Title 
 
 
____________________________________ 
Name of Facility 
 
 
____________________________________ 
Location of Facility (City and State) 
 
 
 
 
 PLEASE COMPLETE AND EMAIL A COPY TO HCRN 
 
 
 


PAC-1 and Entrectinib for Patients with Metastatic Uveal Melanoma 
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SYNOPSIS 
TITLE 
Phase 1B/2 Study of PAC-1 and Entrectinib for Patients with Metastatic 
Uveal Melanoma 
SHORT TITLE 
PAC-1 and Entrectinib for Patients with Metastatic Uveal Melanoma 
PHASE  
1B/2 
OBJECTIVES 
Primary Objectives 
 
Phase 1b: The primary objective of this study component is to determine 
the maximum tolerated dose (MTD) of PAC-1 in combination with 
entrectinib in subjects with metastatic uveal melanoma, by evaluation of 
toxicity and tolerability. 
 
Phase 2: The primary objective of this study component is to measure 3 
months progression-free survival (PFS) rate, using RECIST v1.1, in 
subjects with metastatic uveal melanoma treated with entrectinib and 
PAC-1. 
 
Secondary Objectives 
 
Phase 1b: Evaluate the safety of entrectinib and PAC-1 combination, 
assessed by the incidence and severity of drug-related adverse events 
(AE), in subjects with metastatic uveal melanoma. 
 
Phase 2 
• Evaluate the safety of entrectinib and PAC-1 combination, 
assessed by the incidence and severity of drug-related AEs, in 
subjects with metastatic uveal melanoma. 
• Estimate the ORR in subjects with metastatic uveal melanoma 
treated with entrectinib and PAC-1. 
• Estimate DoR in subjects with metastatic uveal melanoma.  
• Estimate OS rate in subjects with metastatic uveal melanoma 
treated with entrectinib and PAC-1. 
 
Correlative/Exploratory Objectives 
• Determine pharmacokinetics/pharmacodynamics of PAC-1 alone 
after single dosing and after repeated dosing and in combination 
with entrectinib (Phase 1b only). 
• Determine pharmacokinetics/pharmacodynamics of entrectinib 
alone after single dosing and after repeated dosing and in 
combination with PAC-1 (Phase 1b only). 
• Compare procaspase 3 expression in tumor tissue to degree of 
clinical response. 
• Determine correlation between CTC number and clinical response.


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STUDY DESIGN 
Single arm study with dose escalation Phase Ib cohort followed by a 
Phase II cohort. PAC-1 (PO) will be given daily on Days 1 through 21 of 
each cycle (28-day cycle). Entrectinib (PO) will be given daily on Days 1 
through 28 of each cycle. Response will be evaluated after every 2 cycles. 
Treatment will continue until disease progression based on RECIST 
criteria or intolerable toxicity. 
ELIGIBILITY 
CRITERIA (See 
Section 3 for 
complete list of 
eligibility criteria) 
Inclusion Criteria 
 
1. Histologically or cytologically confirmed metastatic uveal melanoma. 
2. One or more lesions that could be accurately measured using 
Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. 
3. Eastern Cooperative Oncology Group (ECOG) performance status of 
0 to 1. 
4. Adequate organ function within 14 days of registration. 
5. Subjects must have archival tissue (metastatic disease preferred) 
available or agree to undergo a biopsy prior to C1D1 treatment.  
6. Prior therapy is allowed but must have been completed 21 days prior 
to initiation of protocol therapy and all toxicities must be < Grade 2. 
7. Palliative radiation must have been completed 2 weeks prior to the 
initiation of study therapy. 
8. Patient with known brain metastases must have been treated at least 2 
weeks prior to enrollment, be asymptomatic from brain metastases, 
stable on brain imaging, and not be receiving a supra-physiologic 
dose of steroids (>10 mg prednisone daily or equivalent). 
9. All females of childbearing potential must have a urine HCG test or 
blood HCG test within 2 weeks prior to registration to rule out 
pregnancy.  
 
Exclusion Criteria 
1. Peripheral sensory neuropathy Grade ≥ 2 (per CTCAE v5.0).  
2. Active gastrointestinal disease (e.g., Crohn’s disease, ulcerative 
colitis, or short gut syndrome) or other malabsorption syndromes that 
would reasonably impact drug absorption. 
3. Has known history of Human Immunodeficiency Virus (HIV) (HIV 
1/2 antibodies). 
4. Has known active Hepatitis B or C. Active Hepatitis B is defined as a 
known positive HBsAg result. Active Hepatitis C is defined by a 
known positive Hep C Ab result and known quantitative HCV RNA 
results greater than the lower limits of detection of the assay. For 
patients with past HBV infection or resolved HBV infection (defined 
as the presence of hepatitis B core antibody [HBcAb] and absence of 
HBsAg), the patient is only eligible if they are negative for HBV 
DNA. 
5. Known interstitial lung disease, interstitial fibrosis, or history of 
tyrosine kinase inhibitor-induced pneumonitis. NOTE: Radiation-
induced lung disorders are not included in this exclusion criterion.


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6. History of retinal pigmented epithelial detachment, central serous 
retinopathy, or retinal vein occlusion in the unaffected eye; or 
intraocular pressure 21 mmHg or uncontrolled glaucoma (irrespective 
of intraocular pressure) in the unaffected eye 
7. History of uncontrolled seizures 
8. History of ataxia 
9. Allergies and adverse drug reaction: History of allergy to study drug 
components 
10. Thromboembolic events requiring therapeutic anticoagulation. 
Concomitant anticoagulation with oral anticoagulants (warfarin, 
direct thrombin or factor Xa inhibitors), platelet inhibitors (eg. 
Clopidogrel, high dose aspirin) is prohibited. Low-dose aspirin (<100 
mg/day), low-dose warfarin (<1 mg/day) and prophylactic low 
molecular weight heparin (LMWH) or similar agents are permitted. 
11. History of recent (within the past 3 months) symptomatic congestive 
heart failure or ejection fraction ≤50% observed during screening for 
the study. 
12. History of prolonged QTc interval (e.g., repeated demonstration of a 
QTc interval > 450 milliseconds from ECGs performed at least 24 
hours apart). 
13. History of additional risk factors for torsades de pointes (e.g., family 
history of long QT syndrome). 
14. Cardiovascular disorders including unstable angina pectoris, 
clinically-significant cardiac arrhythmias, myocardial infarction or 
stroke (including transient ischemic attack [TIA], or other ischemic 
event) within 6 months prior to registration. 
15. Active infection requiring intravenous systemic treatment. 
16. Serious non-healing wound/ulcer/bone fracture within 28 days prior 
to registration. 
17. Known uncontrolled, symptomatic brain metastasis or cranial 
epidural disease. 
18. Known additional malignancies which require systemic treatment. 
19. Inability to swallow intact tablets. 
 
 


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STATISTICAL 
CONSIDERATIONS 
 
Phase 2 
The primary endpoint of the study is 3 month progression-free survival 
(PFS) rate, using RECIST v1.1, in subjects with metastatic uveal 
melanoma treated with entrectinib and PAC-1. Kaplan Meier curve will 
be used to evaluate PFS, and OS; descriptive statistics for response rate, 
DoR, and toxicity.  
 
Sample Size 
Previous studies in the target population identified PFS at 3 months of 
38%.6 We hypothesize PFS at 3 months of 65%. Controlling for a 
probability of Type I error at 0.05 (one-sided), our sample size in Phase 2 
is estimated to be 32 to ensure 90% statistical power in successfully 
detecting an alternative progression free survival rate at 3 months of 0.65, 
compared to a null rate of 0.38. With 3 additional patients to account for a 
10% drop off rate, sample size for phase 2 study will be 35. Sample size 
analyses were conducted using the PASS software (NCSS, Kaysville, 
Utah, USA). With Phase 1b study component, the study will need to have 
3 subjects from Dose Level 1 of Phase 1b + 6 subjects from Dose Level 2 
of Phase 1b (and carried over to Phase 2 study).
TOTAL  
NUMBER OF 
SUBJECTS 
Total number of subjects for the study is 38  
ESTIMATED 
ENROLLMENT 
PERIOD 
Estimated 18 months 
ESTIMATED 
STUDY 
DURATION  
Estimated 24 months 
 
 


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TABLE OF CONTENTS 
 
ABBREVIATIONS ...................................................................................................................... 10 
1. 
BACKGROUND AND RATIONALE ................................................................................. 12 
2 
STUDY OBJECTIVES AND ENDPOINTS ........................................................................ 13 
3 
ELIGIBILITY REQUIREMENTS ....................................................................................... 15 
4 
SUBJECT REGISTRATION ............................................................................................... 18 
5 
OVERALL DESIGN AND TREATMENT PLAN .............................................................. 18 
6 
DOSE DELAYS/DOSE MODIFICATIONS ....................................................................... 24 
7 
STUDY CALENDAR & EVALUATIONS ......................................................................... 28 
8. 
CORRELATIVE STUDIES AND PROCEDURES ............................................................. 31 
9. 
CRITERIA FOR DISEASE EVALUATION ....................................................................... 33 
11. 
ADVERSE EVENTS ........................................................................................................ 39 
12 STATISTICAL CONSIDERATIONS.................................................................................. 45 
13 TRIAL MANAGEMENT ..................................................................................................... 49 
14 DATA HANDLING AND RECORD KEEPING ................................................................ 51 
15 ETHICS................................................................................................................................. 52 
16 REFERENCES ..................................................................................................................... 53 
APPENDIX 1: ECOG PERFORMANCE STATUS .................................................................... 55 
APPENDIX 2: DRUG INTERACTIONS WITH ENTRECTINIB .............................................. 56 
 
 
 
 


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PHASE 1b SCHEMA 
The primary objective of the Phase Ib study is to establish the maximum tolerated dose (MTD) 
of PAC-1 in combination with entrectinib for subjects with metastatic uveal melanoma, by 
evaluation of toxicity and tolerability. 
 
 
 
Dose 
Level* 
PAC-1 Dose 
(mg, orally) 
Entrectinib 
(mg, orally) 
# of Subjects# 
-1 
625 daily 
400 daily 
3-6 
1 
625 daily 
600 daily 
3-6 
2 
750 daily 
600 daily 
3-6 
#MTD cohort will be initially expanded to 6 patients, and if no DLT, to Phase 2 study. 
 
 
Phase 1b 
Subjects with metastatic uveal melanoma 
PAC-1 (PO), Days 1-21 
Entrectinib (PO), Days 1-28 
Cycle = 28 days 
Disease assessment every 2 cycles 
CR, PR, or SD 
Progression or significant toxicity 
Continue treatment up to progression 
Discontinue treatment 
Follow for survival every 2 months for 12 
months from start of treatment, then every 3 
months for up to 24 months 


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PHASE 2 SCHEMA 
The primary objective of the Phase 2 Study is to estimate 3 month progression-free survival 
(PFS) using RECIST v1.1 in subjects with metastatic uveal melanoma. 
 
 
 
 
Entrectinib dosed at 600 mg once daily; PAC-1 dosed once daily at RP2D from Phase 1b study.
Phase II 
Subjects with metastatic uveal melanoma 
PAC-1 (PO), Days 1-21 
Entrectinib (PO), Days 1-28 
Cycle = 28 days 
Disease assessment every 2 cycles 
CR, PR, or SD 
Progression or significant toxicity 
Continue treatment up to progression 
Discontinue treatment 
Follow for survival every 2 months for 12 
months from start of treatment, then every 3 
months for up to 24 months 


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ABBREVIATIONS 
Abbreviation  
 
 
Definition 
_____________________________________________________________________________ 
AE 
 
 
adverse event 
ANC  
 
absolute neutrophil count 
ALK  
 
anaplastic lymphoma kinase 
ALT 
 
 
alanine aminotransferase 
ASCO  
 
American Society of Clinical Oncology 
AST 
 
 
aspartate aminotransferase 
BUN  
 
blood urea nitrogen 
CBC  
 
complete blood count 
cm 
 
 
centimeter 
CMP  
 
comprehensive metabolic panel 
CNS 
 
 
central nervous system 
CR 
 
 
complete response 
CT 
 
 
computed tomography 
CTCAE 
 
(NCI) Common Terminology Criteria for Adverse Events 
CTEP  
 
Cancer Therapy Evaluation Program 
CYP 
 
 
cytochrome P450 
dL 
 
 
deciliter 
DOR  
 
duration of response 
ECG  
 
electrocardiogram 
ECOG  
 
Eastern Cooperative Oncology Group 
ERK  
 
extracellular signal-regulated kinase  
FDA  
 
Food and Drug Administration 
FDAAA 
 
Food and Drug Administration Amendments Act 
FDAMA 
 
Food and Drug Administration Modernization Act 
GFR 
 
 
glomerular filtration rate 
h 
 
 
hour 
Hgb 
 
 
hemoglobin 
IB 
 
 
Investigator’s Brochure 
IND 
 
 
Investigational New Drug 
IRB 
 
 
institutional review board 
kg 
 
 
kilogram 
lbs 
 
 
pounds 
LDH  
 
lactic dehydrogenase 
mg 
 
 
milligram 
min 
 
 
minute 
mL 
 
 
milliliter 
mm3 
 
 
cubic millimeters 


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MRI 
 
 
magnetic resonance imaging 
MTD  
 
maximum tolerated dose 
NSCLC 
 
non-small cell lung cancer 
NTRK  
 
neurotrophic tyrosine kinase 
ORR  
 
overall response rate 
OS 
 
 
overall survival 
PAC-1  
 
first procaspase-activating compound 
PFS 
 
 
progression-free survival 
PK 
 
 
pharmacokinetics 
PR 
 
 
partial response 
PT 
 
 
prothrombin time 
PTT 
 
 
partial thromboplastin time 
RECIST 
 
Response Evaluation Criteria in Solid Tumor 
ROS1  
 
ROS proto-oncogene 1  
SAE 
 
 
serious adverse event 
SDEA  
 
Safety Data Exchange Agreement 
TKI 
 
 
tyrosine kinase inhibitor 
Trk 
 
 
tropomyosin-related kinase 
ULN  
 
upper limit of normal 
US  
 
 
United States 
WHO  
 
World Health Organization 
WOCP  
 
women of childbearing potential 
wt 
 
 
weight 
 


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1. 
BACKGROUND AND RATIONALE 
 
1.1 
Uveal Melanoma 
Uveal melanoma arises from the uveal tract of the eye, which includes the choroid, ciliary body, 
and iris, and is the most common primary intraocular malignancy in adults.1 Uveal melanoma is 
biologically different from cutaneous melanoma2 and accounts for approximately 3% to 5% of all 
melanoma. There are currently no approved or effective systemic treatment options for 
individuals with metastatic uveal melanoma. Mutations in GNAQ or GNA11 are found in more 
than 80% of uveal melanomas, resulting in constitutive activation of the RAS/RAF/MEK/ERK 
pathway.3-5  
 
1.2 
Current Treatment of Uveal Melanoma  
There are more than 40 clinical trials reported in uveal melanoma with average response rate of 
4%. Current standard of care is dacarbazine. In a recent randomized clinical SUMMIT trial of 
selumetinib in combination with dacarbazine in patients with metastatic uveal melanoma the 
objective response rate (ORR) was 3%, with progression-free survival (PFS) of 2.8 months in 
selumetinib plus dacarbazine treatment group. Three- and 6-month PFS rates were 38% and 
10%, respectively.6 Overall survival (OS) was only 10 months. 
 
1.3 
Entrectinib 
Entrectinib is a potent tyrosine kinase inhibitor (TKI) that targets the product of oncogenic 
rearrangements in neurotrophic tyrosine kinase (NTRK), ROS proto-oncogene 1 (ROS1), and 
anaplastic lymphoma kinase (ALK). Two phase I trials demonstrated activity in TKI-naïve 
patients along with substantial intracranial activity. In ROS1-rearranged lung cancers, entrectinib 
resulted in durable disease control and prolonged PFS. The drug was well tolerated and has a 
safety profile that includes adverse events mediated by on-target tropomyosin-related kinase 
(Trk) A/B/C inhibition. Refer to the current investigator’s brochure for details regarding adverse 
events related to entrectinib. 
 
1.4 
First Procaspase-Activating Compound  
Members of the caspase family of cysteine proteases are key players in both the initiation and 
execution of apoptosis.8 Most critical to apoptosis is the proteolytic conversion of procaspase-3 
to caspase-3. As both the intrinsic and extrinsic apoptotic pathways converge to activate 
procaspase-3, and as caspase-3 has over 100 cellular substrates, the activation of procaspase-3 to 
caspase-3 is a pivotal and committed event in the apoptotic cascade.9 Procaspase-3 levels are 
elevated in a variety of tumors including glioblastoma10, breast cancer11 , colon cancer12, lung 
cancer13, lymphoma14, neuroblastoma15, melanoma16, and liver cancer17. First procaspase-
activating compound (PAC-1) is a small molecule, which enhances procaspase-3 activity in 
vitro18, induces apoptotic death of cancer cells in culture9,18,19, and has efficacy in multiple 
mouse xenograft models18,20.  There is a strong correlation between cellular procaspase-3 levels 
and the apoptosis-inducing properties of PAC-1.18 PAC-1 has shown toxicity in mice, rats and 
dogs. The toxicity is more typically observed with high doses. However, in one study testing 
relatively lower doses of PAC-1 given orally daily for 28 days in dogs, there was evidence of 
minimal-mild neurodegeneration (unpublished study). Overall, PAC-1 has several attributes 
which makes this a potentially efficacious anticancer drug in humans. Accordingly, we are 
presently conducting a study consisting of two components: to determine the maximum tolerated 


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dose (MTD) of PAC-1 in solid tumor or hematologic malignancy (NCT02355535), and to 
determine the maximum tolerated dose of PAC-1 when combined with the front-line 
chemotherapeutic agent, temozolomide, in patients with primary brain tumors (NCT03332355). 
Primary endpoints are evaluation of tolerability and toxicity. Neurological symptoms of CNS 
toxicity are being assessed throughout the trial.  
 
PAC-1 has been dosed in 44 human patients through 7 dose levels of PAC-1 (range: 75-750 mg). 
Two patients progressed during the first cycle of PAC-1 therapy. Thirty-two patients received 
PAC-1 for at least 2 dosing cycles (a cycle is 21 days of daily dosing followed by 7 days of no 
drug).  As a result of stable disease responses, six patients received PAC-1 for 4 cycles, three 
patients received PAC-1 for 6 cycles and two patients received PAC-1 for 10 cycles. No serious 
adverse events (SAEs) associated with PAC-1 administration have been observed.  Further, after 
careful review of all neurological and neurocognitive assessments and data collected through 
dose level 7 (750 mg) there were no signs of neurotoxicity associated with PAC-1 dosing.  In this 
study, physicians will utilize the MOCA-Montreal Cognitive Assessment Test Form for subject 
assessment at screening and Day 1 of each Cycle. 
 
1.5 
Rationale 
We have performed an in vitro study of PAC-1 and entrectinib combination in seven uveal 
melanoma cell lines (GNAQ mutant; MEL270, 92.1, MEL202, OMM2.5, GNA11 mutant: 
OMM1, and GNAQ and GNA11 wild type: MEL285, and MEL290). In all seven cell lines we 
saw a synergistic killing effect of PAC-1 and entrectinib (data unpublished). We propose that 
entrectinib will synergize with PAC-1 in human patients with metastatic melanoma and will 
produce superior prolongation of PFS. 
 
2 
STUDY OBJECTIVES AND ENDPOINTS 
 
2.1 
Primary Objectives 
 
2.1.1 Phase 1b 
The primary objective of this study component is to determine the maximum tolerated dose 
(MTD) of PAC-1 in combination with entrectinib in patients with metastatic uveal melanoma, by 
evaluation of toxicity and tolerability. 
 
2.1.2 Phase 2 
The primary objective of this study component is to measure 3 months progression-free survival 
(PFS) rate in subjects with metastatic uveal melanoma treated with entrectinib and PAC-1. 
 
2.2 
Secondary Objectives  
 
2.2.1 Phase 1b 
Evaluate the safety of entrectinib and PAC-1 combination, assessed by the incidence and severity 
of drug-related adverse events (AE), in subjects with metastatic uveal melanoma. 
 


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2.2.2 Phase 2 
• Evaluate the safety of entrectinib and PAC-1 combination, assessed by the incidence and 
severity of drug-related adverse events (AE), in subjects with metastatic uveal melanoma. 
• Estimate the ORR in subjects with metastatic uveal melanoma treated with entrectinib 
and PAC-1. 
• Estimate DoR in subjects with metastatic uveal melanoma.  
• Estimate OS rate in subjects with metastatic uveal melanoma treated with entrectinib and 
PAC-1. 
 
2.3 
Correlative/Exploratory Objectives 
• Determine pharmacokinetics (PK)/pharmacodynamics (PD) of PAC-1 alone after single 
dosing and after repeated dosing and in combination with entrectinib (Phase 1b only). 
• Determine pharmacokinetics/pharmacodynamics of entrectinib alone after single dosing 
and after repeated dosing and in combination with PAC-1 (Phase 1b only). 
• Compare procaspase 3 expression in tumor tissue to degree of clinical response 
• Determine correlation between CTC number and clinical response. 
 
2.4 
Primary Endpoints 
 
2.4.1 Phase 1b 
• The MTD of PAC-1 in combination with entrectinib is the highest tested dose of PAC-1 
combined with entrectinib with DLT rate of less than 33% in first cycle of therapy (i.e., 
≤1 out of 6 subjects with DLT).  
 
2.4.2 Phase 2 
• PFS at 3 months; this is defined as proportion of alive subjects with metastatic uveal 
melanoma at 3 months from treatment initiation with PAC-1 in combination with 
entrectinib without evidence of radiological disease progression by RECIST 1.1. 
 
2.5 
Secondary Endpoints  
 
2.5.1 Phase 1b 
Safety and tolerability by NCI Common Terminology Criteria for Adverse Events (NCI CTCAE) 
Version 5 on treatment with PAC-1 in combination with entrectinib in subjects with metastatic 
uveal melanoma. 
 
2.5.2 Phase 2 
• Safety and tolerability by NCI Common Terminology Criteria for Adverse Events (NCI 
CTCAE) Version 5 on treatment with PAC-1 in combination with entrectinib in subjects 
with metastatic uveal melanoma. 
• ORR; which will include CR + PR determined as per RECIST1.1 on treatment with 
PAC-1 in combination with entrectinib in subjects with metastatic uveal melanoma. 
• DoR on treatment with PAC-1 in combination with entrectinib in subjects with metastatic 
uveal melanoma. DoR is defined as the time that measurement criteria are met for 
complete or partial response (whichever status is recorded first) until the date that 


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recurrent or progressive disease is objectively documented (taking as reference for 
progressive disease the smallest measurements recorded since treatment started). 
• OS; this is defined as the time from treatment initiation with PAC-1 in combination with 
entrectinib until death as a result of any cause in subjects with metastatic uveal 
melanoma. 
 
2.6 
Correlative/Exploratory Endpoints 
• PK endpoints of PAC-1 include plasma concentration-time curve from time 0 to 24 hours 
(AUC0-24) for days 1 and 21 (see section on Pharmacokinetic Analysis for other 
endpoints) (Phase 1b only).  
• PK endpoints of entrectinib include plasma concentration-time curve from time 0 to 24 
hours (AUC0-24) for days 3 and 21 (see section on Pharmacokinetic Analysis for other 
endpoints) (Phase 1b only).  
• Compare procaspase 3 expression in tumor tissue to degree of clinical response. 
• Determine correlation between CTC number and clinical response. 
 
3 
ELIGIBILITY REQUIREMENTS 
 
3.1 
Inclusion Criteria 
Study entry is open to adults regardless of gender or ethnic background. While there will be 
every effort to seek out and include men and minorities, the subject population is expected to be 
no different than that of other advanced solid tumor cancer studies at each participating 
institution. 
 
Subject must meet all of the following applicable inclusion criteria to participate in this study: 
 
1. Written informed consent and HIPAA authorization for release of personal health 
information prior to registration. NOTE:  HIPAA authorization may be included in the 
informed consent or obtained separately. Patients must be willing and able to provide 
written informed consent for this trial. 
 
2. Age ≥ 18 years at the time of consent. 
 
3. Histologically or cytologically confirmed metastatic uveal melanoma. Staging per AJCC 
manual edition 8. 
 
4. One or more lesions that could be accurately measured using Response Evaluation 
Criteria in Solid Tumors (RECIST) 1.1. 
 
5. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 (Appendix 
1). 
 
6. Subjects must have archival tissue (metastatic disease preferred) available or undergo a 
biopsy prior to Cycle 1 Day 1 of treatment. Subjects that do not have archival tissue or 
cannot undergo a biopsy are not eligible for the study. 
 


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7. Demonstrate adequate organ function as defined in the table below. All screening labs to 
be obtained within 14 days prior to registration.  
 
System 
Laboratory Value 
Hematological 
Leukocytes 
≥ 2,000 µ/l 
Absolute Neutrophil Count (ANC)
≥ 1,500 K/mm3 
Platelets 
≥ 100,000/ mm3
Hemoglobin (Hgb) 
≥ 9 g/dL 
Renal 
Serum Creatinine 
≤ 1.5 x ULN
Calculated creatinine clearance1 
≥ 40 mL/min  
Hepatic 
Total Bilirubin 
≤ 1.5 mg/dL; (except for subjects with Gilbert 
Syndrome, who can have total bilirubin <3.0 mg/dl)
Aspartate aminotransferase (AST) 
≤ 2.5 × ULN 
Alanine aminotransferase (ALT) 
≤ 2.5 × ULN 
Alkaline Phosphatase 
≤ 2.5 × ULN; (<5 x ULN if liver metastases present)
Coagulation 
Partial Thromboplastin Time (PTT)
< 1.5 × ULN  
 
1 Cockcroft-Gault formula will be used to calculate creatinine clearance  
 
8. Prior therapy is allowed but must have been completed 21 days prior to initiation of 
protocol therapy and all toxicities must be < Grade 2. 
 
9. Palliative radiation must have been completed 2 weeks prior to the initiation of study 
therapy. 
 
10. Patient with known brain metastases must have been treated at least 2 weeks prior to 
enrollment, be asymptomatic from brain metastases, stable on brain imaging, and not be 
receiving a supra-physiologic dose of steroids (>10 mg prednisone daily or equivalent). 
 
11. Women must not be pregnant or breastfeeding. All women of childbearing potential 
(WOCBP) must have a blood human chorionic gonadotrophin (hCG) test or urine hCG 
test within 2 weeks prior to registration to rule out pregnancy.  
 
12. Women of childbearing potential (WOCBP) must agree to use contraception as outlined 
in Section 5.8 from the time of informed consent, during the study and for 3 months after 
the last dose of study drug(s). Abstinence from heterosexual intercourse is an acceptable 
form of contraception. Women of childbearing potential are those who have not been 
surgically sterilized or have not been free of menses >1 year. 
 
13. Male patients who are sexually active with WOCBP must agree to use contraception as 
outlined in Section 5.8 from the time of initiation of study treatment, during the study and 
for 3 months after the last dose of study drug(s). Abstinence from heterosexual 
intercourse is an acceptable form of contraception.  
 


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14. The participant is capable of understanding and complying with the protocol and has 
signed informed consent document. 
 
3.2 
Exclusion Criteria 
Subjects meeting any of the criteria below may not participate in the study: 
 
1. Peripheral sensory neuropathy Grade ≥ 2 (per CTCAE v5.0).  
 
2. Active gastrointestinal disease (e.g., Crohn’s disease, ulcerative colitis, or short gut 
syndrome) or other malabsorption syndromes that would reasonably impact drug 
absorption. 
 
3. Has known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies). 
 
4. Has known active Hepatitis B or C. Active Hepatitis B is defined as a known positive 
HBsAg result. Active Hepatitis C is defined by a known positive Hep C Ab result and 
known quantitative HCV RNA results greater than the lower limits of detection of the 
assay. For patients with past HBV infection or resolved HBV infection (defined as the 
presence of hepatitis B core antibody [HBcAb] and absence of HBsAg), the patient is 
only eligible if they are negative for HBV DNA. 
 
5. Known interstitial lung disease, interstitial fibrosis, or history of tyrosine kinase inhibitor-
induced pneumonitis. NOTE: Radiation-induced lung disorders are not included in this 
exclusion criterion. 
 
6. History of retinal pigmented epithelial detachment, central serous retinopathy, or retinal 
vein occlusion in the unaffected eye; or intraocular pressure 21 mmHg or uncontrolled 
glaucoma (irrespective of intraocular pressure) in the unaffected eye. 
 
7. History of uncontrolled seizures. 
 
8. History of ataxia. 
 
9. Allergies and adverse drug reaction: History of allergy to study drug components. 
 
10. Thromboembolic events requiring therapeutic anticoagulation. Concomitant 
anticoagulation with oral anticoagulants (warfarin, direct thrombin or factor Xa 
inhibitors), platelet inhibitors (e.g. Clopidogrel, high dose aspirin) is prohibited. Low-
dose aspirin (<100 mg/day), low-dose warfarin (<1 mg/day) and prophylactic low 
molecular weight heparin (LMWH) or similar agent are permitted. 
 
11. History of recent (within the past 3 months) symptomatic congestive heart failure or 
ejection fraction ≤50% observed during screening for the study. 
 
12. History of prolonged QTc interval (e.g., repeated demonstration of a QTc interval > 450 
milliseconds from ECGs performed at least 24 hours apart). 


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13. History of additional risk factors for torsades de pointes (e.g., family history of long QT 
syndrome). 
 
14. Cardiovascular disorders including unstable angina pectoris, clinically-significant cardiac 
arrhythmias, myocardial infarction or stroke (including transient ischemic attack [TIA], 
or other ischemic event) within 6 months prior to registration. 
 
15. Active infection requiring intravenous systemic treatment. 
 
16. Serious non-healing wound/ulcer/bone fracture within 28 days prior to registration. 
 
17. Known uncontrolled, symptomatic brain metastasis or cranial epidural disease. 
 
18. Known additional malignancies which require systemic treatment. 
 
19. Inability to swallow intact tablets. 
 
20. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality 
that may increase the risk associated with study participation or study drug administration 
or may interfere with the interpretation of study results and, in the judgment of the 
Investigator, would make the patient inappropriate for entry into this study or could 
compromise protocol objectives in the opinion of the Investigator and/or the sponsor-
investigator. 
 
4 
SUBJECT REGISTRATION 
All subjects must be registered through HCRN’s electronic data capture (EDC) system. A subject 
is considered registered when an “On Study” date is entered into the EDC system. Subjects must 
be registered prior to starting protocol therapy. Subjects must begin therapy within 7 business 
days of registration.  
 
5 
OVERALL DESIGN AND TREATMENT PLAN 
 
5.1 
Phase 1b Dose Escalation Plan 
This Phase Ib dose escalation study will evaluate entrectinib in combination with PAC-1 in 
subjects with metastatic uveal melanoma. Entrectinib will be taken orally on Days 1-28 of each 
28 day cycle and PAC-1 will be taken orally on Days 1-21 of each 28-day cycle (see exception 
for Cycle 1 below), and response to treatment will be evaluated after every 2 cycles. Treatment 
will continue until disease progression (based on RECIST 1.1 criteria), unacceptable toxicity, 
subject withdrawal of informed consent, or subject death either from progression of disease, the 
therapy itself, or from other causes. Subjects who withdrew from study treatment, have 
progressive disease, or unacceptable toxicities will be followed for survival every 2 months for 
12 months from start of study treatment, then every 3 months for up to 24 months. 
 
Pharmacokinetic (PK) and pharmacodynamic (PD) assay for PAC-1 will be performed during 
Days 1 and 21 of Cycle 1. PAC-1 will be given on Day 1 of Cycle 1, withheld on Day 2 and Day 
3 of Cycle 1 then reinitiated on Day 4 of Cycle 1 to continue to Day 21 of the 28-day cycle. For 


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each successive cycle, PAC-1 therapy will be initiated on Day 1 and continue to Day 21 of the 
28-day cycle.  
 
Pharmacokinetic and pharmacodynamic assay for entrectinib will be performed during Days 3 
and 21 of Cycle 1. Entrectinib therapy will be withheld on Day 1 and Day 2 of Cycle 1, initiated 
on Day 3 of Cycle 1 and continue for the remainder of the cycle. For each successive cycle, 
entrectinib will be initiated on Day 1 and continue for the remainder of the 28 day cycle.  
 
Cycle 1 of Treatment (Cycle = 28 Days) 
Drug 
Dose 
Route 
Cycle 1 Frequency  
PAC-1 
TBD 
Orally 
Day 1 then Day 4 to Day 21;  
HELD Day 2 and Day 3  
Entrectinib 
600 mg 
Day 3 to Day 28;  
HELD Day 1 and Day 2  
 
Cycle 2 and Subsequent (Cycle = 28 Days) 
Drug 
Dose 
Route 
Frequency  
PAC-1 
TBD 
Orally 
Day 1 to Day 21  
Entrectinib 
600 mg 
Day 1 to Day 28  
 
Study Treatment Dose Levels 
Dose Level* 
PAC-1 Dose (mg, orally) 
Entrectinib (mg, orally) 
# of Subjects^ 
-1 
625 daily 
400 daily 
3-6 
1 (starting) 
625 daily 
600 daily 
3-6 
2 
750 daily 
600 daily 
3-6 
*Pharmacokinetics analysis will be performed at both dose levels during Cycle 1.  
^MTD cohort will be initially expanded to 6 patients, and if no DLT move to Phase 2 study. 
 
5.1.1 Dose Escalation Rules and MTD Definition 
• Three subjects will initially be enrolled at dose level 1. If none of the 3 subjects 
experience a dose limiting toxicity (DLT) during the first cycle of therapy, three subjects 
will be enrolled at dose level 2. If all subjects in dose level 2 complete the first cycle of 
therapy without DLT, 3 more subjects will be enrolled into dose level 2 to ensure only 0-
1 of 6 subjects have a DLT. There will be no further escalation beyond dose level 2. 
• Alternatively, if 1 of the first 3 subjects within a dose level cohort experiences a DLT, the 
cohort will be expanded to 6 subjects. If this happens within dose level 1 and only 1 of 
the total 6 subjects in dose level 1 experience DLT, the study will proceed to dose level 2. 
If 2 or more of 6 subjects in a cohort experience DLTs, or 2 subjects within a cohort of 3 
subjects experience DLT during the first cycle of therapy (>33% of subjects experiencing 
DLT), the MTD is exceeded. If this occurs at dose level 1, additional subjects will be 
accrued to dose level -1. If this occurs at dose level 2, 3 additional subjects will be 


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enrolled into dose level 1, unless there have been 6 subjects already enrolled into dose 
level 1. 
• The MTD of PAC-1 in combination with entrectinib is the highest tested dose of PAC-1 
combined with entrectinib with DLT rate of less than 33% in the first cycle of therapy 
(i.e., ≤1 out of 6 subjects with DLT). That dose will be recommended for the Phase 2 
study.  
• At the discretion of the sponsor-investigator, a lower Phase 2 dose may be recommended 
if other toxicity emerges during the Phase 1b study which does not meet DLT criteria but 
limits the dose that can be administered cumulatively. 
 
5.1.2 Definition of Dose-Limiting Toxicity 
Toxicity and adverse events will be classified according to NCI's Common Terminology Criteria 
for Adverse Events Version 5.0 (CTCAE v.5).  
 
Dose limiting toxicity (DLT) is defined as one of the following events that are at least possibly 
related to study medications occurring during Cycle 1 (first 28 days):   
• Grade 3 or greater hematologic toxicity during the first cycle (28 days) of therapy.  
• Cerebrovascular ischemia or cerebrovascular hemorrhage of any duration or grade. 
• Grade 3 or greater clinical non-hematological toxicity (excluding ≥ grade 3 nausea, 
vomiting, or diarrhea lasting less than < 72 hours with maximal medical intervention 
and/or prophylaxis) during the first cycle (28 days) of therapy. 
• Delay of Cycle 2 treatment start by more than 2 weeks due to incomplete hematologic 
recovery (ANC > 1.5 x 109/L or platelets > 100 x 109/L) or unresolved treatment related 
grade 3 or greater non-hematologic toxicity. 
• Grade 2 or greater treatment related neurological toxicity occurring during the first cycle 
of therapy and lasting more than 72 hours. 
• Hepatic labs meeting Hy’s Law (concomitant elevations of AST/ALT and bilirubin of 3x 
ULN and 2xULN respectively without alternative etiology) 
 
DLT’s will be counted based on the number of patients with DLT at a given dose level, not the 
absolute number of DLTs.  No single patient can trigger more than one DLT event. Additional 
patient cohorts will not be enrolled until all patients at the current dose level complete all 
planned treatment for Cycle 1 and are able to start Cycle 2 with no more than a 2-week delay. 
 
Intra-subject dose escalation is not permitted. Once the MTD of PAC-1 in combination with 
entrectinib is determined, enrollment will continue until at least 6 subjects total are accrued at the 
maximum tolerated dose. 
 
 
 


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5.2 
Phase 2 Study 
At the completion of the phase 1b study, the safety of the PAC-1 and entrectinib combination 
will be assessed and recommendations will be provided regarding whether to proceed to the 
phase 2 portion of the study. The sponsor-investigator, Vanquish Oncology, and Genentech will 
review the DSMB recommendations, and make a decision regarding whether this combination is 
safe to warrant further study of this combination in a phase 2 study.  
 
The primary objective of the Phase II trial is to determine the activity of the combination of 
PAC-1 and entrectinib for subjects with uveal melanoma as assessed by PFS at 3 months. 
Entrectinib, 600 mg orally, will be given Days 1 to Day 28 of each cycle and the recommended 
phase 2 dose (RP2D) of PAC-1 (PO) will be given on Days 1 to Day 21. Each cycle is 28 days. 
Treatment will continue until disease progression (based on RECIST 1.1 criteria), unacceptable 
toxicity, subject withdrawal of informed consent, or subject death either from progression of 
disease, the therapy itself, or from other causes. Subjects who voluntarily withdrew from study 
treatment, have progressive disease, or unacceptable toxicities will be followed for survival 
every 2 months for 12 months from start of study treatment, then every 3 months for up to 24 
months. 
 
5.3 
Administration of Study Drugs 
Criteria for the initiation of a new cycle of treatment can be found in Section 6.1. All tablets are 
to be ingested as dispensed by research team (e.g. tablets may not be broken or crushed by 
subject); patients who have difficulty swallowing tablets will be excluded from the study. If 
vomiting occurs during the course of treatment, no re-dosing of the patient is allowed before the 
next scheduled dose. Missed doses will not be made up.  A window of ± 3 days may be applied 
to all study visits to accommodate observed holidays, inclement weather, scheduling conflicts 
etc. Date and time of each drug administration should be clearly documented in subject’s chart 
and electronic case report forms (eCRFs). 
 
Patients will keep a drug diary to record each dose of the study drugs and time of day when 
administered, and any side effects they are experiencing. Research staff will record information 
from the diaries, discuss any concerns the patient has regarding the treatment, and will also 
collect any unused medication during these visits. Patients will be closely monitored for 
toxicities and CTCAE v5 will be used to assess toxicities. 
 
5.3.1 Entrectinib 
Entrectinib (PO) will be dosed at 600 mg daily in the evening on Days 1-28 of each 28 day cycle 
(for exception in Cycle 1, see below). During Cycle 1 for each dose cohort, subjects will be 
instructed to administer their daily dose at the same approximate time (+/- 1 hour) each evening. 
The study drug will be administered in the evening. Patients will be instructed to take each oral 
dose of entrectinib with 8 ounces of water (1 cup, 240 mL) and with food.  
 
Entrectinib therapy will be withheld on Days 1 and 2 and initiated during Cycle 1 on Day 3 to 
continue for the remainder of the cycle. Administration of entrectinib on Days 3 and 21 of Cycle 
1 will occur in the morning. Entrectinib administration will occur 1 hour before PAC-1 on Day 
21. Information on the time and number of entrectinib doses received for the 96 hours prior to 
the dose on Day 21 will be obtained from subjects. 


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5.3.2 PAC-1 
In Phase 1b, PAC-1 (PO) will be dosed at 625 or 750 mg daily in the morning on Days 1-21 of 
each 28 day cycle (for exception in cycle 1, see below). The dose which is determined to be the 
MTD will be taken in the morning on Days 1-21 of the cycle in Phase 2.   
 
During Cycle 1 for each dose level, subjects will be instructed to administer their daily dose at 
the same approximate time (+/- 1 hour) each morning. Subsequent cycles must meet the criteria 
found in section 6.1. The study drug will be administered in the morning and on an empty 
stomach with the patient remaining NPO (nothing by mouth), except for water and prescribed 
medications, for 2 hours before and 1 hour after each dose.  Patients will be instructed to take 
each oral dose of PAC-1 with 8 ounces of water (1 cup, 240 mL).  
 
For Cycle 1, PAC-1 will be given on Day 1 and withheld on Days 2 and 3. The dose on these 
days are being held in order to determine the PK of single-agent entrectinib on Day 3 of the 
cycle. PAC-1 treatment will be re-initiated on Day 4 and continue to Day 21 of the 28-day cycle. 
Administration of PAC-1 on Days 1 and 21 of Cycle 1 will occur in the morning. Information on 
the time and number of PAC-1 doses received for the 96 hours prior to the dose on Day 21 will 
be obtained from subjects. 
 
5.4 
Supportive Care 
Optimal care should be given to all subjects. Subjects should receive full supportive care during 
the study, including transfusion of blood and blood products, treatment with antibiotics, 
analgesics, erythropoietin, or bisphosphonates, when appropriate. Although acetaminophen at 
doses of ≤ 2 grams/day is permitted, it should be used with caution in subjects with impaired 
liver function.  
 
Nausea/vomiting: Nausea and vomiting should be treated aggressively, and consideration should 
be given in subsequent cycles to the administration of prophylactic antiemetic therapy according 
to standard institutional practice. If prophylactic antiemetic therapy is needed, 5-HT3 receptor 
antagonists (without corticosteroids) should be tried first. Due to the potential of 
benzodiazepines to cause sedation, the use of benzodiazepines for antiemetic prophylaxis should 
be reserved for subjects who cannot be satisfactorily managed otherwise. Subjects should be 
strongly encouraged to maintain liberal oral fluid intake. 
 
5.5 
Concomitant Medications 
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing trial. If there is a clinical indication for one of these or other medications or 
vaccinations specifically prohibited during the trial, discontinuation from trial therapy or 
vaccination may be required. The investigator should discuss any questions regarding this with 
the sponsor-investigator by contacting the HCRN Project Manager. The final decision on any 
supportive therapy or vaccination rests with the investigator and/or the subject's primary 
physician. 
 
5.5.1 Permitted Concomitant Medications 
Medications required to treat AEs, manage cancer symptoms, concurrent diseases and supportive 
care agents, such as pain medications, anti-emetics and anti-diarrheal medications are allowed. In 


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general, the use of any concomitant medication deemed necessary for the care of the subject is 
permitted in this study, except as specifically prohibited below. 
 
The subject must be told to notify the investigational site about any new medications subject 
takes after the start of the study treatment. All medications (other than study drugs) and 
significant non-drug therapies (including vitamins, herbal medications, physical therapy and 
blood transfusions) administered within 30 days of study entry and during the study must be 
listed on the Concomitant medications/Significant non-drug therapies section of the subject 
record. 
 
Although acetaminophen at doses of ≤ 2 grams/day is permitted, it should be used with caution 
in subjects with impaired liver function.  
 
5.6.2 Permitted Concomitant Therapy Requiring Caution 
Entrectinib is mainly eliminated through hepatic clearance and CYP3A4 plays a significant role 
in the biotransformation of entrectinib. Co-administration of strong or moderate CYP3A4 
inhibitors and inducers should be avoided. In vitro, entrectinib exhibited potential to inhibit and 
induce the activities of CYP3A, and potential for inhibition of CYP2C9 and CYP2D6, which 
suggests a potential for interaction with other drugs metabolized by these isoforms. Because of 
this, entrectinib should be administered with caution with the drugs listed in Appendix 2.  
 
In addition, since absorption of entrectinib is pH sensitive, patients using H2-receptor 
antagonists, proton pump inhibitors (PPIs), and/or antacids should discontinue these drugs prior 
to starting entrectinib. If not possible, or if after discontinuation such therapy needs to be 
resumed, patients should be instructed to take only H2 receptor antagonists or antacids, if 
possible, as the duration of action of these drugs is relatively transient compared with PPIs that 
have longer half-lives, and thus may be administered at safe intervals in relation to entrectinib. 
These medications should be taken at a time point that is not proximal to entrectinib 
administration (at least 3-4 hours before or after entrectinib administration). 
 
Medications that prolong QT/QTc interval should be avoided. Subjects that require medications 
that prolong QT/QTc interval should be monitored closely during treatment. 
 
5.6.3 Prohibited Medications 
Subjects are prohibited from receiving the following therapies during the Screening and 
Treatment Phase of this trial: 
• Anti-cancer systemic chemotherapy or biological therapy not specified in this protocol 
• Concomitant use of chemotherapy  
• Investigational agents other than entrectinib or PAC-1  
• Radiation therapy  
• Herbal medications (e.g., St. John’s Wort) 
 
Subjects who, in the assessment by the investigator, require the use of any of the aforementioned 
treatments for clinical management, but not for progressive disease, should be removed from the 
trial and replaced. 
 


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5.7 
Diet 
Subjects should maintain a normal diet unless modifications are required to manage an AE such 
as diarrhea, nausea, or vomiting. Patients are to be instructed to refrain from using alcohol while 
enrolled in this study.  Consumption of grapefruit and/or grapefruit juice should be avoided 
during the treatment period. 
 
5.8 Reproductive Information 
Participants of childbearing potential who are sexually active and their partners must agree to (1) 
abstain from heterosexual intercourse or (2) use 2 forms of effective methods of contraception as 
outlined below (one from each list). 
 
Primary Forms 
Secondary Forms 
tubal sterilization (tubes tied)  
male latex condom with or without spermicide
partner’s vasectomy  
diaphragm with spermicide
intrauterine device (IUD) 
cervical cap with spermicide 
hormonal contraceptives-  
(includes transdermal patch, injectables, 
implantables 
vaginal sponge (contains spermicide)  
 
Female participants of child bearing potential must agree to use contraception from the time of 
informed consent, during the study and for 3 months after the last dose of study drug(s). Male 
participants must agree to use contraception from the time of initiation of study treatment, during 
the study and for 3 months after the last dose of study drug(s). 
 
6 
DOSE DELAYS/DOSE MODIFICATIONS 
Toxicity and adverse events will be classified according to NCI's Common Terminology Criteria 
for Adverse Events Version 5.0 (CTCAE v.5). Subjects will be evaluated for adverse events (all 
grades), serious adverse events, and adverse events requiring protocol therapy interruption or 
discontinuation at each study visit for the duration of their participation in the study.   
 
6.1 
Start of a New Cycle 
A new treatment cycle will only be initiated when all of the following conditions are met: 
• ANC ≥ 1,500/mm3 
• platelets ≥ 100,000/mm3 
• non-hematologic treatment related toxicities have improved to ≤ Grade 1 or to the 
patient’s baseline values (except alopecia) 
 
If blood counts are below this threshold, blood work is to be repeated weekly until counts are at 
an acceptable level.  Treatment will be restarted with appropriate dose modifications.  If 
treatment is unable to restart within 4 weeks of the planned treatment date, the patient will be 
permanently discontinued from study therapy.  NOTE:  For Cycle 1 of the Phase 1b study only, 
the inability to restart therapy within 2 weeks of the planned date is a DLT (per section 5.1.2); 
however the patient is allowed an additional week of recovery and is allowed to remain on study 
if treatment restarts within 4 weeks. 
 


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For subjects who present to the clinic with toxicity during a current treatment cycle, the study 
drug may be stopped per the discretion of the site investigator if the toxicity is determined to be 
clinically significant. 
 
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 subject 
vacation, and/or holidays). Subjects should be placed back on study therapy within 4 weeks of 
the scheduled interruption, unless otherwise discussed with the sponsor-investigator. The reason 
for interruption should be documented in the patient's subject's study record. 
 
6.2 
Dose Modifications for PAC-1 Toxicity 
CTCAE v 5 Adverse Effects Terms & 
Descriptions)  
PAC-1 Dose Modifications 
Any other grade 3 non-hematologic toxicity 
Hold dose until improvement to grade ≤ 1 then 
decrease dose by one dose level below level that 
caused toxicity. 
Grade ≥ 2 neurologic toxicity detected at any time 
while on study treatment 
Hold dose until improvement to grade ≤ 1 then 
decrease dose by one dose level below level that 
caused toxicity.
Any grade cerebrovascular ischemia or 
hemorrhage 
Discontinue treatment. 
Any other grade 4 non-hematologic toxicity 
Discontinue treatment. 
Neutrophils < 500 cells/mm3 
Hold dose until improvement to grade ≤ 1 then 
decrease dose by one dose level below level that 
caused toxicity. 
Febrile Neutropenia 
Hold dose until improvement to grade ≤ 1 then 
decrease dose by one dose level below level that 
caused toxicity. 
Platelets < 25,000/mm3or platelets < 50,000/mm3 
with bleeding 
Hold dose until improvement to grade ≤ 1 then 
decrease dose by one dose level below level that 
caused toxicity. 
Any other grade 3 hematologic toxicity 
Hold dose until improvement to grade ≤ 1 then 
decrease dose by one dose level below level that 
caused toxicity. 
Any other grade 4 hematologic toxicity  
Discontinue treatment. 
 
 
 


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6.2.1 PAC-1 Dose Reduction  
Dose Reductiona,b,c 
Dose 
Dose 
Starting Dose 
750 mg daily 
625 mg daily 
First Dose Reduction 
625 mg daily
500 mg daily 
Second Dose Reduction 
500 mg daily
375 mg daily 
Third Dose Reduction 
375 mg daily
250 mg daily 
Fourth Dose Reduction 
250 mg daily
NA 
a In the event a dose modification is needed, initiation of re-treatment should be delayed 1 to 2 
weeks to allow for recovery from treatment-related toxicity 
b If the patient has not recovered after a 2-week delay, discontinue treatment 
c Up to four dose reductions are allowed if the starting dose is 750 mg. If subsequent cycles require 
additional dose reductions, treatment will be discontinued. 
 
6.3 
Dose Modifications for Entrectinib Toxicity 
 
Dose Modifications for Entrectinib-Related Adverse Events 
 
Toxicity* 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Non-hematologic 
Continue at same 
dose level 
Continue at same 
dose level 
Withhold dose until 
toxicity is ≤ G1 or 
has returned to 
baseline, then 
reduce by 1 dose 
level and resume 
treatment 
Withhold dose until 
toxicity is ≤ G1 or has 
returned to baseline, 
then reduce by 1 dose 
level and resume 
treatment; or discontinue 
treatment as per the 
Investigator’s discretion 
Central Nervous 
System Effects 
Continue at 
same dose level 
Intolerable Grade 
2;  
Withhold dose 
until recovery to ≤ 
Grade 1 or to 
baseline. 
 
Resume at same 
dose or reduced 
dose, as 
clinically 
appropriate. 
Withhold dose until 
recovery to ≤ to 
Grade 1 or to 
baseline. 
 
Resume at same 
dose or reduced 
dose, as clinically 
appropriate. 
Discontinue treatment 
permanently  


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Hematologic 
Continue at 
same dose 
level 
Continue at 
same dose 
level 
Withhold dose until 
toxicity is ≤ G2, or 
has returned to 
baseline, then 
resume treatment at 
the same dose level 
or reduce by 1 dose 
level as per the 
Investigator’s 
discretion 
Grade 3 lymphopenia 
without other dose- 
limiting events (e.g., 
opportunistic 
infection) may 
continue study 
treatment without 
interruption 
Withhold dose until 
toxicity is ≤ G2, or has 
returned to baseline, 
then reduce the dose by 
1 dose level and resume 
treatment 
Grade 4 lymphopenia 
without other dose- 
limiting events (e.g., 
opportunistic infection) 
may continue study 
treatment without 
interruption 
QT Interval 
Prolongation 
QTc greater than 500 ms 
Withhold entrectinib until QTc interval recovers to 
baseline. 
 
Resume at same dose if factors that cause QT 
prolongation are identified and corrected. 
 
Resume at reduced dose if other factors that cause QT 
prolongation are not identified. 
Torsade de pointes; 
polymorphic ventricular 
tachycardia; signs/symptoms 
of serious arrhythmia 
Permanently discontinue entrectinib 
 
Vision Disorders 
Grade 2 or above 
Withhold entrectinib until improvement or 
stabilization. 
 
Resume at same dose or reduced dose, as 
clinically appropriate. 
Anemia or 
neutropenia 
Grade 3 or 4 
Withhold entrectinib until recovery to less than 
or equal to Grade 2. 
 
Resume at the same dose or reduced dose, as 
clinically appropriate. 
Congestive 
heart failure 
Continue at 
same dose level 
Withhold dose 
until toxicity is 
≤ G1 or has 
returned to 
baseline, then 
reduce by 1 
dose level and 
resume 
treatment 
Withhold dose 
until toxicity is ≤ 
G1 or has 
returned to 
baseline, then 
reduce by 1 dose 
level and resume 
treatment 
Discontinue treatment 
permanently 


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Pneumonitis (in 
absence of disease 
progression, 
pulmonary 
embolism, positive 
cultures or radiation 
effect) 
Withhold dose until 
toxicity is Grade 0, 
then resume 
treatment at same 
dose 
Discontinue 
treatment 
permanently if 
pneumonitis recurs
Withhold dose 
until toxicity is 
Grade 0, then 
resume treatment 
at same dose 
Discontinue 
treatment 
permanently if 
pneumonitis 
recurs 
Discontinue 
treatment 
permanently 
Discontinue treatment 
permanently 
Hyperuricemia 
symptomatic or 
Grade 4 
Initiate urate-lowering medication. 
• Withhold entrectinib until improvement of signs or symptoms. 
• Resume entrectinib at same or reduced dose. 
Hepatotoxicity 
Continue at same 
dose level 
Continue at same 
dose level 
Withhold dose until 
recovery to ≤ to 
Grade 1 or to 
baseline. 
 
Resume at same 
dose if resolution 
occurs within 4 
weeks. 
 
Permanently 
discontinue if 
adverse reaction 
does not resolve 
within 4 weeks. 
 
Resume at a 
reduced dose for 
recurrent Grade 3 
events that resolve 
within 4 weeks. 
Withhold dose until 
recovery to ≤ to Grade 
1 or to baseline. 
 
Resume at same dose if 
resolution occurs 
within 4 weeks. 
 
Permanently 
discontinue if adverse 
reaction does not 
resolve within 4 
weeks.  
 
Permanently 
discontinue for 
recurrent Grade 4 
events 
 
ALT or AST greater than 3 times ULN with concurrent total bilirubin greater than 1.5 times
ULN (in the absence of cholestasis or hemolysis) permanently discontinue treatment. 
Other Clinically 
Relevant Adverse 
Reactions 
Grade 3 or 4 
Withhold entrectinib until adverse reaction resolves or 
improves to recovery or improvement to Grade 1 or 
baseline. 
 
Resume at the same or reduced dose, if resolution occurs 
within 4 weeks. 
 
Permanently discontinue if adverse reaction does not 
resolve within 4 weeks. 
 
Permanently discontinue for recurrent Grade 4 events. 
*dose modifications to be based on worst toxicity grade as per NCI CTCAE v5.0 
 
 


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6.3.2 Entrectinib Dose Reduction  
Dose Reductiona,b,c 
Dose 
Starting Dose 
600 mg daily 
First Dose Reduction 
400 mg daily 
Second Dose Reduction 
200 mg daily 
a In the event a dose modification is needed, initiation of re-treatment should be delayed 1 to 2 
weeks to allow for recovery from treatment-related toxicity 
b If the patient has not recovered after a 2-week delay, discontinue treatment 
c Two dose reductions are allowed. If subsequent cycles require additional dose reductions, 
treatment will be discontinued. 
 
6.4 
Protocol Therapy Discontinuation 
In addition to discontinuation from therapy related to toxicities as outlined above, a subject will 
also be discontinued from protocol therapy and followed per protocol under the following 
circumstances outlined below.  The reason for discontinuation of protocol therapy will be 
documented on the electronic case report form (eCRF)   
• If there is evidence of disease progression  
• If the treating physician thinks a change of therapy would be in the best interest of the 
subject 
• If the subject requests to discontinue protocol therapy 
• If the protocol therapy exhibits unacceptable toxicity 
• If a female subject becomes pregnant  
• If there is a ≥ 4 week delay between cycles due to a treatment related adverse event.  
• Subjects can stop study participation at any time. However, if they decide to stop, 
subjects will continue to be followed as per Section 7 calendar 
 
6.5 
Protocol Discontinuation  
If a subject decides to discontinue from the protocol (and not just from protocol therapy) all 
efforts should be made to complete and report study assessments as thoroughly as possible. A 
complete final evaluation at the time of the subject’s protocol withdrawal should be made with 
an explanation of why the subject is withdrawing from the protocol. If the reason for removal of 
a subject from the study is an adverse event, it will be recorded on the eCRF. 
 
 
 
 
 
 
 


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7 STUDY CALENDAR & EVALUATIONS 
 
Study Evaluation  
Cycle = 28 days 
Screening 
Cycle 1 
Cycle 2 and Subsequent 
Safety follow 
up visit12 
Long-term 
Follow up13 
-28 days 
Day 1 
± 3 days
Day 1 
± 3 days
30 days post 
last dose
Every 2-3 
months
REQUIRED ASSESSMENTS 
Informed Consent 
X
Medical History1 
X
Diagnosis and Disease Staging1 
X
Physical Exam2 
X
X
X
X
Vital signs and ECOG Performance Status2 
X
X
X
X
ECG3 
X
X3 
X3 
X
ECHO3 
X
 
Mini Mental Status Exam (MMSE) and Neurologic exam4 
X
X
X4 
X4 
AEs & concomitant medications 
X
X
X
X
LABORATORY ASSESSMENTS 
Complete Blood Cell Count with diff (CBC)
X
X11 
X
X
Comprehensive Metabolic Profile (CMP)5 
X
X11 
X
X
Ammonia, Lactate Dehydrogenase and Uric Acid5 
X
X11 
X
PT/INR and aPTT5 
X
 
Pregnancy test (serum or urine) (WOCBP)5 
X
X5 
Urinalysis5 
X
DISEASE ASSESSMENT 
CT of chest6 
X
X6 
X6 
CT or MRI of abdomen and pelvis6 
X
X6 
X6 
MRI Brain6 
X6 
TREATMENT EXPOSURE 
PAC-17 
X7 
X7 
Entrectinib7 
X7 
X7 
SPECIMEN COLLECTION  
Plasma for PAC-1 PK/PD8 
X8 
Plasma for Entrectinib PK/PD8 
X8 
Blood sample for somatic baseline9 
X9 
Blood samples for CTCs, MOA and ctDNA9 
X9 
C2D1 
X9 
Archival or Fresh Tumor Tissue10 
X10 
X10 
FOLLOW-UP 
Survival Status, Subsequent Therapy 
X


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Key to Footnotes  
 
1: Medical History including all prior anti-cancer treatment. Other data to obtained during this assessment includes a smoking history 
questionnaire and trial awareness question.  Diagnosis and staging to include pathology report and TNM staging documentation. AJCC manual 
Edition 8. 
 
2: During the physical exam if the subject is experiencing visual changes, further investigation may be warranted with an ophthalmologic exam 
including at least the visual acuity and slit-lamp tests. This determination will be at the discretion of the site investigator. Vital signs to include 
temperature, pulse, respirations, blood pressure weight, and height (screening only) and ECOG performance status.   
 
3: ECG will be performed at screening then Day 1 of each Cycle. An ECHO will be performed at screening to assess LVEF. Testing during and 
after study treatment is at the discretion of the site investigator. 
 
4: A basic neurologic exam will be performed by the site investigator at screening, Day 1 of each Cycle of treatment and at the D30 safety follow 
up visit to monitor for neurologic toxicity.  The Mini Mental Status Exam (MMSE) will be performed by a member of the research staff at 
screening and Day 1 of each Cycle of treatment to monitor for cognitive toxicity. The results of the MMSE and neurologic exam will be reviewed 
by the site investigator who will determine whether dose reduction of study drug(s) is required. This information should be retained. 
 
5: CBC with differential and platelet to include: WBC, ANC, ALC, Hgb, PLT. Comprehensive metabolic profile (CMP) will be done at screening 
then Day 1 of each Cycle. During Cycle 1, a CMP should be performed at Cycle 1 Day 15. CMP to include glucose, calcium, BUN, creatinine, 
sodium, potassium, chloride, serum albumin, total bilirubin, alkaline phosphatase, AST, and ALT, ammonia, LDH and uric acid. Coagulation 
studies (PT/INR and PTT) will be done at screening then at the discretion of the treating investigator during treatment. For women of childbearing 
potential (WOCBP): urine or serum βhCG if clinically appropriate. If a urine test is done and it is positive or cannot be confirmed as negative, a 
serum pregnancy test will be required.  Testing is required within 72 hours prior to initiation of study treatment. Urinalysis will be performed at 
screening. 
 
6: Tumor response assessment will consist of evaluation by CT scans of chest and MRI or CT of abdomen and pelvis at screening and every odd 
numbered cycle starting after screening with CT scan before Cycle 3 (imaging selected for each subject should remain the same throughout the 
study); tumor imaging to be done at the safety follow up visit is at discretion of site investigator. If tumor assessments are available for subjects 
who have not yet experienced progressive disease (PD) at the time treatment is discontinued, the follow-up tumor evaluations will be documented 
in the eCRF until PD or death is confirmed, or until another treatment is initiated.  MRI of the brain will be performed per standard of care for 
those subjects with a history of brain metastasis.  A window of - 7 days may be used. CT/MRI images are to be submitted for central analysis. 
Images will be de-identified prior to sending to a central location. Central analysis to be performed upon receipt of funding. 
 
7: Cycle = 28 days. PAC-1 will be taken once daily, Days 1-21. For Cycle 1, PAC-1 will be given on Day 1 and withheld on Days 2 and 3. The 
dose on these days is being held in order to determine the PK of single-agent entrectinib on Day 3 of the cycle. PAC-1 treatment will be re-


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initiated on Day 4 and continue until Day 21 of the 28 day cycle. Administration of PAC-1 on Days 1 and 21 of Cycle 1 will occur in the morning. 
Entrectinib will be taken once daily, Days 1-28. Entrectinib therapy will be withheld on Days 1 and 2 and initiated during Cycle 1 on Day 3 to 
continue until Day 28 of the 28 day cycle. Administration of entrectinib on Days 3 and 21 of Cycle 1 will occur in the morning. Entrectinib 
administration will occur 1 hour before PAC-1 on Day 21. 
 
8: The PK and PD analyses will occur with each dose level during Phase Ib. Pharmacokinetic and pharmacodynamic sample collections will occur 
in the mornings on Day 1(PAC-1 only), Day 3 (entrectinib only), and Day 21 (PAC-1 and entrectinib) of the first cycle. Day 1 Cycle 1: Subjects 
receive only PAC-1. Blood samples are collected immediately prior to oral ingestion of PAC-1 and at the following time points after ingestion:  
0.5, 1, 2, 3, 4, 6, 7, and 24 hours. Day 3 Cycle 1:  Subjects receive only entrectinib. Blood samples are collected immediately prior to oral 
ingestion of entrectinib and at the following time points after ingestion:  0.5, 1, 2, 3, 4, 6, 7, and 24 hours. Day 21 Cycle 1: Subjects receive both 
PAC-1 and entrectinib. Entrectinib will be taken 1 hour before PAC-1. Blood samples are collected immediately prior to oral ingestion of 
entrectinib, 0.5 hour before ingestion of PAC-1, and at the following time points after ingestion of PAC-1:  0.5, 1, 2, 3, 4, 6, 7, and 24 hours. See 
Correlative Laboratory Manual (CLM) for additional details regarding these samples. 
 
9: Subject consent will be obtained for collection of peripheral blood samples prior to treatment on Cycle 1 Day 1, Cycle 2 Day 1 and at 
progression (safety visit). For subjects who come off treatment due to progression, the sample may be obtained during the safety visit. Specimens 
will be used for analysis of circulating tumor cells (CTCs), analysis related to mechanisms of action as well as ctDNA. Somatic baseline testing 
will be performed prior to treatment Cycle 1 Day 1. Blood that is leftover after initial protocol specific testing is performed will be stored for 
future correlative testing as described in Section 8. See CLM for additional details regarding these samples.  
 
10: Archival tissue (metastatic disease preferred) is required if available and should be identified at screening and shipped prior to Cycle 1 Day 1. 
If archival tissue is not available, a biopsy is required prior to Cycle 1 Day 1 treatment (Cap of 15 biopsies). Tissue that is leftover after initial 
protocol specific testing is performed will be stored for future correlative testing as described in Section 8. See CLM for additional details 
regarding these samples.  
 
11: If screening (baseline) CBC, CMP, magnesium, Lactate Dehydrogenase, uric acid and PT/PTT/INR were performed within 7 days of Cycle 1 
Day 1 of treatment, these do not need to be repeated.  All laboratory assessments should be done prior to treatment. 
 
12: Safety Follow Up: The safety follow-up visit should only occur when subjects permanently stop study treatment for whatever reasons (toxicity, 
progression, or other reason) and should be performed 30 days (+ 7 days) after the last dose of treatment. Subjects with unresolved treatment-
related toxicity should be followed as medically appropriate or until stabilization of toxicity.   
 
13: Long Term Follow Up: Radiographic disease assessment should be performed at physician discretion. Subjects will be followed for survival 
every 2 months (+14 days) for 12 months from Cycle 1 Day 1 then every 3 months (+21 days) for up to 24 months. Follow up may be 
accomplished via clinic visit, phone call, or other avenues as appropriate.  
 


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8. 
CORRELATIVE STUDIES AND PROCEDURES 
Please see the correlative laboratory manual (CLM) for additional details about the correlatives 
described below. The analyses described below will be performed upon receipt of funding. 
 
8.1 
Peripheral Blood Samples 
 
8.1.1 Plasma for Pharmacokinetics and Pharmacodynamics 
In phase 1b, the pharmacokinetics (PK) and pharmacodynamics (PD) of PAC-1 will be assessed 
following doses administered on Days 1 and 21 of the first cycle. In phase 1b, the PK and PD of 
entrectinib will be assessed following the dose administered on Days 3 and 21 of the first cycle. 
Entrectinib will be withheld on Days 1 and 2 to allow assessment of PAC-1 PK when 
administered as single agent. PAC-1 will be withheld on Days 2 and 3 to allow assessment of 
entrectinib PK when administered as single agent on Day 3. PKs of both drugs will be assessed 
on Day 21 to determine effects of repeated dosing or combining of the two drugs. The PK and 
PD analyses will occur with each dose level.  
 
Administration of PAC-1 on Days 1 and 21 and entrectinib on Days 3 and 21 of Cycle 1 will 
occur in the morning. Entrectinib administration will occur 1 hour before PAC-1 on Day 21.  The 
dose timing on this day is being specified to accommodate a sampling schedule that minimizes 
the number of blood draws needed from the patient.  Information on the time and number of 
PAC-1 and entrectinib doses received for the 96 hours prior to the dose on Day 21 will be 
obtained from subjects. Patients will not receive their PAC-1 dose on Days 2 and 3 of Cycle 1.  
The doses on these days are being held in order to accurately define the absorption and 
metabolism of entrectinib when administered as a single agent on Day 3. Likewise, patients will 
not receive their entrectinib dose on Days 1 and 2 of Cycle 1.  The doses on these days are being 
held in order to accurately define the absorption and metabolism of PAC-1 when administered as 
a single agent on Day 1. Actual and nominal sample collection times will be recorded on the case 
report forms and sample tubes.   
 
Sample collections will occur in the mornings on Day 1 (PAC-1 only), Day 3 (entrectinib only), 
and Day 21 (PAC-1 and entrectinib) of the first cycle.  
● Day 1, Cycle 1: Subjects receive only PAC-1.  
o Blood samples are collected immediately prior to oral ingestion of PAC-1 and at the 
following time points after ingestion:  0.5, 1, 2, 3, 4, 6, 7, and 24 hours. 
● Day 3, Cycle 1:  Subjects receive only entrectinib.  
o Blood samples are collected immediately prior to oral ingestion of entrectinib and at 
the following time points after ingestion:  0.5, 1, 2, 3, 4, 6, 7, and 24 hours. 
● Day 21, Cycle 1: Subjects receive both PAC-1 and entrectinib.  
o Entrectinib administered 1 hour before PAC-1.  
o Blood samples are collected immediately prior to oral ingestion of entrectinib, 0.5 
hour before ingestion of PAC-1, and at the following time points after ingestion of 
PAC-1:  0.5, 1, 2, 3, 4, 6, 7, and 24 hours. The sample volume is 10-mL at each time 
point.      
  
 
 


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8.1.1.1 
Pharmacokinetic Analysis 
Non-compartment analysis: Non-compartmental analysis of the PAC-1 plasma concentration-
time data following doses on Days 1 and 21 for Cycle 1 for each dose level. Also on Days 3 and 
21 of Cycle 1, entrectinib plasma concentration data will be performed using WinNonlin 6.3 
(Pharsight, St Louis, MO) for subjects in whom complete PK profiles are obtained. 
Pharmacokinetic parameters to be estimated following each dose include: 1). area under the 
PAC-1 plasma concentration-time curve from time 0 to 24 hours (AUC0-24) for days 1 and 21, 2) 
area under the entrectinib plasma concentration-time curve from 0 to 24 hours (AUC0-24) for 
Days 3 and 21, 3). area under the PAC-1 plasma concentration-time curves from time 0 to 
infinity (AUC0-∞) on Day 1 only, 4). area under the entrectinib plasma concentration-time curves 
from time 0 to infinity (AUC0-∞) on Day 3 only, maximum PAC-1 and entrectinib plasma 
concentrations (Cmax), 5). terminal elimination rate constant for both drugs (λz), and 6). oral 
clearance (CL/F) for both drugs.  
 
Statistical Analysis: The influence of multiple dosing (e.g., PAC-1 Day 1 AUC0-∞ vs. Day 21 
AUC0-24 and entrectinib Day 3 AUC0-∞  vs. Day 21 AUC0-24), concurrent administration of PAC-
1 and dose on the pharmacokinetics of entrectinib (e.g., Day 3 AUC0-∞ vs. Day 21 AUC0-24), and 
concurrent administration of entrectinib and dose on the pharmacokinetics of PAC-1 (e.g., Day 1 
AUC0-∞ vs. Day 21 AUC0-24), will be evaluated using a generalized linear models approach.  
PAC-1 AUC0-24, AUC0-∞, Cmax and CL/F will be log transformed before statistical analysis. 
Entrectinib AUC0-24, AUC0-∞, Cmax and CL/F will be log transformed before statistical analysis.  
Geometric means will be calculated for the parameters on each study day. The 90% confidence 
intervals for the geometric mean ratios will be constructed for every comparison. 
 
8.1.1.2 
Pharmacodynamic Assessment 
The pharmacodynamic (PD) effects of PAC-1 (Days 1 and 21 of Cycle 1), and entrectinib (Days 
3 and 21 of Cycle 1), may be used to assess the systemic responses of individuals following 
PAC-1 or entrectinib doses administered orally. Systemic variables are defined as plasma 
concentrations of PAC-1 or entrectinib, which will be measured and used to assess whether 
PAC-1 or entrectinib has affected the production of these biological markers.  Measures of 
toxicity (e.g., changes in WBC counts, differential cell populations, platelets, etc.) are also 
considered systemic PD variables. 
 
8.1.2 Mechanisms of Action Analysis  
Subject consent will be obtained for collection of peripheral blood samples for whole blood, 
plasma and serum prior to treatment on Cycle 1 Day 1, Cycle 2 Day 1 and at progression (safety 
visit). This specimen will be used for analysis related to Mechanisms of Action.  
 
8.1.3 Circulating Tumor Cells (CTCs) 
Subject consent will be obtained for collection of peripheral blood samples prior to treatment on 
Cycle 1 Day 1, Cycle 2 Day 1 and at progression (safety visit). This specimen will be analyzed 
for total CTCs. Spearman correlation will be computed using PROC CORR in SAS (Cary, NC). 
CTC number or change from Cycle Day 1 to Cycle 2 Day 1 will be correlated with ORR 
assessed by imaging (revised RECIST 1.1 criteria). Spearman correlation will be computed using 
PROC CORR in SAS (Cary, NC).   
 


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8.1.4 Somatic Baseline 
Whole blood will be collected prior to treatment Cycle 1 Day 1 for somatic baseline testing. 
 
8.1.5 Plasma for ctDNA 
Subject consent will be obtained for collection of peripheral blood samples for ctDNA prior to 
treatment on Cycle 1 Day 1, Cycle 2 Day 1 and at progression (safety visit).  
 
8.2 
Tissue Samples 
 
8.2.1 Archival or Fresh Tissue 
Archival tumor tissue (metastatic disease preferred) is required if available and should be 
identified at screening and shipped by Cycle 1 Day 1. If archival tissue is not available, a biopsy 
is required prior to Cycle 1 Day 1 of treatment. There is a cap of 15 biopsies.  
 
8.2.2 Immunohistochemistry (IHC) 
IHC for markers such as but not limited to procaspase 3.  Determine correlation between 
procaspase 3 expression in tumor tissue and clinical response. Procaspase 3 expression will be 
correlated with ORR assessed by imaging (revised RECIST 1.1 criteria). Spearman correlation 
will be computed using PROC CORR in SAS (Cary, NC).   
 
8.2.3 Imaging  
Imaging may also be performed in an effort to elucidate aspects of the mechanism of action. 
 
8.2.4 Genomic Analysis 
Genomic analysis may also be performed in an effort to elucidate aspects of the mechanism of 
action.  
 
8.3 
Confidentiality of Biospecimens 
Samples that are collected will be identified by a subject’s study number assigned at the time of 
registration to the trial. Any material issued to collaborating researchers will be anonymized and 
only identified by the subject’s study number. 
 
8.4 
Storage of Biospecimens 
Remaining specimens once protocol described biospecimen-based studies are complete will be 
stored for future unspecified cancer related research after consent is obtained from subjects.  
 
9. 
CRITERIA FOR DISEASE EVALUATION 
Tumor response will be defined by the Response Evaluation Criteria in Solid Tumors (RECIST) 
Version 1.1.21 
 
9.1 
Measurable Disease 
The presence of at least one measurable lesion. If the measurable disease is restricted to a 
solitary lesion, its neoplastic nature should be confirmed by cytology/histology. 
 


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9.2 
Measurable Lesions 
Measurable lesions are defined as the presence of at least one measurable lesion. 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, as >10 mm with CT scan, or >10 mm with 
calipers by clinical exam. All tumor measurements must be recorded in millimeters (or decimal 
fractions of centimeters). 
 
9.3 
Non-measurable Lesions 
All other lesions (or sites of disease), including small lesions (longest diameter <10 mm or 
pathological lymph nodes with ≥ 10 to <15 mm short axis), are considered non-measurable 
disease. Bone lesions, leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis 
cutis/pulmonitis, inflammatory breast disease, and abdominal masses (not followed by CT or 
MRI), are considered as non-measurable. 
 
NOTE:  Cystic lesions that meet the criteria for radiographically defined simple cysts should not 
be considered as malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts. ‘Cystic lesions’ thought to represent cystic metastases can be considered 
as measurable lesions, if they meet the definition of measurability described above. However, if 
non-cystic lesions are present in the same subject, these are preferred for selection as target 
lesions. 
 
9.4 
Target Lesions 
All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, 
representative of all involved organs, should be identified as target lesions and recorded and 
measured at baseline. Target lesions should be selected on the basis of their size (lesions with the 
longest diameter), be representative of all involved organs, but in addition should be those that 
lend themselves to reproducible repeated measurements. It may be the case that, on occasion, the 
largest lesion does not lend itself to reproducible measurement in which circumstance the next 
largest lesion which can be measured reproducibly should be selected. A sum of the diameters 
(longest for non-nodal lesions, short axis for nodal lesions) for all target lesions will be 
calculated and reported as the baseline sum diameters. If lymph nodes are to be included in the 
sum, then only the short axis is added into the sum. The baseline sum diameters will be used as 
reference to further characterize any objective tumor regression in the measurable dimension of 
the disease. 
 
9.5 
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. 
 
9.6 
Evaluation of Target Lesions 
NOTE: Please see the international criteria proposed by the Response Evaluation Criteria in 
Solid Tumors (RECIST) Committee, version 1.1 (Eur J Cancer 45;2009:228-247) for special 
notes on the assessment of target lesions.  
 


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Complete Response (CR) 
Disappearance of all target lesions.  Any pathological lymph 
nodes (whether target or non-target) must have reduction in short 
axis to <10 mm.
Partial Response (PR) 
At least a 30% decrease in the sum of the diameters of target 
lesions, taking as reference the baseline sum diameters 
Progressive Disease (PD) 
At least a 20% increase in the sum of the diameters of target 
lesions, taking as reference the smallest sum on study (this 
includes the baseline sum if that is the smallest on study).  In 
addition to the relative increase of 20%, the sum must also 
demonstrate an absolute increase of at least 5 mm.  (Note:  the 
appearance of one or more new lesions is also considered 
progressions).
Stable Disease (SD) 
Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum 
diameters while on study
 
9.7 
Evaluation of Non-target Lesions 
 
Complete Response (CR) 
Disappearance of all non-target lesions and normalization of 
tumor marker level. 
Incomplete Response/Stable 
Disease 
Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal limits
Progressive Disease (PD) 
Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions.  
 
Although a clear progression of “non-target” lesions only is exceptional, the opinion of the site 
investigator should prevail in such circumstances, and the progression status should be 
confirmed at a later time by the sponsor-investigator. 
 
9.8 
Evaluation of Best Overall Response 
NOTE: Revise table if response rate is primary objective of the study, and confirmation of 
response is required.  See Eur J Cancer 45;2009:228-247 for complete details. 
 
Target Lesions 
Non-Target Lesions 
New Lesions 
Overall 
Response** 
CR 
CR
No
CR 
CR 
Non-CR/ Non-PD
No
PR 
CR 
Not evaluated
No
PR 
PR 
Non-PD/ or not all evaluated
No
PR 
SD 
Non-PD or not all evaluated
No
SD 
Not all evaluated 
Non-PD
No
Non-evaluable
PD 
Any
Yes or No
PD 
Any 
PD*
Yes or No
PD 
Any 
Any
Yes
PD 
n exceptional circumstances, unequivocal progression in non-target lesions may be accepted 
as disease progression. 
All responses will require confirmation with repeat imaging or physical exam at ≥ 4 weeks.
 
 
 


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Subjects with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be classified as having 
“symptomatic deterioration.” Every effort should be made to document the objective progression 
even after discontinuation of treatment. 
 
In some circumstances, it may be difficult to distinguish residual disease from normal tissue. 
When the evaluation of complete response depends on this determination, it is recommended that 
the residual lesion be investigated (fine needle aspirate/biopsy) to confirm the complete response 
status. 
 
9.9 
Definitions for Response Evaluation  
 
9.9.1 Duration of Response 
Duration of response—the period measured from the time that measurement criteria are met for 
complete or partial response (whichever status is recorded first) until the date that recurrent or 
progressive disease is objectively documented (taking as reference for progressive disease the 
smallest measurements recorded since treatment started). 
 
9.9.2 Objective Response Rate  
The objective response rate is the proportion of all subjects with confirmed PR or CR according 
to RECIST 1.1, from the start of treatment until disease progression/recurrence (taking as 
reference for progressive disease the smallest measurements recorded since the start of 
treatment). 
 
9.9.3 Progression-Free Survival 
A measurement from the date of the start of treatment until the criteria for disease progression is 
met as defined by RECIST 1.1 or death occurs. Subjects who have not progressed will be right-
censored at the date of the last disease evaluation. 
 
9.9.4 Overall Survival 
Overall survival is defined by the date of the start of treatment to date of death from any cause. 
 
10. 
DRUG INFORMATION 
 
10.1 
PAC-1 
Please refer to the current version of the Investigator’s Brochure (IB) for additional information 
regarding this drug. 
 
10.1.1 Classification 
Ortho-hydroxyl N-acyl hydrazone that enhances the enzymatic activity of procaspase-3 and 
induces apoptosis in cancer cells. 
 
10.1.2 Availability 
PAC-1 will be provided by Vanquish Oncology, Inc. with approval of the FDA for 
investigational purposes (IND# 120544). 
 


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10.1.3 Description 
PAC-1 will be provided in strengths of 250 mg tablets. Each tablet contains PAC-1 in 
combination with Avicel PH 101 & 200 (microcrystalline cellulose filler, NF), Pearlitol 100 SD 
(mannitol filler, USP), Explotab (sodium starch glycolate disintegrant, NF), Cabosil (fumed 
silica glidant, NF), hydroxypropyl cellulose (binder, NF) and Sodium Stearyl Fumarate 
(lubricant, NF). PAC-1 tablets will be supplied to the experimental pharmacy where the correct 
dose for one cycle will be packaged for each patient. 
 
10.1.4 Storage, Handling and Accountability 
Bottles containing PAC-1 tablets will be provided to the investigative site. Bottles will be stored 
at room temperature, 15ºC to 27ºC upon arrival at the site. A packing list will be included with 
the shipment of clinical study material. Upon receipt of study drug, the site will inspect the 
shipment for any damage, and compare contents against the packing list. The site will 
acknowledge receipt of the shipment by contacting Vanquish Oncology, Inc., noting any 
discrepancies or damages. 
 
10.1.5 Dosage and Administration 
Doses of 625 and 750 mg will be tested in the Phase 1b study and the RP2D will be tested in the 
Phase 2 study. Tablets are taken with water. 
 
PAC-1 will be supplied as 250 mg dose with a 125 mg dose score mark tablets.  Approximately 
1000 tablets are bulk-packaged into 950 cc HDPE Bottles with five 1-Gram desiccant packets 
per bottle, capped with 53 mm child-resistant closures with FS M1/.035 Pulp Liner, induction 
sealed, and labeled. Tablets will be distributed to patients by licensed pharmacist according to 
the clinical protocol and the separate Investigator Brochure.  
 
10.1.6 Side Effects 
The risks of oral PAC-1 in humans are unknown. However, PAC-1 has shown toxicity in mice, 
rats, and dogs. In a rat study, deaths occurred in 2 out of 12 rats administered 600 mg/kg/day 
over a 7-day interval – it should be noted this is a dose over 10 times higher than the planned 
maximum daily dose to be tested in this trial, 3000 mg (i.e., 50 mg/kg for a 60 kg individual).  In 
one dog study involving repeated oral dosing of PAC-1, gastro-intestinal symptoms were 
observed (diarrhea, vomiting) accompanied by weight loss. As well, one of the dogs in that study 
had a seizure that was resolved by administration of diazepam. In another dog study, daily 
administration of oral PAC-1 at doses of 25 and 50 mg/kg for 28 days was associated with 
minimal-mild neurodegeneration at multiple sites in the gray matter of the cerebrum.  An 84-day 
oral toxicity and toxicokinetic study of PAC-1 with 1 month and 3 months recovery periods in 
male and female beagle dogs was recently completed.  Daily oral administration (via capsules) of 
PAC-1 at 6, 13, or 25 mg/kg for 21 consecutive days with a 7-day wash-out period between 
cycles and repeated for 3 cycles dose-responsive, minimal to mild test article-related vacuolation 
in different sections of the brains of animals given 13 and 25 mg/kg.  The extent and severity of 
the vacuolization was similar to that seen in the 28-day study. The observed brain vacuolization 
did not show evidence of recovery after 3 months of being off study drug.  No PAC-1 associated 
neurological or neurocognitive changes have been observed through dose level 7 (750 mg) of 
Component 1 of phase 1 study NCT02355535. 
 


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10.1.7 Warnings and Precautions 
Observation and assessment of hematological and non-hematological markers of toxicity in 
research dogs raised a possibility that PAC-1 may cause neurodegenerative changes in the brain, 
and therefore neurological and neurocognitive examinations was performed in NCT02355535 
study. No neurologic nor neurocognitive changes were seen in this study, therefore these 
evaluations will not be performed in this study. 
   
In NCT02355535 (Procaspase Activating Compound-1 (PAC-1) in the Treatment of Advanced 
Malignancies - Component 1), one Component 1 patient who was in the 625mg/day cohort 
experienced an intracranial hemorrhage related to brain metastases where a possible attribution 
to PAC-1 could not be ruled out.  In order to monitor and ensure patient safety, patients should 
have a baseline brain MRI for future comparison if needed.  Coagulation tests will be done prior 
to dosing on Day 1 of each treatment cycle. 
 
10.2 
Entrectinib 
Please refer to the current version of the IB for additional information regarding this drug. 
 
10.2.1 Classification 
Entrectinib is an approved in United States for the treatment of locally advanced or metastatic 
solid tumors that harbor NTRK1/2/3 or ROS1 gene fusions. It is a selective, CNS-active tyrosine 
kinase inhibitor designed to inhibit the kinase activity of the TRKA/B/C and ROS1 proteins, 
whose activating fusions drive proliferation in certain types of cancer. Entrectinib can block 
ROS1 and NTRK kinase activity and may result in the death of cancer cells with ROS1 or 
NTRK gene fusions.  
 
10.2.2 Availability 
Genentech will supply entrectinib at no charge to subjects participating in this clinical trial. The 
investigator shall take responsibility for and shall take all steps to maintain appropriate records 
and ensure appropriate supply, storage, handling, distribution, and usage of investigational 
product in accordance with the protocol and any applicable laws and regulations. 
 
10.2.3 Description 
Entrectinib will be provided as white size 2 and 0 hydroxypropyl methylcellulose (HPMC) 
capsules. Each capsule contains the following compendial excipients: tartaric acid (acidulant), 
lactose anhydrous, hydroxypropyl methylcellulose, microcrystalline cellulose, crospovidone, 
colloidal silicon dioxide, and magnesium stearate.  Entrectinib capsules will be supplied to the 
experimental pharmacy where the correct dose for one cycle will be packaged for each patient. 
 
10.2.4 Storage, Handling and Accountability 
Clinical supplies must be stored in a secure, limited-access location under the storage conditions 
specified on the label. Entrectinib must be stored in the original packaging at controlled room 
temperature (please refer to the bottle label for more specific expiry and storage conditions). 
Receipt and dispensing of trial medication must be recorded by an authorized person at the trial 
site. Clinical supplies may not be used for any purpose other than that stated in the protocol. 
 


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10.2.5  Dosage and Administration 
An entrectinib dose of 600 mg will be tested in the Phase 1b and Phase 2 studies. Capsules are 
taken with water and food. 
 
Entrectinib will be supplied as 200 and 400 mg capsules. Entrectinib capsules are packaged in 
white high-density polyethylene bottles with child resistant closures and a tamper-proof heat 
induction seal.  Capsules will be distributed to patients by licensed pharmacist according to the 
clinical protocol and the separate Investigator Brochure.  
 
10.2.6 Side Effects 
Please refer to the current version of the Investigator’s Brochure for a complete list of adverse 
events.  
 
11. 
ADVERSE EVENTS 
Safety assessments will consist of monitoring and reporting adverse events (AEs) and serious 
adverse events (SAEs) per protocol. This includes all events of death, and any study specific 
issue of concern. The adverse event severity grading scale for the NCI CTCAE (v5.0) will be 
used for assessing adverse event severity. 
 
11.1 
Definitions 
 
11.1.1 Adverse Events 
An AE is any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of an investigational medicinal product 
(IMP) or other protocol-imposed intervention, regardless of attribution. 
 
This includes the following: 
• AEs not previously observed in the subject that emerge during the protocol-specified AE 
reporting period, including signs or symptoms associated with uveal melanoma that were 
not present prior to the AE reporting period. 
• Complications that occur as a result of protocol-mandated interventions (e.g., invasive 
procedures such as cardiac catheterizations) 
• If applicable, AEs that occur prior to assignment of study treatment associated with 
medication washout, no treatment run-in, or other protocol-mandated intervention. 
• Preexisting medical conditions (other than the condition being studied) judged by the 
investigator to have worsened in severity or frequency or changed in character during the 
protocol-specified AE reporting period. 
 
 
 


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11.1.2 Serious Adverse Events 
An AE should be classified as an SAE if the following criteria are met: 
• It results in death (i.e., the AE actually causes or leads to death). NOTE: Death due to 
disease progression should not be reported as a SAE, unless it is attributable by the site 
investigator to the study drug(s) 
• It is life threatening (i.e., the AE, in the view of the investigator, places the subject at 
immediate risk of death. It does not include an AE that, had it occurred in a more severe 
form, might have caused death.). 
• It requires or prolongs inpatient hospitalization. Any AE that results in hospitalization or 
prolonged hospitalization should be documented and reported as an SAE. If a subject is 
hospitalized to undergo a medical or surgical procedure as a result of an AE, the event 
responsible for the procedure, not the procedure itself, should be reported as the SAE. For 
example, if a subject is hospitalized to undergo coronary bypass surgery, record the heart 
condition that necessitated the bypass as the SAE. Hospitalizations for the following 
reasons do not require reporting: 
o Hospitalization or prolonged hospitalization for diagnostic or elective surgical 
procedures for preexisting conditions 
o Hospitalization or prolonged hospitalization required to allow efficacy 
measurement for the study or 
o Hospitalization or prolonged hospitalization for scheduled therapy of the target 
disease of the study 
• It results in persistent or significant disability/incapacity (i.e., the AE results in 
substantial disruption of the subject’s ability to conduct normal life functions). 
• It results in a congenital anomaly/birth defect in a neonate/infant born to a mother 
exposed to the study drug. 
• It is considered a significant medical event by the investigator based on medical 
judgment (e.g., may jeopardize the subject or may require medical/surgical intervention 
to prevent one of the outcomes listed above). 
o See Section 11.8 for additional descriptions of reportable events 
 
11.1.3 AEs of Special Interest (AESIs) 
AESIs are a subset of Events to Monitor (EtMs) of scientific and medical concern specific to the 
study drug, for which ongoing monitoring and rapid communication by the site investigator to 
the sponsor-investigator is required. Such an event might require further investigation in order to 
characterize and understand it. Depending on the nature of the event, rapid communication by 
the sponsor-investigator to other parties (e.g., Regulatory Authorities) may also be warranted. 
 
11.1.3.1 
The Entrectinib Events of Special Interest are 
• Grade ≥ 2 Congestive Heart Failure 
• Grade ≥ 2 QT Prolongation 
• Any grade syncope 
• Grade ≥ 2 cognitive disturbances 
• Any grade fracture 
 
 
 


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11.1.3.2 
The PAC-1 Events of Special Interest are 
• Grade ≥ 3 Neurologic disturbances 
• Grade ≥ 3 Cognitive disturbances 
  
11.1.3.3 
Non drug specific adverse events of special interest for this study include the 
following 
• Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice, as defined by Hy’s law: 
o Treatment-emergent ALT or AST > 3 X ULN in combination with total bilirubin 
> 2 X ULN 
o Treatment-emergent ALT or AST > 3 X ULN in combination with clinical 
jaundice 
• Suspected transmission of an infectious agent by the study drug, as defined below: 
o Any organism, virus, or infectious particle (e.g., prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is 
considered an infectious agent.  A transmission of an infectious agent may be 
suspected from clinical symptoms or laboratory findings that indicate an infection 
in a patient exposed to a medicinal product.  This term applies only when a 
contamination of the study drug is suspected 
 
11.2 
Other Definitions 
 
11.2.1 Diagnosis vs. Signs and Symptoms 
If known at the time of reporting, a diagnosis should be reported rather than individual signs and 
symptoms (e.g., record only liver failure or hepatitis rather than jaundice, asterixis, and elevated 
transaminases). However, if a constellation of signs and/or symptoms cannot be medically 
characterized as a single diagnosis or syndrome at the time of reporting, it is acceptable to report 
the information that is currently available. If a diagnosis is subsequently established, it should be 
reported as follow-up information. 
 
11.2.2 Preexisting Medical Conditions 
A preexisting medical condition is one that is present at the start of the study. Such conditions 
should be reported as medical and surgical history. A preexisting medical condition should be re-
assessed throughout the trial and reported as an AE or SAE only if the frequency, severity, or 
character of the condition worsens during the study. When reporting such events, it is important 
to convey the concept that the preexisting condition has changed by including applicable 
descriptors (e.g., “more frequent headaches”). 
 
11.2.3 Unexpected Adverse Event 
For this study, an AE is considered unexpected when it varies in nature, intensity or frequency 
from information provided in the current IB, prescribing information or when it is not included in 
the informed consent document as a potential risk. Unexpected also refers to AEs that are 
mentioned in the IB as occurring with a class of drugs or are anticipated from the 
pharmacological properties of the drug, but are not specifically mentioned as occurring with the 
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11.2.4 Relatedness 
AEs will be categorized according to the likelihood that they are related to the study drug(s). 
Relatedness should be assessed for both study drugs individually. Specifically, they will be 
categorized using the following terms:  
 
Unrelated 
Adverse Event is not related to the study drug(s)  
Unlikely 
Adverse Event is doubtfully related to the study drug(s)  
Possible 
Adverse Event may be related to the study drug(s)  
Probable 
Adverse Event is likely related to the study drug(s)  
Definite 
Adverse Event is clearly related to the study drug(s)  
 
11.2.5 Assessment of Severity 
The adverse event severity grading scale for the NCI CTCAE (v5.0) will be used for assessing 
adverse event severity. The following table should be used for assessing severity for adverse 
events that are not specifically listed in the NCI CTCAE. 
 
Grade 
Severity
1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic 
observations only; or intervention not indicated
2 
Moderate; minimal, local, or non-invasive intervention indicated; or 
limiting age-appropriate instrumental activities of daily living a 
3 
Severe or medically significant, but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; 
or limiting self-care activities of daily living b,c
4 
Life-threatening consequences or urgent intervention indicated d 
5 
Death related to adverse event d
      
NCI CTCAE = National Cancer Institute Common Terminology Criteria for Adverse Events. 
NOTE:  Based on the most recent version of NCI CTCAE (v5.0), which can be found at:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
a) Instrumental activities of daily living refer to preparing meals, shopping for groceries or 
clothes, using the telephone, managing money, etc. 
b) Examples of self-care activities of daily living include bathing, dressing and undressing, 
feeding oneself, using the toilet, and taking medications, as performed by patients who 
are not bedridden. 
c) If an event is assessed as a "significant medical event," it must be reported as a serious 
adverse event  
d) Grade 4 and 5 events must be reported as serious adverse events 
 
 
 


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11.3 
Reporting 
 
11.3.1 Adverse Events  
• AEs will be recorded from time of signed informed consent until 90 days after 
discontinuation of study drug(s) or until a new anti-cancer treatment starts, whichever 
occurs first.  
• AEs will be recorded regardless of whether or not they are considered related to the study 
drug(s).   
• All AEs will be recorded in the subject’s medical record and on the appropriate study 
specific eCRF form within the EDC system. 
 
11.3.2 Serious Adverse Events (SAEs) and AESIs 
 
11.3.2.1 
Site Requirements for Reporting SAEs and AESI’s to HCRN 
• SAEs and AESI’s will be reported from time of signed informed consent until 90 days 
after discontinuation of study drug(s) or until a new anti-cancer treatment starts, 
whichever occurs first.  
• SAEs and AESI’s will be reported on the SAE Submission Form within 1 business day 
of discovery of the event.   
• SAEs include events related and unrelated to the study drug(s).  
• All SAEs will be recorded in the subject’s medical record and on the appropriate study 
specific eCRF form within the EDC system.   
 
The site will submit the completed SAE Submission Form to HCRN within 1 business day of 
discovery of the event. The form will be submitted to HCRN electronically to 
safety@hoosiercancer.org. The site investigator is responsible for informing the IRB and/or other 
local regulatory bodies as per local requirements. The original copy of the SAE Submission 
Form and the email correspondence must be kept within the study file at the study site. Once the 
SAE has resolved, sites must submit a follow-up SAE Submission Form within a reasonable 
timeframe to HCRN electronically to safety@hoosiercancer.org.   
 
11.3.2.2 
HCRN Requirements for Reporting SAEs and AESI’s to Vanquish and 
Genentech/Roche  
HCRN will report all SAEs and AESI’s to Vanquish and Genentech within 1 business day of 
receipt of the SAE Submission Form from a site. Follow-up information will be provided to 
Vanquish and Genentech as it is received from site.  
 
Contact information for Genentech/Roche  
Attn: Worldwide Product Safety; FAX  650-238-6067 OR Email: usds_aereporting-
d@gene.com.  
 
Contact information for Vanquish Oncology, Inc. Attn: Product Safety; FAX 855 250-2953 
Email:  vodrugsafety@vanquishoncology.com 
 


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11.4 Sponsor-Investigator Responsibilities 
HCRN will send a SAE summary to the sponsor-investigator within 1 business day of receipt of 
SAE Submission Form from a site.  The sponsor-investigator will promptly review the SAE 
summary and assess for expectedness and relatedness.   
 
11.5 
HCRN Responsibilities to FDA 
If an IND is assigned, HCRN will manage the Investigational New Drug Application (IND) 
associated with this protocol on behalf of the sponsor-investigator. HCRN will cross-reference 
this submission to Vanquish and Genentech’s parent IND at the time of submission.  
 
For protocols conducted under an IND, HCRN will be responsible for all communication with 
the FDA in accordance with 21CFR312 including but not limited to the 7 and 15 Day Reports, as 
well as an Annual Progress Report.  
 
11.6 
IND Safety Reports Unrelated to This Trial 
Genentech and Vanquish Oncology, Inc. will provide to HCRN IND safety reports from external 
studies that involve the study drug(s) per their guidelines.  HCRN will forward safety reports to 
the sponsor-investigator who will review these reports and determine if revisions are needed to 
the protocol or consent. HCRN will forward these reports to participating sites within 1 business 
day of receiving the sponsor-investigator’s review.  Based on the sponsor-investigator’s review, 
applicable changes will be made to the protocol and informed consent document (if required).  
All IND safety reports will also be made available to sites via the EDC system.    
 
Upon receipt from HCRN, site investigators (or designees) are responsible for submitting these 
safety reports to their respective IRBs, as per their IRB policies. 
 
11.7 
Other Reportable Events 
 
11.7.1 Pregnancy 
If a female subject becomes pregnant while receiving the study drugs or within 90 days after the 
last dose of study drugs, or if the female partner of a male study subject becomes pregnant while 
the study subject is receiving the study drugs or within 90 days after the last dose of study drugs, 
a SAE report should be completed and expeditiously submitted within the timeframe described 
in the SAE reporting section. Follow-up to obtain the outcome of the pregnancy should also 
occur. Abortion, whether accidental, therapeutic, or spontaneous, should always be classified as 
serious, and expeditiously reported as an SAE. Similarly, any congenital anomaly/birth defect in 
a child born to a female subject exposed to the study drug should be reported as an SAE. Sites 
will report to HCRN within 1 business day and HCRN will report to Funders within 1 business 
day. 
 
11.7.2 Special Situation Reports 
Special Situation Reports should be collected even in the absence of an Adverse Event.  Sites 
will report to HCRN within 1 business day and HCRN will report to Funders within 1 business 
day. 
• Data related to the product usage during breastfeeding 


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• Data related to overdose, abuse, misuse or medication error (including potentially 
exposed or intercepted medication errors) 
 
In addition, reasonable attempts should be made to obtain and submit the age or age group of the 
patient, in order to be able to identify potential safety signals specific to a particular population. 
 
11.7.3 Product Complaints 
A Product Complaint is defined as any written or oral information received from a complainant 
that alleges deficiencies related to identity, quality, safety, strength, purity, reliability, durability, 
effectiveness, or performance of a product after it has been released and distributed to the 
commercial market or clinical trial. All Product Complaints (with or without an AE) shall be 
forwarded to HCRN who will report to Genentech and Vanquish. The timeframe from the site 
reporting to HCRN and HCRN reporting to Genentech and Vanquish must be within fifteen (15) 
calendar days of the awareness date.  
 
Genentech/Roche 
Product complaints with an AE: Worldwide Product Safety; FAX  650-238-6067 OR Email: 
usds_aereporting-d@gene.com.  
 
Product complaints without an AE: kaiseraugst.global_impcomplaint_management@roche.com 
 
Vanquish Oncology, Inc.  
Drug Safety: Fax: (855) 250-2953 or or at vodrugsafety@vanquishoncology.com. 
 
11.7.4 Post-Study Adverse Events  
After the end of the adverse event reporting period (defined as 90 days after the last dose of 
study drug) all deaths, (regardless of cause), and any serious adverse event believed to be related 
to prior exposure to study drug will be reported from the site to HCRN and HCRN to the 
Funders. This will include development of cancer or a congenital anomaly in a subsequently 
conceived offspring of a female subject (including pregnancy occurring in the partner of a male 
study subject).  
 
12. 
STATISTICAL CONSIDERATIONS 
 
12.1 
Study Design 
This is a single arm study.  
 
Phase 1b: The primary objective of the Phase Ib dose escalation cohort study is to establish the 
MTD of PAC-1 in combination with entrectinib in subjects with metastatic uveal melanoma. A 
standard “3+3” design will be used to establish the MTD. PAC-1 (PO) will be given daily on 
Days 1 through 21 of each cycle. Entrectinib (PO) will be given daily on Days 1 through 28 of 
each cycle. Each cycle will equal 28 days. Response will be evaluated after every 2 cycles. 
Treatment will continue until disease progression based on RECIST criteria or intolerable 
toxicity. 
 


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Phase 2: The primary objective of the Phase II trial is to estimate 3 months PFS using RECIST 
v1.1 in subjects with metastatic uveal melanoma treated with PAC-1 in combination with 
entrectinib. PAC-1 (PO) will be given daily on Days 1 through 21 of each cycle. Entrectinib 
(PO) will be given daily on Days 1 through 28 of each cycle. Each cycle will equal 28 days. 
Response will be evaluated after every 2 cycles. Treatment will continue until disease 
progression based on RECIST criteria or intolerable toxicity. Subjects who voluntarily stop the 
study, have progressive disease, or unacceptable toxicities will be followed for survival every 2 
months for 12 months from start of study treatment, then every 3 months for up to 24 months. 
 
Correlative research analyses include examining the relationship between procaspase 3 
expression in archived tumor tissue to degree of clinical response.   
 
12.2 
Criteria for Stopping Study 
After the first 15 subjects are enrolled, the study will be stopped if 2 or more subjects develop 
treatment related grade 5 toxicity (death). 
 
12.3 
Sample Size and Accrual 
Previous studies in the target population identified PFS at 3 months of 38%.6 We hypothesize 
PFS at 3 months of 65%. Controlling for a probability of Type I error at 0.05 (one-sided), our 
sample size in Phase 2 is estimated to be 32 to ensure 90% statistical power in successfully 
detecting an alternative PFS rate at 3 months of 0.65, compared to a null rate of 0.38. With 3 
additional patients to account for a 10% drop off rate, sample size for phase 2 study will be 35. 
Sample size analyses were conducted using the PASS software (NCSS, Kaysville, Utah, USA). 
With phase1b study component, the study will need to have 3 subjects from Dose Level 1 of 
Phase 1b + 6 subjects from Dose Level 2 of Phase 1b (and carried over to Phase 2 study). The 
total number of subjects for the study is 38. 
 
12.3.1 Number of subjects to be enrolled 
Number to be enrolled: 
 
Phase 1b: minimum of 9, maximum of 12 
Phase 2: 6 subjects from MTD level in Phase 1b and an additional 29 subjects for a projected 
sample size of 35. 
 
12.4 
Analysis Datasets 
 
12.4.1 Evaluable for Safety  
This will be comprised of all subjects who receive at least one dose of trial drug. 
 
12.4.2 Evaluable for Efficacy  
Only those patients 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 
response.  These patients will have their response classified according to the definitions stated 
below.  (NOTE:  Patients who exhibit objective disease progression prior to the end of Cycle 1 
will also be considered evaluable.) 
 


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12.5 
Data Analysis Plans 
 
12.5.1 Analysis Plans for Primary Endpoint 
 
Phase Ib Analysis of Primary Endpoint 
The primary endpoint is determination of the MTD of PAC-1 in combination with entrectinib. 
The MTD will be defined as the highest explored dose of PAC-1 combined with 600 mg of 
entrectinib at which ≤1 out of 6 subjects have experienced a DLT within the first cycle of 
therapy. That dose will be recommended for the Phase 2 study (i.e., will be declared the RP2D). 
At the discretion of the sponsor-investigator, a lower Phase 2 dose may be recommended if other 
toxicity emerges during the Phase Ib study which does not meet DLT criteria but limits the dose 
that can be administered cumulatively. 
 
Phase II Analysis of Primary Endpoint 
The primary endpoint is determination of the activity of the combination of PAC-1 and 
entrectinib for treatment of metastatic uveal melanoma, as assessed by 3 months PFS based on 
RECIST v1.1. Median PFS times will be computed with associated 95% confidence intervals. 
Kaplan-Meier curves will be plotted. 
 
12.5.2 Analysis Plans for Secondary Endpoints 
 
12.5.2.1 
Phase 1b Analysis of Secondary Endpoints 
Safety and tolerability by NCI Common Terminology Criteria for Adverse Events (NCI CTCAE) 
Version 5 on treatment with PAC-1 in combination with entrectinib in subjects with metastatic 
uveal melanoma. 
 
Proportion of subjects with each grade of adverse events as defined by CTCAE v.5.0 will be 
computed along with 95% confidence intervals and reported in a tabular and descriptive manner. 
 
PFS at 3 month in subjects with metastatic uveal melanoma treated with PAC-1 in combination 
with entrectinib. 
 
PFS will be analyzed using the Kaplan-Meier method, and median PFS will be computed with 
associated 95% confidence interval. Subjects who have not progressed will be right-censored at 
the date of the last disease evaluation. Kaplan-Meier curves will be plotted. Data will be 
analyzed using the PROC LIFETEST in SAS. 
 
ORR in subjects with metastatic uveal melanoma treated with PAC-1 in combination with 
entrectinib.  
 
ORR will be estimated according to RECIST 1.1, by dividing the total number of responders 
(complete plus partial responses) by number of subjects with measurable disease and the exact 
95% confidence interval will be computed.  
 
DoR on treatment with PAC-1 in combination with entrectinib in subjects with metastatic uveal 
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DoR will be evaluated for subjects who achieve CR or PR using the Kaplan-Meier method. For 
such patients, DoR is defined as the number of months from the start date of CR or PR 
(whichever response status is observed first) and subsequently confirmed, to the first date that 
recurrent or progression disease (PD) is objectively documented. If a subject dies, irrespective of 
cause, without documentation of recurrent or PD beforehand, then the subject’s date of death will 
be used to denote the response end date. Subjects who have not progressed will be right-censored 
at the date of the last disease evaluation. Median DoR will be computed with associated 95% 
confidence interval, and Kaplan-Meier curves will be plotted. 
 
OS of subjects with metastatic uveal melanoma treated with PAC-1 in combination with 
entrectinib. 
 
OS will be analyzed using the Kaplan-Meier method, and median OS times will be computed 
with associated 95% confidence intervals. Subjects who have not died will be right-censored at 
the date of the last follow-up, and Kaplan-Meier curves will be plotted. Data will be analyzed 
using the PROC LIFETEST in SAS. 
 
12.5.2.2 
Phase 2 Analysis of Secondary Endpoints 
Safety and tolerability by NCI Common Terminology Criteria for Adverse Events (NCI CTCAE) 
Version 5 on treatment with PAC-1 in combination with entrectinib in subjects with metastatic 
uveal melanoma. 
 
Proportion of subjects with each grade of adverse events as defined by CTCAE v.5.0 will be 
computed along with 95% confidence intervals, and reported in a tabular and descriptive manner. 
 
ORR in subjects with metastatic uveal melanoma treated with PAC-1 in combination with 
entrectinib.  
 
ORR will be estimated according to RECIST 1.1, by dividing the total number of responders 
(complete plus partial responses) by number of subjects with measurable disease and the exact 
95% confidence interval will be computed.  
 
DoR on treatment with PAC-1 in combination with entrectinib in patients with metastatic uveal 
melanoma. 
 
DoR will be evaluated for subjects who achieve CR or PR using the Kaplan-Meier method. For 
such subjects, DoR is defined as the number of months from the start date of CR or PR 
(whichever response status is observed first) and subsequently confirmed, to the first date that 
recurrent or progression disease (PD) is objectively documented. If a subject dies, irrespective of 
cause, without documentation of recurrent or PD beforehand, then the subject’s date of death will 
be used to denote the response end date. Subjects who have not progressed will be right-censored 
at the date of the last disease evaluation. Median DoR will be computed with associated 95% 
confidence interval, and Kaplan-Meier curves will be plotted. 
 
 
 


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OS of subjects with metastatic uveal melanoma treated with PAC-1 in combination with 
entrectinib. 
 
OS will be analyzed using the Kaplan-Meier method, and median OS times will be computed 
with associated 95% confidence intervals. Subjects who have not died will be right-censored at 
the date of the last follow-up, and Kaplan-Meier curves will be plotted. Data will be analyzed 
using the PROC LIFETEST in SAS. 
 
12.5.3 Analysis Plans for Correlative Objectives 
Pharmacokinetic analyses of PAC-1 and entrectinib. Compare procaspase 3 expression in tumor 
tissue to degree of clinical response. 
 
Tumor specimen either collected at diagnosis or obtained at enrollment will be submitted to Dr 
Tim Fan, University of Illinois and will be correlated with ORR assessed by imaging (revised 
RECIST 1.1 criteria). Spearman correlation will be computed using PROC CORR in SAS (Cary, 
NC). 
 
12.5.4 Other Planned Analyses  
Descriptive statistics will be provided to summarize demographics and baseline characteristics 
parameters. Categorical data will be summarized as frequency and its corresponding percentage. 
For continuous data, frequency (n), mean, standard deviation, median (as appropriate), 
minimum, and maximum will be provided for each of the parameters. 
 
12.6 
Interim Analysis/Criteria for Stopping Study 
No interim analyses are planned for this study. However, the Data Safety Monitoring Board will 
be reviewing study safety and treatment activity periodically and provide recommendations 
regarding need for stopping study. See Section 13 for additional information. 
 
13 
TRIAL MANAGEMENT 
 
13.1 
Data and Safety Monitoring Plan (DSMP) 
 
HCRN oversight activities include: 
• Review and processing of all adverse events requiring expedited reporting as defined in 
the protocol 
• Provide trial accrual progress, safety information and data summary reports to the 
sponsor-investigator  
• Submit data summary reports to the DSMB for review according to DSMB Charter  
 
This study will have a Data and Safety Monitoring Board (DSMB). The DSMB is chaired by an 
independent medical oncologist external to this trial. The DSMB will provide a recommendation 
to the sponsor-investigator after all information is reviewed. This information will also be 
provided to HCRN who will distribute to the site investigator/participating sites for submission 
to their respective IRB according to the local IRB’s policies and procedures. 
 
 
 


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The DSMB review will include but is not limited to: 
• Adverse event summary report 
• Audit results if applicable 
• Data related to stopping/decision rules described in study design 
• Study accrual patterning 
• Protocol deviations 
 
The DSMB will meet twice annually during the active study drug administration phase. 
Additional DSMB meetings may be convened upon request of the Sponsor-Investigator, DSMB, 
or other applicable oversight body. 
 
13.2 
Data Quality Oversight Activities 
Remote validation of the EDC system data will be completed on a continual basis throughout the 
life cycle of the study. Automated edit check listings will be used to generate queries in the EDC 
system and transmitted to the site to address in a timely fashion. Corrections will be made by the 
study site personnel.  
 
Participating sites may also be subject to quality assurance audits by Genentech and Vanquish 
Oncology, Inc. or their designees as well as inspection by appropriate regulatory agencies. 
 
13.2.1 Onsite Monitoring 
Monitoring visits to the trial sites may be made periodically during the trial to ensure key aspects 
of the protocol are followed. For cause visits may occur as necessary. Selected source documents 
will be reviewed for verification of agreement with data entered into the EDC system.  It is 
important for the site investigator and their relevant personnel to be available for a sufficient 
amount of time during the monitoring visits or audit, if applicable. The site investigator and 
institution guarantee access to source documents by HCRN or its designee. 
 
The trial site may also be subject to quality assurance audit by Genentech/Roche and Vanquish 
Oncology, Inc. or their designees as well as inspection by appropriate regulatory agencies. 
 
13.3 
Compliance with Trial Registration and Results Posting Requirements 
Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and the 
Food and Drug Administration Amendments Act (FDAAA), the sponsor-investigator of the trial 
is solely responsible for determining whether the trial and its results are subject to the 
requirements for submission to the Clinical Trials Data Bank, http://www.clinicaltrials.gov. All 
results of primary and secondary objectives must be posted to CT.gov within a year of 
completion.  The sponsor-investigator has delegated responsibility to HCRN for registering the 
trial and posting the results on clinicaltrials.gov. Information posted will allow subjects to 
identify potentially appropriate trials for their disease conditions and pursue participation by 
calling a central contact number for further information on appropriate trial locations and study 
site contact information.   
 
 
 


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14 
DATA HANDLING AND RECORD KEEPING 
 
14.1 
Data Management 
HCRN will serve as the Clinical Research Organization for this trial. Data will be collected 
through a web based clinical research platform, a system compliant with Good Clinical Practices 
and Federal Rules and Regulations.  HCRN personnel will coordinate and manage data for 
quality control assurance and integrity. Select data will be collected and entered into the EDC 
system by study site personnel from participating institutions.   
 
14.2 
Case Report Forms and Submissions 
Generally, clinical data will be electronically captured in the EDC system and correlative results 
will be captured in the EDC system or other secure database(s). If procedures on the study 
calendar are performed for standard of care, at a minimum, that data will be captured in the 
source document. Select standard of care data will also be captured in the EDC system, 
according to study-specific objectives.  
 
The completed dataset is the sole property of the sponsor-investigator’s institution and should 
not be exported to third parties, except for authorized representatives of appropriate 
Health/Regulatory Authorities, without permission from the sponsor-investigator and HCRN. 
 
14.3 
Record Retention 
To enable evaluations and/or audits from Health Authorities/HCRN, the site investigator agrees 
to keep records, including the identity of all subjects (sufficient information to link records; e.g., 
hospital records), all original signed informed consent forms, copies of all source documents, and 
detailed records of drug disposition. All source documents are to remain in the subject’s file and 
retained by the site investigator in compliance with the site contract with HCRN.  No records 
will be destroyed until HCRN confirms destruction is permitted. 
 
14.4 
Confidentiality 
There is a slight risk of loss of confidentiality of subject information. All records identifying the 
subjects will be kept confidential and, to the extent permitted by the applicable laws and/or 
regulations, will not be made publicly available. Information collected will be maintained on 
secure and password protected electronic systems. Paper files that contain personal information 
will be kept in locked and secure locations only accessible to the study site personnel.  
 
Subjects will be informed in writing that some organizations including the sponsor-investigator 
and his/her research associates, HCRN, Genentech and Vanquish Oncology, Inc., the IRB, or 
government agencies, like the FDA, may inspect their medical records to verify the information 
collected, and that all personal information made available for inspection will be handled in 
strictest confidence and in accordance with local data protection laws. 
 
If the results of the study are published, the subject’s identity will remain confidential. 
 
 
 


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15 
ETHICS 
 
15.1 
Institutional Review Board (IRB) Approval 
The final study protocol and the final version of the informed consent form must be approved in 
writing by an IRB. The site investigator must submit written approval by the IRB to HCRN 
before he or she can enroll subjects into the study.   
 
The site investigator is responsible for informing the IRB of any amendment to the protocol in 
accordance with local requirements. In addition, the IRB must approve all advertising used to 
recruit subjects for the study. The protocol must be re-approved by the IRB, as local regulations 
require.  
 
Progress reports and notifications of serious and unexpected adverse events will be provided to 
the IRB according to local regulations and guidelines. 
 
15.2 
Ethical Conduct of the Study 
The study will be performed in accordance with ethical principles originating from the 
Declaration of Helsinki.  Conduct of the study will be in compliance with ICH Good Clinical 
Practice, and with all applicable federal (including 21 CFR parts 56 & 50), state, or local laws. 
 
15.3 
Informed Consent Process 
The site investigator will ensure the subject is given full and adequate oral and written 
information about the nature, purpose, possible risks and benefits of the study. Subjects must 
also be notified they are free to discontinue from the study at any time. The subject should be 
given the opportunity to ask questions and allowed time to consider the information provided. 
 
The subject’s signed and dated informed consent must be obtained before conducting any 
procedure specifically for the study. The site investigator must store the original, signed 
informed consent form. A copy of the signed informed consent form must be given to the 
subject.  
 
 
 


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16 
REFERENCES 
 
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Oncogenic mutations in GNAQ occur early in uveal melanoma. Invest Ophthalmol Vis 
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14. Izban KF, Wrone-Smith T, Hsi ED, Schnitzer B, Quevedo ME, Alkan S. Characterization 
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17. Persad R, Liu C, Wu TT, Houlihan PS, Hamilton SR, Diehl AM, Rashid A. 
Overexpression of caspase-3 in hepatocellular carcinomas. Mod Pathol. 2004; 17:861-7. 
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20. Pach N, Thomas DL, Pondenis H, et al. Therapeutic duality of the procaspase-3 activator 
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APPENDIX 1: ECOG PERFORMANCE STATUS 
 
ECOG Score 
Performance Status
0 
Asymptomatic
1 
Symptomatic, fully ambulatory
2 
Symptomatic, in bed < 50% of the day
3 
Symptomatic, in bed > 50% of the day but not bedridden 
4 
Bedridden
5 
Dead 
 
 
 


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APPENDIX 2: DRUG INTERACTIONS WITH ENTRECTINIB  
Because of the potential for drug interactions, entrectinib should be administered with caution 
with the drugs listed in the tables below. 
 
Cytochrome P450 CYP3A4 Inhibitors and Inducers 
 
Inhibitors 
Inducers 
Strong: Boceprevir, clarithromycin, conivaptan, 
grapefruit juice, indinavir, itraconazole, 
ketoconazole, lopinavir/ritonavir, mibefradil, 
nefazodone, nelfinavir, posaconazole, ritonavir, 
saquinavir, telaprevir, telithromycin, voriconazole 
 
Moderate: Aprepitant, cimetidine, ciprofloxacin, 
clotrimazole, crizotinib, cyclosporine, 
dronedarone, erythromycin, fluconazole, 
fluvoxamine, imatinib, tofisopam, verapamil 
Strong: Alfentanil, cyclosporine, 
dihydroergotamine, ergotamine, fentanyl, 
pimozide, quinidine, sirolimus, tacrolimus, 
rifampin, St. John’s Wort 
 
Moderate: Bosentan, efavirenz, etravirine, 
modafinil 
 
Cytochrome P450 Substrates 
 
 
Sensitive Substrates 
Substrates with Narrow 
Therapeutic Range 
CYP2C9 Substrates 
Celecoxib 
Warfarin 
CYP2D6 Substrates 
Atomoxetine, desipramine, 
dextromethorphan, metoprolol, nebivolol, 
perphenazine, tolterodine, venlafaxine 
Thioridazine, pimozide 
CYP3A Substrates 
Alfentanil, aprepitant, budesonide, 
buspirone, conivaptan, darifenacin, 
darunavir, dasatinib, dronedarone, 
eletriptan, eplerenone, everolimus, 
felodipine, indinavir, fluticasone, lopinavir, 
lovastatin, lurasidone, maraviroc, 
midazolam, nisoldipine, quetiapine, 
saquinavir, sildenafil, simvastatin, 
sirolimus, tolvaptan, tipranavir, triazolam, 
ticagrelor, vardenafil 
Alfentanil, cyclosporine, 
dihydroergotamine, ergotamine, 
fentanyl, pimozide, quinidine, 
sirolimus, tacrolimus