Clinical trial NCT03332589
Conditions: Malignant Melanoma Brain Metastases
Keywords: Melanoma CNS metastases BRAF V600 mutation E6201 Dabrafenib
Sponsor: Spirita Oncology, LLC
Start date: 2018-07-02; Completion date: 2021-10-11
Enrollment: 4 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
This is a Phase 1 study of E6201 plus dabrafenib for the treatment of CNS metastases in BRAF V600-mutated metastatic melanoma. A total of up to N=28-34 subjects with melanoma metastasized to the CNS will be included.

Detailed description:
Selected subjects will be: both males and females age ≥18 years; histologically confirmed melanoma with BRAF V600 mutation with CNS metastasis; archived tumor sample from the primary, recurrent or metastatic disease with documented BRAF mutation; recovered from all acute toxicities (≤ Grade 1) due to prior immunotherapy; determined to have adequate renal and hepatic function, and no known history of significant cardiac disease.

Monotherapy Safety Run-in Phase: Following screening, a total of up to 4 subjects were enrolled. E6201 was administered by intravenous (IV) infusion over a 2-hour period at a dose of 320 mg/m\^2 twice weekly (Days 1, 4, 8, 11, 15 and 18) for three weeks, repeated every 28 days (1 cycle) until progression of disease, observation of unacceptable adverse events, intercurrent illness or changes in the subject's condition that prevents further study participation.

Combination Safety Run-in Phase: Following screening, a total of 6-12 subjects are anticipated to establish the recommended doses of E6201 plus dabrafenib. E6201 will be administered by IV infusion over a 2-hour period twice weekly (Days 1, 4, 8, 11, 15 and 18) repeated every 28 days plus dabrafenib orally twice daily (=1 cycle).

Dose Level 1: E6201 320 mg/m\^2 twice weekly plus dabrafenib 150 mg BID. Dose Level -1: E6201 240 mg/m\^2 twice weekly plus dabrafenib 150 mg BID. Dose Level -2: E6201 240 mg/m\^2 twice weekly plus dabrafenib 100 mg BID. Dose Level -3: E6201 160 mg/m\^2 twice weekly plus dabrafenib 100 mg BID Dose Level -4: E6201 160 mg/m\^2 twice weekly plus dabrafenib 75 mg BID. Dose Level -5: E6201 160 mg/m\^2 twice weekly plus dabrafenib 50 mg BID.

A total of 6 subjects will be treated at the combined MTD doses for both drugs in the Combination Safety Run-in Phase before beginning the Expansion Phase.

Expansion Phase: An additional cohort of up to N=18 subjects will be treated at the E6201 plus dabrafenib combined MTD. Subjects treated at the MTD in the Combination Safety Run-in Phase will count towards accrual in the Expansion Phase.

CNS disease response will be assessed according to 2 methodologies: Response Evaluation Criteria in Solid Tumors (RECIST v. 1.1) and Response Assessment in Neuro-Oncology - Brain Metastases (RANO-BM). Non-CNS systemic disease will be assessed according to RECIST v. 1.1.

Blood for hematology and serum chemistry determinations will be collected and ECGs will be taken during the study. Assessments will be obtained at Week 8 and every 8 weeks thereafter until documented progression of disease (PD). Subjects who demonstrate clinical benefit will be allowed to continue therapy with E6201 until progression of disease, observation of unacceptable adverse events, intercurrent illness or changes in the subject's condition that prevents further study participation.

Arms: arm 1: E6201 320 mg/m\^2 administered IV over 2 hours twice weekly on Days 1, 4, 8, 11, 15 and 18, repeated every 28 days (=1 cycle).

Dose reductions for toxicity are 240 mg/m\^2 (Dose Level -1) and 160 mg/m\^2 (Dose Level -2) twice weekly. arm 2: Dose Level 1: E6201 320 mg/m\^2 twice weekly plus dabrafenib 150 mg BID. Dose Level -1: E6201 240 mg/m\^2 twice weekly plus dabrafenib 150 mg BID. Dose Level -2: E6201 240 mg/m\^2 twice weekly plus dabrafenib 100 mg BID. Dose Level -3: E6201 160 mg/m\^2 twice weekly plus dabrafenib 100 mg BID Dose Level -4: E6201 160 mg/m\^2 twice weekly plus dabrafenib 75 mg BID. Dose Level -5: E6201 160 mg/m\^2 twice weekly plus dabrafenib 50 mg BID. arm 3: A total of up to N=18 will be treated at the E6201 plus dabrafenib combined MTD.
Interventions: intervention 1: E6201 intervention 2: E6201 plus dabrafenib
Intervention descriptions: intervention 1: E6201 formulated in cyclodextrin for IV administration. intervention 2: E6201 formulated in cyclodextrin for IV administration. Dabrafenib capsules for oral administration.

Protocol documents:
Prot_SAP_000.pdf: 
Protocol No. STX-101-02 
 
Spirita Oncology, LLC 
 
 
Confidential 
 
1 
December 31, 2019 
 
Protocol Amendment 4 
 
 
 
 
 
 
 
 
CLINICAL STUDY PROTOCOL 
 
Protocol Number: 
 
 
 
STX-101-02 
Protocol Title: 
A Phase 1 Study of E6201 for the Treatment of Central 
Nervous System (CNS) Metastases From BRAF V600- 
Mutated Metastatic Melanoma 
 
Sponsor Contact and  
Linda J. Paradiso, DVM, MBA 
Medical Monitor: 
Chief Development Officer 
Spirita Oncology, LLC 
27 Strathmore Road 
Natick, MA 01760 
Telephone: 713-898-8965 
Email: linda.paradiso@spiritaoncology.com 
 
 
 
 
 
Original Protocol 
 
 
 
Date: 18 January 2018 
Amendment 1 
 
 
 
 
Date: 14 June 2018 
Amendment 2 
 
 
 
 
Date: 19 January 2019 
Amendment 3 
 
 
 
 
Date: 04 October 2019 
Amendment 4 
 
 
 
 
Date: 31 December 2019 


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Protocol Amendment 4 
 
 
INVESTIGATOR SIGNATURE PAGE 
 
I have reviewed the above-titled protocol and agree that it contains all the information necessary 
to conduct the study as required. I will conduct the trial in accordance with the principles of the 
International Conference on Harmonisation (ICH) Good Clinical Practice, the Declaration of 
Helsinki and the applicable U.S. Food and Drug Administration (FDA) regulations. 
I will maintain as confidential all written and verbal information provided to me by the Sponsor, 
including but not limited to, the protocol, case report forms, investigator’s brochure, material 
supplied at investigator meetings, minutes of teleconferences, etc. Such material will only be 
provided as necessary to site personnel involved in the conduct of the trial, the Institutional Review 
Board (IRB) or local regulatory authorities. 
I will obtain written informed consent from each prospective trial subject or each prospective trial 
subject’s legal representative prior to conducting any protocol-specified procedures. The Informed 
Consent Document (ICD) used will have the approval of the IRB. 
I will maintain adequate source documents and record all observations, treatments and procedures 
pertinent to trial subjects in their medical records. I will accurately complete and submit the 
electronic case report forms supplied by the Sponsor in a timely manner. I will ensure that my 
facilities and records will be available for inspection by representatives of Spirita Oncology, the 
IRB or local regulatory authorities. I will ensure that I and my staff are available to meet with 
representatives of Spirita Oncology during regularly scheduled monitoring visits. 
I will notify the Medical Monitor within 24 hours of any serious adverse events.  Following this 
notification, a written report describing the serious adverse event will be provided to Spirita 
Oncology as soon as possible, but no later than 5 days following the initial notification. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Printed Name of Investigator 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Investigator 
 
 
 
 
 
 
 
 
Date 
 


Protocol No. STX-101-02 
 
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1. 
SYNOPSIS 
Protocol Number: STX-101-02 
Name of Sponsor/Company: 
Spirita Oncology, LLC 
Name of Investigational Product: 
E6201 
Name of Active Ingredient: (3S,4R,5Z,8S,9S,11E)-14- 
(Ethylamino)-8,9,16-trihydroxy- 3,4-dimethyl-3,4,9,10-tetrahydro- 1H-2-benzoxacyclotetradecine- 
1,7(8H)-dione 
Title of Study: A Phase 1 Study of E6201 for the Treatment of Central Nervous System (CNS) 
Metastases From BRAF V600-Mutated Metastatic Melanoma 
Principal Investigator(s): Hani Babiker, MD (University of Arizona) (Study Chair), and additional 
study centers as needed to ensure timely study accrual. 
Study Period (30 months):  
Date First Subject Enrolled: November 16, 2018 
Estimated Date Last Subject Completed: April 2021 
Phase of Development: 1 
 
Objectives:  
Primary: 
• 
To determine the overall rate of response of brain metastases in subjects with CNS metastases 
due to metastatic melanoma with a BRAF V600 mutation who have relapsed or progressed from 
initial or systemic disease 
Secondary: 
• 
To determine the intracranial disease duration of response, duration of stable disease (SD) and 
time to progression of CNS metastases 
• 
To determine the objective response rate of systemic disease other than in the CNS 
• 
To evaluate progression-free survival (PFS) 
• 
To evaluate overall survival (OS) 
• 
To evaluate the impact of the BRAF mutational status (e.g., type, heterozygosity or 
homozygosity) in archival tissue with clinical outcome  
• 
To evaluate the safety of E6201as monotherapy and in combination with dabrafenib in this 
population  
Methodology:  
This is a Phase 1 study of E6201 for the treatment of CNS metastases in BRAF V600-mutated metastatic 
melanoma. A total of N = 28 – 34 subjects with melanoma metastasized to the CNS will be included.  
Selected subjects will be: both males and females age ≥18 years; histologically confirmed melanoma 
with BRAF V600 mutation with CNS metastasis; archived tumor sample from the primary, recurrent or 
metastatic disease with documented BRAF mutation; no prior treatment with BRAF or MEK inhibitors 
for systemic disease; recovered from all acute toxicities (≥ Grade 1) due to prior immunotherapy; 
determined to have adequate renal and hepatic function; and no known history of significant cardiac 
disease. 


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Protocol Number: STX-101-02 
Monotherapy Safety Run-in Phase: Following screening, a total of 4 subjects were enrolled. E6201 
was administered by intravenous (IV) infusion over a 2-hour period at a dose of 320 mg/m2 twice 
weekly (Days 1, 4, 8, 11, 15 and 18) for 3 weeks, repeated every 28 days (1 cycle) until progression of 
disease, observation of unacceptable adverse events, intercurrent illness or changes in the subject’s 
condition that prevented further study participation. 
Combination Safety Run-in Phase: Following screening, a total of 6 – 12 subjects are anticipated to 
establish the recommended doses of E6201 plus dabrafenib. E6201 will be administered by IV infusion 
over a 2-hour period twice weekly (Days 1, 4, 8, 11, 15 and 18) repeated every 28 days plus dabrafenib 
orally twice daily (=1 cycle), according to the schedule below.  
Dose Level 
E6201 (IV) 
Dabrafenib (PO) 
1 
320 mg/m2 (MTD monotherapy) 
150 mg BID (market dose) 
-1a 
240 mg/m2 (Dose Level -1) 
150 mg BID 
-2a 
240 mg/m2 (Dose Level -1) 
100 mg BID (Dose Level -1) 
-3a 
160 mg/m2 (Dose Level -2) 
100 mg BID (Dose Level -1) 
-4a 
160 mg/m2 (Dose Level -2) 
75 mg BID (Dose Level -2) 
-5a 
160 mg/m2 (Dose Level -2) 
50 mg BID (Dose Level -3) 
a If necessary based on DLT (≥ 1 of 3 or ≥ 2 of 6 subjects experience DLT at the previous dose level) 
Subjects who demonstrate clinical benefit (objective response or stable disease) will be allowed to 
continue therapy with E6201 plus dabrafenib until progression of disease, observation of unacceptable 
adverse events, intercurrent illness or changes in the subject’s condition that prevents further study 
participation.  
Dose-limiting toxicity (DLT) is defined as any one of the following events: 
• 
Grade 4 hematologic toxicity for > 1 day 
• 
Grade 3 hematologic toxicity with complications (e.g., thrombocytopenia with bleeding) 
• 
Failure of Grade 3 thrombocytopenia, absolute neutrophil count (ANC), hemoglobin to recover 
to Grade ≤ 1 within 4 weeks despite the use of platelet and red blood cell (RBC) transfusions 
and/or growth factors 
• 
≥ Grade 3 non-hematologic toxicity not due to disease progression (excluding Grade 3 nausea, 
vomiting or diarrhea that is adequately controlled with supportive care and resolves to ≤ Grade 
2 within 48 hours, or Grade 3 electrolyte disturbances responsive to correction within 24 hours) 
• 
≥ Grade 3 liver function tests (LFTs) lasting > 72 hours 
• 
Treatment interruption > 14 days due to toxicity 
• 
Other important medical event  
Subjects who require a dose reduction due to toxicity will be considered to have had a DLT.  
No DLTs were experienced in the Monotherapy Safety Run-in Phase. If a DLT is experienced in ≥ 2 
of 6 subjects in the Combination Safety Run-in Phase during Cycle 1, no further subjects will be 
enrolled at that dose level. Subjects who experience a DLT may continue treatment at the next lower 
dose level until disease progression or unacceptable toxicity. The maximum tolerated dose (MTD) is 
defined as the doses of E6201 plus dabrafenib at which ≤ 1 of 6 subjects experiences a DLT.  


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Protocol Number: STX-101-02 
Subjects who experience E6201- and/or dabrafenib-related toxicity requiring a dose reduction may 
continue treatment at the next lower dose level for either drug until disease progression or unacceptable 
toxicity. 
E6201 dose reductions for suspected E6201-related toxicity will be 240 mg/m2 twice weekly (Dose 
Level -1) and 160 mg/m2 twice weekly (Dose Level -2), administered over the same schedule as above, 
Days 1, 4, 8, 11, 15 and 18, repeated every 28 days.  
Dabrafenib dose reductions for suspected dabrafenib-related toxicity will be 100 mg (Dose Level -1), 
75 mg (Dose Level -2) and 50 mg (Dose Level -3) orally twice daily, according to the U.S. Product 
Label.  
A total of 6 subjects will be treated at the combined MTD doses for both drugs in the Combination 
Safety Run-in Phase before beginning the Expansion Phase.   
Expansion Phase: Following screening, an additional cohort of up to N=18 subjects will be treated at 
the E6201 plus dabrafenib combined MTD. Subjects treated at the MTD in the Combination Safety 
Run-in Phase will count towards accrual in the Expansion Phase. E6201 will be administered by IV 
infusion over a 2-hour period at the MTD and schedule determined in the Combination Safety Run-in 
phase, repeated every 28 days (=1 cycle), and dabrafenib will be administered orally twice daily at the 
MTD determined in the Combined Safety Run-in phase. Both regimens will be subject to dose 
reductions for toxicity, as described. Subjects who demonstrate clinical benefit (objective response or 
stable disease) will be allowed to continue therapy with E6201 plus dabrafenib until progression of 
disease, observation of unacceptable adverse events, intercurrent illness or changes in the subject’s 
condition that prevents further study participation. 
During the study, a Safety Review Committee (SRC), consisting of the actively recruiting investigators, 
the Sponsor Medical Monitor and study staff will review data from the Monotherapy and Combination 
Safety Run-in Phases before beginning the Expansion Phase, and will review data from the Expansion 
Phase on an ongoing basis.  
The statistical objective is the evaluation intracranial disease objective response (OR) rate, defined as 
complete response (CR) or partial response (PR), on treatment with E6201 plus dabrafenib. The sample 
size is based on a one-arm binomial design H0 ≤ 0.05 (≤ 5% response rate for historical control group) 
versus H1 > 0.05 (> 5% response rate for experimental group). An objective response (OR) rate of 25% 
or greater is deemed clinically important. A total of 3 or more responses in a sample size of 18 subjects 
indicates the true OR rate is ≥ 25%, with power = 80%, alpha = 0.05, and provides evidence of clinical 
utility to move forward. 
CNS disease response will be assessed according to 2 methodologies: Response Evaluation Criteria in 
Solid Tumors (RECIST v. 1.1) and Response Assessment in Neuro-Oncology – Brain Metastases 
(RANO-BM) and. Clinical benefit is defined as best response of CR, PR or SD.  
Non-CNS systemic disease will be assessed according to RECIST v. 1.1. 
Blood for hematology and serum chemistry determinations will be collected within 28 days of Cycle 1 
Day 1 and on Day 1 of each cycle and at the End of Treatment Visit.  
Electrocardiograms (ECGs) will be taken within 28 days prior to Cycle 1 Day 1, pre-infusion and 5 
minutes following the end of the E6201 2-hour infusion, on Day 1 of every cycle thereafter, and at the 
End of Treatment visit. 
CNS and non-CNS systemic disease assessments will be based on magnetic resonance image (MRI) or 
computed tomography (CT) if unable to perform MRI for intracranial disease. Assessments will be 
obtained at Week 8 and every 8 weeks thereafter until documented progression of disease (PD). 
Subjects who demonstrate clinical benefit will be allowed to continue therapy until progression of 


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Protocol Number: STX-101-02 
disease, observation of unacceptable adverse events, intercurrent illness or changes in the subject’s 
condition that prevents further study participation. 
Number of Subjects and Centers (planned): A total of 4 subjects were enrolled in the Monotherapy 
Safety Run-in Phase. A total of 6 – 12 subjects are anticipated in the Combination Safety Run-in Phase. 
A total of up to 18 subjects will be enrolled in the Expansion Phase for a total N = 28 – 34 for the study. 
Study centers include University of Arizona (Hani Babiker, MD - Study Chair) and additional study 
centers as needed to ensure timely study accrual. 
Duration of Study: Accrual is expected to be 24 months, with the last subject followed for up to 6 
months. The total study duration is expected to be 30 months. The anticipated accrual rate is 1 – 2 
subjects per month. 
Inclusion Criteria:  
• 
Males and females  18 years of age 
• 
Histologically or cytologically confirmed Stage IV metastatic BRAF V600-mutated melanoma  
• 
Documented metastasis of the primary tumor to the CNS 
• 
BRAF-mutation melanoma tumor status will be established prior to entry based on previous 
BRAF-gene analysis reports from a CLIA qualified laboratory. If a report is not available, the 
mutation analysis will be performed at Screening on archival tissue. 
• 
Other metastatic melanoma systemic disease allowed   
• 
At least one measurable brain metastasis, 0.5 – 3.0 cm, as assessed by MRI ≤ 3 weeks prior to 
initiation of study treatment, and does not require immediate local intervention (surgery or 
radiosurgery)  
• 
Prior stereotactic radiosurgery and/or excision of up to 3 brain metastases is allowed > 3 weeks 
before initiation of study treatment, provided neurological sequelae have resolved completely 
and at least one measurable metastasis with documented disease progression is present on MRI 
• 
One prior line of immunotherapy for metastatic disease is allowed, if ≥ 2 weeks has elapsed 
between the end of therapy and initiation of study treatment 
• 
Prior melanoma adjuvant immunotherapy is allowed, if ≥ 6 months has elapsed between the 
end of therapy and initiation of study treatment 
• 
Prior melanoma adjuvant BRAF/MEK inhibitor therapy is allowed, if ≥ 12 months has elapsed 
between the end of therapy and initiation of study treatment 
• 
Able to swallow and retain oral medication with no clinically significant gastrointestinal 
abnormalities that may alter absorption, such as malabsorption syndrome or major resection of 
the stomach or bowels (Combination Safety Run-in and Expansion Phases of the study only) 
• 
Asymptomatic or symptomatic CNS metastasis is allowed 
• 
Stable dose of corticosteroids for CNS metastasis for > 7 days is allowed 
• 
Patients with seizures due to CNS metastases must be controlled with stable anti-epileptic 
treatment for > 14 days 
• 
Bisphosphonates and/or denosumab are allowed 
• 
Adequate performance status: Eastern Cooperative Oncology Group (ECOG) ≤ 2  
• 
Life expectancy of ≥ 3 months  
 


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Protocol Number: STX-101-02 
• 
Adequate hematologic parameters without ongoing transfusional support: 
o Hemoglobin (Hb) ≥ 9 g/dL 
o Absolute neutrophil count (ANC) ≥ 1.0 x 109 cells/L 
o Platelets ≥ 75 x 109 cells/L 
• 
Adequate renal and hepatic function: 
o Creatinine ≤ 1.5 x the upper limit of normal (ULN), or calculated creatinine clearance ≥ 50 
mL/minute x 1.73 m2 per the Cockcroft-Gault formula 
o Total bilirubin ≤ 2 times the upper limit of normal (ULN) unless due to Gilbert’s disease 
o ALT/AST ≤ 2.5 times ULN, or < 5 times ULN for subjects with liver metastases 
• 
Negative serum pregnancy test within 14 days prior to the first dose of study therapy for women 
of child-bearing potential (WCBP), defined as a sexually mature woman who has not 
undergone a hysterectomy or who has not been naturally post-menopausal for at least 24 
consecutive months (i.e., who has had menses any time in the preceding 24 consecutive 
months). Sexually active WCBP and male subjects must agree to use adequate methods to avoid 
pregnancy (oral, injectable, or implantable hormonal contraceptive; tubal ligation; intra-uterine 
device; barrier contraceptive with spermicide; or vasectomized partner) throughout the study 
and for 28 days after the completion of study treatment.  
• 
Ability to provide written informed consent 
Exclusion Criteria: 
• 
Urgent need of treatment to prevent acute neurologic deterioration, including urgent 
neurosurgery or radiotherapy 
• 
Symptoms of uncontrolled intracranial pressure 
• 
Symptomatic or untreated spinal cord compression 
• 
Prior treatment with any chemotherapeutic or investigational agent 
• 
Prior treatment with any BRAF and/or MEK inhibitor for metastatic disease 
• 
Prior treatment with > 1 line of immunotherapy for metastatic disease 
• 
Serious cardiac condition within the last 6 months, such as uncontrolled arrhythmia, myocardial 
infarction, unstable angina or heart disease defined by the New York Heart Association 
(NYHA) Class III or Class IV  
• 
QT interval corrected for rate (QTc) > 480 msec on the ECG obtained at Screening using 
Fridericia method for QTc calculation 
• 
Active infection with human immunodeficiency virus (HIV), hepatitis B virus (HBV) or 
hepatitis C virus (HCV) requiring systemic antiviral treatment within the last week prior to 
study treatment  
• 
Other active infection requiring IV antibiotic usage within the last week prior to study treatment 
• 
Any other medical intervention or other condition which, in the opinion of the Principal 
Investigator, could compromise adherence to study requirements or confound the interpretation 
of study results 
• 
Pregnant or breast-feeding 
 


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Protocol Number: STX-101-02 
Criteria for evaluation: 
Safety: Safety will be assessed through the monitoring of adverse events (AEs), clinical laboratory 
parameters (hematology, serum chemistry), vital sign measurements, ECGs and physical examinations. 
Adverse events will be classified according to the Medical Dictionary for Regulatory Affairs 
(MedDRA) and graded according to the National Cancer Institute Common Terminology Criteria for 
Adverse Events (NCI CTCAE) version 4.03. 
Efficacy: Efficacy assessments will be determined on the basis of MRI and/or CT scans with best 
treatment response at any protocol-specified time point for intracranial disease, duration of response, 
duration of stable disease, and time to CNS metastasis disease progression. Response rates also will be 
determined for non-CNS systemic disease. Progression-free survival (PFS) and overall survival (OS) 
will be evaluated. 
Pharmacodynamics: A correlation will be made between BRAF mutational status (e.g., type, 
heterozygosity or homozygosity) in archival tissue with clinical outcome. 
Investigational Product, Dosage and Mode of Administration: E6201 for Injection is a natural 
product analog and inhibitor of mitogen-activated protein kinase/extracellular-signal regulated kinase 
kinase-1 (MEK1). It is a sterile white lyophilized powder containing 60 mg of E6201 formulated in 
cyclodextrin to improve E6201 solubility in water. E6201 for Injection is packaged in a 20-mL capacity 
Type I glass vial with a bromobutyl rubber stopper and an aluminum cap. Reconstituted and diluted 
E6201 solutions should be stored refrigerated (2 to 8°C) and protected from light before administration. 
Reference Therapy: None 
Statistical Methods: 
Efficacy Endpoints and Analyses: Intracranial response rates will be summarized using number and 
percentage of subjects with a best response of CR, PR, SD or PD assessed by RECIST v 1.1 and RANO-
BM, along with 2-sided, 95% confidence intervals for the proportions. Non-CNS systemic disease 
response rates will be determined by RECIST v 1.1. For determination of intracranial disease duration 
of response, duration of stable disease, and time to progression of CNS metastases, and for PFS and 
overall survival, the Kaplan-Meier product- limit method will be used to estimate the median survival. 
Subjects who do not have disease progression will be censored at the last follow-up time. 
Duration of intracranial disease response or stable disease will be calculated from the date of first 
response or stable disease to the date of progression or death. 
Time to progression of CNS metastases will be calculated from the date of first treatment to the date of 
first evidence of progression of CNS disease. 
Progression-free survival will be calculated from the date of first treatment to the date of first evidence 
of progression or death. 
Overall survival will be calculated from the date of first treatment to the date of death from any cause; 
subjects who do not experience death will be censored at the last follow-up time.  
All efficacy endpoints will be summarized separately for monotherapy and combination therapy phases 
of the study. 
SAS Version 9.3 for Windows (SAS Institute, Cary, NC) or higher will be used for all analyses. 
Pharmacodynamic Endpoint Analyses: A correlation will be made between BRAF mutational status 
(e.g., type, heterozygosity or homozygosity) in archival tissue with clinical outcome for monotherapy 
and combination therapy study phases.  


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Protocol Number: STX-101-02 
Safety Endpoints and Analyses: Safety endpoints for AEs include the following: incidences of all 
treatment-emergent adverse events (TEAEs) and all serious adverse events (SAEs); incidences of 
TEAEs and SAEs by severity; incidences of TEAEs and SAEs by relationship to study medications; 
incidences of all Grade 3 and 4 TEAEs and by severity and relationship to study medications; and 
discontinuation of subjects from the study due to AEs or death. Safety endpoints for AEs, clinical 
laboratory tests, vital signs, ECGs and physical examinations will be specified in the statistical analysis 
plan. All safety endpoints will be summarized separately for monotherapy and combination therapy 
phases of the study using descriptive statistics. 
 
 


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TABLE OF CONTENTS 
1. 
SYNOPSIS ...................................................................................................................3 
2. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................15 
3. 
INTRODUCTION ......................................................................................................19 
3.1. 
E6201 Summary .........................................................................................................19 
3.1.1. 
Preclinical Pharmacology ...........................................................................................19 
3.1.2. 
Preclinical Pharmacokinetics ......................................................................................20 
3.1.3. 
Preclinical Toxicology ................................................................................................21 
3.1.4. 
Phase 1 Solid Tumor Study ........................................................................................22 
3.2. 
Rationale for CNS Metastases Indication ...................................................................24 
3.2.1. 
Clinical Unmet Need ..................................................................................................24 
3.2.2. 
CNS Penetration – Preclinical Study ..........................................................................26 
3.3. 
Preclinical Evaluation of E6201 Plus Dabrafenib ......................................................27 
3.4. 
Dose Rationale ............................................................................................................28 
3.4.1. 
E6201 ..........................................................................................................................28 
3.4.2. 
Dabrafenib ..................................................................................................................28 
4. 
TRIAL OBJECTIVES AND PURPOSE ....................................................................29 
4.1. 
Primary Objective .......................................................................................................29 
4.2. 
Secondary Objectives .................................................................................................29 
5. 
INVESTIGATIONAL PLAN .....................................................................................30 
5.1. 
Overall Study Design ..................................................................................................30 
5.2. 
Number of Subjects and Centers ................................................................................32 
5.3. 
Treatment Assignment ................................................................................................32 
5.4. 
Duration of Study .......................................................................................................33 
5.5. 
Dose Adjustment Criteria ...........................................................................................33 
5.5.1. 
Safety Criteria for Adjustment or Stopping Doses .....................................................33 
5.5.1.1. 
Toxicity Grading Criteria ...........................................................................................33 
5.5.1.2. 
Dose Modifications and Dose Reductions ..................................................................33 
5.5.1.3. 
Schedule Adjustments for Toxicity ............................................................................38 
5.5.2. 
Supportive Care Guidelines ........................................................................................38 
5.6. 
Criteria for Study Termination ...................................................................................38 


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6. 
STUDY POPULATION .............................................................................................39 
6.1. 
Subject Inclusion Criteria ...........................................................................................39 
6.2. 
Subject Exclusion Criteria ..........................................................................................40 
6.3. 
Discontinuation of Subjects ........................................................................................41 
6.3.1. 
Procedures for Withdrawal .........................................................................................41 
6.3.2. 
Replacement of Study Subjects ..................................................................................41 
7. 
TREATMENT OF SUBJECTS ..................................................................................42 
7.1. 
Description of Treatment Plan ....................................................................................42 
7.1.1. 
Treatment Duration .....................................................................................................42 
7.2. 
Concomitant Medications ...........................................................................................42 
7.2.1. 
Permitted Medications ................................................................................................42 
7.2.2. 
Prohibited Medications ...............................................................................................42 
7.3. 
Treatment Compliance ................................................................................................42 
7.4. 
Randomization and Blinding ......................................................................................42 
8. 
STUDY DRUG MATERIALS AND MANAGEMENT ...........................................43 
8.1. 
E6201 ..........................................................................................................................43 
8.2. 
Study Drug Description ..............................................................................................43 
8.3. 
Study Drug Packaging and Labeling ..........................................................................43 
8.4. 
Study Drug Storage .....................................................................................................43 
8.5. 
Study Drug Preparation ..............................................................................................43 
8.6. 
Administration ............................................................................................................44 
8.7. 
Dabrafenib ..................................................................................................................44 
8.7.1. 
Description ..................................................................................................................44 
8.7.2. 
Packaging and Labeling ..............................................................................................44 
8.7.3. 
Storage ........................................................................................................................44 
8.7.4. 
Administration ............................................................................................................44 
8.8. 
Study Drug Accountability .........................................................................................45 
8.9. 
Study Drug Handling and Disposal ............................................................................45 
9. 
STUDY PROCEDURES ............................................................................................46 
9.1. 
Screening Procedures ..................................................................................................46 
9.2. 
Requirements During Treatment Cycle 1 ...................................................................46 
9.2.1. 
Cycle 1, Day 1 ............................................................................................................46 


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9.2.2. 
Cycle 1, Day 8 (± 1 day) .............................................................................................47 
9.2.3. 
Cycle 1, Day 15 (± 1 day) ...........................................................................................47 
9.3. 
Requirements During Treatment Cycles After Cycle 1 (Cycle 2 and beyond) 
[± 3 days] ....................................................................................................................47 
9.4. 
At Relapse or Progression of Disease .........................................................................48 
9.5. 
End of Treatment (28 Days After Last Dose of E6201 and/or Dabrafenib 
Study Medication ± 5 days) ........................................................................................48 
9.6. 
Long-Term Follow-Up ...............................................................................................49 
10. 
DESCRIPTION OF ASSESSMENTS .......................................................................50 
10.1. 
Safety Assessments .....................................................................................................50 
10.2. 
Safety Parameters .......................................................................................................50 
10.2.1. 
Vital Signs ..................................................................................................................50 
10.2.2. 
Weight and Height ......................................................................................................50 
10.2.3. 
Physical Examination .................................................................................................50 
10.2.4. 
Electrocardiogram (ECG) ...........................................................................................50 
10.2.5. 
Laboratory Assessments .............................................................................................50 
10.3. 
Adverse and Serious Adverse Events .........................................................................51 
10.3.1. 
Definition of Adverse Events .....................................................................................51 
10.3.1.1. 
Adverse Event (AE) ....................................................................................................51 
10.3.1.2. 
Serious Adverse Event (SAE) ....................................................................................52 
10.3.1.3. 
Unexpected Adverse Event .........................................................................................52 
10.3.1.4. 
Adverse Event Reporting Period ................................................................................53 
10.3.1.5. 
Recording of Adverse Events .....................................................................................53 
10.3.1.6. 
Adverse Event Reporting ............................................................................................54 
10.3.1.7. 
Adverse Event and Serious Adverse Event Follow-Up ..............................................55 
10.3.1.8. 
7.1.8. Ongoing Safety Evaluation ...............................................................................55 
10.4. 
Efficacy Assessments .................................................................................................55 
10.4.1. 
Efficacy Endpoints ......................................................................................................56 
10.4.1.1. 
Primary Efficacy Endpoint .........................................................................................56 
10.4.1.2. 
Secondary Efficacy Endpoints ....................................................................................56 
10.4.2. 
Timing of Assessments to Determine Objective Response ........................................56 
10.5. 
Pharmacodynamic Assessment ...................................................................................56 


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11. 
STATISTICAL METHODOLOGY ...........................................................................57 
11.1. 
Determination of Sample Size ....................................................................................57 
11.2. 
Analysis Populations ..................................................................................................57 
11.3. 
Statistical Analysis Methods.......................................................................................57 
11.3.1. 
Safety Analysis ...........................................................................................................57 
11.3.1.1. 
Adverse Events ...........................................................................................................57 
11.3.1.2. 
Laboratory Data ..........................................................................................................58 
11.3.1.3. 
Vital Signs ..................................................................................................................58 
11.3.1.4. 
Other Safety Data .......................................................................................................58 
11.3.2. 
Efficacy Analysis ........................................................................................................58 
11.3.2.1. 
Primary Efficacy Endpoint .........................................................................................58 
11.3.2.2. 
Secondary Efficacy Endpoints ....................................................................................58 
11.3.3. 
Pharmacodynamic Endpoint Analysis ........................................................................59 
12. 
STUDY MANAGEMENT .........................................................................................60 
12.1. 
Data Management .......................................................................................................60 
12.2. 
Monitoring ..................................................................................................................60 
12.3. 
Audits and Inspections ................................................................................................60 
12.4. 
Amendments ...............................................................................................................60 
12.5. 
Institutional Review Board (IRB) ...............................................................................61 
13. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................62 
14. 
ETHICS ......................................................................................................................63 
14.1. 
Ethics Review .............................................................................................................63 
14.2. 
Ethical Conduct of the Study ......................................................................................63 
14.3. 
Written Informed Consent ..........................................................................................63 
15. 
DATA HANDLING AND RECORDKEEPING .......................................................64 
15.1. 
Health Insurance Portability Accountability Act of 1996 ..........................................64 
15.2. 
Financial Disclosure ...................................................................................................64 
15.3. 
Inspection of Records .................................................................................................64 
15.4. 
Access to Original Records ........................................................................................64 
15.5. 
Retention of Records ..................................................................................................64 
16. 
LIST OF REFERENCES ............................................................................................65 


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APPENDIX A. EASTERN COOPERATIVE GROUP (ECOG) PERFORMANCE 
STATUS SCALE ........................................................................................................68 
APPENDIX B. COCKCROFT-GAULT FORMULA FOR CALCULATION OF 
CREATININE CLEARANCE ....................................................................................69 
APPENDIX C. NEW YORK HEART ASSOCIATION (NYCA) CLASSIFICATION 
FOR HEART FAILURE NYHA CLASSIFICATION - THE STAGES OF 
HEART FAILURE .....................................................................................................70 
APPENDIX D. SCHEDULE OF STUDY PROCEDURES .......................................................71 
APPENDIX E. RESPONSE EVALUATION CRITERIA IN SOLID TUMORS 
(RECIST 1.1)38 ...........................................................................................................73 
APPENDIX F. RESPONSE ASSESSMENT IN NEURO-ONCOLOGY BRAIN 
METASTASES (RANO-BM)39 .................................................................................86 
APPENDIX G. ETHICAL STANDARDS .................................................................................88 
 
LIST OF FIGURES 
Figure 1: E6201 Plus Dabrafenib BRAF V600E+ PDX Metastatic Melanoma Mouse 
Model ..........................................................................................................................27 
 
LIST OF TABLES 
Table 1: Abbreviations and Specialist Terms ................................................................................15 
Table 2: Brain Penetration of Known BRAF/MEK Inhibitors ......................................................26 
Table 3: BRAF V600E+ PDX Metastatic Melanoma Mouse Model, E6201 
Tumor:Plasma Concentrations ....................................................................................27 
Table 4: E6201 Dose Modification Guidelines .............................................................................35 
Table 5: E6201 Dose Modification Guidelines for QTc Prolongation ..........................................36 
Table 6: Dabrafenib (TAFINLAR) Dose Reduction Guidelines36 .............................................36 
Table 7: Dabrafenib (TAFINLAR) Dose Modification Guidelines36 ............................................37 
Table 8: E6201 Investigational Product .........................................................................................43 
Table 9: Clinical Laboratory Parameters .......................................................................................51 
Table 10: Reporting Guidelines for Adverse Events .....................................................................54 
 
 
 


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2. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
The following abbreviations and specialist terms are used in this study protocol. 
Table 1: Abbreviations and Specialist Terms  
Abbreviation or Specialist Term 
Explanation 
A 
Adenosine receptor 
Abl 
Abelson kinase 
AE 
Adverse event 
ALT (SGPT) 
Alanine transaminase 
AML 
Acute myeloid leukemia 
ANC 
Absolute neutrophil count 
AST (SGOT) 
Aspartate transaminase 
BBB 
Blood brain barrier 
BRAF, B-Raf 
BRAF is the human proto-oncogene that encodes the 
serine/threonine-protein kinase B-Raf 
BUN 
Blood urea nitrogen 
BZDp 
Benzodiazepine receptor 
C 
Centigrade 
CB2 
Cannabinoid receptor 
CCKA 
Cholecystokinin A 
CFR 
Code of Federal Regulations 
CHO 
Chinese hamster ovary cells 
Cmax  
Peak concentration 
CNS 
Central nervous system 
CR 
Complete response 
CRF 
Case report form 
CT 
Computed tomography 
CTC 
Circulating tumor cell 
CTCAE 
Common terminology criteria for adverse events 
CYP 
Cytochrome P450 
dL 
Decaliter 
DLT 
Dose limiting toxicity 
DNA 
Deoxyribonucleic acid 


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Abbreviation or Specialist Term 
Explanation 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EGF 
Epidermal growth factor 
EphA2 
Ephrin type A receptor 
FAS 
Full analysis set 
FDA 
Food and Drug Administration 
FLT3 
FMS-like tyrosine kinase-3 
G1 
Gap-1 cell cycle phase 
GCP 
Good Clinical Practice 
G-CSF 
Granulocyte colony-stimulating factor 
GI 
Gastro-intestinal 
GM-CSF 
Granulocyte-macrophage colony-stimulating factor 
GSH 
Glutathione 
GST 
Glutathione-S-transferase 
HBV 
Hepatitis B virus 
HCG 
Human chorionic gonadotropin 
HCV 
Hepatitis C virus 
hERG 
Human ether a-go-go 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
Human immunodeficiency virus 
IC50 
Concentration of an inhibitor to reduce the response by one-half 
ICD 
Informed consent document 
ICH 
International Conference on Harmonisation 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
IV 
Intravenous 
IWG 
International Working Group 
Kg 
Kilogram 
L 
Liter 
LDH 
Lactate dehydrogenase 
LFT 
Liver function test 


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Abbreviation or Specialist Term 
Explanation 
LTB4 
Leukotriene B4 receptor 
m2 
Meters squared 
MAPK 
Mitogen-activated protein kinase 
MedDRA 
Medical Dictionary for Regulatory Activities 
Mg 
Milligram 
mL 
Milliliter 
µ 
Micro 
M 
Molar 
MEK1 
Mitogen-activated protein kinase/extracellular-signal regulated 
kinase kinase-1 
MEKK1 
Mitogen-activated protein kinase/extracellular signal-regulated 
kinase kinase kinase-1 
MRI 
Magnetic resonance imaging 
MT1 
Melatonin ML1A receptor 
MTD 
Maximum tolerated dose 
N 
Number 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for 
Adverse Events 
NK 
Neurokinin receptor 
NOAEL 
No adverse effect level 
NYHA 
New York Heart Association 
OR 
Objective response 
OS 
Overall survival 
PD 
Pharmacodynamic, progressive disease 
PDE 
Phosphodiesterase 
PFS 
Progression-free survival 
PK 
Pharmacokinetic 
PPS 
Per protocol set 
PR 
Partial response 
QTc 
QT interval corrected for rate 
RANO-BM 
Response Assessment in Neuro-Oncology – Brain Metastases 
RAS/RAF 
RAS: family of GTPases that act as molecular switches, to turn on 
downstream RAF protein kinases (e.g., BRAF).  


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Abbreviation or Specialist Term 
Explanation 
RBC 
Red blood cell 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
Serious adverse event 
SD 
Stable disease 
SRC 
Safety Review Committee 
Src 
Family of proto-oncogenic tyrosine kinases 
TEAE 
Treatment-emergent adverse event 
TrkB 
Tropomyosin-related kinase 
TXA2/PGH2 
Thromboxane A2/prostaglandin H2 receptor 
U 
Units 
UDS 
Unscheduled DNA synthesis 
ULN 
Upper limit of normal 
UT II 
Urotensin II receptor 
V 
Vasopressin receptor 
V600E 
BRAF gene mutation in which valine (V) is substituted by glutamic 
acid (E) at amino acid 600  
V600K 
BRAF gene mutation in which valine (V) is substituted by lysine 
(K) at amino acid 600 
V600D 
BRAF gene mutation in which valine (V) is substituted by aspartic 
acid (D) at amino acid 600 
WBC 
White blood cell 
WCBP 
Woman of child-bearing potential 
WT 
Wild-type 
 
 
 
 
 


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3. 
INTRODUCTION 
3.1. 
E6201 Summary  
E6201, a synthetic analog of a natural product, is a potent inhibitor of mitogen-activated protein 
kinase/extracellular-signal regulated kinase kinase-1 (MEK1) and mitogen-activated protein 
kinase/extracellular signal-regulated kinase kinase kinase-1 (MEKK1). The RAS/RAF/MEK/ERK 
signaling pathway has long been viewed as a promising target in the development of novel 
anticancer therapies, based upon its central role in regulating the growth and survival of cells from 
a broad spectrum of human tumors.1 Importantly, MEK1 is downstream of GTPase RAS and 
serine/threonine kinase RAF proteins, which are often mutated and abnormally active in cancer. 
Davies et al identified B-type RAF (BRAF) kinase, an upstream kinase of MEK1 in the signal 
transduction cascade, with somatic missense mutations in 67% of malignant melanomas and 12% 
of colorectal cancers.2 All mutations were within the kinase domain with a predominant single 
substitution such as the valine-to-glutamic acid substitution at amino acid residue 600 (V600E). 
Mutated BRAF proteins have elevated kinase activity, leading to  activation of MEK1, which then 
triggers extracellular signal-related kinase (ERK) phosphorylation, and activates downstream 
pathways.2,3,4 These reports strongly suggest that cancers with elevated MEK1 activity may be 
promising therapeutic targets for  E6201.5 In addition to strong MEK1 inhibition, E6201 inhibits 
cancer-relevant kinases including the Src family tyrosine kinases (Lyn, Fyn, Lck, Yes, cSrc), 
tropomyosin-related kinase B (TrkB), FMS- related tyrosine kinase 3 (Flt3), Abelson kinase (Abl), 
and ephrin type-A receptor 2 (EphA2) kinase activities.6,7 The results of in vitro and in vivo 
pharmacology studies show that E6201 may be useful for the treatment of cancers associated with 
the elevation of MEK1 kinase activity such as the BRAF mutation. In cell-systems cultured in 
vitro, E6201 demonstrated cytostatic growth inhibition of BRAF-mutated human cancer cells. In 
vivo, intermittent intravenous (IV) administration of E6201 caused statistically significant 
anticancer activity in BRAF-mutated human cancer xenografts. Changes in expression levels of 
phospho-ERK, cyclin D1, and phosphorylated pRb (p-Rb) in cancer cells or tumors may serve as 
pharmacodynamic (PD) biomarkers for MEK1 signaling pathway inhibition and efficacy of 
E6201. In addition to changes in these proteins, E6201 inhibited the spontaneous secretion of 
interleukin-6 (IL-6) and IL-8 in LOX melanoma cell lines. IL-8 has been identified as a 
transcriptional target of RAS/RAF/MEK signaling,8 suggesting that its expression might be 
affected by BRAF mutation. Therefore, measurement of these cytokines in plasma and their 
messenger RNA (mRNA) in tumor tissue may also serve as PD markers to measure biological 
response to E6201. 
The following information is taken from the E6201 for Injection Investigator’s Brochure.9 
3.1.1. 
Preclinical Pharmacology  
E6201 is a potent MEK1 inhibitor with a half-maximal inhibitory concentration (IC50) value of46.3 
nmol/L. In addition to strong MEK1 inhibition, E6201 also inhibits the Src family tyrosine kinases 
(Lyn, Fyn, Lck, Yes, cSrc), TrkB, Flt3, Abl, and EphA2 and MEKK1 kinase activities with IC50 
values ranging from 15.0 to 163.0 nmol/L. E6201 inhibited growth of 5 human cancer cell lines 
(SK-MEL-28 and LOX melanomas, MDA-MB-435 breast cancer, DBTRG-05MG glioblastoma, 
and COLO 205 colon cancer) which carry BRAF activating mutation. The IC50 values for E6201 


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in these 5 cell lines ranged from 43.7-463.6 nmol/L. AU-565 human breast cancer cells, without a 
BRAF mutation, were resistant to E6201 (IC50 >10 μmol/L). E6201 also inhibited human 
keratinocyte proliferation stimulated by epidermal growth factor (EGF) which activates the 
RAS/RAF/MEK/ERK pathway with an IC50 value of 160 nmol/L. E6201 was shown to completely 
block the cell cycle in the gap-1 phase (G1) of the cell cycle in SK-MEL-28 cells with no evidence 
of a hypodiploid cell population (apoptosis), indicating the cytostatic nature of E6201. The 
anticancer activity of E6201 was evaluated in vivo following IV administration on a Q4Dx3 
schedule in 3 BRAF-mutated human cancer xenograft models (LOX melanoma, COLO 205 colon 
cancer, and DBTRG-05MG glioblastoma). Administration of E6201 at doses of 5, 10, 20, and 40 
mg/kg resulted in statistically significant anticancer activity in these 3 models. 
In a secondary PD study, E6201 or E6201 Captisol® formulation was examined against a panel of 
126 receptors, channels, transporters, and enzymes of important physiological function. In these 
studies, E6201 showed significant binding or inhibition (>50% at 1 μmol/L) to human adenosine 
A1 receptor (A1) and enzyme activity of phosphodiesterase, PDE4. 
E6201 inhibited IL-2 production by phytohemagglutinin-P-stimulated human lymphocytes with 
an IC50 value of 18 nmol/L. 
In vitro studies of E6201 at 10 μmol/L and above caused a statistically significant inhibition of 
potassium tail current in human ether a-go-go (hERG) complementary deoxyribonucleic acid 
(cDNA)-transfected Chinese hamster ovary (CHO) cells; the IC50 value was 10.6 μmol/L (4128 
ng/mL). E6201 at 1 and 10 μmol/L applied by perfusion for 30 minutes to isolated papillary 
muscles of guinea pigs showed no effects on the action potential parameters. 
In vivo studies of E6201 at doses up to 60 mg/kg administered as a 30-minute IV infusion, showed 
no effects on central nervous system or respiratory function in rats. In dogs, E6201 at doses up to 
30 mg/kg administered as a 30-minute IV infusion showed no effects on heart rate (HR), blood 
pressure (BP), or electrocardiogram (ECG) parameters. 
Additional in vivo safety pharmacology studies in anesthetized dogs revealed that both vehicle 
(30% Captisol) and E6201 (6-30 mg/kg in 30% Captisol) administered as a 5-minute IV bolus 
injection exhibited effects on cardiopulmonary function, including increased mean BP, systolic 
left ventricular pressure, left ventricular end-diastolic pressure, mean right atrial pressure, mean 
pulmonary artery pressure, pulmonary artery wedge pressure, and cardiac output. These effects 
were possibly due to the physiochemical properties of Captisol (high osmolality and high 
viscosity). Similar effects were not apparent when E6201 was administered as a 30-minute IV 
infusion, except for a 36.5% increase in cardiac output observed when E6201 was administered at 
a dose of 30 mg/kg in 30% Captisol solution compared with the vehicle alone (30% Captisol). 
E6201 at doses up to 18 mg/kg in 18% Captisol solution administered as a 30-minute IV infusion 
had no effects on cardiopulmonary function.  
3.1.2. 
Preclinical Pharmacokinetics  
Pharmacokinetic (PK) studies were performed in Sprague-Dawley rats and dogs administered 
E6201 as 30-minute IV infusions on Days 1, 8, and 15 in which E6201 and ER-813010 (the much 
less active E isomer, trans enone of E6201) were measured. In rats administered doses ranging 
from 6 to 60 mg/kg, the exposure of E6201 and ER-813010 was proportional to dose increases 


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with no differences observed between males and females and were similar on Days 1 and 15, 
thereby suggesting no drug accumulation.   In dogs administered doses ranging from 6 to 30 mg/kg, 
the exposure of E6201 and ER-813010 was roughly proportional to dose increases with slightly 
higher exposure observed in females than males and were similar on Days 1 and 15, thereby 
suggesting no drug accumulation. The PK profile of E6201 in rats was characterized by moderately 
extensive distribution and fast clearance and elimination, while in dogs the distribution was 
moderately small. The elimination half-life of E6201 averaged < 1.5 hours in rats and dogs. 
In vivo studies of E6201 at doses up to 60 mg/kg administered as a 30-minute IV infusion resulted 
in estimated Cmax values of 16.2 µg/mL in the male rat and 9.1 to 15.3 µg/mL in the dog. 
Additionally, E6201 18 mg/kg in 18% Captisol solution administered as a 30-minute IV infusion 
resulted in an estimated Cmax value of 7.4 µg/mL and 30 mg/kg in 30% Captisol administered as a 
5-minute IV bolus injection resulted in an estimated Cmax value of 11.6 µg/mL. 
In vitro, the major metabolic pathway of E6201 appears to be zusammen/entgegen (Z/E) 
isomerization mediated by glutathione-S-transferase (GST). Cytochrome P450 (CYP) enzymes 
CYP1A2, CYP2D6, and CYP3A4/5 appear to convert E6201 into N-de-ethylated and mono- 
oxygenated metabolites that are then conjugated by GSTs with glutathione (GSH). Additional 
metabolism of E6201 appears to be through NADPH-dependent reduction and glucuronidation. 
The Z/E- and NADPH-dependent metabolisms demonstrated species specificity; humans were the 
moderately active species. Therefore, E6201 metabolism is expected to be catalyzed by CYPs, 
GSTs, UDP-glucuronosyltransferases (UGTs), and nicotinamide adenine dinucleotide phosphate 
(NADPH)-dependent reductases. 
E6201 did not demonstrate any inhibitory effects on CYP enzymes in vitro. Protein binding in 
vitro in mouse, rat, dog, and human plasma was greater than 97%, suggesting that a majority of 
the drug will likely be in a protein-bound state in human studies. 
Profile studies of E6201  showed  significant  binding  of  E6201  at  concentrations  of 1 and 
50 μmol/L in a variety of targets: adenosine receptors A1, A2, and A3, angiotensin II type 1 
receptor (AT1), peripheral benzodiazepine receptor (BZDp), peripheral cannabinoid receptor 
(CB2), cholecystokinin A receptor (CCKA), dopamine D1 receptor (D1), leukotriene B4 receptor 
(LTB4), melatonin ML1A receptor (MT1), neurokinin receptors NK1 and NK2, κ-opioid receptor 
(κ[KOP]), thromboxaneA2/prostaglandin H2 receptor (TXA2/PGH2), urotensin-II receptor (UT-
II), vasopressin V2 receptor (V2), calcium and chloride channels, and norepinephrine and 
dopamine transporters. Significant enzyme inhibition was observed with E6201 at the same 
concentrations in phosphodiesterases PDE1, PDE2, PDE4, and PDE6. 
3.1.3. 
Preclinical Toxicology 
When E6201 was administered as a single IV bolus injection to rats using a Captisol solution (up 
to 60 mg/kg), pulmonary toxicity was observed. Most of the animals administered either 20 or 
60 mg/kg of E6201 showed decreased activity and/or ptosis, which disappeared within 1 day. 
Some animals also showed severe clinical signs such as bradypnea, resulting in death in some 
cases; the incidence of mortality was 1/40 (2.5%) and 4/76 (5.3%) at 20 and 60 mg/kg, 
respectively. In animals with severe clinical signs, especially decedent animals, histopathological 
findings of perivascular edema/hemorrhage and alveolar edema were observed. These changes 
suggested that the most probable cause of death was acute pulmonary edema. As they were also 


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observed in the 30% Captisol/water solution group, the causes of the pulmonary edema were 
possibly related to the E6201 formulation (30% Captisol solution) rather than E6201 per se (ie, the 
high osmolality and high viscosity of Captisol). The osmolality of 30% Captisol solution was 
almost the same as that of 6 mg/mL E6201 in 30% Captisol solution. There was no evidence of 
degenerative change in the alveoli or any cardiac histopathological changes. These effects were 
obviated by changing administration from an IV bolus to a 30-minute infusion. These observations 
suggest that E6201 has little, if any, direct effect on the lung. 
In a single IV bolus toxicity study in dogs (6, 18, or 30 mg/kg doses), E6201-related clinical signs 
were limited to transient decreased activity and abnormal gait at 30 mg/kg. In a PK study, 
gastrointestinal (GI) toxicity and deteriorating physical condition were observed at 33.22 mg/kg. 
Based on the single-dose toxicity studies, repeat-dose IV toxicity studies in rats and dogs (Q7Dx3) 
were performed using 30-minute infusions to reduce formulation-related pulmonary toxicity. 
E6201 was administered to rats (6, 20, or 60 mg/kg) and dogs (6, 18, or 30 mg/kg) using a 30% 
Captisol solution; these doses were the maximum deemed feasible based on the solubility 
limitations (6 mg/mL) and the maximum dose volume in these animals (10 and 5 mL/kg in rats 
and dogs, respectively). There were no E6201-related effects observed at any dose in rats, while 
limited clinical signs of transient tremors, salivation and emesis were observed in dogs at doses 
≥18 mg/kg without any clinical pathological or histopathological correlates. Consequently, the no 
observed adverse effect levels (NOAELs) were determined to be 60 and 6 mg/kg in rats and dogs, 
respectively, and the maximum tolerated dose (MTD) was ≥30 mg/kg in dogs. 
In a 4-week study in rats, E6201 at doses up to 10 mg/kg/day were administered by bolus injection 
using another prototype formulation (20% hydroxypropyl-β-cyclodextrin solution) with no 
toxicity (including pulmonary toxicity) induced. 
 E6201 was negative in the reverse mutation assay in bacteria (Ames test), with or without 
metabolic activation, and the in vivo rat micronucleus and unscheduled DNA synthesis (UDS) 
tests. In the mouse lymphoma tk assay using the 3-hour treatment method, E6201 was negative in 
the absence of S9 mix, but positive in the presence of S9 mix. E6201 was characterized as 
clastogenic in this assay. However, in both the rat micronucleus assay and the UDS test, results 
were negative even at very high doses that would have generated sufficient amounts of 
metabolite(s) with high systemic exposures. Thus, the evidence suggests that risk of E6201 
genotoxicity in humans is low. 
3.1.4. 
Phase 1 Solid Tumor Study 
This Phase 1 first-in-human study was designed to determine the MTD, dose-limiting toxicities 
(DLTs) and safety, and establish a recommended E6201 dose in patients with advanced solid 
tumors, expanded to patients with advanced melanoma. Pharmacokinetics (PK) and preliminary 
efficacy also were evaluated.10,11 
Part A (dose escalation): Sequential cohorts received E6201 IV over 30 minutes once-weekly (D1, 
8, 15 of a 28-day cycle), starting at 20 mg/m2 and increased up to 720 mg/m2.  
Part B (expansion): Patients with BRAF-mutated or wild-type (WT) melanoma received E6201 
320 mg/m2 IV over 60 minutes once-weekly (D1, 8, and 15 of a 28-day cycle) or 160 mg/m2 IV 
twice-weekly (D1, 4, 8, 11, 15, and 18 of a 28-day cycle; BRAF-mutated only).  


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In Part A (n=25), the MTD of E6201 was determined to be 320 mg/m2 when administered as a 30-
minute IV infusion once-weekly for the first 3 weeks of a 28-day cycle. DLTs included QTc 
prolongation (ie, QTcF prolongation >500 ms or QTcF increase from screening >60 ms) and CNS 
toxicity (ie, confusion).  In Part B (n=30), the E6201 infusion time was increased from 30 to 60 
minutes to decrease Cmax and reduce the potential for QTc prolongation.  E6201 320 mg/m2 once 
weekly was confirmed as the MTD in Part B.  At the time of data cutoff for Part B, no DLTs had 
been observed. 
All subjects in all dose groups reported at least one treatment-emergent adverse event (TEAE).  
The most common TEAEs were nausea, fatigue, constipation, vomiting, hypokalemia, abdominal 
pain, and decreased appetite.  Eleven (44.0%) subjects in Part A and 19 (63.3%) subjects in Part 
B had at least one TEAE assessed by the investigator as treatment-related (possibly or probably 
related to study medication or missing a causality assessment). The most common treatment-
related AEs (possibly or probably related) in Part A were nausea (3 [12.0%] subjects), ECG QT 
prolonged (3 [12.0%] subjects), and hypokalemia (3 [12.0%] subjects). The most common 
treatment-related AEs (possibly or probably related) in Part B were nausea (8 [26.7%] subjects), 
vomiting (5 [16.7%] subjects), fatigue (4 [13.3%] subjects), hypokalemia (4 [13.3%] subjects), 
and decreased appetite (3 [10.0%] subjects). Grade 3 or 4 TEAEs were reported in 11 (44.0%) 
subjects in Part A and 15 (50.0%) subjects in Part B. The most common Grade 3/4 AEs in Part A 
were abdominal pain (2 [8.0%] subjects), hyperbilirubinemia (2 [8.0%] subjects), ECG QT 
prolonged (2 [8.0%] subjects), and syncope (2 [8.0%] subjects). Of these common Grade 3/4 AEs, 
only one was Grade 4 (abdominal pain). The most common Grade 3/4 AEs were abdominal pain 
(2 [6.7%] subjects) and dyspnea (2 [6.7%] subjects). No Grade 4 AE occurred in more than one 
subject. Overall, the incidence of TEAEs across treatment groups was small and variable. No dose-
related or mutation-status-related trends were observed. 
During Part A of the study when E6201 was administered as a 30-minute IV infusion once-weekly, 
postbaseline QTcB or QTcF prolongation of 450 to 500 ms was recorded in 0 to 7 (28.0%) subjects 
at selected assessment time points.  Postbaseline QTcB/QTcF >500 ms was recorded in 1 subject 
in the 480 mg/m2 dose group.  QTcB or QTcF increases from baseline of 30 to 60 ms were recorded 
in 0 to 5 (20.0%) subjects and QTcB or QTcF increases from baseline of >60 ms were recorded in 
0 to 2 (8.0%) subjects at selected assessment time points in Part A. ECG QT prolongation was 
reported as an AE in 3 (12.0%) subjects in Part A: 1 subject in the 320 mg/m2 dose group and 
2 subjects in the 480 mg/m2 dose group. All 3 ECG QT prolongation AEs met criteria for DLT.  
The frequency of QTc prolongation events appeared to be higher in the 320 to 480 mg/m2 dose 
groups.   
During Part B when E6201 was administered as a ≥60-minute IV infusion once-weekly, 
postbaseline QTcB or QTcF prolongation of 450 to 500 ms was recorded in 0 to 9 (30.0%) subjects 
at selected assessment time points.  Postbaseline QTcB >500 ms was recorded in 2 subjects in the 
BRAF-WT 320 mg/m2 once-weekly treatment group.  QTcB or QTcF increases from baseline of 
30 to 60 ms were recorded in 0 to 7 (23.3%) subjects at selected assessment time points in Part B.  
A QTc increase from baseline of ≥60 ms was recorded in 1 subject in the BRAF-mutated 
320 mg/m2 once-weekly treatment group.  ECG QT prolongation was reported as an AE in 1 
(3.3%) subject in Part B:  320 mg/m2 once-weekly BRAF-WT dose group.  None of the QTc events 


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in Part B met protocol specified DLT criteria (QTcF prolongation >500 ms or QTcF increase from 
screening >60 ms).  No dose-related or mutation-status-related trends were observed. 
In Part A, there was one PR, in a patient with V600E BRAF-mutated papillary thyroid cancer 
(KRAS-WT, PTEN weakly reactive) receiving E6201 480 mg/m2, who had a response for 4 cycles. 
In Part B, there were two PRs in patients with V600E BRAF-mutated melanoma (primary tumor 
on right leg, KRAS-WT, AKT-positive, PTEN-positive; primary tumor on right inguinal node, 
other mutation status unknown due to lack of tissue for testing), who had responses for >40 cycles 
(36.8 months), and one PR in a patient with BRAF WT, KRAS-WT melanoma (primary tumor on 
nose) who had a response for more than 2 cycles (3.0 months); all 3 patients were receiving 320 
mg/m2 once-weekly. Of particular note, one of the patients with stage IV malignant melanoma 
(MM) BRAF-mutated (V600E) with metastases to the bladder, liver, spleen, left adrenal gland, and 
brain (right thalamic and left occipital) achieved a durable PR beginning at the end of Cycle 2 and 
remains on E6201 therapy for > 8 years. The metastases to the liver, spleen, and left adrenal gland 
in this patient have completely resolved and are not visible on scans. Her brain lesions are currently 
stable for several years with the thalamic lesion currently barely discernible. This exceptional 
durable response led the team to conduct a complete exome and transcriptome sequencing analysis 
of the patient’s archival tissue genome that revealed homozygous BRAF V600E and homozygous 
CDKN2A deletion (>90% DNA and RNA alteration frequency).12 
E6201 exposure was dose-related, with PK characterized by extensive distribution and fast 
elimination. 
A decrease in at least one of the following PD markers was observed in 9 of the 10 subjects with 
evaluable tumor tissue: p-ERK, Ki67, Cyclin D1, p-Rb.  There were no evident trends in any of 
the circulating tumor cell (CTC) biomarkers with respect to initial E6201 treatment group (320 
mg/m2 once weekly or 160 mg/m2 twice weekly) or mutation status (BRAF-mutated or WT).  
Although IL-6 and IL-8 derived from subjects could be detected, baseline measurements varied 
widely from individual to individual.  There were no consistent trends in any of IL-6 and IL-8 
biomarkers with respect to treatment groups. 
In conclusion, an intermittent regimen of E6201 320 mg/m2 IV once-weekly for the first 3 weeks 
of a 28-day cycle was reasonably well tolerated in patients with advanced solid tumors with 
evidence of clinical efficacy, including patients with metastatic melanoma with extension to the 
brain. 
3.2. 
Rationale for CNS Metastases Indication  
3.2.1. 
Clinical Unmet Need 
Brain metastases arise in 10-20% of patients with solid tumors, most commonly in lung cancer, 
breast cancer and melanoma. Among patients with solid tumor brain metastases, approximately 
75% have 1 to 3 lesions.13 The incidence of brain metastases is expected to increase due to longer 
survival of patients on improved systemic therapies and increased surveillance for metastases. 
Prognostic scoring has been developed for patients with brain metastases for specific tumors, so 
therapy can be individualized to minimize treatment complications.13 Improved treatment of 
metastases has been hampered because these patients have often been excluded from clinical trials.  


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The expanding mass of a brain metastasis underlies the clinical signs and symptoms they cause. 
Headache is the most common but focal neurologic deficits, changes in cognition, seizures and 
stroke all occur. Patients who receive only supportive care or steroids have a median survival of 
only one to 3 months.14  
Besides systemic therapy against the specific malignancy, treatment for brain metastases consists 
of whole brain and targeted radiotherapy and surgery. Supportive care consists primarily of 
glucocorticoids and antiepileptics. Directed systemic therapy is hampered by the blood brain 
barrier (BBB).  Brain metastases have variable BBB protection leading to inconsistencies in 
responses to systemic therapy.13 Once brain metastases are established, targeted and immuno-
oncology therapies appear to have mixed responses.13,15 Delivery of a drug to a brain metastasis 
would depend on physicochemical variables such as permeability, rate of flow to the metastases 
and distribution values. The first two would be expected to be increased with small molecules such 
as tyrosine kinase inhibitors. Micrometastases may be even more protected by the BBB.16 If a drug 
cannot access the CNS or brain metastases, the patient may receive little benefit regardless of a 
systemic response. A drug which is an effective agent against brain metastases is particularly 
valuable. There are several features about melanoma brain metastases worth noting.  A high 
percentage of patients develop them: up to 75% of melanoma patients will develop a brain 
metastasis.17 It is not clear that brain metastases and melanoma are correlated with specific 
mutations, although patients with NRAS mutations may be at higher risk.18 Melanoma is generally 
regarded as radio-resistant and brain metastases appear to respond at roughly the same rate as 
lesions elsewhere if combined with directed therapy such as vemurafenib.19 Melanoma brain 
metastases have shown  initial responses to molecularly targeted therapies, e.g., mutant BRAF 
inhibitors such as vemurafenib and dabrafenib.20,21,22,23,24 Patients with melanoma NRAS 
mutations have responded to MEK1 inhibition.18 However, initial impressive response rates have 
been followed by eventual relapse associated with resistance, mainly occurring due to paradoxical 
activation of the MAPK pathway via heterodimerization of RAF and hyperactivated downstream 
MEK signaling. Combination therapy with BRAF and MEK inhibitors provides improved 
responses compared to single-agent therapy.25,26,27 Interestingly, both types of agents are not be 
expected to cross the BBB, thus, suggesting a disrupted BBB in CNS melanoma, and other brain 
metastases Thus, the importance of drug penetration through the intact BBB in patients with brain 
metastases is uncertain.28  Matched analysis of brain metastases and systemic melanoma tumors 
suggests the PI-3K/AKT pathway is activated in brain metastases.17 
While NRAS mutations in melanoma may be associated with increased risk for brain metastases, 
their occurrence is not absolutely specific and thus any melanoma patient with brain metastases 
could have any of the mutations associated with melanoma including BRAF V600 mutations. The 
presence of a BRAF mutation would need to be assured for patients receiving BRAF targeted 
therapy. This is true for non-melanoma patients as well. BRAF mutations have been found in up 
to 10% of colon carcinomas, papillary thyroid carcinoma's and a variety of lung cancers. Both lung 
and colon cancer as noted earlier can frequently have brain metastases. There are some suggestive 
data that over-expression/representation of mutant BRAF through a variety of molecular means 
(e.g.  gene amplification, polysomy) are associated with enhanced sensitivity to BRAF inhibitors. 
Such over-representation appears to be limited to melanomas as opposed to other malignancies 
based on a review of the literature.29 However, other variables may be important, such as the extent 


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of blood brain barrier disruption, presence of mutations in cell transporters leading to changes in 
drug concentration and other factors. 
3.2.2. 
CNS Penetration – Preclinical Study 
A blood brain barrier penetration study of E6201 was conducted in FVBn mice.30,31 E6201, given 
its target activity, may have a role in treating brain metastases of several cancers, especially 
melanoma. Resistance in peripheral tumor sites may be overcome with the appropriate targeted 
therapy, however, for the subsequent brain metastases, targeted therapies must reach the metastatic 
sites that can be behind an intact BBB. Many targeted therapies have been shown to be substrates 
of efflux transport proteins (p‐glycoprotein, mdr1, and breast cancer resistance protein, bcrp) that 
are expressed on the luminal surface of the BBB capillary endothelial cells. In developing a rational 
dosing regimen for brain metastases, it is necessary to know the rate, extent, and mechanism of 
BBB penetration. To date, studies using BRAF/MEK inhibitors have shown low brain penetration 
relative to plasma.28,32, 33,34 
FVBn mice were administered E6201 as a single dose, and brain‐to‐plasma E6201 concentration 
ratios were determined at different time points post-dose.  The objective was to evaluate the brain 
distribution of E6201 in mouse models and examine the role of efflux transporters at the BBB on 
the CNS exposure of E6201.  
Four “BBB genotype” mice were used; FVBn wild‐type (control), mdr1a/b (‐/‐) (p‐glycoprotein 
deficient), bcrp1 (‐/‐) (brcp deficient), and mdr1a/b(‐/‐):bcrp1(‐/‐) (dual knockout of both efflux 
proteins).  LC‐MS assays for both plasma and brain concentrations of E6201 were developed and 
used to determine the concentration‐time profile (AUC) in both brain and plasma.  Rapid 
equilibrium dialysis was used to determine unbound fractions of E6201 in brain and plasma, and 
a brain “partition coefficient” were determined for both total and unbound drug. 
Pharmacokinetic data showed brain penetration in all four mouse types with AUC∞ ratios ranging 
from 2.66 to 5.39. The distribution advantages in the mutated mice versus the wile type (control) 
were 1.64, 1.39, and 2.03 respectively for mdr1a/b (‐/‐) (p‐glycoprotein deficient), bcrp1 (‐/‐) (brcp 
deficient), and mdr1a/b(‐/‐):bcrp1(‐/‐) (dual knockout of both efflux proteins). The brain 
penetration of E6201 in each of the four strains of mice ranged from 11% (wild type) to 22% (dual 
knock out), where 10%-20% was considered good penetration. Compared to vemurafenib, 
dabrafenib, trametinib and cobimetinib, E6201 brain penetration was shown to be superior (see 
Table 2). 
Table 2: Brain Penetration of Known BRAF/MEK Inhibitors  
BRAF/MEK Drug 
Brain Penetration 
Vemurafenib32 
0.4% 
Dabrafenib33 
2.3% 
Cobimetinib34 
2.7% 
Trametinib28 
15% 
E620130,31 
266% 


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3.3. 
Preclinical Evaluation of E6201 Plus Dabrafenib 
Dabrafenib is a 4-(3-aminosulfonylphenyl)-5-(pyrimidin-3-yl) thiazole, and a potent and selective 
inhibitor of B-RAF kinase activity with a mode of action consistent with adenosine triphosphate 
(ATP)-competitive inhibition.  
In a BRAF V600E+ metastatic melanoma patient-derived xenograft (PDX) mouse model, E6201 
plus dabrafenib demonstrated increased tumor growth suppression relative to trametinib plus 
dabrafenib with 2-fold higher E6201 concentrations in tumor versus plasma (Figure 1, Table 3).35  
 
Figure 1: E6201 Plus Dabrafenib BRAF V600E+ PDX Metastatic Melanoma Mouse Model 
 
Table 3: BRAF V600E+ PDX Metastatic Melanoma Mouse Model, E6201 Tumor:Plasma 
Concentrations 
Group 
E6201 Dose 
(mg/kg) 
Mean Plasma Conc. 
(SD) (µg/mL) 
Mean Flank Tumor 
Conc. (SD) µg/g 
T:P Ratio (SD) 
N=7 
40 
3.81 (1.52) 
7.08 (1.28) 
2.21 (1.34) 
N=3  
30 
0.96 (0.15) 
1.57 (0.21) 
1.63 (0.05) 


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3.4. 
Dose Rationale 
3.4.1. 
E6201 
E6201 is a multi-targeted kinase inhibitor that targets both the FLT3 and MAPK pathways. In a 
Phase 1/2a study in FLT3+ or Ras+ acute myeloid malignancies, a total of 27 subjects were treated 
with E6201 weekly at doses of 240 and 320 mg/m2 for 4 weeks repeated q28 days, and twice 
weekly at doses of 160, 240 and 320 mg/m2 4 weeks, repeated q28 days. E6201 was well-tolerated 
at all doses and both weekly and twice weekly schedules of administration. Drug-related adverse 
events on the twice weekly schedule included increased ALT, increased AST, neutropenia, 
confusion, delirium and capillary leak syndrome in 1 patient each receiving 160 mg/m2; 
thrombocytopenia and nausea in 1 patient each receiving 240 mg/m2; abnormal liver function test 
(undefined) and decreased appetite in 1 patient each, and fatigue in 2 patients receiving 320 mg/m2. 
Grade 3 or 4 drug-related adverse events on the twice weekly schedule included neutropenia in 1 
patient receiving 160 mg/m2; thrombocytopenia in 1 patient receiving 240 mg/m2 and fatigue in 1 
patient receiving 320 mg/m2. No drug-related serious adverse events were observed on the twice 
weekly schedule. 37 However, no objective responses were seen. Biomarkers of FLT3 and MAPK 
kinase pathway inhibition were evaluated in peripheral blood and bone marrow following dosing. 
Higher and more durable inhibition of phospho-ERK was observed with 320 mg/m2 twice weekly 
versus once weekly dosing.  
E6201 has been well tolerated in the current study Monotherapy Safety Run-in Phase at a dose of 
320 mg/m2 twice weekly Days 1, 4, 8, 11, 15 and 18 for 3 weeks, repeated every 28 days. No DLTs 
were noted and no dose reductions for toxicity. Only 1 E6201-related AE was reported, Grade 2 
thrombocytopenia in a patient whose medical history included thrombocytopenia. Two of the 4 
subjects achieved stable disease of both intracranial and extracranial disease through C2 and C4, 
respectively. All 4 subjects have discontinued study due to progressive disease (3) or adverse event 
(1) (worsening mentation), not related to E6201 study drug. 
3.4.2. 
Dabrafenib 
Dabrafenib will be evaluated at the approved dose and schedule for treatment of metastatic 
melanoma, 150 mg orally twice daily. This dose also was found to be effective and safe for 
treatment of metastatic melanoma in combination with trametinib in the COMBI-V and COMBI-
D studies and in the BREAK-MB study of melanoma metastasized to the brain.36   
Therefore, to maximize the potential for activity in subjects with CNS metastases from BRAF- or 
MEK-mutated melanoma, under Amendment 3 of the study,  E6201 will be evaluated at a dose of 
320 mg/m2 twice weekly Days 1, 4, 8, 11, 15 and 18, repeated every 28 days during the 
Combination Safety Run-In Phase, plus dabrafenib at a dose of 150 mg orally twice daily, with 
E6201 and dabrafenib dose reduction criteria for management of toxicity.   
 
 


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4. 
TRIAL OBJECTIVES AND PURPOSE 
4.1. 
Primary Objective  
To determine the overall rate of response of brain metastases in subjects with CNS metastases due 
to metastatic melanoma with a BRAF V600 mutation who have relapsed or progressed from initial 
or systemic disease 
4.2. 
Secondary Objectives  
• To determine the intracranial disease duration of response, duration of stable disease (SD) 
and time to progression of CNS metastases 
• To determine the objective response rate of systemic disease other than in the CNS 
• To evaluate progression-free survival (PFS) 
• To evaluate overall survival (OS)  
• To evaluate the impact of the BRAF mutational status (e.g., type, heterozygosity or 
homozygosity) in archival tissue with clinical outcome  
• To evaluate the safety of E6201 as monotherapy and in combination with dabrafenib in 
this population 


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5. 
INVESTIGATIONAL PLAN 
5.1. 
Overall Study Design 
This is a Phase 1 study of E6201 for the treatment of CNS metastases in BRAF V600-mutated 
metastatic melanoma. A total of N = 28 – 34 subjects with melanoma metastasized to the CNS will 
be included.  
Selected subjects will be: both males and females age ≥18 years; histologically confirmed 
melanoma with BRAF V600 mutation with CNS metastasis; archived tumor sample from the 
primary, recurrent or metastatic disease with documented BRAF  mutation; no prior treatment with 
BRAF or MEK inhibitors for systemic disease; recovered from all acute toxicities (≥ Grade 1) due 
to prior immunotherapy; determined to have adequate renal and hepatic function, and no known 
history of significant cardiac disease. 
Monotherapy Safety Run-in Phase: Following screening, a total of 4 subjects were enrolled. 
E6201 was administered by intravenous (IV) infusion over a 2-hour period at a dose of 320 mg/m2 
twice weekly (Days 1, 4, 8, 11, 15 and 18) for 3 weeks, repeated every 28 days (1 cycle), until 
progression of disease, observation of unacceptable adverse events, intercurrent illness or changes 
in the subject’s condition that prevented further study participation.  
Combination Safety-Run-in Phase: Following screening, a total of 6 – 12 subjects are anticipated 
to establish the recommended doses of E6201 plus dabrafenib. E6201 will be administered by IV 
infusion over a 2-hour period twice weekly (Days 1, 4, 8, 11, 15 and 18) repeated every 28 days 
plus dabrafenib orally twice daily (=1 cycle), according to the schedule below.  
Dose Level 
E6201 (IV) 
Dabrafenib (PO) 
1 
320 mg/m2 (MTD monotherapy) 
150 mg BID (market dose) 
-1a 
240 mg/m2 (Dose Level -1) 
150 mg BID 
-2a 
240 mg/m2 (Dose Level -1) 
100 mg BID (Dose Level -1) 
-3a 
160 mg/m2 (Dose Level -2) 
100 mg BID (Dose Level -1) 
-4a 
160 mg/m2 (Dose Level -2) 
75 mg BID (Dose Level -2) 
-5a 
160 mg/m2 (Dose Level -2) 
50 mg BID (Dose Level -3) 
a If necessary based on DLT (≥ 1 of 3 or ≥ 2 of 6 subjects experience DLT at the previous dose level) 
Subjects who demonstrate clinical benefit (objective response or stable disease) will be allowed to 
continue therapy with E6201 plus dabrafenib until progression of disease, observation of 
unacceptable adverse events, intercurrent illness or changes in the subject’s condition that prevents 
further study participation.  
Dose-limiting toxicity (DLT) is defined as any one of the following events: 
• Grade 4 hematologic toxicity for > 1 day 
• Grade 3 hematologic toxicity with complications (e.g., thrombocytopenia with bleeding) 
• Failure of Grade 3 thrombocytopenia, absolute neutrophil count (ANC), hemoglobin to 
recover to Grade ≤ 1 within 4 weeks despite the use of platelet and red blood cell (RBC) 
transfusions and/or growth factors 


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• ≥ Grade 3 non-hematologic toxicity not due to disease progression (excluding Grade 3 
nausea, vomiting or diarrhea that is adequately controlled with supportive care and resolves 
to ≤ Grade 2 within 48 hours, or Grade 3 electrolyte disturbances responsive to correction 
within 24 hours) 
• ≥ Grade 3 liver function tests (LFTs) lasting > 72 hours 
• Treatment interruption > 14 days due to toxicity 
• Other important medical event  
Subjects who require a dose reduction due to toxicity will be considered to have had a DLT.  
If a DLT is experienced in ≥ 2 of 6 subjects in the Combination Safety Run-in Phase during Cycle 
1, no further subjects will be enrolled at that dose level. Subjects who experience a DLT may 
continue treatment at the next lower dose level until disease progression or unacceptable toxicity. 
The MTD is defined as the doses of E6201 plus dabrafenib at which ≤ 1 of 6 subjects experiences 
a DLT. 
E6201 dose reductions for suspected E6201-related toxicity will be 240 mg/m2 twice weekly (Dose 
Level -1) and 160 mg/m2 twice weekly (Dose Level -2), administered over the same schedule as 
above, Days 1, 4, 8, 11, 15 and 18, repeated every 28 days.  
Dabrafenib dose reductions for suspected dabrafenib-related toxicity will be 100 mg (Dose Level 
-1), 75 mg (Dose Level -2) and 50 mg (Dose Level -3) orally twice daily, according to the U.S. 
Product Label.36  
A total of 6 subjects will be treated at the combined MTD doses for both drugs established in the 
Combination Safety Run-in Phase before beginning the Expansion Phase.   
Expansion Phase: Following screening, an additional cohort of up to N=18 subjects will be treated 
at the E6201 plus dabrafenib combined MTD. Subjects treated at the MTD in the Combination 
Safety Run-in Phase will count towards accrual in the Expansion Phase. E6201 will be 
administered by IV infusion over a 2-hour period at the MTD and schedule determined in the 
Combination Safety Run-in phase, repeated every 28 days (=1 cycle), and dabrafenib will be 
administered orally twice daily at the MTD determined in the Combined Safety Run-in phase.  
Both regimens will be subject to dose reductions for toxicity, as described. Subjects who 
demonstrate clinical benefit (objective response or stable disease) will be allowed to continue 
therapy with E6201 plus dabrafenib until progression of disease, observation of unacceptable 
adverse events, intercurrent illness or changes in the subject’s condition that prevents further study 
participation. 
During the study, a Safety Review Committee (SRC), consisting of the actively recruiting 
investigators, the Sponsor Medical Monitor and study staff will review data from the Monotherapy 
and Combination Safety Run-in Phases before beginning the Expansion Phase, and will review 
data from the Expansion Phase on an ongoing basis.  
The statistical objective is the evaluation of the intracranial disease objective response (OR) rate, 
defined as complete response (CR) or partial response (PR), on treatment with E6201 plus 
dabrafenib. The sample size is based on a one-arm binomial design H0 ≤ 0.05 (≤ 5% response rate 
for historical control group) versus H1 > 0.05 (> 5% response rate for experimental group). An 
objective response (OR) rate of 25% or greater is deemed clinically important. A total of 3 or more 


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responses in a sample size of 18 subjects indicates the true OR rate is ≥ 25%, with power of = 
80%, alpha = 0.05, and provides evidence of clinical utility to move forward.   
CNS disease response will be assessed according to 2 methodologies: Response Evaluation 
Criteria in Solid Tumors (RECIST v. 1.1).38 and Response Assessment in Neuro-Oncology – Brain 
Metastases (RANO-BM).39 Clinical benefit is defined as best response of CR), (PR) or stable 
disease (SD).  
Non-CNS systemic disease will be assessed according to RECIST v. 1.1. 
Blood for hematology and serum chemistry determinations will be collected within 28 days of 
Cycle 1 Day 1 and on Day 1 of each cycle and at the End of Treatment Visit.  
ECGs will be taken within 28 days prior to Cycle 1 Day 1, pre-infusion and 5 minutes following 
the end of the E6201 2-hour infusion, on Day 1 of every cycle thereafter, and at the End-of-Study 
visit. 
CNS and non-CNS systemic disease assessments will be based on magnetic resonance image 
(MRI) or computed tomography (CT) if unable to perform MRI for intracranial disease. 
Assessments will be obtained at Week 8 and every 8 weeks thereafter until documented 
progression of disease (PD). Subjects who demonstrate clinical benefit will be allowed to continue 
therapy until progression of disease, observation of unacceptable adverse events, intercurrent 
illness or changes in the subject’s condition that prevents further study participation. 
Safety will be assessed through the monitoring of adverse events (AEs), clinical laboratory 
parameters (hematology and serum chemistry), vital sign measurements, ECGs and physical 
examinations. Adverse events will be classified according to the Medical Dictionary for 
Regulatory Affairs (MedDRA) and graded according to the National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03. 
Efficacy assessments will be determined on the basis of MRI and/or CT scans with best treatment 
response at any protocol-specified time point for intracranial disease, duration of response, 
duration of stable disease, and time to CNS metastasis disease progression based on RECIST v.1.1 
and RANO-BM. Response rates also will be determined for non-CNS systemic disease. 
Progression-free survival (PFS) and overall survival (OS) will be evaluated.  
A correlation will be made between BRAF mutational status (e.g., type, heterozygosity or 
homozygosity) in archival tissue with clinical outcome. 
5.2. 
Number of Subjects and Centers 
A total of 4 subjects were enrolled in the Monotherapy Safety Run-in Phase. A total of 6 – 12 
subjects are anticipated in the Combination Safety Run-in Phase. A total of up to 18 subjects will 
be enrolled in the Expansion Phase for a total of N = 28 – 34 for the study. Study centers include 
University of Arizona (Hani Babiker, MD), and additional study centers as needed to ensure timely 
accrual to the study.  
5.3. 
Treatment Assignment 
This is an open-label study. In the Monotherapy Safety Run-in Phase, subjects received E6201 by 
IV infusion over a 2-hour period at a dose of 320 mg/m2 twice weekly (Day 1, 4, 8, 11,15 and 18) 


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for 3 weeks of a 28-day cycle. In the Combination Safety Run-in and Expansion Phases, subjects 
will receive E6201 by IV infusion over a 2-hour period at a dose of 320 mg/m2 twice weekly (Day 
1, 4, 8, 11, 15and 18) of a 28-day cycle, plus dabrafenib at a dose of 150 mg orally twice daily. 
5.4. 
Duration of Study  
Accrual is expected to be 24 months, with the last subject followed for up to 6 months. The total 
study duration is expected to be 30 months. The anticipated accrual rate is 1 – 2 subjects per month. 
5.5. 
Dose Adjustment Criteria 
Subjects who experience a toxicity requiring dose reduction may continue at the next lower dose 
level until disease progression or unacceptable toxicity. Adverse events considered for dose 
reduction should not include the events assessed by the investigator as exclusively related to 
underlying disease or other medical condition or concomitant treatment. 
5.5.1. 
Safety Criteria for Adjustment or Stopping Doses 
5.5.1.1. 
Toxicity Grading Criteria 
Toxicity grading is based on NCI Common Terminology Criteria for Adverse Events Version 4.03 
(CTCAE v4.03); http://evs.nci.nih.gov/ftp1/CTCAE/About.html. 
5.5.1.2. 
Dose Modifications and Dose Reductions 
Dose-limiting toxicity (DLT) is defined as any one of the following events: 
• Grade 4 hematologic toxicity for > 1 day 
• Grade 3 hematologic toxicity with complications (e.g., thrombocytopenia with bleeding) 
• Failure of Grade 3 thrombocytopenia, absolute neutrophil count (ANC), hemoglobin to 
recover to Grade ≤ 1 within 4 weeks despite the use of platelet and red blood cell (RBC) 
transfusions and/or growth factors 
• ≥ Grade 3 non-hematologic toxicity not due to disease progression (excluding Grade 3 
nausea, vomiting or diarrhea that is adequately controlled with supportive care and resolves 
to ≤ Grade 2 within 48 hours, or Grade 3 electrolyte disturbances responsive to correction 
within 24 hours) 
• ≥ Grade 3 liver function tests (LFTs) lasting > 72 hours 
• Treatment interruption > 14 days due to toxicity 
• Other important medical event  
Subjects who require a dose reduction due to toxicity will be considered to have had a DLT.  
No DLTs were experienced in the Monotherapy Safety Run-in Phase and no dose reductions were 
required for toxicity. If a DLT is experienced in ≥ 2 of 6 subjects in the Combination Safety Run-
in Phase during Cycle 1, no further subjects will be enrolled at that dose level. Subjects who 
experience a DLT may continue treatment at the next lower dose level until disease progression or 


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unacceptable toxicity. The MTD is defined as the doses of E6201 plus dabrafenib at which ≤ 1 of 
6 subjects experiences a DLT. 
Subjects who experience E6201- and/or dabrafenib-related toxicity requiring a dose reduction may 
continue treatment at the next lower dose level for either drug until disease progression or 
unacceptable toxicity. Adverse events considered for dose reduction should not include the events 
assessed by the investigator as exclusively related to underlying disease or other medical condition 
or concomitant treatment. If treatment must be delayed for reasons other than toxicity, contact the 
Medical Monitor to discuss the reasons for delay and plans for resuming study therapy. 
The E6201 dose modification guidelines are outlined in Table 4. Provisions are not made for dose 
levels below 160 mg/m2 twice weekly. If 160 mg/m2 twice weekly is determined to be unsuitable 
based on toxicity as defined above, the subject will be permanently discontinued from E6201 
treatment. 
 
 


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Table 4: E6201 Dose Modification Guidelines 
E6201-Related Toxicitya 
During a Cycle 
Dose Adjustment for Next 
Treatment Day 
Grade 1 
 
Continue treatment 
Maintain dose level 
Grade 2 
First incidence 
Interrupt until resolved to Grade 0-1 or 
baseline 
Maintain dose level 
Second incidence 
Interrupt until resolved to Grade 0-1 or 
baseline 
240 mg/m2 twice weekly 
(75% of dose) 
Third incidence despite 
dose reduction 
Interrupt until resolved to Grade 0-1 or 
baseline 
160 mg/m2 twice weekly 
(50% of dose) 
Fourth incidence despite 
dose reduction 
Discontinue treatment permanently 
NA 
Grade 3 
First incidence 
Interrupt until resolved to Grade 0-1 or 
baseline 
240 mg/m2 twice weekly 
(75% of dose) 
Second incidence 
Interrupt until resolved to Grade 0-1 or 
baseline 
160 mg/m2 twice weekly 
(50% of dose) 
Third incidence despite 
dose reduction 
Discontinue treatment permanently 
NA 
Grade 4 
First incidenceb 
Interrupt until resolved to Grade 0-1 or 
baseline 
160 mg/m2 twice weekly 
(50% of dose) 
Second incidence despite 
dose reduction 
Discontinue treatment permanently 
NA 
NA = not applicable. 
a: Excluding Grade 3 nausea and vomiting not controlled by antiemetics, insomnia, obesity/weight 
gain, infertility, amenorrhea, galactorrhea, glucose intolerance due to dexamethasone used as an 
antiemetic, asymptomatic hypercholesterolemia or hypertriglyceridemia, and any  Grade 3 
nonhematological toxicities due to disease and disease progression. 
b: Grade 4 toxicities judged to be E6201-related and considered life-threatening require 
discontinuation of study treatment.  E6201 treatment following non-life-threatening Grade 4 toxicities 
could resume following discussion with sponsor. 
 
 
 
 


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E6201 Dose modifications for QTc prolongation are defined in Table 5 below. 
 
Table 5: E6201 Dose Modification Guidelines for QTc Prolongation 
QTc Criteria 
E6201 Dose 
QTc greater than 500 msec or ≥ 60 msec from 
baseline on at least 2 separate ECGs 
Withhold until recovery to baseline, then resume 
at reduced unit dose (50%) 
QTc interval prolongation with signs/symptoms of 
life-threatening arrhythmia 
Permanently discontinue 
Dabrafenib dose reduction guidelines are outlined in Table 6. 
Table 6: Dabrafenib (TAFINLAR) Dose Reduction Guidelines36 
Action 
Recommended Dose 
First Dose Reduction 
100 mg orally twice daily 
Second Dose Reduction 
75 mg orally twice daily 
Third Dose Reduction 
50 mg orally twice daily 
Subsequent Modification 
Permanently discontinue if unable to tolerate 
dabrafenib 50 mg orally twice daily 
Recommended dabrafenib dose modification guidelines outlined in the U.S. Product Label are 
found in Table 7. 


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Table 7: Dabrafenib (TAFINLAR) Dose Modification Guidelines36 
Severity of Adverse Reactiona 
Dosage Modification for TAFINLARb  
New Primary Malignancies 
Non-Cutaneous RAS Mutation-positive 
Malignancies  
Permanently discontinue TAFINLAR.  
Cardiomyopathy 
• Symptomatic congestive heart failure  
• Absolute decrease in LVEF of greater than 20% 
from baseline that is below LLN  
Withhold TAFINLAR until LVEF improves to 
at least the institutional LLN and absolute 
decrease to less than or equal to 10% compared 
to baseline, then resume at same dose.  
Uveitis 
• Uveitis, including iritis and iridocyclitis  
For mild or moderate uveitis that does not 
respond to ocular therapy, or for severe uveitis, 
withhold TAFINLAR for up to 6 weeks. 
• If improved to Grade 0-1, then resume 
TAFINLAR at same or lower dose.  
• If not improved, permanently discontinue 
TAFINLAR.  
Febrile Reactions 
• Fever of 101.3°F to 104°F  
Withhold TAFINLAR until fever resolves, 
then resume at same or lower dose.  
• Fever higher than 104°F  
• Fever complicated by rigors, hypotension, 
dehydration, or renal failure  
• Withhold TAFINLAR until fever resolves, 
then resume at lower dose.  
Or  
• Permanently discontinue TAFINLAR.  
Skin Toxicity 
• Intolerable Grade 2 
• Grade 3 or 4  
Withhold TAFINLAR for up to 3 weeks. 
• If improved, resume TAFINLAR at lower 
dose. 
• If not improved, permanently discontinue 
TAFINLAR.  
Other Adverse Reactionsc, including Hemorrhage 
• Intolerable Grade 2 
• Any Grade 3  
Withhold TAFINLAR. 
• If improved to Grade 0-1, resume 
TAFINLAR at lower dose. 
• If not improved, permanently discontinue 
TAFINLAR.  
• First occurrence of any Grade 4  
• Withhold TAFINLAR until improves to 
Grade 0-1, then resume at a lower dose.  
Or  
• Permanently discontinue TAFINLAR.  
• Recurrent Grade 4  
Permanently discontinue TAFINLAR.  
aNational Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 
4.0. 
bSee Table 6 for recommended dose reductions of TAFINLAR.  
cDose modification of TAFINLAR is not required for new primary cutaneous malignancies. 


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5.5.1.3. 
Schedule Adjustments for Toxicity 
• Dosing delays are permitted for either E6201 or dabrafenib. Once a toxicity has resolved 
to ≤ Grade 1, the subject may resume treatment. The dose level must be reduced to the next 
lower dose level when treatment is re- initiated following a delay for drug-related toxicity 
unless otherwise specified. 
• The maximum delay allowed between treatment cycles for either E6201 or dabrafenib is 2 
weeks. If toxicity has not resolved after 2 weeks of delay, the Medical Monitor should be 
contacted to discuss permission for resuming treatment after a longer delay for subjects 
who are experiencing clinical benefit. 
5.5.2. 
Supportive Care Guidelines 
• Medications may be administered for the management of symptoms associated with the 
administration of E6201 or dabrafenib, as required. 
• Prophylactic pre-medication will not be used routinely. Adequate treatment for nausea 
and/or vomiting and diarrhea is permitted during Cycle 1. After Cycle 1, prophylaxis of 
nausea and/or vomiting and diarrhea is permitted. 
• Granulocyte stimulating growth factors (e.g., G-CSF or GM-CSF) are allowed according 
to standard ASCO guidelines. 
• Erythropoiesis-stimulating agents, transfusions, etc. are permitted for management of 
hematologic toxicities. 
5.6. 
Criteria for Study Termination 
If the sponsor, investigators, study monitor or regulatory officials discover conditions arising 
during the study that indicate that the study should be halted or that the study site should be 
terminated, this action may be taken after appropriate consultation between the sponsor and 
investigators. 
Conditions that may warrant termination include, but are not limited to, the following: 
• The discovery of an unexpected, serious, or unacceptable risk to subjects enrolled in the 
study 
• A decision on the part of the sponsor to suspend or discontinue testing, evaluation, or 
development of the product 
• Failure of an investigator to enroll subjects into the study at an acceptable rate 
• Failure of an investigator to comply with pertinent FDA regulations 
• Submission of knowingly false information from the study site to the sponsor, study 
monitor or the FDA 
• Insufficient adherence to protocol requirements 
• Study termination and follow-up would be performed in compliance with the conditions 
set forth in 21 CFR 312.50 and 21 CFR 312.56. 


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6. 
STUDY POPULATION 
6.1. 
Subject Inclusion Criteria 
Subjects must meet all of the following criteria to participate in the study: 
• Males and females  18 years of age 
• Histologically or cytologically confirmed Stage IV metastatic BRAF V600-mutated 
melanoma  
• Documented metastasis of the primary tumor to the CNS  
• BRAF-mutation melanoma tumor status will be established prior to entry based on previous 
BRAF-gene analysis reports from a CLIA qualified laboratory. If a report is not available, 
the mutation analysis will be performed at Screening on archival tissue. 
• Other metastatic melanoma systemic disease allowed   
• At least one measurable brain metastasis 0.5 – 3.0 cm, as assessed by MRI ≤ 3 weeks prior 
to initiation of study treatment, and does not require immediate local intervention (surgery 
or radiosurgery) 
• Prior stereotactic radiosurgery and/or excision of up to 3 brain metastases is allowed > 3 
weeks before initiation of study treatment, provided neurological sequelae have resolved 
completely and at least one measurable metastasis with documented disease progression is 
present on MRI 
• One prior line of immunotherapy for metastatic disease is allowed, if ≥ 2 weeks has elapsed 
between the end of therapy and initiation of study treatment 
• Prior melanoma adjuvant immunotherapy is allowed, if ≥ 6 months has elapsed between 
the end of therapy and initiation of study treatment 
• Prior melanoma adjuvant BRAF/MEK inhibitor treatment is allowed if ≥ 12 months has 
elapsed between the end of therapy and initiation of study treatment 
• Able to swallow and retain oral medication with no clinically significant gastrointestinal 
abnormalities that may alter absorption, such as malabsorption syndrome or major 
resection of the stomach or bowels (Combination Safety Run-in and Expansion Phases of 
the study only) 
• Asymptomatic or symptomatic CNS metastasis is allowed 
• Stable dose of corticosteroids for CNS metastasis for > 7 days is allowed 
• Patients with seizures due to CNS metastases must be controlled with stable anti-epileptic 
treatment for > 14 days 
• Bisphosphonates and/or denosumab are allowed 
• Adequate performance status: Eastern Cooperative Oncology Group (ECOG) ≤ 2 
(APPENDIX A) 
• 
Life expectancy of ≥ 3 months   
• Adequate hematologic parameters without ongoing transfusional support: 
o Hemoglobin (Hb) ≥ 9 g/dL 


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o Absolute neutrophil count (ANC) ≥ 1.0 x 109 cells/L 
o Platelets ≥ 75 x 109 cells/L 
• Adequate renal and hepatic function: 
o Creatinine ≤ 1.5 x the upper limit of normal (ULN), or calculated creatinine clearance 
≥ 50 mL/minute x 1.73 m2 per the Cockcroft-Gault formula (APPENDIX B) 
o Total bilirubin ≤ 2 times the upper limit of normal (ULN) unless due to Gilbert’s 
disease 
o ALT/AST ≤ 2.5 times ULN, or < 5 times ULN for subjects with liver metastases 
• Negative serum pregnancy test within 14 days prior to the first dose of study therapy for 
women of child-bearing potential (WCBP), defined as a sexually mature woman who has 
not undergone a hysterectomy or who has not been naturally post-menopausal for at least 
24 consecutive months (i.e., who has had menses any time in the preceding 24 consecutive 
months). Sexually active WCBP and male subjects must agree to use adequate methods to 
avoid pregnancy (oral, injectable, or implantable hormonal contraceptive; tubal ligation; 
intra-uterine device; barrier contraceptive with spermicide; or vasectomized partner) 
throughout the study and for 28 days after the completion of study treatment.  
• Ability to provide written informed consent 
6.2. 
Subject Exclusion Criteria 
Subjects who meet any of the following criteria will be excluded from the study: 
• Urgent need of treatment to prevent acute neurologic deterioration, including urgent 
neurosurgery or radiotherapy 
• Symptoms of uncontrolled intracranial pressure 
• Symptomatic or untreated spinal cord compression 
• Prior treatment with any chemotherapeutic or investigational agent 
• Prior treatment with any BRAF and/or MEK inhibitor for metastatic disease 
• Prior treatment with > 1 line of immunotherapy for metastatic disease 
• Serious cardiac condition within the last 6 months, such as uncontrolled arrhythmia, 
myocardial infarction, unstable angina or heart disease defined by the New York Heart 
Association (NYHA) Class III or Class IV (APPENDIX C) 
• QT interval corrected for rate (QTc) > 480 msec on the ECG obtained at Screening using 
Fridericia method for QTc calculation 
• Active infection with human immunodeficiency virus (HIV), hepatitis B virus (HBV) or 
hepatitis C virus (HCV) requiring systemic antiviral treatment within the last week prior to 
study treatment  


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• Other active infection requiring IV antibiotic usage within the last week prior to study 
treatment 
• Any other medical intervention or other condition which, in the opinion of the Principal 
Investigator, could compromise adherence to study requirements or confound the 
interpretation of study results 
• Pregnant or breast-feeding 
6.3. 
Discontinuation of Subjects 
6.3.1. 
Procedures for Withdrawal 
Any subject may be removed from study for the following reasons: 
• Subject withdrawal of the informed consent 
• Subject noncompliance 
• An increasing or unexpected pattern of unacceptable toxicity 
• Disease progression or confirmed loss of clinical response 
• Investigator judgment when the well-being and best interest of the subject is compromised 
Subjects experiencing unacceptable toxicity should be removed from the study once complete 
resolution of toxicity has been documented. Individual subjects may be discontinued from the 
study by the investigator or sponsor at any time if either determines that it is not in the best interest 
of the subject to continue. 
Any subject who becomes pregnant during the study must be discontinued from the study 
immediately but should be followed through delivery or termination of the pregnancy. Subjects 
should also notify the investigator if they become pregnant within 28 days following the last dose 
of study drug. Spirita Oncology also must be notified if a subject becomes pregnant on study. 
If a subject is discontinued from the study before completing the specified duration of treatment, 
they should be encouraged to complete the end-of-study assessments and to agree to report any 
serious adverse events for 28 days following the last dose of study drug. The date the subject is 
withdrawn and the primary reason for discontinuation will be recorded on the case report form 
(CRF). 
6.3.2. 
Replacement of Study Subjects 
Subjects who are screened but do not receive E6201 or dabrafenib in Combination Safety Run-in 
and Expansion Phases, and subjects treated in Cycle 1 who do not complete 4 of 6 doses (e.g., D1, 
4, 8, 11, 15 and18) of their prescribed E6201 study drug treatment, or do not complete 67% of 
their daily dabrafenib doses, or do not complete the C1D28 evaluation due to progression of 
disease, withdrawal of consent or non-drug-related adverse events, will be replaced. Subjects who 
meet one of the above criteria but also experience a DLT will not be replaced with respect to 
assessment of an MTD for the combination treatment regimen of E6201 plus dabrafenib.  


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7. 
TREATMENT OF SUBJECTS 
7.1. 
Description of Treatment Plan  
7.1.1. 
Treatment Duration 
Treatment will continue until confirmation of disease progression, unacceptable toxicity, or subject 
decision to discontinue therapy. 
7.2. 
Concomitant Medications 
7.2.1. 
Permitted Medications 
All medications and other treatments taken by subjects 4 weeks before and throughout the study 
period will be recorded in the CRF module. Any changes in documented, permitted concomitant 
medications being taken at the beginning of the clinical trial or added during the time the subject 
is participating in this study (through the End of Treatment Visit) must be recorded in the CRF 
module. 
7.2.2. 
Prohibited Medications 
Concurrent anti-tumor therapy of any kind or any other investigational agent is prohibited. Follow 
dabrafenib (TAFINLAR) U.S. Product Label recommendations for management of concomitant 
medications that may cause drug interactions.36 
7.3. 
Treatment Compliance 
E6201 will be administered by IV infusion in clinic by the clinic staff and dose recorded.  
Dabrafenib (TAFINLAR) will be supplied by prescription to the subject by the investigator or 
trained designee for the subject to take on an outpatient basis between visits.  Subjects will be 
supplied with a Patient Diary to record their daily dabrafenib treatment and any missed doses.  The 
Diary will be reviewed by the clinic staff at each patient visit to assess treatment compliance.  
7.4. 
Randomization and Blinding 
Not applicable. This study is a non-randomized, sequential-arm study.  


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8. 
STUDY DRUG MATERIALS AND MANAGEMENT 
8.1. 
E6201 
8.2. 
Study Drug Description 
E6201 for Injection is a natural product analog and inhibitor of mitogen-activated protein 
kinase/extracellular-signal regulated kinase kinase-1 (MEK1). It is a sterile white lyophilized 
powder containing 60 mg of E6201 formulated in cyclodextrin to improve E6201 solubility in 
water. See Table 8 for a description of the drug product. The final study drug product will be 
administered at 320 mg/m2 in a total volume of 250 mL intravenously over a 2-hour period twice 
weekly. 
Table 8: E6201 Investigational Product 
 
Investigational Product 
Product Name: 
E6201 
Dosage Form: 
E6201 is a lyophilized powder reconstituted in water followed by 
final dilution into 250 mL normal saline 
Unit Dose 
320 mg/m2 
Route of Administration 
Intravenous 
Physical Description 
White lyophilized powder 
Manufacturer 
Eisai, Inc. 
8.3. 
Study Drug Packaging and Labeling 
E6201 is packaged in a 20-mL Type I glass vial with a bromobutyl rubber stopper and an aluminum 
cap for intravenous administration. The study drug vials will be labeled with strength and other 
information as per local regulatory requirements. 
8.4. 
Study Drug Storage 
E6201 is demonstrated to be stable when stored in the defined container closure system. E6201 
should be stored at 2-8°C and protected from light. Reconstituted and diluted E6201 solutions 
should be stored refrigerated (2 to 8°C) and protected from light before administration. 
8.5. 
Study Drug Preparation 
E6201 will be provided directly from the Spirita Oncology drug distribution center. 
Each vial contains 60 mg of E6201 and will be reconstituted with 8.5 mL Sterile Water to provide 
a solution of 10 mL at a concentration of 6.0 mg/mL and pH of 4.5. Once the Sterile Water is 
added, gently swirl to mix and let sit until totally dissolved. This may take up to 30 minutes to go 
into solution. Each reconstituted vial will contain 10 mL of E6201 solution. After reconstitution, 
the appropriate number of vials may be combined as needed per dose calculation. The resulting 


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solution will be diluted to 250 mL in 0.9% Sodium Chloride. Reconstituted and diluted E6201 
solutions can be stored at 2-8 °C and for up to 24 hours. 
8.6. 
Administration 
Subjects should be scheduled to begin study therapy following completion of Screening. E6201 
will be administered at the dose level prescribed per protocol by IV infusion over 2 hours (± 10 
minutes). In the Monotherapy Safety Run-in Phase, subjects received E6201 twice weekly on days 
1, 4, 8, 11, 15 and 18 of a 28-day schedule. In the Combination Safety Run-in and Expansion 
Phases, subjects will receive E6201 twice weekly on days 1, 4, 8, 11, 15 and 18 of a 28-day 
schedule. 
In the absence of lengthy clinical experience, E6201 should be considered an irritant and 
precautions should be taken to avoid extravasation. With IV administration of E6201, 
extravasation may occur with, or without an accompanying stinging or burning sensation (even if 
blood returns on aspiration of the infusion needle). If any signs or symptoms of extravasation 
occur, the infusion should be immediately terminated and restarted in another vein. The application 
of ice over the site of extravasation for approximately 30 minutes may be helpful in alleviating the 
local reaction. 
E6201 must not be given by intramuscular or subcutaneous route. 
8.7. 
Dabrafenib 
8.7.1. 
Description 
Dabrafenib mesylate (TAFINLAR) is an inhibitor of some mutated forms of BRAF kinases, 
including BRAF V600E, V600K, V600D. Dabrafenib also inhibits wild-type BRAF and CRAF 
kinases. Dabrafenib inhibits cell growth of various BRAF V600 mutation-positive tumors in vitro 
and in vivo. 
Dabrafenib is supplied as 50 mg and 75 mg capsules for oral administration. Each 50 mg capsule 
contains 59.25 mg dabrafenib mesylate equivalent to 50 mg of dabrafenib free base. Each 75 mg 
capsule contains 88.88 mg dabrafenib mesylate equivalent to 75 mg of dabrafenib free base.  
See the dabrafenib (TAFINLAR) U.S. Product Label for additional information on study drug 
description.36 
8.7.2. 
Packaging and Labeling 
See the dabrafenib (TAFINLAR) U.S. Product Label.36 
8.7.3. 
Storage 
See the dabrafenib (TAFINLAR) U.S. Product Label.36 
8.7.4. 
Administration 
Subjects should be instructed to take dabrafenib at least 1 hour before or at least 2 hours after a 
meal. Doses should be approximately 12 hours apart. Subjects should be advised to avoid 
concurrent administration of strong inhibitors of CYP3A4 or CYP2C8. The subject may be advised 


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to read the FDA-approved patient labeling (Medication Guide) found in the TAFINLAR U.S. 
Product Label. See TAFINLAR prescribing information for additional information.36 
8.8. 
Study Drug Accountability 
The investigator must maintain accurate records of receipt of E6201 study drug, dispensing 
information, and the prompt return or destruction of unused supplies. A drug accountability log 
will be supplied to each clinical site for purposes of recording E6201 study drug dispensation for 
the study and will be monitored by Sponsor personnel. If the site has an electronic study drug 
accountability form that is in keeping with institutional practice and the form collects the same 
information as the form supplied by the Sponsor, this form may be substituted for the Sponsor’s 
drug accountability form.  
8.9. 
Study Drug Handling and Disposal 
Unused or expired E6201 will be destroyed per institutional policy. Unused dabrafenib will be 
handled according to institutional policy. 
 


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9. 
STUDY PROCEDURES 
See Schedule of Study Procedures in APPENDIX D.  
9.1. 
Screening Procedures 
The following evaluations are to be performed within 28 days of study treatment to determine 
subject eligibility: 
• Administration of informed consent 
• Medical history, physical examination and vital signs 
• ECOG Performance Status 
• Height and weight 
• The following laboratory tests: 
− Hematology 
− Serum Chemistry 
• Beta HCG pregnancy test for WCBP 
• 12-lead ECG 
• Review of concomitant medications 
• Baseline CT or MRI of systemic and intracranial disease 
9.2. 
Requirements During Treatment Cycle 1 
9.2.1. 
Cycle 1, Day 1 
• Abbreviated physical examination 
• Vital signs 
• ECOG Performance Status 
• Weight 
• The following lab tests 
− Hematology, if not performed within previous 24 hours 
− Serum chemistry, if not performed within previous 24 hours 
• E6201 study drug administration (Day 1 and Day 4) 
• Begin twice daily dabrafenib treatment and provide Dabrafenib Patient Medication 
Diary to subject (applicable to Combination Phases of study only) 
• 12-lead ECG, pre-dose, at 5 minutes after the infusion ends (± 5 minutes)  
• Review of concomitant medications 


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• Assessment of adverse events 
• Assessment for survival 
9.2.2. 
Cycle 1, Day 8 (± 1 day) 
• Vital signs 
• ECOG Performance Status 
• E6201 study drug administration (Day 8 and Day 11) 
• Continue dabrafenib twice daily treatment 
• Review Dabrafenib Patient Medication Diary with subject (applicable to Combination 
Phases of study only)  
• Review of concomitant medications 
• Assessment of adverse events 
• Assessment for survival 
9.2.3. 
Cycle 1, Day 15 (± 1 day) 
• Vital signs 
• ECOG Performance Status 
• E6201 study drug administration (Day 15 and Day 18) 
• Continue dabrafenib twice daily treatment 
• Review Dabrafenib Patient Medication Diary with subject (applicable to Combination 
Phases of study only)  
• Review of concomitant medications 
• Assessment of adverse events 
• Assessment for survival 
9.3. 
Requirements During Treatment Cycles After Cycle 1 (Cycle 2 and 
beyond) [± 3 days] 
• Abbreviated physical examination (Day 1 only) 
• Vital signs 
• ECOG Performance Status 
• Weight (Day 1) 
• The following lab tests: 
− Hematology, if not performed within previous 24 hours 


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− Serum chemistry, if not performed within previous 24 hours 
• E6201 study drug administration (Days 1, 4, 8, 11, 15 and18) 
• Continue dabrafenib twice daily treatment 
• Review Dabrafenib Patient Medication Diary with subject (applicable to Combination 
Phases of study only)  
• 12-lead ECG pre-dose, at 5 minutes after the infusion ends (± 5 minutes) 
• Review of concomitant medications 
• Assessment of adverse events 
• Assessment for survival 
• CT or MRI of systemic and intracranial disease for re-staging (Day 28 of even 
numbered cycles, ± 7 days) 
9.4. 
At Relapse or Progression of Disease 
• Disease assessment for response 
• Review of concomitant medications 
• Assessment of adverse events 
• Assessment for survival 
9.5. 
End of Treatment (28 Days After Last Dose of E6201 and/or 
Dabrafenib Study Medication ± 5 days) 
• Physical examination 
• Vital signs 
• ECOG Performance Status 
• Weight 
• The following lab tests 
− Hematology 
− Serum chemistry 
• 12-lead ECG 
• Review of concomitant medications 
• Assessment of adverse events  
• Review Dabrafenib Patient Medication Diary (applicable to Combination Phases of 
study only)  
• Assessment for survival 


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9.6. 
Long-Term Follow-Up 
Long-term follow-up will consist of a clinic visit or telephone call to assess survival every 3 
months for up to 6 months. 


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10. 
DESCRIPTION OF ASSESSMENTS 
10.1. 
Safety Assessments 
Safety will be assessed through the monitoring of adverse events (AEs), clinical laboratory 
parameters (hematology, serum chemistry), vital sign measurements, ECGs and physical 
examinations. Adverse events will be classified according to the Medical Dictionary for 
Regulatory Affairs (MedDRA) and graded according to the National Cancer Institute Common 
Terminology Adverse Event (NCI CTCAE) version 4.03. 
10.2. 
Safety Parameters 
10.2.1. 
Vital Signs 
Vital sign measurements include temperature, blood pressure and pulse rate. Additional 
measurements may be obtained if clinically indicated. Any value considered clinically significant 
by the investigator will be recorded as an AE on the CRF. Clinically significant changes compared 
to baseline values should be followed until clinical resolution. 
10.2.2. 
Weight and Height 
Weight will be measured at Screening, Day 1 of each treatment cycle, and the End of Treatment 
Visit. Height will be measured at screening. 
10.2.3. 
Physical Examination 
Complete physical examinations include the following body system evaluations: General 
Appearance, Skin, Musculo-skeletal, Eyes, Ears, Nose, Throat, Cardiovascular, Chest, Abdomen, 
Lymph Nodes, and Neurological.  Symptom-oriented (abbreviated) evaluations will be performed 
at study visits where indicated, and otherwise when clinically indicated. 
10.2.4. 
Electrocardiogram (ECG) 
ECGs will be taken within 28 days prior to Cycle 1 Day 1, pre-infusion, 5 minutes following the 
end of the E6201 2-hour infusion, Day 1 of every cycle thereafter (pre-infusion and 5 minutes 
following the end of the infusion), and at the End of Treatment visit. 
10.2.5. 
Laboratory Assessments 
Clinical laboratory tests include hematology and serum chemistry (Table 9). 
 
 
 
 


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Table 9: Clinical Laboratory Parameters 
Hematology 
Serum Chemistry 
Red blood cell count 
Serum creatinine 
Hemoglobin 
BUN 
Hematocrit 
Glucose (non-fasting) 
White blood cell count 
Albumin 
Differential: 
AST 
   Neutrophils 
ALT 
   ANC 
LDH 
   Lymphocytes 
Total bilirubin 
   Monocytes 
Total protein 
   Eosinophils 
Alkaline phosphatase 
   Basophils 
Calcium 
Platelets 
Phosphorus 
 
Magnesium 
 
Sodium 
 
Potassium 
 
Chloride 
 
Bicarbonate 
10.3. 
Adverse and Serious Adverse Events 
10.3.1. 
Definition of Adverse Events 
10.3.1.1. Adverse Event (AE) 
An adverse event (AE) includes any noxious, pathological, or unintended change in anatomical, 
physiological, or metabolic functions as indicated by physical signs, symptoms, and/or laboratory 
changes occurring whether or not temporally associated with study drug administration and 
whether or not considered related to study drug. This definition includes an exacerbation of pre-
existing medical conditions or events, intercurrent illnesses, hypersensitivity reactions, drug 
interactions, or clinically significant laboratory findings. 
An AE does not include the following: 
• Medical or surgical procedures, e.g., tooth extraction, transfusion, surgery (The medical 
condition that leads to the procedure is to be recorded as an AE.) 
• Pre-existing conditions or procedures present or detected at the start of the study that do 
not worsen 


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• Hospitalization for elective surgeries or for other situations in which an untoward medical 
event has not occurred 
• Abnormal laboratory value, unless it is clinically significant 
• Overdose of study drug or concomitant medication unaccompanied by signs/symptoms (If 
sign/symptoms occur, the final diagnosis should be recorded as an AE.) 
• Pregnancy by itself, unless a complication occurs during pregnancy leading to 
hospitalization; in this case (The medical condition that leads to the hospitalization is to be 
recorded as the AE.) 
• A significant worsening of the disease under investigation which is captured as an efficacy 
parameter in this study and, thus, is not to be recorded as an AE. 
10.3.1.2. Serious Adverse Event (SAE) 
A serious adverse event (SAE) is defined as an adverse event that results in any of the following 
outcomes: 
• Death 
• Life-threatening, i.e., immediate risk of death from the event as it occurred; (This does 
not include an adverse event that, had it occurred in a more serious form, might have 
caused death.) 
• Persistent or substantial disability/incapacitation 
• Results in or prolongs an existing inpatient hospitalization 
• Congenital anomaly/birth defect 
Important medical events that may not result in death, be life-threatening, or require hospitalization 
may be considered serious when, based on medical judgment, they may jeopardize the subject or 
may require medical or surgical intervention to prevent one of the outcomes listed in this definition. 
10.3.1.3. Unexpected Adverse Event 
An AE or suspected adverse reaction is considered "unexpected" if it is not listed in the 
Investigator’s Brochure or is not listed at the specificity or severity that has been observed; or, is 
not consistent with the risk information described in the protocol or elsewhere. For example, under 
this definition, hepatic necrosis would be unexpected (by virtue of greater severity) if the 
Investigator’s Brochure referred only to elevated hepatic enzymes or hepatitis. Similarly, cerebral 
thromboembolism and cerebral vasculitis would be unexpected (by virtue of greater specificity) if 
the Investigator’s Brochure listed only cerebral vascular accidents. 
"Unexpected," as used in this definition, also refers to AEs or suspected adverse reactions that are 
mentioned in the Investigator’s Brochure as occurring with a class of drugs or as anticipated from 
the pharmacological properties of the investigational therapy but are not specifically mentioned as 
occurring with the investigational therapy. 


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10.3.1.4. Adverse Event Reporting Period 
The adverse event reporting period begins from the date of the first dose of study drug(s) to 28 
days following the last dose of study drug(s). 
10.3.1.5. Recording of Adverse Events 
Each AE should be recorded in standard medical terminology on the AE CRF module. Whenever 
possible, the AE should be evaluated and reported as a diagnosis rather than as individual signs or 
symptoms. For example, cough, runny nose, sneezing, sore throat, and head congestion should be 
reported as 'upper respiratory infection'. If a definitive diagnosis is not possible, the individual 
signs and symptoms should be recorded. Dates of start (onset) and stop (recovery), action taken, 
and outcome will be recorded in the AE CRF module. 
All clinically significant abnormal changes in laboratory parameters will be recorded as an AE on 
the AE module, with the following exceptions: clinically significant abnormal laboratory changes 
determined to be related to the study condition and concomitant conditions, e.g., diabetes, of which 
the investigator was previously aware and that have not worsened. 
The investigator will evaluate all AEs with regard to maximum intensity and relationship to study 
drug, as follows. 
10.3.1.5.1. Maximum Intensity 
Maximum intensity should be assigned using one of the severity grades as outlined in the National 
Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE v4.03); if the 
AE is not specifically listed in CTCAE v4.03, use the following grades: 
• Grade 1: mild 
• Grade 2: moderate 
• Grade 3: severe 
• Grade 4: life-threatening or disabling 
• Grade 5: death 
10.3.1.5.2. Relationship to Study Drug 
The degree of certainty with which an AE is attributed to study drug (or alternative causes, e.g., 
natural history of the underlying diseases, concomitant therapy, etc.) will be determined by how 
well the event can be understood in terms of known pharmacology of the study drug and/or 
reactions of similar nature previously observed with study drug. Each AE will be assigned one of 
the following five categories: 
Not related: There is not a temporal relationship to the study drug (e.g., too early, too late), or there 
is a reasonable causal relationship to another drug, concurrent illness, or circumstance. 
• Unlikely related: There is a temporal relationship to study drug, but there is not a reasonable 
causal relationship between the time of study drug administration and the AE (i.e., it is 
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factors, including underlying disease, complications, concomitant drugs, or concurrent 
treatment. 
• Possibly related: There is a reasonable temporal sequence from time of study drug 
administration (e.g., occurred in a time frame relevant to study drug dose); or for which the 
possibility of the study drug being the causative factor (e.g., existence of similar reports 
attributed to the study drug; reactions attributable to the pharmacological effect) could not 
be excluded, although other factors such as underlying disease, complications, concomitant 
drugs, or concurrent treatment are presumable. 
• Probably related: There is a reasonable temporal sequence from time of study drug 
administration; and for which the possibility of factors other than the study drug 
administration, such as underlying disease, complications, concomitant drugs, or 
concurrent treatment, could not be excluded as the cause. 
• Definitely related: Follows a clear temporal sequence from time of study drug 
administration; could not be possibly explained by the known characteristics of the 
subject's clinical state, environmental or toxic factors, or other modes of therapy 
administered to the subject; follows a response pattern known to be associated with study 
drug administration. 
10.3.1.6. Adverse Event Reporting 
Each AE is to be reported by the investigator as serious or non-serious according to the definitions 
above. This classification determines the regulatory reporting procedures to be followed as 
described in Table 10. 
Table 10: Reporting Guidelines for Adverse Events 
Gravity of AE 
Reporting Time to Spirita Oncology 
Type of Report 
Serious 
Within 24 hours after the site becomes 
aware of the event 
Initial SAE Report 
Non-Serious 
Per AE CRF module 
Completed AE CRF Module 
Any SAE, regardless of relationship to investigational therapy that occurs within 28 days following 
the last dose of study drug must be reported to the Medical Monitor within 24 hours after the site 
becomes aware of the event. The investigator is encouraged to discuss with the Medical Monitor 
any adverse experiences for which the issue of reportability is unclear or questioned. The initial 
report should be followed by submission of a more detailed SAE Report when follow-up 
information is available. 
If the SAE occurs more than 28 days after the last dose of study drug, SAEs should be reported 
only if considered related to E6201 or dabrafenib. In the event of subject death, the reason for 
death should be recorded as the SAE, with 'death' recorded as the outcome on the SAE CRF 
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The SAE also will be recorded as an AE on the AE CRF module. Note: the SAE Report is different 
from the AE CRF. In areas of both forms where the same data are reported, the forms will be 
completed in a consistent manner. For example, the same term should be used for the AE on both 
forms, with the same start and stop dates, action taken, outcome, etc. A checkbox on the AE CRF 
module for whether the AE resulted in an SAE, will link the two types of report for a given event. 
An SAE Report should be prepared with as much available information concerning the event as 
possible so that a written report can be filed with the appropriate regulatory authorities. If causality 
cannot be determined definitively at the time of the SAE occurrence, it is important to notify Spirita 
Oncology within the timeline stated above, and to attribute the relationship as 'Not Assessable' 
(only applicable for the initial SAE Report). When new significant information is obtained, and 
the outcome and attribution of the event is known, the investigator will communicate this in a 
follow-up SAE Report. This relevant information will be provided in a timely manner to allow 
reporting to regulatory authorities within the required reporting period. Any SAE follow-up 
information requested by Spirita Oncology should be provided in a timely manner. 
As necessary, the SAE Report should be accompanied by relevant pages from the CRFs, e.g., 
medical history, AEs, concomitant medications. Additional information may be requested by 
Spirita Oncology in an expedited manner to ensure that the initial reporting of the SAE made to 
the regulatory authorities complies with the required time frame. Spirita Oncology may be required 
to collect and report additional information to the regulatory authorities in a follow-up report, 
containing a final evaluation of the event, including copies of hospital reports, autopsy reports, or 
other relevant information. 
10.3.1.7. Adverse Event and Serious Adverse Event Follow-Up 
All AEs and SAEs should be followed until resolution, return to baseline, or until the point it is 
deemed that further recovery is unlikely. All measures required for AE management and the 
ultimate outcome of the AE will be recorded in the source document and AE CRF module. 
10.3.1.8. 7.1.8. Ongoing Safety Evaluation 
A study safety evaluation will be conducted on a regular (monthly) basis by teleconference. Dose 
exposure, dose-limiting toxicity, AE/SAE profiles and clinical laboratory abnormalities, and other 
safety measures will be reviewed during each convened meeting. Subject accrual will not be 
interrupted during the regular scheduled safety evaluations. These discussions will be led by the 
Spirita Oncology Medical Monitor and Principal Investigator. 
10.4. 
Efficacy Assessments  
Efficacy assessments will be determined on the basis of MRI and/or CT scans with best treatment 
response at any protocol-specified time point for intracranial disease, duration of response, 
duration of stable disease, and time to intracranial lesion disease progression. Response rates also 
will be determined for non-CNS systemic disease. Progression-free survival (PFS) and overall 
survival (OS) will be evaluated. 


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10.4.1. 
Efficacy Endpoints 
10.4.1.1. Primary Efficacy Endpoint 
The primary efficacy endpoint is the proportion of subjects with intracranial OR following E6201 
plus dabrafenib treatment. OR for subjects with CNS metastases from metastatic melanoma 
include a best response of CR or PR, as defined by RECIST v.1.138 (APPENDIX E) and RANO-
BM39 (APPENDIX F). 
10.4.1.2. Secondary Efficacy Endpoints 
To evaluate intracranial disease duration of response, duration of SD and time to progression of 
CNS metastases, progression-free survival and overall survival, as defined below: 
• Duration of Response: length of time from the first evidence of objective response (CR, 
PR) of intracranial disease lesions to the first objective evidence of progression 
• Duration of Stable Disease: length of time from first evidence of stable disease of 
intracranial disease lesions (CR, PR, SD) to for objective evidence of disease progression 
or death, whichever is earlier 
• Time to Progression of CNS Metastases: length of time from date of first administration of 
study drug to first objective evidence of disease progression of intracranial lesions 
• Progression-Free Survival: length of time from the date of first administration of study 
drug to the first objective evidence of disease progression or death, whichever is earlier 
• Overall Survival: length of time from the date of first administration of study drug to the 
date of death from any cause. 
10.4.2. 
Timing of Assessments to Determine Objective Response 
Disease assessments will be made at the end of Cycle 2 every even numbered cycle thereafter. 
Disease assessments may be made at other time points at the discretion of the Investigator. 
10.5. 
Pharmacodynamic Assessment 
A correlation will be made between BRAF mutational status (e.g., type, heterozygosity or 
homozygosity) in archival tissue with clinical outcome. 


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11. 
STATISTICAL METHODOLOGY 
11.1. 
Determination of Sample Size 
The statistical objective is the evaluation of the intracranial disease OR rate, defined as CR or PR, 
on treatment with E6201 plus dabrafenib. The sample size is based on a one-arm binomial design 
H0 ≤ 0.05 (≤ 5% response rate for historical control group) versus H1 > 0.05 (> 5% response rate 
for experimental group). An objective response rate (OR) of 25% or greater is deemed clinically 
important. A total of 3 or more responses in a sample size of 18 subjects indicates the true OR rate 
is ≥ 25%, with power = 80%, alpha = 0.05, and provides evidence of clinical utility to move 
forward. 
11.2. 
Analysis Populations 
The full analysis set (FAS) includes all subjects who are administered any fraction of a dose of 
either E6201 or dabrafenib study medication. For a particular measure, the per-protocol set (PPS) 
includes those subjects in the FAS who have a valid baseline and one or more post-treatment 
assessments for that measure of interest. 
The PD population consists of all subjects in the FAS who complete a baseline and at least one 
follow-up PD assessment. 
Efficacy analyses will be conducted separately for monotherapy and combination therapy phases 
of the study.   
11.3. 
Statistical Analysis Methods 
All data will be analyzed using Statistical Analysis System (SAS Version 9.3 or higher for 
Windows, SAS Institute, Cary, NC). Continuous variables will be summarized using number, 
mean, standard deviation, median, minimum, and maximum. Categorical variables will be 
summarized using number and frequencies. 
11.3.1. 
Safety Analysis 
11.3.1.1. Adverse Events 
All safety endpoints will be summarized using descriptive statistics and will be based on the FAS 
dataset. 
All AEs will be coded based on the Medical Dictionary for Regulatory Affairs (MedDRA; Version 
17.0 or higher). An AE will be considered a treatment emergent adverse event (TEAE) if the onset 
is after the first dose of study drug or if the condition was present at baseline but worsened after 
the first dose. 
All AEs for each subject will be listed, including intensity grading, relationship to study drug, 
action taken and outcome. Subject listings of deaths, SAEs, and AEs leading to treatment 
discontinuation will be provided. Subject narratives will be provided for deaths, SAEs and other 
significant AEs. Summary tables will be prepared to examine TEAE severity and relationship to 
study treatment. 


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AE summaries will be produced separately for each dose cohort and overall, each disease cohort 
by dose and overall, and by monotherapy combination phases of the study. All summaries will 
show, by subject group, dose cohort and overall, the number and percentage of subjects 
experiencing at least 1 TEAE of each preferred term, arranged by system organ class, and the 
number of occurrences of the event. Separate summaries will be produced by relationship to study 
medication, by severity, and for those events with an incidence rate of at least 2% in any group or 
overall. 
SAEs will be summarized in a similar manner; overall, by relationship to study medication, and 
by severity. 
In addition to the above, summaries of the number and percentage of subjects discontinuing the 
study due to AEs and, due to death, will be presented. 
11.3.1.2. Laboratory Data 
Laboratory data will be listed by subject. Values above and below normal ranges will be indicated, 
and whether statistically significant. All laboratory values will be graded according to the NCI-
CTCAE version 4.03 criteria. Laboratory data will be summarized by actual value and change 
from baseline using number of non-missing observations, mean standard deviation, median, 
minimum and maximum. In addition, shift tables and the incidence of Grade 3 or 4 laboratory 
values will be presented. 
11.3.1.3. Vital Signs 
Vital signs will be listed by subject. Values above and below normal ranges will be indicated as 
will clinical significance. Vital sign data will be summarized by actual value and change from 
baseline using number of non-missing observations, mean, standard deviation, median, minimum 
and maximum. 
11.3.1.4. Other Safety Data 
Data collected for physical examinations, ECGs and related measures will be listed. 
11.3.2. 
Efficacy Analysis 
11.3.2.1. Primary Efficacy Endpoint 
The primary efficacy endpoint is the proportion of subjects with intracranial OR following E6201 
plus dabrafenib treatment. Intracranial response rates will be summarized using number and 
percentage of subjects with a best response of CR, PR, SD or PD assessed by RECIST v. 1.1 and 
RANO-BM, along with 2-sided, 95% confidence intervals for the proportions. 
11.3.2.2. Secondary Efficacy Endpoints 
Non-CNS systemic disease response rates will be determined by RECIST v 1.1. For determination 
of intracranial disease duration of response, duration of stable disease and time to progression of 
CNS metastases, and for PFS and overall survival, the Kaplan-Meier product- limit method will 
be used to estimate the median survival. Subjects who do not have disease progression will be 
censored at the last follow-up time. 


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Duration of intracranial disease response or stable disease will be calculated from the date of first 
response or stable disease to the date of progression or death. 
Time to progression of CNS metastases will be calculated from the date of first treatment to the 
date of first evidence of progression of intracranial lesions. 
Progression-free survival will be calculated from the date of first treatment to the date of first 
evidence of progression or death. 
Overall survival will be calculated from the date of first treatment to the date of death from any 
cause; subjects who do not experience death will be censored at the last follow-up time.  
SAS Version 9.3 for Windows (SAS Institute, Cary, NC) or higher will be used for all analyses. 
11.3.3. 
Pharmacodynamic Endpoint Analysis 
A correlation will be made between BRAF mutational status (e.g., type, heterozygosity or 
homozygosity) in archival tissue with clinical outcome. 
 


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12. 
STUDY MANAGEMENT 
12.1. 
Data Management 
The investigator is responsible for completing and maintaining adequate and accurate source 
documentation.  Source documentation constitutes original records, which may include progress 
notes, medication administration records, laboratory reports, ECG tracings, discharge summaries, 
CRF worksheets, etc. Data for this study will be submitted electronically. Access to the database 
will be provided following a brief on-line training session. Each user will receive a unique 
username and password, which should not be shared. The investigator must sign the investigator’s 
statement for each subject indicating that the data reported are accurate. 
12.2. 
Monitoring 
The sponsor, Spirita Oncology, is responsible for ensuring the proper conduct of the study with 
regard to ethics, protocol adherence, site procedures, integrity of the data, and applicable laws 
and/or regulations. At regular intervals during the study and following completion of the study, 
the sponsor’s study monitors will contact the study site via visits to the site, telephone calls, and 
letters in order to review study progress, CRF completion, and address any concerns or questions 
regarding the study conduct.  During monitoring visits, the following aspects of study conduct will 
be carefully reviewed:  informed consent of subjects, subject recruitment, subject compliance with 
the study procedures, source data verification, drug accountability, use of concomitant therapy by 
subjects, AE and SAE documentation and reporting, and quality of data.  Records pertaining to 
these aspects are expected to be kept current. 
12.3. 
Audits and Inspections 
Authorized representatives of Spirita Oncology, a regulatory authority, an Independent Ethics 
Committee or an Institutional Review Board may visit the site to perform audits or inspections, 
including source data verification.  The purpose of a Spirita Oncology audit or inspection is to 
systematically and independently examine all study-related activities and documents to determine 
whether these activities were conducted, and data were recorded, analyzed, and accurately reported 
according to the protocol, Good Clinical Practice guidelines of the International Conference on 
Harmonization, and any applicable regulatory requirements.  The investigator should contact 
Spirita Oncology immediately if contacted by a regulatory agency about an inspection. 
12.4. 
Amendments 
Any amendments to the protocol will be written and approved by Sponsor, Spirita Oncology. All 
amendments must be submitted to the IRB for approval prior to implementing the changes. In 
some instances, an amendment requires changes to the informed consent form, which also must 
be submitted for IRB approval prior to administration to subjects. If any changes to the CRF are 
required, Spirita Oncology will issue supplemental or revised CRF pages on behalf of the sponsor. 


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12.5. 
Institutional Review Board (IRB) 
The Principal Investigator must obtain IRB approval for the investigation.  Initial IRB approval, 
and all materials approved by the IRB for this study including the subject consent form and 
recruitment materials must be maintained by the Investigator and made available for inspection. 


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13. 
QUALITY CONTROL AND QUALITY ASSURANCE 
To ensure compliance with Good Clinical Practices and all applicable regulatory requirements, 
Spirita Oncology, LLC may conduct a quality assurance audit.  See Section 12.3 for more details 
regarding the audit process. 


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14. 
ETHICS 
14.1. 
Ethics Review 
The final study protocol, including the final version of the Informed Consent Form, must be 
approved or given a favorable opinion in writing by an IRB or IEC as appropriate.  The investigator 
must submit written approval to Spirita Oncology, LLC before he or she can enroll any subject 
into the study. 
The Principal Investigator is responsible for informing the IRB or IEC of any amendment to the 
protocol in accordance with local requirements.  In addition, the IRB or IEC must approve all 
advertising used to recruit subjects for the study.  The protocol must be re-approved by the IRB or 
IEC upon receipt of amendments and annually, as local regulations require. 
The Principal Investigator is also responsible for providing the IRB with reports of any reportable 
serious adverse drug reactions from any other study conducted with the investigational product.  
Spirita Oncology will provide this information to the Principal Investigator. 
Progress reports and notifications of serious adverse drug reactions will be provided to the IRB or 
IEC according to local regulations and guidelines. 
14.2. 
Ethical Conduct of the Study 
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with ICH/Good Clinical Practice, applicable regulatory 
requirements and corporate policy on Ethical Standards (APPENDIX G). 
14.3. 
Written Informed Consent 
The Principal Investigator(s) at each center will ensure that the subject is given full and adequate 
oral and written information about the nature, purpose, possible risk and benefit of the study.  
Subjects must also be notified that 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 study 
procedures. 
The Principal Investigator(s) must maintain the original, signed Informed Consent Form.  A copy 
of the signed Informed Consent Form must be given to the subject. 


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15. 
DATA HANDLING AND RECORDKEEPING 
15.1. 
Health Insurance Portability Accountability Act of 1996 
The investigator agrees to comply with all applicable federal, state, and local laws and regulations 
relating to the privacy of subject health information, including, but not limited to, the Standards 
for Individually Identifiable Health Information, 45 CFR. Parts 160 and 164 (the Health Insurance 
Portability Accountability Act of 1996 [HIPAA] Privacy Regulation). The investigator shall 
ensure that study subjects authorize the use and disclosure of protected health information in 
accordance with HIPAA Privacy Regulation and in a form satisfactory to the sponsor.  
15.2. 
Financial Disclosure 
The investigator shall provide to the sponsor sufficient accurate financial information to allow 
Spirita Oncology to submit complete and accurate financial certification or disclosure statements 
to the FDA. The investigator shall promptly update this information yearly and for one year 
following completion of the study. 
15.3. 
Inspection of Records 
Spirita Oncology will be allowed to conduct site visits to the investigation facilities for the purpose 
of monitoring any aspect of the study.  The Investigator agrees to allow the monitor to inspect the 
drug storage area, study drug stocks, drug accountability records, subject charts and study source 
documents, and other records relative to study conduct. 
15.4. 
Access to Original Records 
It is an expectation of regulatory authorities that monitors, auditors, and representatives of national 
and international government regulatory agency bodies have access to original source 
documentation to ensure data integrity. “Original” in this context is defined as the first 
documentation of an observation and does not differentiate between hard copy and electronic 
records. 
15.5. 
Retention of Records 
Study-related records must be retained for at least 2 years after the last approval of a marketing 
application in an ICH region and until there are no pending or contemplated marketing applications 
in an ICH region, or at least 2 years have elapsed since the formal discontinuation of clinical 
development of the investigational product.  These documents should be retained for a longer 
period, however, if required by applicable regulatory requirements or by an agreement with the 
Sponsor. 
The investigator must not destroy any study-related records without receiving approval from the 
sponsor. The investigator must notify the sponsor in the event of accidental loss or destruction of 
any study records. If the investigator leaves the institution where the study was conducted, the 
sponsor must be contacted to arrange alternative record storage options. 
 


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16. 
LIST OF REFERENCES 
1. Wallace EM, Lyssikatos JP, Yeh T, Winkler JD, Koch K. Progress towards therapeutic 
small molecule MEK inhibitors for use in cancer therapy. Curr Top Med Chem. 
2005;5:215-229. 
2. Davies H, Bignell GR, Cox C, et al. Mutations of the BRAF gene in human cancer. Nature. 
2002;417:949-954. 
3. Kumar R, Angelini  S,  Snellman  E, Hemminki K. BRAF mutations are common somatic 
events in melanocytic nevi. J Invest Dermatol. 2004;122:342-348. 
4. Mercer K, Giblett S, Green S, et al. Expression of endogenous oncogenic V600E B- RAF 
induces proliferation and developmental defects in mice and transformation of primary 
fibroblasts. Cancer Res. 2005;65:11493-11500 (corrected per Amendment 01). 
5. Wang YJ, Wilcoxen KM, Nomoto K, Wu S. Recent advances of MEK inhibitors and their 
clinical progress. Curr Top Med Chem. 2007;7(14):1364-1378. 
6. Mikalsen T, Gerits N, Moens U. Inhibitors of signal transduction protein kinases as targets 
for cancer therapy. Biotechnol Ann Rev. 2006;17:153-223. 
7. Hunter SG, Zhuang G, Brantley-Sieders D, Swat W, Cowan CW, Chen J. Essential role of 
Vav family guanine nucleotide exchange factors in EphA receptor-mediated angiogenesis. 
Mol Cell Biol. 2006;26(13):4830-4842. 
8. Kim IJ, Kang HC, Jang SG, et al. Oligonucleotide microarray analysis of distinct gene 
expression patterns in colorectal cancer tissues harboring BRAF and K-RAS mutations. 
Carcinogenesis. 2006;27:392-404. 
9. E6201 for Injection Investigator’s Brochure, Edition 6, 22 January, 2014. 
10. A Phase 1, Multicenter, Open-Label, Dose-Escalation, Safety, Pharmacokinetic, and 
Pharmacodynamic Study of E6201 in Subjects with Advanced Melanoma, E201-A001-
102, Clinical Study Report, 25 July, 2013.  
11. Tibes R, Borad M, Dutcus CD, Reyderman L, Feit K, Eisen A, Verbel DA, Von Hoff DD. 
Safety, pharmacokinetics, and preliminary efficacy of E6201 in patients with advanced 
solid tumours, including melanoma: results of a phase 1 study. Br J Cancer. 
2018;118:1580-1585. 
12. Babiker HM, Byron SA, Hendricks WPD, Elmquist WF, Gampa G, Vondrak J, Aldrich J, 
Cuyugan L, Adkins J, De Luca V, Tibes R, Borad MJ, Marceau K, Myers TJ, Paradiso LJ, 
Liang WS, Korn RL, Cridebring D, Von Hoff DD, Carpten JD, Craig DW, Trent JM, 
Gordon MS. E6201, an intravenous MEK1 inhibitor, achieves an exceptional response in 
BRAF V600E-mutated metastatic malignant melanoma with brain metastases. Inv New 
Drugs. 2018; https://doi.org/10.1007/s10637-018-0668-8. 
13. Lin X, DeAngelis LM. Treatment of brain metastases. J Clin Onc. 2015;33:3475-3485. 
14. Uptodate.com Overview of the clinical manifestations, diagnosis, and management of 
patients with brain metastases. Accessed May 2016. 


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15. Gabay MP, Wirth SM, Stachnik JM, Overley CL, Long KE, Bressler LR, Vilano JL. Oral 
targeted therapies and central nervous system (CNS) metastases. CNS Drugs. 2015; 
29(11):935-952. 
16. Bohn J, Pall G, Stockhammer G, Steurer M. Targeted therapies for the treatment of brain 
metastases and solid tumors. Target Oncol. 2016;Jun11(3):263-265. 
17. Chen G, Chakravarti N, Aardalen K, Lazar AJ, Tetzlaff MT, Wubbenhorst B, Kim S,  
Kopetz S, Ledoux A, Gopal Y, Pereira C, Deng W, Lee J, Nathanson K, Aldape KD,  Prieto 
VG, Stuart D, Davies MA. Molecular profiling of patient-matched brain and extracranial 
melanoma metastases implicates the PI3K pathway as a therapeutic target. Clin Can Res. 
2014;20(21):5537-5546. 
18. Goldinger SM, Panje C, Nathan P. Treatment of melanoma brain metastases. Current 
Opinion Oncology. 2016;28(2):159-165. 
19. Ajithkumar T, Parkinson C, Fife K, Corrie P, Jefferies S. Evolving treatment options for 
melanoma brain metastases. Lancet Oncology. 2015;16:E486-E497. 
20. Dummer R, Goldinger SM, Turtschi CP, Eggmann NB, Michielin O, Mitchell L, et al. 
Vemurafenib in patients with BRAF(V600E) mutation-positive melanoma with 
symptomatic brain metastases: final results of an open-label pilot study. Eur J Cancer. 
2014;50(3):6110621. 
21. Rochet NM, Dronca RS, Kottschade LA, Chavan RN, Gorman B, Gilbertson JR et al. 
Melanoma brain metastases and vemurafenib: need for further investigation. Mayo Clin 
Proc. 2012;87(10):976-81. 
22. Long GV, Trefzer U, Davies MA, Kefford RF, Ascierto PA, Chapman PB et al. Dabrafenib 
in patients with Val600Glu or Val600Lys BRAF-mutant melanoma metastatic to the brain 
(BREAK-MB): a multicentre, open-label, phase 2 trial. Lancet Oncol. 2012;13(11):1087-
95. 
23. Falchook GS, Long GV, Kurzrock R, Kim KB, Arkenau TH, Brown MP et al. Dabrafenib 
in patients with melanoma, untreated brain metastases, and other solid tumours: a phase 1 
dose-escalation trial. Lancet. 2012;379(9829):1893- 901. 
24. Spagnolo F, Picasso V, Lambertini M, Ottaviano V, Dozin B, Queirolo P. Survival of 
patients with metastatic melanoma and brain metastases in the era of MAP-kinase 
inhibitors and immunologic checkpoint blockade antibodies: A systematic review. Cancer 
Treat Rev. 2016;45:38-45. 
25. Flaherty KT, Infante JR, Daud A, Gonzalez R, Kefford RF, Sosman J et al. Combined 
BRAF and MEK Inhibition in Melanoma with BRAF V600 Mutations. N Engl J Med. 
2012;367(18):1694-1703. 
26. Larkin J, Ascierto PA, Dreno B, Atkinson V, Liszkay G, Maio M et al. Combined 
vemurafenib and cobimetinib in BRAF-mutated melanoma. N Engl J Med. 
2014;371(20):1867-1876. 


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27. Ribas A, Gonzalez R, Pavlick A, Hamid O, Gajewski TF, Daud A et al. Combination of 
vemurafenib and cobimetinib in patients with advanced BRAF(V600)-mutated melanoma: 
a phase 1b study. Lancet Oncol. 2014;15(9):954-965. 
28. Vaidhyanathan, S., R. K. Mittapalli, J.N. Sarkaria, W. F. Elmquist. Factors influencing the 
CNS distribution of a novel MEK-1/2 Inhibitor: implications for combination therapy for 
melanoma brain metastases. Drug metabolism and Disposition. 2014;42:1292-1300. 
29. Byron, S., TGen (personal communication). 
30. Gampa G, Elmquist W. Brain Distribution of E6201, A Novel MEK Inhibitor, final report 
2017. 
31. Gampa G, Kim M, Cook-Rostie N, Laramy JK, Sarkaria JN, Paradiso L, DePalatis L, 
Elmquist WF. Brain distribution of a novel MEK inhibitor E6201: Implications in the 
treatment of melanoma brain metastases. Drug Met Disp. 2018;46:658-666. 
32. Mittapalli RK, Vaidhyanathan S, Sane R, Elmquist WF. Impact of P-glycoprotein 
(ABCB1) and breast cancer resistance protein (ABCG2) on the brain distribution of a novel 
BRAF inhibitor: vemurafenib (PLX4032). J Pharmacol Exp Ther. 2012;342(1):33-40. 
33. Mittapalli RK, Vaidhyanathan S, Dudek AZ, Elmquist WF. Mechanisms limiting 
distribution of the threonine-protein kinase B-RaF(V600E) inhibitor dabrafenib to the 
brain: implications for the treatment of melanoma brain metastases. J Pharmacol Exp Ther. 
2013;344(3):655-64. 
34. Choo EF, Ly J, Chan J, Shahidi-Latham SK, Messick K, Plise E, Quiason CM, Yang L. 
Role of p-glycoprotein on the brain penetration and brain pharmacodynamic activity of the 
MEK inhibitor, cobimetinib. Molec Pharmaceutics. 2014;11:4199-4207. 
35. Burgenske D, Gampa G. In vivo efficacy of E6201 in BRAF+ melanoma PDX models. 
Data on file, 2019. 
36. Dabrafenib (TAFINLAR) U.S. Product Label, 2019. 
37. Phase 1/2a Study of E6201 for the Treatment of Advanced Hematologic Malignancies with 
FLT3 and/or Ras Mutations (Protocol BSC-101-01), Clinical Study Report, January 26, 
2018. 
38. Eisenhaur EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck 
S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, 
Verweij J. New response evaluation criteria in solid tumors: Revised RECIST guideline 
(version 1.1). E Jour Cancer. 2009;45:228-247. 
39. Wen PY, Chang SM, Van den Bent MJ, Vogelbaum MA, Macdonald DR, Lee EQ. 
Response assessment in neuro-oncology clinical trials. J Clin Oncol. 2017;35(21):2439-
2449. 
 
 


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APPENDIX A. EASTERN COOPERATIVE GROUP (ECOG) 
PERFORMANCE STATUS SCALE 
 
ECOG PERFORMANCE STATUS* 
Grad
e
ECOG 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or 
sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all selfcare but unable to carry out any work activities. Up and about 
more than 50% of waking hours 
3 
Capable of only limited selfcare, confined to bed or chair more than 50% of waking hours 
4 
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair 
5 
Dead 
 
* From ECOG, Robert Comis, MD, Group Chair 
 
Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., McFadden, E.T., Carbone, 
P.P.: Toxicity And Response Criteria Of The Eastern Cooperative Oncology Group. Am J Clin 
Oncol 5:649-655, 1982. 
 
 


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APPENDIX B. COCKCROFT-GAULT FORMULA FOR CALCULATION 
OF CREATININE CLEARANCE 
Creatinine clearance must either be measured or estimated using the Cockroft-Gault formula, as 
outlined below. 
 
* Cockcroft DW, Gault MH.  Prediction of creatinine clearance from serum creatinine. Nephron. 
1976;16(1):31-41. 
 


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APPENDIX C. NEW YORK HEART ASSOCIATION (NYCA) 
CLASSIFICATION FOR HEART FAILURE NYHA 
CLASSIFICATION - THE STAGES OF HEART FAILURE 
Class 
Patient Symptoms 
Class I (Mild) 
No limitation of physical activity. Ordinary physical activity does not cause 
undue fatigue, palpitation, or dyspnea (shortness of breath). 
Class II (Mild) 
Slight limitation of physical activity. Comfortable at rest, but ordinary physical 
activity results in fatigue, palpitation, or dyspnea. 
Class III (Moderate) 
Marked limitation of physical activity. Comfortable at rest, but less than 
ordinary activity causes fatigue, palpitation, or dyspnea. 
Class IV (Severe) 
Unable to carry out any physical activity without discomfort. Symptoms of 
cardiac insufficiency at rest. If any physical activity is undertaken, discomfort 
is increased. 
 
 
 


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APPENDIX D. SCHEDULE OF STUDY PROCEDURES 
 
Study Activity 
Screeninga 
Treatment Cycle 1 
Treatment Cycles after Cycle 1 
Progression 
or Relapse 
End of 
Treatmentl 
Long-Term 
Follow-Upn 
Day 
1 
Day 
8i 
Day 
15i 
 
Day 1 
End of 
Cycle 2j,k 
 
 
 
Signed ICD 
X 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
Physical Examination 
X 
X 
 
 
Xh 
 
 
X 
 
Vital Signs 
X 
X 
X 
X 
X 
 
 
X 
 
ECOG Perform. Status 
X 
X 
X 
X 
X 
 
 
X 
 
Height  
X 
 
 
 
 
 
 
 
 
Weight 
X 
X 
 
 
X 
 
 
X 
 
Hematologyb 
X 
X 
 
 
X 
 
 
X 
 
Serum Chemistryc 
X 
X 
 
 
X 
 
 
X 
 
Beta-hCG for WCBP 
X 
 
 
 
 
 
 
 
 
12-lead ECG 
X 
Xd 
 
 
Xd 
 
 
X 
 
Concomitant Medications 
X 
Continuous 
AE Assessment 
 
Continuous 
Disease Assessmente 
X 
 
 
 
 
X 
X 
 
 
E6201 Administrationf 
 
X (+D4) 
X         
(+D11) 
X 
(+D18) 
X 
(D 1, 4, 8, 11, 15, 18) 
 
 
 
 
Dabrafenib Dosingg,m 
 
X 
X 
X 
X 
 
 
Xm 
 
Assessment of Survival  
 
X 
 
 
X 
X 
X 
X 
X 


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a Screening to be performed within 28 days of Cycle 1, Day 1 
b Hematology parameters collected at Screening, Cycle 1 Day 1 (only if not performed in the previous 24 hours), Day 1 of each subsequent cycle (within 3 days 
of Day 1 of each subsequent cycle) and End of Treatment. See Table 9 for tests to be conducted at each time point. 
c Serum chemistry collected at Screening, Cycle 1 Day 1 (only if not performed within the previous 24 hours), Day 1 of each subsequent cycle (within 3 days of 
Day 1 of each subsequent cycle) and End of Treatment. See Table 9 for tests to be conducted at each time point.  
d ECGs performed pre-dose and at the end of the E6201 2-hour infusion (± 5 minutes)  
e Disease Assessment may include CT, MRI, and/or physical exam  
f E6201 IV twice weekly Day 1,4, 8, 11, 15 and 18 of each 28-day cycle 
g Dabrafenib dose orally twice daily, continuously. Provide Dabrafenib Patient Medication Diary.  
h Abbreviated physical exam 
i Day 8, 15 (±1 day) 
j Day 28 (±7 days) 
k Perform at the end of every even numbered cycle thereafter 
l End of Treatment visit should be within 28 days from last dose of study medication (±5 days) 
m Review Dabrafenib Patient Medication Diary (each clinic visit + End of Treatment) 
n Long-term follow-up for 6 months consists of clinic visits or telephone calls every 3 months to assess survival status 


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APPENDIX E. RESPONSE EVALUATION CRITERIA IN SOLID 
TUMORS (RECIST 1.1)38  
1. Measurability of Tumor at Baseline 
1.1 Definitions 
At baseline, tumor lesions/lymph nodes will be categorized measurable or non-measurable as 
follows: 
1.1.1. Measurable 
Tumor lesions: Must be accurately measured in at least one dimension (longest diameter in the 
plane of measurement is to be recorded) with a minimum size of: 
• 10mm by CT scan (CT scan slice thickness no greater than 5 mm) 
• 10mm caliper measurement by clinical exam (lesions which cannot be accurately 
measured with calipers should be recorded as non-measurable) 
• 20mm by chest X-ray 
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph 
node must be ≥ 15mm in short axis when assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 5 mm). At baseline and in follow-up, only the short axis 
will be measured and followed. See also notes below on ‘Baseline documentation of target and 
non-target lesions’ for information on lymph node measurement. 
1.1.2. Non-measurable 
All other lesions, including small lesions (longest diameter <10mm or pathological lymph 
nodes with ≥ 10 to < 15mm short axis) as well as truly non-measurable lesions. Lesions 
considered truly non-measurable include: leptomeningeal disease, ascites, pleural or 
pericardial effusion, inflammatory breast disease, lymphangitic involvement of skin or lung, 
abdominal masses/abdominal organomegaly identified by physical exam that is not measurable 
by reproducible imaging techniques. 
1.1.3. Special considerations regarding lesion measurability 
Bone lesions, cystic lesions, and lesions previously treated with local therapy require particular 
comment: 
Bone lesions: 
• Bone scan, PET scan or plain films are not considered adequate imaging techniques to 
measure bone lesions. However, these techniques can be used to confirm the presence 
or disappearance of bone lesions. 
• Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue 
components, that can be evaluated by cross sectional imaging techniques such as CT 
or MRI can be considered as measurable lesions if the soft tissue component meets the 
definition of measurability described above. 


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• Blastic bone lesions are non-measurable. 
Cystic lesions: 
• Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they 
are, by definition, simple cysts. 
• ‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if 
noncystic lesions are present in the same patient, these are preferred for selection as 
target lesions. 
Lesions with prior local treatment: 
• Tumor lesions situated in a previously irradiated area, or in an area subjected to other 
loco-regional therapy, are usually not considered measurable unless there has been 
demonstrated progression in the lesion. Study protocols should detail the conditions 
under which such lesions would be considered measurable. 
1.2. Specifications by methods of measurements 
1.2.1. Measurement of lesions 
All measurements should be recorded in metric notation, using calipers if clinically assessed. 
All baseline evaluations should be performed as close as possible to the treatment start and 
never more than 4 weeks before the beginning of the treatment. 
1.2.2. Method of assessment 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging based evaluation 
should always be done rather than clinical examination unless the lesion(s) being followed 
cannot be imaged but are assessable by clinical exam. 
Clinical lesions: Clinical lesions will only be considered measurable when they are superficial 
and P10mm diameter as assessed using calipers (e.g. skin nodules). For the case of skin lesions, 
documentation by color photography including a ruler to estimate the size of the lesion is 
suggested. As noted above, when lesions can be evaluated by both clinical exam and imaging, 
imaging evaluation should be undertaken since it is more objective and may also be reviewed 
at the end of the study. 
Chest X-ray: Chest CT is preferred over chest X-ray, particularly when progression is an 
important endpoint, since CT is more sensitive than X-ray, particularly in identifying new 
lesions. However, lesions on chest X-ray may be considered measurable if they are clearly 
defined and surrounded by aerated lung.  
CT, MRI: CT is the best currently available and reproducible method to measure lesions 
selected for response assessment. This guideline has defined measurability of lesions on CT 
scan based on the assumption that CT slice thickness is 5mm or less. When CT scans have 
slice thickness greater than 5 mm, the minimum size for a measurable lesion should be twice 
the slice thickness. MRI is also acceptable in certain situations (e.g. for body scans). More 


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details concerning the use of both CT and MRI for assessment of objective tumour response 
evaluation are provided in Appendix II of the paper. 
Ultrasound: Ultrasound is not useful in assessment of lesion size and should not be used as a 
method of measurement. Ultrasound examinations cannot be reproduced in their entirety for 
independent review at a later date and, because they are operator dependent, it cannot be 
guaranteed that the same technique and measurements will be taken from one assessment to 
the next. If new lesions are identified by ultrasound in the course of the study, confirmation by 
CT or MRI is advised. If there is concern about radiation exposure at CT, MRI may be used 
instead of CT in selected instances. 
Endoscopy, laparoscopy: The utilization of these techniques for objective tumor evaluation 
is not advised. However, they can be useful to confirm complete pathological response when 
biopsies are obtained or to determine relapse in trials where recurrence following complete 
response or surgical resection is an endpoint. 
Tumor markers: Tumor markers alone cannot be used to assess objective tumor response. If 
markers are initially above the upper normal limit, however, they must normalize for a patient 
to be considered in complete response. Because tumor markers are disease specific, 
instructions for their measurement should be incorporated into protocols on a disease specific 
basis. Specific guidelines for both CA-125 response (in recurrent ovarian cancer) and PSA 
response (in recurrent prostate cancer), have been published. In addition, the Gynecologic 
Cancer Intergroup has developed CA125 progression criteria which are to be integrated with 
objective tumor assessment for use in first-line trials in ovarian cancer. 
Cytology, histology: These techniques can be used to differentiate between PR and CR in rare 
cases if required by protocol (for example, residual lesions in tumor types such as germ cell 
tumors, where known residual benign tumors can remain). When effusions are known to be a 
potential adverse effect of treatment (e.g. with certain taxane compounds or angiogenesis 
inhibitors), the cytological confirmation of the neoplastic origin of any effusion that appears 
or worsens during treatment can be considered if the measurable tumor has met criteria for 
response or stable disease in order to differentiate between response (or stable disease) and 
progressive disease. 
2. Tumor response evaluation 
2.1. Assessment of overall tumor burden and measurable disease 
To assess objective response or future progression, it is necessary to estimate the overall tumor 
burden at baseline and use this as a comparator for subsequent measurements. Only patients 
with measurable disease at baseline should be included in protocols where objective tumor 
response is the primary endpoint. Measurable disease is defined by the presence of at least one 
measurable lesion (as detailed above in Section 1). In studies where the primary endpoint is 
tumor progression (either time to progression or proportion with progression at a fixed date), 
the protocol must specify if entry is restricted to those with measurable disease or whether 
patients having non-measurable disease only are also eligible. 
 
 


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2.2. Baseline documentation of ‘target’ and ‘non-target’ lesions 
When more than one measurable lesion is present at baseline all lesions up to a maximum of 
five lesions total (and a maximum of two lesions per organ) representative of all involved 
organs should be identified as target lesions and will be recorded and measured at baseline 
(this means in instances where patients have only one or two organ sites involved a maximum 
of two and four lesions respectively will be recorded). For evidence to support the selection of 
only five target lesions, see analyses on a large prospective database in the article by Bogaerts 
J, et al, Eur Jour Cancer,2009;45:248-260. 
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.  
Lymph nodes merit special mention since they are normal anatomical structures which may be 
visible by imaging even if not involved by tumor. As noted in Section 1, pathological nodes 
which are defined as measurable and may be identified as target lesions must meet the criterion 
of a short axis of ≥ 15mm by CT scan. Only the short axis of these nodes will contribute to the 
baseline sum. The short axis of the node is the diameter normally used by radiologists to judge 
if a node is involved by solid tumor. Nodal size is normally reported as two dimensions in the 
plane in which the image is obtained (for CT scan this is almost always the axial plane; for 
MRI the plane of acquisition may be axial, sagittal or coronal). The smaller of these measures 
is the short axis. For example, an abdominal node which is reported as being 20mm· 30mm 
has a short axis of 20mm and qualifies as a malignant, measurable node. In this example, 20mm 
should be recorded as the node measurement. All other pathological nodes (those with short 
axis ≥ 10mm but <15 mm) should be considered non-target lesions. Nodes that have a short 
axis <10mm are considered non-pathological and should not be recorded or followed. 
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 as noted above, 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. 
All other lesions (or sites of disease) including pathological lymph nodes should be identified 
as non-target lesions and should also be recorded at baseline. Measurements are not required 
and these lesions should be followed as ‘present’, ‘absent’, or in rare cases ‘unequivocal 
progression’. In addition, it is possible to record multiple nontarget lesions involving the same 
organ as a single item on the case record form (e.g. ‘multiple enlarged pelvic lymph nodes’ or 
‘multiple liver metastases’). 
 
 
 
 


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2.3. Response criteria 
This section provides the definitions of the criteria used to determine objective tumor response 
for target lesions.  
2.3.1. Evaluation of target lesions 
Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to <10 mm. 
Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking 
as reference the baseline sum diameters. 
Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline sum if that is the 
smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate 
an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also 
considered progression). 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on study. 
2.3.2. Special notes on the assessment of target lesions 
Lymph nodes. Lymph nodes identified as target lesions should always have the actual short 
axis measurement recorded (measured in the same anatomical plane as the baseline 
examination), even if the nodes regress to below 10mm on study. This means that when lymph 
nodes are included as target lesions, the ‘sum’ of lesions may not be zero even if complete 
response criteria are met, since a normal lymph node is defined as having a short axis of 
<10mm. Case report forms or other data collection methods may therefore be designed to have 
target nodal lesions recorded in a separate section where, in order to qualify for CR, each node 
must achieve a short axis <10mm. For PR, SD and PD, the actual short axis measurement of 
the nodes is to be included in the sum of target lesions.  
Target lesions that become ‘too small to measure’. While on study, all lesions (nodal and non-
nodal) recorded at baseline should have their actual measurements recorded at each subsequent 
evaluation, even when very small (e.g. 2mm). However, sometimes lesions or lymph nodes 
which are recorded as target lesions at baseline become so faint on CT scan that the radiologist 
may not feel comfortable assigning an exact measure and may report themas being ‘too small 
to measure’. When this occurs it is important that a value be recorded on the case report form. 
If it is the opinion of the radiologist that the lesion has likely disappeared, the measurement 
should be recorded as 0mm. If the lesion is believed to be present and is faintly seen but too 
small to measure, a default value of 5mm should be assigned (Note: It is less likely that this 
rule will be used for lymph nodes since they usually have a definable size when normal and 
are frequently surrounded by fat such as in the retroperitoneum; however, if a lymph node is 
believed to be present and is faintly seen but too small to measure, a default value of 5 mm 
should be assigned in this circumstance as well). This default value is derived from the 5mm 
CT slice thickness (but should not be changed with varying CT slice thickness). The 
measurement of these lesions is potentially non-reproducible, therefore providing this default 
value will prevent false responses or progressions based upon measurement error. To reiterate, 


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however, if the radiologist is able to provide an actual measure, that should be recorded, even 
if it is below 5mm. 
Lesions that split or coalesce on treatment. As noted in Appendix II of the paper, when non-
nodal lesions ‘fragment’, the longest diameters of the fragmented portions should be added 
together to calculate the target lesion sum. Similarly, as lesions coalesce, a plane between them 
may be maintained that would aid in individual lesion. If the lesions have truly coalesced such 
that they are no longer separable, the vector of the longest diameter in this instance should be 
the maximal longest diameter for the ‘coalesced lesion’. 
2.3.3. Evaluation of non-target lesions 
This section provides the definitions of the criteria used to determine the tumor response for 
the group of non-target lesions. While some non-target lesions may actually be measurable, 
they need not be measured and instead should be assessed only qualitatively at the time points 
specified in the protocol. 
Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor 
marker level. All lymph nodes must be non-pathological in size (<10mm short axis). 
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of tumor 
marker level above the normal limits. 
Progressive Disease (PD): Unequivocal progression (see comments below) of existing non-
target lesions. (Note: the appearance of one or more new lesions is also considered 
progression). 
2.3.4. Special notes on assessment of progression of nontarget disease 
The concept of progression of non-target disease requires additional explanation as follows:  
When the patient also has measurable disease. In this setting, to achieve ‘unequivocal 
progression’ on the basis of the non-target disease, there must be an overall level of substantial 
worsening in non-target disease such that, even in presence of SD or PR in target disease, the 
overall tumor burden has increased sufficiently to merit discontinuation of therapy. A modest 
‘increase’ in the size of one or more non-target lesions is usually not sufficient to quality for 
unequivocal progression status. The designation of overall progression solely on the basis of 
change in non-target disease in the face of SD or PR of target disease will therefore be 
extremely rare. 
When the patient has only non-measurable disease. This circumstance arises in some Phase III 
trials when it is not a criterion of study entry to have measurable disease. The same general 
concepts apply here as noted above, however, in this instance there is no measurable disease 
assessment to factor into the interpretation of an increase in non-measurable disease burden. 
Because worsening in non-target disease cannot be easily quantified (by definition: if all 
lesions are truly non-measurable) a useful test that can be applied when assessing patients for 
unequivocal progression is to consider if the increase in overall disease burden based on the 
change in non-measurable disease is comparable in magnitude to the increase that would be 
required to declare PD for measurable disease: i.e., an increase in tumor burden representing 
an additional 73% increase in ‘volume’ (which is equivalent to a 20% increase diameter in a 


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measurable lesion). Examples include an increase in a pleural effusion from ‘trace’ to ‘large’, 
an increase in lymphangitic protocols as ‘sufficient to require a change in therapy’. If 
‘unequivocal progression’ is seen, the patient should be considered to have had overall PD at 
that point. While it would be ideal to have objective criteria to apply to non-measurable disease, 
the very nature of that disease makes it impossible to do so, therefore the increase must be 
substantial. 
2.3.5. New lesions 
The appearance of new malignant lesions denotes disease progression; therefore, some 
comments on detection of new lesions are important. There are no specific criteria for the 
identification of new radiographic lesions; however, the finding of a new lesion should be 
unequivocal: i.e. not attributable to differences in scanning technique, change in imaging 
modality or findings thought to represent something other than tumor (for example, some 
‘new’ bone lesions may be simply healing or flare of pre-existing lesions). This is particularly 
important when the patient’s baseline lesions show partial or complete response. For example, 
necrosis of a liver lesion may be reported on a CT scan report as a ‘new’ cystic lesion, which 
it is not. 
A lesion identified on a follow-up study in an anatomical location that was not scanned at 
baseline is considered a new lesion and will indicate disease progression. An example of this 
is the patient who has visceral disease at baseline and while on study has a CT or MRI brain 
ordered which reveals metastases. The patient’s brain metastases are considered to be evidence 
of PD even if he/she did not have brain imaging at baseline. 
If a new lesion is equivocal, for example because of its small size, continued therapy and 
follow-up evaluation will clarify if it represents truly new disease. If repeat scans confirm there 
is definitely a new lesion, then progression should be declared using the date of the initial scan.  
While FDG-PET response assessments need additional study, it is sometimes reasonable to 
incorporate the use of FDG-PET scanning to complement CT scanning in assessment of 
progression (particularly possible ‘new’ disease). New lesions on the basis of FDG-PET 
imaging can be identified according to the following algorithm: 
a. Negative FDG-PET at baseline, with a positive FDG-PET (=FDG avid with an uptake 
greater than twice that of the surrounding tissue on the attenuation corrected image) at 
follow-up is a sign of PD based on a new lesion. 
b. No FDG-PET at baseline and a positive FDG-PET at follow- up: 
• If the positive FDG-PET at follow-up corresponds to a new site of disease 
confirmed by CT, this is PD.  
• If the positive FDG-PET at follow-up is not confirmed as a new site of disease on 
CT, additional follow-up CT scans are needed to determine if there is truly progression 
occurring at that site (if so, the date of PD will be the date of the initial abnormal FDG-
PET scan).  
• If the positive FDG-PET at follow-up corresponds to a pre-existing site of disease 
on CT that is not progressing on the basis of the anatomic images, this is not PD.  


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2.4. Evaluation of best overall response 
The best overall response is the best response recorded from the start of the study treatment 
until the end of treatment taking into account any requirement for confirmation. On occasion 
a response may not be documented until after the end of therapy so protocols should be clear 
if post-treatment assessments are to be considered in determination of best overall response. 
Protocols must specify how any new therapy introduced before progression will affect best 
response designation. The patient’s best overall response assignment will depend on the 
findings of both target and non-target disease and will also take into consideration the 
appearance of new lesions. Furthermore, depending on the nature of the study and the protocol 
requirements, it may also require confirmatory measurement (See Section 1.6). Specifically, 
in non-randomized trials where response is the primary endpoint, confirmation of PR or CR is 
needed to deem either one the ‘best overall response’. This is described further below. 
2.4.1. Time point response 
It is assumed that at each protocol specified time point, a response assessment occurs. Table 1 
provides a summary of the overall response status calculation at each time point for patients 
who have measurable disease at baseline. 
When patients have non-measurable (therefore non-target) disease only, Table 2 is to be used. 
Table 1: Criteria for Overall Response for Target (+/- Non-target) Disease 
Table 2: Criteria for Overall Response for Non-target Disease Only 
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 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
CR = complete response, PR= partial response, SD=stable disease, PD= progressive disease, NE=inevaluable 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD 
Not all evaluated 
No 
NE 


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2.4.2. Missing assessments and inevaluable designation 
When no imaging/measurement is done at all at a particular time point, the patient is not 
evaluable (NE) at that time point. If only a subset of lesion measurements are made at an 
assessment, usually the case is also considered NE at that time point, unless a convincing 
argument can be made that the contribution of the individual missing lesion(s) would not 
change the assigned time point response. This would be most likely to happen in the case of 
PD. For example, if a patient had a baseline sum of 50mm with three measured lesions and at 
follow-up only two lesions were assessed, but those gave a sum of 80 mm, the patient will 
have achieved PD status, regardless of the contribution of the missing lesion. 
2.4.3. Best overall response: all time points 
The best overall response is determined once all the data for the patient is known.  
Best response determination in trials where confirmation of complete or partial response IS 
NOT required: Best response in these trials is defined as the best response across all time points 
(for example, a patient who has SD at first assessment, PR at second assessment, and PD on 
last assessment has a best overall response of PR). When SD is believed to be best response, it 
must also meet the protocol specified minimum time from baseline. If the minimum time is 
not met when SD is otherwise the best time point response, the patient’s best response depends 
on the subsequent assessments. For example, a patient who has SD at first assessment, PD at 
second and does not meet minimum duration for SD, will have a best response of PD. The 
same patient lost to follow-up after the first SD assessment would be considered inevaluable. 
Best response determination in trials where confirmation of complete or partial response IS 
required: Complete or partial responses may be claimed only if the criteria for each are met at 
a subsequent time point as specified in the protocol (generally 4 weeks later). In this 
circumstance, the best overall response can be interpreted as in Table 3. 
 
Table 3: Best Overall Response When Confirmation of CR and PR is Required 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
CR = complete response, PR= partial response, SD=stable disease, PD= progressive disease, NE=inevaluable 
Overall Response First 
Time Point 
Overall Response 
Subsequent Time Point 
BEST Overall Response 
CR 
CR 
CR 
CR 
PR 
SD, PD, or PDa 
CR 
SD 
SD provided minimum criteria for SD 
duration met, otherwise, PD 
CR 
PD 
SD provided minimum criteria for SD 
duration met, otherwise, PD 


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2.4.4. Special notes on response assessment 
When nodal disease is included in the sum of target lesions and the nodes decrease to ‘normal’ 
size (<10 mm), they may still have a measurement reported on scans. This measurement should 
be recorded even though the nodes are normal in order not to overstate progression should it 
be based on increase in size of the nodes. As noted earlier, this means that patients with CR 
may not have a total sum of ‘zero’ on the case report form (CRF).  
In trials where confirmation of response is required, repeated ‘NE’ time point assessments may 
complicate best response determination. The analysis plan for the trial must address how 
missing data/assessments will be addressed in determination of response and progression. For 
example, in most trials it is reasonable to consider a patient with time point responses of PR-
NE-PR as a confirmed response.  
Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
‘symptomatic deterioration’. Every effort should be made to document objective progression 
even after discontinuation of treatment. Symptomatic deterioration is not a descriptor of an 
objective response: it is a reason for stopping study therapy. The objective response status of 
such patients is to be determined by evaluation of target and non-target disease as shown in 
Tables 1–3. 
Conditions that define ‘early progression, early death and inevaluability’ are study specific and 
should be clearly described in each protocol (depending on treatment duration, treatment 
periodicity). 
CR 
NE 
SD provided minimum criteria for SD 
duration met, otherwise, NE 
PR 
CR 
PR 
PR 
PR 
PR 
PR 
SD 
SD 
PR 
PD 
SD provided minimum criteria for SD 
duration met, otherwise, PD 
PR 
NE 
SD provided minimum criteria for SD 
duration met, otherwise, NE 
NE 
NE 
NE 
CR = complete response, PR= partial response, SD=stable disease, PD= progressive disease, 
NE=inevaluable 
aIf a CR is truly met at first time point, then any disease seen at a subsequent time point, even disease 
meeting PR criteria relative to baseline, makes the disease PD at that point (since disease must have 
reappeared after CR). Best response would depend on whether minimum duration for SD was met. 
However, sometimes ‘CR’ may be claimed when subsequent scans suggest small lesions were likely still 
present and, in fact, the patient had PR, not CR at the first time point. Under these circumstances, the 
original CR should be changed to PR, and the best response is PR. 


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In some circumstances, it may be difficult to distinguish residual disease from normal tissue. 
When the evaluation of complete response depends upon this determination, it is recommended 
that the residual lesion be investigated (fine needle aspirate/biopsy) before assigning a status 
of complete response. FDG-PET may be used to upgrade a response to a CR in a manner 
similar to a biopsy in cases where a residual radiographic abnormality is thought to represent 
fibrosis or scarring. The use of FDG-PET in this circumstance should be prospectively 
described in the protocol and supported by disease specific medical literature for the indication. 
However, it must be acknowledged that both approaches may lead to false positive CR due to 
limitations of FDG-PET and biopsy resolution/ sensitivity. 
For equivocal findings of progression (e.g. very small and uncertain new lesions; cystic 
changes or necrosis in existing lesions), treatment may continue until the next scheduled 
assessment. If at the next scheduled assessment, progression is confirmed, the date of 
progression should be the earlier date when progression was suspected. 
2.5. Frequency of tumor re-evaluation 
Frequency of tumor re-evaluation while on treatment should be protocol specific and adapted 
to the type and schedule of treatment. However, in the context of phase II studies where the 
beneficial effect of therapy is not known, follow-up every 6–8 weeks (timed to coincide with 
the end of a cycle) is reasonable. Smaller or greater time intervals than these could be justified 
in specific regimens or circumstances. The protocol should specify which organ sites are to be 
evaluated at baseline (usually those most likely to be involved with metastatic disease for the 
tumor type under study) and how often evaluations are repeated. Normally, all target and non-
target sites are evaluated at each assessment. In selected circumstances, certain non-target 
organs may be evaluated less frequently. For example, bone scans may need to be repeated 
only when complete response is identified in target disease or when progression in bone is 
suspected. 
After the end of the treatment, the need for repetitive tumor evaluations depends on whether 
the trial has as a goal the response rate or the time to an event (progression/death). If ‘time to 
an event’ (e.g. time to progression, disease-free survival, progression-free survival) is the main 
endpoint of the study, then routine scheduled re-evaluation of protocol specified sites of 
disease is warranted. In randomized comparative trials in particular, the scheduled assessments 
should be performed as identified on a calendar schedule (for example: every 6–8 weeks on 
treatment or every 3–4 months after treatment) and should not be affected by delays in therapy, 
drug holidays or any other events that might lead to imbalance in a treatment arm in the timing 
of disease assessment. 
2.6. Confirmatory measurement/duration of response 
2.6.1. Confirmation 
In non-randomized trials where response is the primary endpoint, confirmation of PR and CR 
is required to ensure responses identified are not the result of measurement error. This will also 
permit appropriate interpretation of results in the context of historical data where response has 
traditionally required confirmation in such trials (see Bogaerts J, et al, Eur Jour 
Cancer,2009;45:248-260). However, in all other circumstances, i.e. in randomized trials (phase 
II or III) or studies where stable disease or progression are the primary endpoints, confirmation 


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of response is not required since it will not add value to the interpretation of trial results. 
However, elimination of the requirement for response confirmation may increase the 
importance of central review to protect against bias, in particular in studies which are not 
blinded. 
In the case of SD, measurements must have met the SD criteria at least once after study entry 
at a minimum interval (in general not less than 6–8 weeks) that is defined in the study protocol. 
2.6.2. Duration of overall response 
The duration of overall response is measured from the time measurement criteria are first met 
for CR/PR (whichever is first recorded) until the first date that recurrent or progressive disease 
is objectively documented (taking as reference for progressive disease the smallest 
measurements recorded on study). 
The duration of overall complete response is measured from the time measurement criteria are 
first met for CR until the first date that recurrent disease is objectively documented.  
2.6.3. Duration of stable disease 
Stable disease is measured from the start of the treatment (in randomized trials, from date of 
randomization) until the criteria for progression are met, taking as reference the smallest sum 
on study (if the baseline sum is the smallest, this is the reference for calculation of PD).  
The clinical relevance of the duration of stable disease varies in different studies and diseases. 
If the proportion of patients achieving stable disease for a minimum period of time is an 
endpoint of importance in a particular trial, the protocol should specify the minimal time 
interval required between two measurements for determination of stable disease.  
Note: The duration of response and stable disease as well as the progression-free survival are 
influenced by the frequency of follow-up after baseline evaluation. It is not in the scope of this 
guideline to define a standard follow-up frequency. The frequency should take into account 
many parameters including disease types and stages, treatment periodicity and standard 
practice. However, these limitations of the precision of the measured endpoint should be taken 
into account if comparisons between trials are to be made.  
2.7. Progression-free survival/proportion progression-free 
2.7.1. Phase II trials 
This guideline is focused primarily on the use of objective response endpoints for phase II 
trials. In some circumstances, ‘response rate’ may not be the optimal method to assess the 
potential anticancer activity of new agents/regimens. In such cases ‘progression-free survival’ 
(PFS) or the ‘proportion progression-free’ at landmark time points, might be considered 
appropriate alternatives to provide an initial signal of biologic effect of new agents. It is clear, 
however, that in an uncontrolled trial, these measures are subject to criticism since an 
apparently promising observation may be related to biological factors such as patient selection 
and not the impact of the intervention. Thus, phase II screening trials utilizing these endpoints 
are best designed with a randomized control. Exceptions may exist where the behavior patterns 
of certain cancers are so consistent (and usually consistently poor), that a non-randomized trial 


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is justifiable. However, in these cases it will be essential to document with care the basis for 
estimating the expected PFS or proportion progression-free in the absence of a treatment effect. 
2.7.2. Phase III trials 
Phase III trials in advanced cancers are increasingly designed to evaluate progression-free 
survival or time to progression as the primary outcome of interest. Assessment of progression 
is relatively straightforward if the protocol requires all patients to have measurable disease. 
However, restricting entry to this subset of patients is subject to criticism: it may result in a 
trial where the results are less likely to be generalizable if, in the disease under study, a 
substantial proportion of patients would be excluded. Moreover, the restriction to entry will 
slow recruitment to the study. Increasingly, therefore, trials allow entry of both patients with 
measurable disease as well as those with non-measurable disease only. In this circumstance, 
care must be taken to explicitly describe the findings which would qualify for progressive 
disease for those patients without measurable lesions. Furthermore, in this setting, protocols 
must indicate if the maximum number of recorded target lesions for those patients with 
measurable disease may be relaxed from five to three. As found in the ‘special notes on 
assessment of progression’, these guidelines offer recommendations for assessment of 
progression in this setting. Furthermore, if available, validated tumor marker measures of 
progression (as has been proposed for ovarian cancer) may be useful to integrate into the 
definition of progression. Centralized blinded review of imaging studies or of source imaging 
reports to verify ‘unequivocal progression’ may be needed if important drug development or 
drug approval decisions are to be based on the study outcome. Finally, as noted earlier, because 
the date of progression is subject to ascertainment bias, timing of investigations in study arms 
should be the same. 


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APPENDIX F. RESPONSE ASSESSMENT IN NEURO-ONCOLOGY 
BRAIN METASTASES (RANO-BM)39 
Before the RANO brain metastases (RANO-BM) working group convened in 2011, clinical trials 
of patients with brain metastases were notable for their heterogeneity with respect to patient 
population, imaging modality, frequency of assessment, definitions of progression, and response 
(WHO versus modified Macdonald Criteria versus RECIST 1.1 versus ad hoc radiographic 
assessment criteria), among other features. Even though BMs are the most common malignant 
brain tumor, affecting up to one third of adults with cancer, the field lacked the common definitions 
and guidelines for response assessment and clinical trial design that are needed for quality and 
consistency in trial reporting. RANO-BM proposed response assessment on the basis of literature 
review and consensus opinion. For clinical trials of systemic agents, the group recommended the 
use of RECIST 1.1 for non-CNS response assessment and RANO-BM for CNS response 
assessment. With features that were adopted from RECIST and RANO-high grade gliomas 
(RANO-HGG) to meet the particular needs of patients with solid tumor brain metastases, RANO-
BM response assessment is based on the sum diameter of one-dimensional measurements, 
corticosteroid dosing, and clinical status (see Table 1 below). Guidance is also provided for cases 
in which patients were treated with stereotactic radiosurgery or immunotherapy to avoid equating 
treatment effect with tumor progression. 
Several controversies arose during the development of these criteria. As a result of concerns over 
reproducibility and the interpretation of changes in small lesions as well as to maintain consistency 
with RECIST 1.1, measurable disease was defined in RANO-BM as a contrast-enhancing lesion 
that can be accurately measured in at least one dimension with a minimum size of 10 mm. The 
working group acknowledged that many patients present with subcentimeter brain metastases and, 
therefore, RANO-BM provides guidance for investigators who choose to lower the minimum size 
limit of measurable disease to 5 mm. Similarly, the use of one-dimensional versus volumetric 
assessments was debated within the working group. Ultimately, one dimensional measurements 
formed the basis of RANO-BM criteria as the group felt that the existing data on volumetric 
assessments were not strong enough to justify the real-time cost and complexity as for RANO-
HGG. However, RANO-BM does provide guidance for those investigators who wish to include 
volumetric assessment within their trials.  


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Table 1. Neuro-Oncology Response Criteria for Brain Metastases 
Criterion 
CR 
PR 
SD 
PD 
Target lesions 
None 
≥ 30% decrease in sum LD 
relative to baseline 
< 30% decrease relative to 
baseline but < 20% increase 
in sum LD relative to nadir 
≥ 20% increase in sum 
LD relative to nadir* 
Nontarget lesions 
None 
Stable or improved 
Stable or improved 
Unequivocal PD* 
New lesion(s)† 
None 
None 
None 
Present* 
Corticosteroids 
None 
Stable or decreased 
Stable or decreased 
NA‡ 
Clinical status 
Stable or improved 
Stable or improved 
Stable or improved 
Worse* 
Requirement for 
response 
All 
All 
All 
Any‡ 
NOTE. Reprinted from Lin et al, with permission from Elsevier. (Lin NU, Lee EQ, Aoyama H, et al: Response assessment criteria for brain metastases: 
Proposal from the RANO group. Lancet Oncol 16:e270-e278, 2015) 
Abbreviations: CR, complete response; LD, longest dimension; NA, not applicable; PD, progressive disease; PR, partial response; SD, stable disease. 
*Progression occurs when this criterion is met. 
†New lesion = new lesion not present on prior scans and visible in at least two projections. If a new lesion is equivocal, for example, because of its small size, 
continued therapy may be considered and follow-up evaluation will clarify whether it represents truly new disease. If repeat scans confirm there is definitely a 
new lesion, then progression should be declared using the date of the initial scan showing the new lesion. For immunotherapy-based approaches, new lesions 
alone do not define progression. 
‡Increase in corticosteroids alone will not be taken into account in determining progression in the absence of persistent clinical deterioration. 


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APPENDIX G. ETHICAL STANDARDS 
Ethics and Regulatory Considerations 
This study will be conducted according to Good Clinical Practice (GCP), US 21 Code of Federal 
Regulations (CFR) Part 50, (Protection of Human Subjects), US 21 CFR Part 56 (Institutional 
Review Boards), International Conference on Harmonisation Guidance for Industry, E6 Good 
Clinical Practice: Consolidated Guidance, the Nuremberg Code, and the Declaration of Helsinki. 
General Instructions 
The U.S. Food and Drug Administration (FDA) regulates studies of drugs, biologics, and medical 
devices. Consequently, these studies are subject to GCP and FDA regulations and guidance issued 
by the FDA and are included in, but not limited to, the following parts of the CFR and guideline 
document: 
• 21 CFR Part 11 – Electronic Records; electronic signatures 
• 21 CFR Part 50 – Protection of Human Subjects 
• 21 CFR Part 54 – Financial Disclosure 
• 21 CFR Part 56 – Institutional Review Boards 
• 21 CFR Part 312 – Investigational New Drug Application 
• FDA Guidance for Industry:  Oversight of Clinical Investigations – A Risk-Based 
Approach to Monitoring, August 2013 
• FDA Guidance for IRBs, Clinical Investigators, and Sponsors, June 2010 
• FDA Guidance for Industry: Investigator Responsibilities – Protecting the Rights, Safety, 
and Welfare of Study Subjects, October 2009 
• FDA Guidance for Industry and Investigators: Safety Reporting Requirements for INDs 
and BA/BE studies, December 2012 
• Guidance for Industry E6 Good Clinical Practice: Consolidated Guidance, 1996 
Copies of these materials are available from the sponsor upon request. The purpose of these 
regulations and legal obligations is to define the standards and principles for the proper conduct of 
clinical trials that have been developed by the medical, scientific, and regulatory communities. 
They are not intended to impede or restrict clinical research. 
The ethical standards defined within GCP are intended to ensure that: 
• Human subjects are provided with an adequate understanding of the possible risks of their 
participation in the study, and that they have a free choice to participate or not; 
• The study is conducted with diligence and in conformance with the protocol in such a way 
as to insure the integrity of the findings; 
• The potential benefits of the research justify the risks. 
• Spirita Oncology, LLC is the Sponsor of the IND. The Sponsor is responsible for the 
following: 


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• Selecting qualified investigators, 
• Providing investigators with the information they need to properly conduct an 
investigation, 
• Ensuring proper monitoring of the investigation, 
• Ensuring that the study is conducted according to the general investigational plan and 
protocols contained in the IND, 
• Maintaining the IND, and 
• Ensuring that FDA and all participating investigators are properly informed of significant 
new information regarding adverse effects or risks associated with the drug being studied.