Clinical trial NCT04527549
Conditions: Clinical Stage IV Cutaneous Melanoma AJCC v8 Locally Advanced Melanoma Pathologic Stage IIIC Cutaneous Melanoma AJCC v8 Pathologic Stage IV Cutaneous Melanoma AJCC v8 Unresectable Melanoma
Sponsor: ECOG-ACRIN Cancer Research Group
Start date: 2021-06-01; Completion date: 2024-01-08
Enrollment: 5 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This phase II trial investigates how well adding hydroxychloroquine to the standard treatment of dabrafenib and trametinib works to overcome resistance and delay disease progression in treating patients with stage IIIC or IV BRAF V600E/K melanoma. Hydroxychloroquine may cause cell death in tumor cells that rely on a process called "autophagy" for survival. Dabrafenib and trametinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving hydroxychloroquine together with dabrafenib and trametinib may work better than dabrafenib and trametinib alone to shrink and stabilize the cancer.

Detailed description:
PRIMARY OBJECTIVE:

I. To determine the rate of one year progression-free survival (PFS) when hydroxychloroquine sulfate (hydroxychloroquine) or placebo is added to dabrafenib mesylate (dabrafenib) and trametinib dimethyl sulfoxide (trametinib) in advanced BRAFV600E/K melanoma with elevated lactate dehydrogenase (LDH).

SECONDARY OBJECTIVES:

I. To compare the PFS of both arms. II. To evaluate the best overall response rate by treatment arm. III. To evaluate the complete response (CR) rate by treatment arm. IV. To evaluate the adverse event rate by treatment arm. V. To evaluate overall survival (OS) by treatment arm.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM A: Patients receive dabrafenib mesylate orally (PO) twice daily (BID), trametinib dimethyl sulfoxide PO once daily (QD), and hydroxychloroquine sulfate PO BID on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

ARM B: Patients receive dabrafenib mesylate PO BID, trametinib dimethyl sulfoxide PO QD, and placebo PO BID on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 1 year.

Arms: arm 1: Patients receive dabrafenib mesylate PO BID, trametinib dimethyl sulfoxide PO QD, and hydroxychloroquine sulfate PO BID on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. arm 2: Patients receive dabrafenib mesylate PO BID, trametinib dimethyl sulfoxide PO QD, and placebo PO BID on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Interventions: intervention 1: Dabrafenib mesylate intervention 2: Hydroxychloroquine intervention 3: Placebo Administration intervention 4: Trametinib dimethyl sulfoxide
Intervention descriptions: intervention 1: Given PO intervention 2: Given PO intervention 3: Given PO intervention 4: Given PO

Protocol documents:
Prot_SAP_000.pdf: 
 
EA6191 
1 
The BAMM2 (BRAF, Autophagy, MEK inhibition in 
Melanoma) Study: A Randomized Double Blind Phase II 
Study of Dabrafenib and Trametinib with or without 
Hydroxychloroquine in Advanced BRAFV600E/K Melanoma 
with elevated LDH 
STUDY CHAIR: Ravi K. Amaravadi, MD 
STUDY STATISTICIAN: Yue Zheng, MS 
STUDY CO-CHAIR: Janice Mehnert, MD 
MELANOMA COMMITTEE CHAIR: Jedd Wolchok, MD, PhD 
Version Date:  January 19, 2023 
 
STUDY PARTICIPANTS 
 
ACTIVATION DATE 
ALLIANCE / Alliance for Clinical Trials in 
Oncology 
 
October 23, 2020 
Addendum #1 
NRG / NRG Oncology 
 
Addendum #2 
SWOG / SWOG 
 
Addendum #3 
 
 
 
 
 
 
 
 
 
 
 
 
Agents 
NSC# 
Supply 
Dabrafenib 
763760 
Commercial 
Trametinib 
763093 
Commercial 
Hydroxychloroquine 
and matching placebo 
4375 
Sandoz Inc, Division of 
Novartis 
Study Exempt from IND Requirements per 21 CFR 312.2(b) 
 


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Table of Contents 
Schema ...................................................................................................................... 6 
1. Introduction ........................................................................................................ 7 
1.1 
Rationale ................................................................................................... 7 
1.2 
Importance .............................................................................................. 16 
2. Objectives ......................................................................................................... 17 
2.1 
Primary Objective .................................................................................... 17 
2.2 
Secondary Objectives .............................................................................. 17 
3. Selection of Patients ......................................................................................... 18 
3.1 
Eligibility Criteria ..................................................................................... 18 
4. Registration Procedures .................................................................................... 23 
4.1 
Patient Registration ................................................................................ 26 
4.2 
Additional Requirements ........................................................................ 27 
4.3 
Medidata Rave ........................................................................................ 27 
4.4 
Data Quality Portal .................................................................................. 28 
4.5 
Emergency Unblinding ............................................................................ 28 
4.6 
Instructions for Patients who Do Not Start Assigned Protocol Treatment29 
5. Treatment Plan ................................................................................................. 30 
5.1 
Administration Schedule ......................................................................... 30 
5.2 
Adverse Event Reporting Requirements ................................................. 31 
5.3 
Comprehensive Adverse Events and Potential Risks lists (CAEPR) ......... 39 
5.4 
Dose Modifications ................................................................................. 46 
5.5 
Drug interactions: ................................................................................... 62 
5.6 
Supportive Care ....................................................................................... 64 
5.7 
Duration of Therapy ................................................................................ 64 
5.8 
Duration of Follow-up ............................................................................. 64 
6. Measurement of Effect ..................................................................................... 65 
6.1 
Antitumor Effect – Solid Tumors ............................................................. 65 
7. Study Parameters .............................................................................................. 73 
7.1 
Therapeutic Parameters .......................................................................... 73 
7.2 
Biological Sample Submissions ............................................................... 75 
8. Drug Formulation and Procurement ................................................................. 76 
8.1 
Dabrafenib mesylate (NSC 763760) ........................................................ 76 
8.2 
Trametinib dimethyl sulfoxide (NSC 763093) ......................................... 78 
8.3 
Hydroxychloroquine and Matching Placebo ........................................... 80 
9. Statistical Considerations .................................................................................. 86 
9.1 
Study Design and Objectives ................................................................... 86 
9.2 
Study Endpoints ...................................................................................... 86 
9.3 
Sample Size Considerations and Monitoring Plan .................................. 86 
9.4 
Statistical Analysis Plan ........................................................................... 87 
9.5 
Gender and Ethnicity .............................................................................. 87 
9.6 
Study Monitoring .................................................................................... 87 


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10. Specimen Submissions ...................................................................................... 89 
10.1 Submissions to ECOG-ACRIN Central Biorepository and Pathology 
Facility (CBPF) .......................................................................................... 89 
10.2 Shipping Procedures ............................................................................... 91 
10.3 Use of Specimens in Research ................................................................ 92 
10.4 ECOG-ACRIN Sample Tracking System .................................................... 92 
10.5 Sample Inventory Submission Guidelines ............................................... 93 
11. Electronic Data Capture .................................................................................... 94 
12. Patient Consent and Peer Judgment ................................................................ 94 
13. References ........................................................................................................ 94 
Appendix I  Pathology Submission Guidelines ........................................................ 97 
Appendix II  Patient Thank You Letter ................................................................... 102 
Appendix III  Patient Pill Calendar ......................................................................... 103 
Appendix IV  ECOG Performance Status ............................................................... 109 
Appendix V  EA6191 Collection and Shipping Kit Order Instructions .................... 110 
Appendix VI  Tumor Tissue Research Biopsy Reimbursement Instructions .......... 111 
 
 
 


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STUDY CHAIR 
Ravi K. Amaravadi, M.D. 
852 BRB 2/3 
421 Curie Blvd 
Philadelphia, PA 19104 
Phone: 215-796-5159 
E-mail: Ravi.amaravadi@pennmedicine.upenn.edu 
 
STUDY CHAIR LIAISON (SCL) 
Lydia Giles, BSN, RN 
Clinical Research Nurse 
University of Pennsylvania Abramson Cancer Center 
3400 Civic Center Boulevard 
Philadelphia, PA 19104 
Phone: 215-662-6389 
Email: Lydia.Giles@pennmedicine.upenn.edu 
 
 
 


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CANCER TRIALS SUPPORT UNIT (CTSU) ADDRESS AND CONTACT INFORMATION 
For regulatory requirements: 
For patient enrollments: 
For study data 
submission: 
Regulatory documentation 
must be submitted to the 
CTSU via the Regulatory 
Submission Portal. 
(Sign in at www.ctsu.org, and 
select the Regulatory  
Institutions with patients 
waiting that are unable to use 
the Portal should alert the 
CTSU Regulatory Office 
immediately at 1-866-651-
2878 to receive further 
instruction and support. 
Contact the CTSU Regulatory 
Help Desk at 1-866-651-2878 
for regulatory assistance. 
Please refer to the patient enrollment 
section of the protocol for instructions 
on using the Oncology Patient 
Enrollment Network (OPEN) which can 
be accessed at 
https://www.ctsu.org/OPEN_SYSTEM/ 
or https://OPEN.ctsu.org. 
 
Contact the CTSU Help Desk with any 
OPEN-related questions at 
ctsucontact@westat.com. 
Data collection for this 
study will be done 
exclusively through 
Medidata Rave. Please see 
the data submission section 
of the protocol for further 
instructions. 
Do not submit study data or 
forms to CTSU Data 
Operations. Do not copy 
the CTSU on data 
submissions. 
The most current version of the study protocol and all supporting documents must be downloaded 
from the protocol-specific Web page of the CTSU Member Web site located at https://www.ctsu.org. 
Access to the CTSU members’ website is managed through the Cancer Therapy and Evaluation 
Program - Identity and Access Management (CTEP-IAM) registration system and requires user log on 
with CTEP-IAM username and password.  
Permission to view and download this protocol and its supporting documents is restricted and is based 
on person and site roster assignment housed in the CTSU Regulatory Support System (RSS).   
For clinical questions (i.e., patient eligibility or treatment-related) Contact the Study PI of the 
Coordinating Group. 
For non-clinical questions (i.e., unrelated to patient eligibility, treatment, or clinical data 
submission) contact the CTSU Help Desk by phone or e-mail:  
CTSU General Information Line – 1-888-823-5923, or ctsucontact@westat.com. All calls and 
correspondence will be triaged to the appropriate CTSU representative.  
The CTSU Web site is located at   https://www.ctsu.org 
 


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Schema 
Arm A2
Dabrafenib 150 mg PO BID
Trametinib 2 mg PO QD
Hydroxychloroquine 
(HCQ) 600 mg PO BID (3 
pills)
 R1
A
N
D
O
M
I
Z
A
T
I
O
N
1. Randomization will be double blinded 1:1.
2. When a patient has been randomized, the confirmation of the registration will indicate that the patient is on Arm 
X. The patient will actually be on Arm A or B, however, since this is a double-blinded trial, that information 
cannot be displayed.
3. Dabrafenib and trametinib may be continued indefinitely until progression of disease. Due to the risk of retinal 
toxicity HCQ/placebo will be administrated for a maximum of 2 years unless there is sufficient evidence from a 
comprehensive retinal exam that there are no early signs of retinal toxicity and the treating ophthalmologist 
provides a written plan of monitoring more frequently than yearly for treatment beyond 2 years
Arm B2
Dabrafenib 150 mg PO BID
Trametinib 2 mg PO QD
Placebo PO BID (3 pills)
Follow-Up
Continue treatment 
until disease 
progression
OR
unacceptable toxicity3
 
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Introduction 
1.1 
Rationale 
BRAF and MEK inhibition is a standard of care therapy for BRAF mutant 
melanoma patients. Not every patient responds, and most responses are not 
complete responses. Eventually the vast majority of patients progress. A new 
approach to overcome resistance to BRAF and MEK inhibition is needed. 
Autophagy has been identified as a major resistance mechanism to BRAF and/or 
BRAF/MEK inhibition in BRAF mutant cancers (1-10) The only clinically available 
drugs to target autophagy are the chloroquine derivatives. The first 6 clinical trials 
involving combinations of hydroxychloroquine (HCQ) and cancer drugs (11-15) 
have been published and have demonstrated the safety of the approach in 
patients with advanced solid tumors. Finally a series of recent papers has 
convincingly demonstrated that chloroquine derivatives are not simply weak 
bases that deacidify the lysosome. In fact they are targeted therapies that bind 
and inhibit palmitoyl protein thioesterase 1 (PPT1) in the lysosome (16, 17). 
As described below the BAMM (BRAF Autophagy and MEK inhibition for 
Melanoma) trial demonstrates an 85% response rate without significant excess 
toxicity when dabrafenib and trametinib are combined with HCQ in patients with 
anti-PD1 Ab naïve or anti-PD1 Ab refractory Stage IV BRAF mutant melanoma. 
In this study while the response rate was higher than previous response rates 
observed with dabrafenib and trametinib (60-70%), the PFS was not significantly 
different than historical controls from previous randomized trials of dabrafenib 
and trametinib (12 months). One possible explanation for this finding was that the 
BAMM trial had a higher enrollment of subjects with elevated LDH who were 
previously treated with immunotherapy than most of the published trials with 
dabrafenib and trametinib (see below for comparisons and references). Post-hoc 
analysis of the patients with elevated LDH revealed a prolonged PFS compared 
to historical controls. 
Typically BRAF mutant melanoma patients with elevated LDH have low response 
rates and short progression-free survival when treated with BRAF and MEK 
inhibitors. There is an unmet need to develop new therapeutic regimens for 
patients with elevated LDH. Melanoma tumors from patients with elevated serum 
LDH are dependent on glycolytic metabolism driven by hypoxia-induced HIF1 
alpha signaling (21). Hypoxic tumors drive upregulation of glycolysis, leading to 
increased lactate production. Excess lactate in the tumor microenvironment is 
shuttled back into the cancer cell through monocarboxylate transporters. 
Elevation of intracellular lactate drives expression of LDH which is secreted and 
measurable in the serum. Mechanistic studies (Brisson Cancer Cell 2016) have 
demonstrated that elevated LDH within the cancer cell drives lysosomal 
acidification and increases autophagic flux. Hence melanoma tumors with 
elevated LDH are possibly more susceptible to autophagy inhibition than tumors 
with normal LDH. Therefore, with evidence of tolerability and increased response 
rate established the single arm BAMM study, and a mechanistic rationale as well 
as a clinical unmet need that supports investigating this regimen in elevated LDH 
patients, we propose a randomized trial of dabrafenib and trametinib (D+T) with 
HCQ or placebo in Stage III/IV BRAF mutant melanoma patients with elevated 
LDH. 
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Only a randomized trial would answer the question of whether or not the addition 
of HCQ is adding to the activity of targeted therapy in patients with elevated LDH. 
Here we describe a double-blind placebo-controlled phase II trial in patients with 
RECIST measurable unresectable stage IIIC or stage IV BRAF inhibitor naïve 
BRAFV600E/V600K melanoma with elevated LDH who have been previously treated 
with an immune checkpoint inhibitor. Based on the variability of the control arm 
outcomes in multiple targeted therapy trials we propose a 1:1 randomization 
between D+T+ placebo and D+T+HCQ with the primary objective to determine if 
the addition of HCQ significantly improves the rate of progression-free survival 
(PFS) at 12 months. Response will be measured by RECIST 1.1 by investigator 
assessment. 
Given the number of durable CRs observed (see below) and the lack of almost 
any additional grade 3-4 toxicity compared to published reports of D+T toxicity, 
there are already indications that the median PFS for D + T + HCQ will be longer 
than the 5.5 months observed in previous trials of D + T alone in patients with 
LDH for the triple drug combination. The safety of this regimen is in stark contrast 
to the safety of some immunotherapy based regimens. If this randomized study is 
positive, a randomized phase III study would be warranted. This trial is designed 
as a proof of a biological principle and is not a registration trial for regulatory 
agencies. 
Single arm clinical trial data: The BAMM (BRAF, Autophagy MEK inhibition in 
Melanoma) trial is a four-institution (UPENN, Rutgers, Northwestern, Washington 
University) phase I/II trial of dabrafenib (D), trametinib (T) and HCQ 
(NCT02257424). Phase I was completed with no dose limiting toxicities (DLT). 
The recommended phase II dose was HCQ 600 bid with D+T. Phase II 
enrollment was halted after 34 evaluable patients were accrued. 38 patients in 
the phase I and II trial were evaluable for toxicity. Compared to COMBI-V the 
phase III trial of D + T versus vemurafenib (18) D+T+HCQ was well tolerated with 
rash (12%) the only grade 3 toxicity that was slightly increased in the triple 
combination compared to published reports of the standard doublet combination 
(4% grade 3 rash). An initial long term follow-up of the first 10 patients enrolled 
was published and reported no clinically significant ocular toxicity (19). 
Results of BAMM1 (NCT0225742) 
1.1.1 
BAMM1 study eligibility criteria includes: 
• 
Must be ≥ 18 years of age. 
• 
Must have histologically confirmed melanoma Stage IV or 
unresectable Stage III positive for BRAF V600E, V600K V600R or 
V600D mutation by a CLIA approved assay 
• 
Must have ECOG performance status of 0 or 1 
• 
Must have adequate renal, liver, cardiac and hematological 
function 
• 
Must be able to provide written informed consent. 
• 
Patients with brain metastases treated with whole brain radiation 
that have been stable for 2 months are eligible; patients with brain 
metastases treated with gamma knife or surgery are allowed to 
participate after 2 weeks have elapsed since their procedure, and 
must be off steroids for 1 week prior to starting study treatment. 


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• 
May have had any number and type of prior anticancer therapies. 
Patients with prior BRAF or MEK inhibitors are not allowed to 
participate. 
Exclusions: Porphyria, uncontrolled psoriasis, history of retinal 
vein occlusion in either eye, concurrent malignancies within the 
last 2 years except for prostate cancer and breast cancer for 
which no concurrent therapy is indicated. Taking P450 enzyme-
inducing anticonvulsant drugs 
1.1.2 
Final analysis of the BAMM study demonstrates that dabrafenib, 
trametinib and HCQ at 600 mg PO BID is well tolerated with no 
excess toxicities except slightly more grade 1-2 constipation and 
anorexia than might be expected with dabrafenib and trametinib 
alone. The efficacy of the regimen was striking with an 85% response 
rate. However the 11.9 month median progression-free survival did 
not meet the pre-specified criteria for success. One possible 
explanation for lack of difference in the PFS compared to historical 
control is that the BAMM trial had a higher proportion of the patients 
(47%) had elevated LDH and were pre-treated with immunotherapy. 
This is a very different patient population than previously reported 
studies for BRAF and MEK inhibitor combinations, which typically 
have a lower rate of elevated LDH patients and patients who were 
immunotherapy naïve. These data warrant further study of this 
regimen in a randomized phase II setting. 
Patients 
• 
50 patients consented and screened 
• 
38 accrued of target 47 and evaluable for toxicity 
• 
34 of target 47 evaluable for response and PFS 
Patients were typical for a stage IV melanoma population (Table 1). 
Of note there was a lower rate of M1c, elevated LDH and previously 
treated patients. 
Table 1. Demographics 
Age, Median 
(Range) 
58 (30-83) 
Sex 
Female 
11/ 38 (29%) 
Male  
27/38 (71%) 
ECOG Performance Status  
ECOG PS 0 
27/38 (71%) 
ECOG PS 1 
11/38 (29%) 
LDH at Study Entry  
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Table 1. Demographics 
LDH ≤ ULN  
20/38 (53%) 
LDH > ULN  
18/38 (47%) 
Stage at Study Entry  
Unresectable Stage 
IIIC 
0/38 (0%) 
Stage IV M1a 
9/38 (24%) 
Stage IV M1b 
9/38 (24%) 
Stage IV M1c  
15/38 (39%) 
Stage IV M1d 
5/38 (13%) 
# Prior systemic therapies  
0 
18/38 (47%) 
1 
9/38 (24%) 
2 
9/38 (24%) 
3 
2/38 (5%) 
Brain metastases  
5/38 (13%) 
Comparing the demographics between BAMM and COMBI-V we see 
that the BAMM population has a much higher percentage of patients 
with elevated LDH and a much higher percentage of patients 
previously treated with immunotherapy. Both of these are poor 
prognostic factors that significantly reduce the PFS to targeted 
therapy. 
1.1.3 
Phase I dose escalation 
Six patients were enrolled on the phase I dose escalation portion of 
the BAMM study. No DLTs were reported. The recommended phase II 
dose of HCQ 600 mg po bid combined with dabrafenib 150 mg po bid 
and trametinib 2 mg po qd was used for the single arm phase II study. 
All patients in the phase I and II portions of the study were assessed 
for response and toxicity below. 
Response 
The investigator assessed best overall response rate for the study 
population was 85% (Table 2). The complete response rate was 41%. 
Below we provide post-hoc exploratory subgroup analyses of this 
single arms study. The best overall response rate for patients with 
elevated LDH (88%), prior therapy (83%), and baseline tumor size ≥ 5 
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cm (89%), and the complete response rate in elevated LDH (25%), 
prior therapy (39%), and baseline tumor size ≥ 5 cm (33%) suggests 
this regimen is effective at eliciting response in the most aggressive 
Stage IV BRAF mutant melanoma patients. Waterfall plots for the 
overall population and these subgroups demonstrates this further 
(Figure 1). 
Table 2. Response Rates 
Response Investigator 
Assessed 
Rad. Core 
Assessed* LDH≤ULN 
LDH>ULN 
No prior 
therapy 
Prior 
therapy 
BTS< 5 cm BTS ≥ 5 cm 
CR 
14/34 (41%)  
10/18 (56%) 4/16 (25%) 7/16 (44%) 7/18 (39%) 8/16 (50%) 6/18 (33%) 
PR 
15/34 (46%)  
5/18 (27%) 10/16 (63%) 7/16 (44%) 8/18 (44)% 5/16 (31%) 10/18 (56%) 
SD 
3 (8%) 
 
2/18 (11%) 1/16 (6%) 2/16 (12%) 1/18 (6%) 2/16 (13%) 1/18 (6%) 
PD 
2 (5%) 
 
1/18 (6%) 
1/16 (6%) 
0 
2/18 (11%) 1/16 (6%) 
1/18 (5%) 
N  
34 
 
18 
16 
16 
18 
16 
18 
BORR 
29/34 (85%)  
15/18 (83%) 14/16 (88%) 
14/16 
(88%) 
15/18 
(83%) 
14/16 (81%) 16/18 (89%) 
*In process; CR: complete response; PR: partial response; SD: stable disease; PD: progressive disease; 
BORR: Best Overall Response Rate; LDH: lactate dehydrogenase; ULN: upper limit of normal; BTS: Baseline 
Tumor Size 


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Fig. 1 Waterfall Plots for Maximum change in Target lesions. Overall study population B. According to 
LDH status C. According to prior therapy D. According to Baseline tumor size as determined by the sum 
of the RECIST target lesions on baseline scans 
Progression-free survival. The one-year progression-free survival 
rate for the entire study population was 14/24 (41%). The median PFS 
for the entire study population was 11.9 months (Figure 2A). We 
performed post-hoc exploratory sub-group analyses for PFS. The 
median PFS for patients with elevated LDH (8 Mo.; Figure 2B), prior 
therapy (15.5 Mo.; Figure 2C), and baseline tumor size > 5 cm (8.5 
Mo.; Figure 2D) suggests this regimen may have a role in increasing 
the duration of response in previously treated patients with elevated 
LDH.  
Overall Survival. With 38 months of median followup the median 
overall survival was 28 months in the overall population (Figure 3A). 
We performed post-hoc exploratory sub-group analyses for OS. The 
median OS for patients with elevated LDH (25 Mo.; Figure 3B), prior 
therapy (25 Mo.; Figure 3C), and baseline tumor size > 5 cm (25 mo.; 
Figure 3D) suggests this regimen may have a role in increasing 
survival of previously treated patients with elevated LDH. 
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Fig. 2 Progression-free survival A. Overall study population B. According 
to LDH status C. According to prior therapy D. According to baseline tumor 
size as determined by the sum of the RECIST target lesions on baseline 
scans. Tick marks indicate censored patients who never progressed by 
RECIST criteria. 
 
Fig. 3 Overall survival (Median Follow-up 38 months) Overall study 
population B. According to LDH status C. According to prior therapy D. 
According to baseline tumor size as determined by the sum of the RECIST 
target lesions on baseline scans. Tick marks indicate censored patients who 
have not died. 
1.1.4 
BAMM1 Adverse Events 
The addition of HCQ to dabrafenib and trametinib seems to be very 
well tolerated, with no significant increase in grade 3 toxicities. The 
addition of HCQ may result in slightly more GI side effects of 
constipation and anorexia than would be expected from dabrafenib 


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and trametinib, but these adverse events were not dose limiting. The 
most common dose limiting adverse event was fever/ pyrexia which is 
the most common reason for discontinuation of dabrafenib and 
trametinib. 
Table 3. Adverse Events  
 
Dabrafenib + trametinib + HCQ (BAMM) 
Dabrafenib + 
trametinib (COMBI-V)* 
Adverse Event 
Grade 1-2 
Grade 3 
Grade 4 
Any Grade 
Grade 3 
Chills 
14 (56%) 
1 (4%) 
0 
31% 
1% 
Diarrhea 
13 (52%) 
0 
0 
32% 
1% 
Fever 
13 (52%) 
1 (4%) 
0 
53% 
4% 
Nausea 
12 (48%) 
1 (4%) 
0 
35% 
1% 
Fatigue 
11 (44%) 
0 
0 
NR 
NR 
Headache 
9 (36%) 
0 
0 
NR 
NR 
Myalgia 
9 (36%) 
0 
0 
NR 
NR 
Rash 
9 (36%) 
3 (12%) 
0 
22% 
4% 
Anorexia 
8 (32%) 
0 
0 
NR 
NR 
Dry mouth 
7 (28%) 
0 
0 
NR 
NR 
Pruritus 
7 (28%) 
0 
0 
NR 
NR 
Arthralgia 
6 (24%) 
0 
0 
24% 
1% 
Abdominal pain 
5 (20%) 
0 
0 
NR 
NR 
Vomiting 
5 (20%) 
0 
0 
29% 
1% 
Constipation 
4 (16%) 
0 
0 
NR 
NR 
Dysgeusia 
4 (16%) 
0 
0 
NR 
NR 
Creatinine 
increased 
3 (12%) 
0 
0 
NR 
NR 
Dehydration 
3 (12%) 
2 (8%) 
0 
NR 
NR 
Electrocardiogram 
QT corrected 
interval prolonged 
3 (12%) 
1 (4%) 
0 
NR 
NR 
Allergic reaction 
2 (8%) 
0 
0 
NR 
NR 
Anemia 
2 (8%) 
0 
0 
NR 
NR 
Dizziness 
2 (8%) 
0 
0 
NR 
NR 
Other, squamous 
cell carcinoma 
2 (8%) 
0 
0 
1% 
0 
Photosensitivity 
2 (8%) 
0 
0 
4% 
0 
Weight Loss 
2 (8%) 
0 
0 
NR 
NR 
Alanine 
aminotransferase 
increased 
1 (4%) 
2 (8%) 
0 
NR 
NR 


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Table 3. Adverse Events  
 
Dabrafenib + trametinib + HCQ (BAMM) 
Dabrafenib + 
trametinib (COMBI-V)* 
Other, sigmoid 
polyp 
1 (4%) 
0 
0 
NR 
NR 
Ejection fraction 
decreased 
0 
1 (4%) 
0 
8% 
4% 
*From Combi-V Study (Robert et al. NEJM 2015) 
NR: Not reported in the paper 
1.1.5 
Cardiac adverse events of note 
12% of patients experienced asymptomatic Qtc prolongation which 
could be attributed to either dabrafenib and trametinib or the HCQ or 
to both. After consultation with a cardiologist all patients with Qtc 
prolongation were continued on therapy without dose modification and 
monitored with EKGs every cycle. No evidence of troponin elevation 
or acute coronary ischemia were noted. One patient experienced a 
clinically asymptomatic but irreversible drop in ejection fraction (EF) 
from 55% to 40% starting 8 months into therapy. After consultation 
with a cardiologist this was deemed as treatment related as there was 
no evidence of acute cardiac ischemia. The EF stabilized when MEK 
inhibitor was removed. This patient experienced a complete response 
and continued on study treated with dabrafenib and HCQ. He was 
treated on study for 2.5 years. 
1.1.6 
Additional information on tolerability of therapy 
The median duration of therapy (excluding patients who had recently 
enrolled) was 16 months (with a range of 2-33). There were 2/22 
evaluable patients that discontinued therapy earlier than progression 
and 1 additional patient who continued on BRAF and HCQ after echo 
showed decreased EF. Responses continued in patients that 
discontinued treatment early. Treatment was well tolerated enough 
that 3 patients were treated beyond isolated progression after local 
therapy (radiation) was administered. 
Comparison to historical data for dabrafenib and trametinib and 
conclusions. The BAMM trial did not meet its primary objective which 
was a one-year PFS rate that was significantly different than the 
historical control of 40%. Table 4 has an efficacy comparison of the 
BAMM trial data to the data for dabrafenib and trametinib in Robert et 
al. NEJM 2019 and Shadendrof Eur J Cancer 2017. While the addition 
of HCQ increased response rates substantially, in many cases 
responses were transient. However, in patients with elevated LDH, a 
population of patients that historically has poor outcomes with 
targeted therapy, there appears to be increased response rate, 
complete response rate and prolonged PFS with the addition of HCQ 
that could translate into an overall survival benefit. While examination 
of this subset of patients was a post-hoc exploratory analysis, there is 
a mechanistic reason why tumors in patients with elevated LDH may 
be especially sensitive to autophagy inhibition with HCQ. Since there 
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is an unmet clinical need to develop treatments for BRAF mutant 
patients with elevated LDH, further study of dabrafenib, trametinib and 
HCQ is warranted in patients with elevated LDH. 
Table 4. Efficacy Comparison 
 
Overall  
LDH> ULN  
 
D+T* 
BAMM 
D+T* 
BAMM 
% patients with elevated LDH 
34 
47 
 
 
CR (%) 
19 
41 
8
a 
25 
BORR (%) 
68 
85 
50-57
a 
88 
Median PFS, Mo. 
11.1 
11.9 
5.5 
8 
1year PFS (%) 
45 
41 
22 
31 
Median OS, Mo.**  
25.9 
28 
13 
25 
1 yr OS (%) 
79 
77 
50 
75 
2 yr OS (%) 
52 
60 
27 
60 
3 yr OS (%) 
44 
50 
22 
38 
4 yr OS (%) 
37 
45 
17 
38 
5 yr OS (%) 
34 
35 
16 
38 
*All data except (a) for D+T is from Robert et al. N Engl J Med 2019; 
381:626-636 
DOI: 10.1056/NEJMoa1904059 5 year outcomes of dabrafenib and 
trametinib in melanoma  
**BAMM median F/U for OS 38 months; a- from Schadendorf Eur. J Cancer 
2017 Three-year pooled analysis of factors associated with clinical outcomes 
across dabrafenib and trametinib combination therapy phase 3 randomized 
trial  
1.2 
Importance 
The treatment regimen of D + T + HCQ appears tolerable and warrants further 
study in poor-prognosis subsets of BRAF mutant melanoma patients. However 
all of the data supporting these conclusions comes from a single phase II study 
conducted at 4 institutions. It could be that the high response rate could have 
been due to chance in the BAMM phase II cohort. In order to test the hypothesis 
that the addition of HCQ to D + T will result in a significantly better outcomes for 
BRAF mutant melanoma patients with elevated LDH, a randomized clinical trial is 
needed. There is equipoise between the two arms on this study and therefore a 
double-blind placebo-controlled trial with no crossover allowed while on study will 
be conducted. 
The addition of HCQ to dabrafenib and trametinib will overcome targeted therapy 
resistance and significantly increase the rate of 12 month progression-free 
survival for patients with unresectable stage III or stage IV BRAF mutant 
melanoma with elevated LDH and previously treated with immunotherapy. 
 


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Objectives 
2.1 
Primary Objective 
To determine the rate of one year progression-free survival (PFS) when 
hydroxychloroquine or /placebo is added to dabrafenib and trametinib in 
advanced BRAFV600E/K melanoma with elevated LDH. 
2.2 
Secondary Objectives 
2.2.1 
To compare the PFS of both arms. 
2.2.2 
To evaluate the best overall response rate by treatment arm. 
2.2.3 
To evaluate the complete response (CR) rate by treatment arm. 
2.2.4 
To evaluate the adverse event rate by treatment arm. 
2.2.5 
To evaluate overall survival (OS) by treatment arm. 
 


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Selection of Patients 
Each of the criteria in the checklist that follows must be met in order for a patient to be 
considered eligible for this study. Use the checklist to confirm a patient’s eligibility. For 
each patient, this checklist must be photocopied, completed and maintained in the 
patient’s chart.  
In calculating days of tests and measurements, the day a test or measurement is 
done is considered Day 0. Therefore, if a test is done on a Monday, the Monday 
four weeks later would be considered Day 28.  
ECOG-ACRIN Patient No. ____________________________ 
Patient’s Initials (L, F, M) _______________________ 
Physician Signature and Date ___________________ 
NOTE: 
CTEP Policy does not allow for the issuance of waivers to any protocol 
specified criteria 
(http://ctep.cancer.gov/protocolDevelopment/policies_deviations.htm). 
Therefore, all eligibility criteria listed in Section 0 must be met, without 
exception. The registration of individuals who do not meet all criteria listed in 
Section 0 can result in the participant being censored from the analysis of the 
study, and the citation of a major protocol violation during an audit. All 
questions regarding clarification of eligibility criteria must be directed to the 
Group's Executive Officer (EA.ExecOfficer@jimmy.harvard.edu) or the 
Group's Regulatory Officer (EA.RegOfficer@jimmy.harvard.edu). 
NOTE: 
Institutions may use the eligibility checklist as source documentation if it has 
been reviewed, signed, and dated prior to randomization by the treating 
physician. 
3.1 
Eligibility Criteria 
3.1.1 
Patient must be ≥ 18 years of age. 
3.1.2 
Patient must have locally advanced unresectable stage IIIC to stage 
IV melanoma. 
3.1.3 
Patient must have BRAFV600E or BRAFV600K tumor genotype based on 
a CLIA approved assay. 
3.1.4 
Patient must have serum LDH > Upper limit of normal per institution 
standards. 
3.1.5 
Patient must have measurable disease by RECIST 1.1. Baseline 
measurements of sites of disease must be obtained within 3 weeks 
prior to study randomization. 
3.1.6 
Patient must have been treated with prior immune checkpoint inhibitor 
therapy (anti PD-1 antibody, anti-CTLA-4 antibody or a combination 
regimen including either or both agents) either in the adjuvant or 
metastatic setting. Patient may have received investigational agents in 
combination with standard therapy, as long as it was adhering to the 
timeframes outlined below in 3.1.6.3. 
3.1.6.1 
Patient must have discontinued active immunotherapy (IL-
2, interferon, anti-CTLA-4 antibody, anti-PD-1 antibody 
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etc.) or chemotherapy at least 4 weeks prior to 
randomization. 
3.1.6.2 
Patient must have discontinued any oral targeted therapy 
at least 2 weeks prior to randomization.  
3.1.6.3 
Patients must not receive any other investigational 
anticancer therapy during the period on study or the 4 
weeks prior to randomization. 
3.1.7 
Patient may have been treated with prior adjuvant therapy including 
combined BRAF and MEK inhibitor therapy. Patients will be eligible if 
they tolerated this therapy and did not discontinue the therapy due to 
toxicity AND ≥ 6 months have elapsed since the end of adjuvant 
BRAF and MEK inhibition. If patients received BRAF and MEK 
inhibitor therapy in the metastastic setting, they are not eligible. 
3.1.8 
Patient may have been treated with prior chemotherapy or radiation 
therapy. 
3.1.9 
Patients who are known to be experiencing an objective partial 
response to immunotherapy at the time of study enrollment are not 
eligible. 
3.1.10 
Patient must have an ECOG performance status of 0 or 1. 
3.1.11 
Patients with a prior or concurrent malignancy whose natural history 
or treatment does not have the potential to interfere with the safety or 
efficacy assessment of the investigational regimen are eligible for this 
trial. 
3.1.12 
Women must not be pregnant or breast-feeding due to the potential 
harm to an unborn fetus and possible risk for adverse events in 
nursing infants with the treatment regimens being used. 
All females of childbearing potential must have a blood test or urine 
study within 14 days prior to randomization to rule out pregnancy. 
A female of childbearing potential is defined as any woman, 
regardless of sexual orientation or whether they have undergone tubal 
ligation, who meets the following criteria: 1) has achieved menarche 
at some point, 2) has not undergone a hysterectomy or bilateral 
oophorectomy; or 3) has not been naturally postmenopausal 
(amenorrhea following cancer therapy does not rule out childbearing 
potential) for at least 24 consecutive months (i.e., has had menses at 
any time in the preceding 24 consecutive months). 
Female of child bearing potential? ______ (Yes or No) 
Date of blood test or urine study: ___________ 
3.1.13 
Women of childbearing potential and sexually active males must not 
expect to conceive or father children by using accepted and effective 
method(s) of contraception or abstaining from sexual intercourse for 
the duration of their participation in the study and for 4 months after 
the last dose of protocol treatment. 
3.1.14 
Patient must have recovered from clinically significant reversible 
toxicities from previous treatment prior to randomization. Abnormal 


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laboratory values may be grade 1, as long as they meet the eligibility 
criteria outlined in Section 3.1.26. 
3.1.15 
Patient must not have a history of interstitial lung disease (ILD) or 
chronic pneumonitis. 
NOTE: 
If there is radiographic evidence of ILD that is clinically 
insignificant and asymptomatic, the patient would be 
eligible.   
3.1.16 
Patient must not have porphyria or psoriasis due to risk of disease 
exacerbation unless the disease is well controlled and they are under 
the care of a specialist for the disorder who agrees to monitor the 
patient for exacerbations. 
3.1.17 
Patient must not have a previously documented retinal vein occlusion. 
3.1.18 
Patient must not have a history or evidence of increased 
cardiovascular risk including: 
3.1.18.1 
Left ventricular ejection fraction (LVEF) < institutional lower 
limit of normal measured within 14 days prior to 
randomization. 
3.1.18.2 
A QT interval corrected for heart rate using the Bazett‘s 
formula ≥ 480 msec; 
3.1.18.3 
Current clinically significant uncontrolled arrhythmias. 
Exception: Patients with controlled atrial fibrillation for >30 
days prior to randomization are eligible. 
3.1.18.4 
Acute coronary syndromes (including myocardial infarction 
and unstable angina), coronary angioplasty, or stenting 
within 6 months prior to randomization. 
3.1.18.5 
Abnormal cardiac valve morphology (≥ grade 2) 
documented by echocardiogram unless a cardiologist 
concludes the valve abnormality is not clinically significant. 
Patients with grade 1 abnormalities (i.e., mild 
regurgitation/stenosis) are eligible. 
3.1.18.6 
Patients with known history or current symptoms of cardiac 
disease, or history of treatment with cardiotoxic agents, 
should have a clinical risk assessment of cardiac function 
using the New York Heart Association Functional 
Classification. To be eligible for this trial, patients should 
be class 2B or better. 
3.1.19 
Patient must be able to swallow and retain oral medication and must 
not have any clinically significant gastrointestinal abnormalities that 
may alter absorption such as malabsorption syndrome or major 
resection of the stomach or bowels. 
3.1.20 
Patient with known serious concurrent infection or medical illness, 
including psychiatric disorders, which would jeopardize the ability of 
the patient to receive the treatment outlined in this protocol with 
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3.1.21 
Patient must not be receiving concurrent therapy for their tumor (i.e. 
chemotherapeutics or investigational agents). Radiotherapy delivered 
to palliate pain is allowed as long as it is not targeting a lesion that 
meets RECIST criteria for progression. Radiation therapy to the 
surgical bed with gamma knife radiotherapy while on treatment during 
the first cycle is allowed for small volume surgically resected brain 
metastases. Gamma knife radiotherapy for known active, 
asymptomatic small volume CNS lesions may be performed during 
the first cycle while on study. Radiotherapy for new CNS lesions 
identified beyond the first cycle is not allowed on study. 
3.1.22 
Patient must not have a known immediate or delayed hypersensitivity 
reaction or idiosyncrasy to drugs chemically related to study drug, or 
excipients or to dimethyl sulfoxide (DMSO). 
3.1.23 
Patient must not have received cytochrome P450 enzyme –inducing 
anticonvulsant drugs (EIADs) (i.e. phenytoin, carbamazepine, 
Phenobarbital, primidone or oxcarbazepine) within 4 weeks prior to 
randomization. 
3.1.24 
Patient must not have a current use of a prohibited medication as 
described in Section 5.5 on Potential for Drug-Drug Interaction. 
3.1.25 
Patient must have the ability to understand and the willingness to sign 
a written informed consent document. Patients with impaired decision-
making capacity (IDMC) who have a legally authorized representative 
(LAR) or caregiver and/or family member available will also be 
considered eligible. 
3.1.26 
Patient must have adequate organ and marrow function as defined 
below (these labs must be obtained ≤ 14 days prior to protocol 
randomization): 
Absolute neutrophil count ≥ 1,500/mcL 
ANC:__________ Date of Test:__________ 
Platelets ≥ 100,000/mcL 
Platelet:__________ Date of Test:__________ 
Total Bilirubin ≤ institutional upper limit of normal (ULN) 
Total Bilirubin:__________ Institutional ULN:_________ 
Date of Test:__________ 
AST(SGOT)/ALT(SGPT) ≤ 3.0 × Institutional ULN 
ALT:_______ Institutional ULN:_________ 
Date of Test:_______ 
AST:_______ Institutional ULN:______ ___ 
Creatinine ≤ 1.5 x institutional ULN 
Creatinine ______________ Institutional ULN:_________ 
Date of Test:________ 


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3.1.27 
Human immunodeficiency virus (HIV)-infected patients on effective 
anti-retroviral therapy with undetectable viral load within 6 months are 
eligible for this trial. 
3.1.28 
For patients with evidence of chronic hepatitis B virus (HBV) infection, 
the HBV viral load must be undetectable on suppressive therapy, if 
indicated. 
3.1.29 
Patients with a history of hepatitis C virus (HCV) infection must have 
been treated and cured. For patients with HCV infection who are 
currently on treatment, they are eligible if they have an undetectable 
HCV viral load. 
3.1.30 
Patient with asymptomatic new or progressive brain metastases 
(active brain metastases) are eligible if the treating physician 
determines that CNS specific treatment is not required. 
NOTE: 
Patient with treated brain metastases are eligible. No brain 
imaging is required, however, 1 week must elapse after 
gamma knife therapy. Patient treated with whole brain 
radiation that have been stable for 2 months are eligible. 
Patient are excluded if they have leptomeningeal disease 
or metastases causing spinal cord compression that are 
symptomatic or untreated or not stable (documented by 
imaging) for at least 3 months or requiring corticosteroids. 
Patients on a stable dose of corticosteroids for at least 1 
month or who have been off of corticosteroids for at least 1 
week are eligible. 
 
 
 
 
Physician Signature 
 
Date 
OPTIONAL: 
This signature line is provided for use by institutions wishing to 
use the eligibility checklist as source documentation. 
 
 


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Registration Procedures 
Cancer Therapy Evaluation Program Investigator Registration Procedures 
Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) 
policy require all individuals contributing to NCI-sponsored trials to register and to renew 
their registration annually. To register, all individuals must obtain a Cancer Therapy 
Evaluation Program (CTEP) Identity and Access Management (IAM) account at 
https://ctepcore.nci.nih.gov/iam. In addition, persons with a registration type of 
Investigator (IVR), Non-Physician Investigator (NPIVR), or Associate Plus (AP) (i.e., 
clinical site staff requiring write access to OPEN, Rave, or acting as a primary site 
contact) must complete their annual registration using CTEP’s web-based Registration 
and Credential Repository (RCR) at https://ctepcore.nci.nih.gov/rcr. 
RCR utilizes five person registration types. 
• 
IVR - MD, DO, or international equivalent; 
• 
NPIVR - advanced practice providers (e.g., NP or PA) or graduate level researchers 
(e.g., PhD); 
• 
AP - clinical site staff (e.g., RN or CRA) with data entry access to CTSU applications 
such as the Roster Update Management System (RUMS), OPEN, Rave; acting as a 
primary site contact, or with consenting privileges; 
• 
Associate (A) - other clinical site staff involved in the conduct of NCI-sponsored trials; 
and 
• 
Associate Basic (AB) - individuals (e.g., pharmaceutical company employees) with 
limited access to NCI-supported systems. 
RCR requires the following registration documents: 
Documentation Required 
IVR 
NPIVR 
AP 
A 
AB 
FDA Form 1572 
 
 
 
 
 
Financial Disclosure Form 
 
 
 
 
 
NCI Biosketch (education, 
training, employment, license, 
and certification) 
 
 
 
 
 
GCP training 
 
 
 
 
 
Agent Shipment Form (if 
applicable) 
 
 
 
 
 
CV (optional) 
 
 
 
 
 
An active CTEP-IAM user account and appropriate RCR registration is required to 
access all CTEP and Cancer Trials Support Unit (CTSU) websites and applications. In 
addition, IVRs and NPIVRs must list all clinical practice sites and IRBs covering their 
practice sites on the FDA Form 1572 in RCR to allow the following: 
• 
Added to a site roster 
• 
Assigned the treating, credit, consenting, or drug shipment (IVR only) tasks in OPEN 
• 
Act as the site-protocol PI on the IRB approval 
In addition, all investigators act as the Site-Protocol PI, consenting/treating/drug 
shipment, or as the CI on the DTL must be rostered at the enrolling site with a 


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participating organization (i.e., Alliance). Additional information can be found on the 
CTEP website at <https://ctep.cancer.gov/investigatorResources/default.htm>. For 
questions, please contact the RCR Help Desk by email at <RCRHelpDesk@nih.gov>. 
Cancer Trials Support Unit Registration Procedures 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
IRB Approval:   
For CTEP and Division of Cancer Prevention (DCP) studies open to the National Clinical 
Trials Network (NCTN) and NCI Community Oncology Research Program (NCORP) 
Research Bases after March 1, 2019, all U.S.-based sites must be members of the NCI 
Central Institutional Review Board (NCI CIRB). In addition, U.S.-based sites must accept 
the NCI CIRB review to activate new studies at the site after March 1, 2019. Local IRB 
review will continue to be accepted for studies that are not reviewed by the CIRB, or if 
the study was previously open at the site under the local IRB. International sites should 
continue to submit Research Ethics Board (REB) approval to the CTSU Regulatory 
Office following country-specific regulations. 
Sites participating with the NCI CIRB must submit the Study Specific Worksheet for 
Local Context (SSW) to the CIRB using IRBManager to indicate their intent to open the 
study locally. The NCI CIRB’s approval of the SSW is automatically communicated to the 
CTSU Regulatory Office, but sites are required to contact the CTSU Regulatory Office at 
CTSURegPref@ctsu.coccg.org to establish site preferences for applying NCI CIRB 
approvals across their Signatory Network. Site preferences can be set at the network or 
protocol level. Questions about establishing site preferences can be addressed to the 
CTSU Regulatory Office by emailing the email address above or calling 1-888-651-
CTSU (2878). 
Sites using their local IRB or REB, must submit their approval to the CTSU Regulatory 
Office using the Regulatory Submission Portal located in the Regulatory section of the 
CTSU website. Acceptable documentation of local IRB/REB approval includes: 
• 
Local IRB documentation; 
• 
IRB-signed CTSU IRB Certification Form; and/or 
• 
Protocol of Human Subjects Assurance Identification/IRB Certification/Declaration of 
Exemption Form. 
In addition, the Site-Protocol Principal Investigator (PI) (i.e. the investigator on the 
IRB/REB approval) must meet the following criteria to complete processing of the 
IRB/REB approval record: 
• 
Holds an Active CTEP status; 
• 
Rostered at the site on the IRB/REB approval (applies to US and Canadian sites 
only) and on at least one participating roster; 
• 
If using NCI CIRB, rostered on the NCI CIRB Signatory record; 
• 
Includes the IRB number of the IRB providing approval in the Form FDA 1572 in the 
RCR profile; and 
• 
Holds the appropriate CTEP registration type for the protocol. 
Additional Requirements 
Additional requirements to obtain an approved site registration status include: 
• 
An active Federal Wide Assurance (FWA) number; 


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• 
An active roster affiliation with the Lead Protocol Organization (LPO) or a 
Participating Organization (PO); and 
• 
Compliance with all protocol-specific requirements (PSRs). 
Protocol Specific Requirements for EA6191 Site Registration 
Downloading Site Registration Documents: 
• 
Download the site registration forms from the protocol-specific page located on the 
CTSU members’ website. Permission to view and download this protocol and its 
supporting documents is restricted based on person and site roster assignment. To 
participate, the institution and its associated investigators and staff must be 
associated with the LPO or a PO on the protocol. 
• 
Log on to https://www.ctsu.org and log in to the members’ area using your CTEP-
IAM username and password 
• 
Click on the Protocols tab in the upper left of your screen 
• 
Enter the protocol # in the search field at the top of the protocol tree, or 
• 
Click on the By Lead Organization folder to expand then select ECOG-ACRIN, 
and protocol number EA6191; 
• 
Click on Documents, select Site Registration, and download and complete the forms 
provided. (Note: For sites under the CIRB initiative, IRB data will load automatically 
to the CTSU as described above.) 
Submitting Regulatory Documents 
Submit required forms and documents to the CTSU Regulatory Office using the 
Regulatory Submission Portal on the CTSU website.  
To access the Regulatory Submission Portal log in to the CTSU members’ website, go to 
the Regulatory section and select Regulatory Submission. 
Institutions with patients waiting that are unable to use the Regulatory Submission Portal 
should alert the CTSU Regulatory Office immediately at 1-866-651-2878 in order to 
receive further instruction and support. 
Checking Your Site’s Registration Status: 
You can verify your site registration status on the members’ section of the CTSU 
website. 
• 
Log on to the CTSU members’ website; 
• 
Click on Regulatory at the top of your screen; 
• 
Click on Site Registration; 
• 
Enter your 5-character CTEP Institution Code and click on Go 
NOTE: 
The status shown only reflects compliance with site registration requirements 
as outlined above. It does not reflect compliance with protocol requirements 
for individuals participating on the protocol or the enrolling investigator’s 
status with the NCI or their affiliated networks. 
Patient Enrollment 
Patients must not start protocol treatment prior to randomization. 
Treatment should start within 7-10 working days after randomization. 


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Randomization 
Please note that no blinded starter supplies will be available for this study. At the time of 
patient randomization each patient will be assigned a specific blinded drug ID number 
(e.g. DR117). This blinded drug ID number should be included on the drug request form 
that is submitted to the ECOG-ACRIN Drug Team. (See Section 0 for complete details.) 
NOTE: 
When a patient has been successfully randomized, the confirmation of 
randomization will indicate that the patient is on Arm X. The patient will 
actually be randomized to Arm A or B, but as this is a double-blind trial, 
that information cannot be displayed. 
The Oncology Patient Enrollment Network (OPEN) is a web-based registration system 
available on a 24/7 basis. OPEN is integrated with CTSU regulatory and roster data and 
with the Lead Protocol Organization (LPOs) registration/randomization systems or 
Theradex Interactive Web Response System (IWRS) for retrieval of patient 
registration/randomization assignment. OPEN will populate the patient enrollment data in 
NCI’s clinical data management system, Medidata Rave. 
Requirements for OPEN access: 
• 
A valid CTEP-IAM account; 
• 
To perform enrollments or request slot reservations: Be on a LPO roster, ETCTN 
Corresponding roster, or PO roster with the role of Registrar. Registrars must hold a 
minimum of an AP registration type; 
• 
Have an approved site registration for a protocol prior to patient enrollment. 
To assign an Investigator (IVR) or Non-Physician Investigator (NPIVR) as the treating, 
crediting, consenting, drug shipment (IVR only), or receiving investigator for a patient 
transfer in OPEN, the IVR or NPIVR must list the IRB number used on the site’s IRB 
approval on their Form FDA 1572 in RCR. If a DTL is required for the study, the IVR or 
NPIVR must be assigned the appropriate OPEN-related tasks on the DTL. 
Prior to accessing OPEN, site staff should verify the following: 
• 
Patient has met all eligibility criteria within the protocol stated timeframes; and 
• 
All patients have signed an appropriate consent form and HIPAA authorization form 
(if applicable). 
NOTE: 
The OPEN system will provide the site with a printable confirmation of 
registration and treatment information. Please print this confirmation for your 
records. 
Access OPEN at https://open.ctsu.org or from the OPEN link on the CTSU members’ 
website. Further instructional information is in the OPEN section of the CTSU website at 
https://www.ctsu.org or https://open.ctsu.org. For any additional questions, contact the 
CTSU Help Desk at 1-888-823-5923 or ctsucontact@westat.com. 
4.1 
Patient Registration 
The following information is to be provided at the time of registration to the trial: 
4.1.1 
Protocol Number  
4.1.2 
Investigator Identification  
• 
Institution and affiliate name 
• 
Investigator’s name 


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4.1.3 
Patient Identification  
• 
Patient’s initials (first and last) 
• 
Patient’s Hospital ID and/or Social Security number 
• 
Patient demographics 
• 
Gender 
• 
Birth date (mm/yyyy) 
• 
Race 
• 
Ethnicity 
• 
Nine-digit ZIP code 
• 
Method of payment 
• 
Country of residence 
4.1.4 
Eligibility Verification  
Patients must meet all of the eligibility requirements listed in Section 
3.1. 
4.2 
Additional Requirements  
4.2.1 
Patients must provide a signed and dated, written informed consent 
form. 
NOTE: 
Copies of the consent are not collected by the ECOG-
ACRIN Operations Office – Boston. 
4.2.2 
Specimens are to be submitted for future undefined research studies 
as outlined in Section 0. 
4.3 
Medidata Rave 
Medidata Rave is a clinical data management system being used for data 
collection in this clinical trial. Access to the trial in Rave is controlled through the 
CTEP-IAM system and role assignments. 
Requirements to access Rave via iMedidata: 
• 
A valid CTEP-IAM account; and  
• 
Assigned a Rave role on the LPO or PO roster at the enrolling site of: Rave 
CRA, Rave Read Only, Rave CRA (LabAdmin), Rave SLA, or Rave 
Investigator.  
Rave role requirements: 
• 
Rave CRA or Rave CRA (Lab Admin) role must have a minimum of an 
Associate Plus (AP) registration type; 
• 
Rave Investigator role must be registered as an Non-Physician Investigator 
(NPIVR) or Investigator (IVR); and 
• 
Rave Read Only role must have at a minimum an Associates (A) registration 
type. 
Refer to https://ctep.cancer.gov/investigatorResources/default.htm for registration 
types and documentation required. 
Upon initial site registration approval for the study in Regulatory Support System 
(RSS), all persons with Rave roles assigned on the appropriate roster will be sent 


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a study invitation e-mail from iMedidata. To accept the invitation, site staff must 
log in to the Select Login (https://login.imedidata.com/selectlogin) using their 
CTEP-IAM username and password, and click on the accept link in the upper 
right-corner of the iMedidata page. Site staff will not be able to access the study 
in Rave until all required Medidata and study specific trainings are completed. 
Trainings will be in the form of electronic learnings (eLearnings), and can be 
accessed by clicking on the link in the upper right pane of the iMedidata screen. 
If an eLearning is required and has not yet been taken, the link to the eLearning 
will appear under the study name in iMedidata instead of the Rave EDC link; 
once the successful completion of the eLearning has been recorded, access to 
the study in Rave will be granted, and a Rave EDC link will display under the 
study name. 
Site staff that have not previously activated their iMedidata/Rave account at the 
time of initial site registration approval for the study in RSS will also receive a 
separate invitation from iMedidata to activate their account. Account activation 
instructions are located on the CTSU website in the Rave section under the Rave 
resource materials (Medidata Account Activation and Study Invitation 
Acceptance). Additional information on iMedidata/Rave is available on the CTSU 
members’ website in the Data Management > Rave section at 
www.ctsu.org/RAVE/ or by contacting the CTSU Help Desk at 1-888-823-5923 or 
by e-mail at ctsucontact@westat.com.   
4.4 
Data Quality Portal 
The Data Quality Portal (DQP) provides a central location for site staff to manage 
unanswered queries and form delinquencies, monitor data quality and timeliness, 
generate reports, and review metrics. 
The DQP is located on the CTSU members’ website under Data Management. 
The Rave Home section displays a table providing summary counts of Total 
Delinquencies and Total Queries. DQP Queries, DQP Delinquent Forms and the 
DQP Reports modules are available to access details and reports of unanswered 
queries, delinquent forms, and timeliness reports. Review the DQP modules on a 
regular basis to manage specified queries and delinquent forms. 
The DQP is accessible by site staff that are rostered to a site and have access to 
the CTSU website. Staff that have Rave study access can access the Rave study 
data using a direct link on the DQP. 
To learn more about DQP use and access, click on the Help icon displayed on 
the Rave Home, DQP Queries, and DQP Delinquent Forms modules. 
NOTE: 
Some Rave protocols may not have delinquent form details or reports 
specified on the DQP. A protocol must have the Calendar functionality 
implemented in Rave by the Lead Protocol Organization (LPO) for 
delinquent form details and reports to be available on the DQP. Site 
staff should contact the LPO Data Manager for their protocol 
regarding questions about Rave Calendaring functionality 
4.5 
Emergency Unblinding 
The information provided below is for the use by a physician, nurse, CRA 
or pharmacist treating the patient. These contact numbers should not be 
used by patients. Patients should be instructed to call their doctor’s office 


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in the event of an emergency or adverse event that may result in the need 
to unblind the patient. 
In the event of an emergency or severe adverse reaction necessitating 
identification of the medication for the welfare of the patient, please contact the 
EA Drug Team at DrugOrder@ecog-acrin.org during business hours (9am-4pm 
M-F Eastern Time) or AnswerConnect at 1-866-296-8940 outside of those hours.  
The request will require the protocol number (i.e., EA6191), the patient ID 
number (5-digit number), patient initials, patient step, your contact information, as 
well as the reason for unblinding.  ECOG-ACRIN staff may contact you for further 
details in order to determine the validity of the request, and will work to obtain the 
required approvals to unblind the patient.  Once approved, a staff member will 
provide the unblinded treatment identity.  Note that if a patient is unblinded, they 
must discontinue protocol treatment. 
4.6 
Instructions for Patients who Do Not Start Assigned Protocol Treatment 
If a patient does not receive any assigned protocol treatment, baseline and 
follow-up data will still be collected and must be submitted through Medidata 
Rave according to the schedule in the EA6191 Forms Completion Guidelines. 


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Treatment Plan 
5.1 
Administration Schedule 
NOTE: 
When a patient has been successfully randomized, the confirmation of 
registration will indicate that the patient is on Arm X. The patient will 
actually be randomized to Arm A or B, however, as this is a double-
blinded trial, that information cannot be displayed. 
NOTE: 
Dabrafenib, trametinib and hydroxychloroquine/placebo are all oral 
medications, requiring the patient to keep a study diary documenting 
their doses. The diary must be submitted at each clinic visit. See 
Appendix III. 
One cycle = 28 days. 
5.1.1 
Arm A 
• 
Dabrafenib 150 mg by mouth (PO) twice daily (BID) 
• 
Trametinib 2 mg by mouth (PO) once daily (QD) 
• 
Hydroxychloroquine (HCQ) 3 pills by mouth (PO) twice daily (BID) 
5.1.2 
Arm B 
• 
Dabrafenib 150 mg by mouth (PO) twice daily (BID) 
• 
Trametinib 2 mg by mouth (PO) once daily (QD) 
• 
Placebo 3 pills by mouth (PO) twice daily (BID) 
5.1.3 
Dabrafenib and Trametinib administration 
The starting dose for dabrafenib is 150 mg BID. Capsules of 
dabrafenib are available in 50 mg and 75 mg strength doses. 
Dabrafenib will be administered twice daily approximately twelve 
hours apart on an empty stomach – either one (1) hour before meals 
or two (2) hours after. Patients will be instructed to swallow the whole 
capsules in rapid succession without chewing. If a dose is missed, it 
should not be taken if it is less than 6 hours until the next dose. 
The starting dose of trametinib is 2 mg daily. Tablets of trametinib are 
available in 0.5 mg and 2 mg strength. Trametinib will be administered 
once daily on an empty stomach – either one (1) hour before meals or 
two (2) hours after. Patients will be instructed to swallow the whole 
tablet without chewing. If a dose of trametinib is missed, the dose can 
be taken if it is more than 12 hours until the next scheduled dose. 
5.1.4 
Hydroxychloroquine or placebo administration 
The starting dose of HCQ/placebo is 600 mg BID. The HCQ/placebo 
tablets are available in 200 mg strength, therefore patients taking 3 
tablets BID will be receiving a starting dose of 600 mg. HCQ/Placebo 
pills should be taken in the morning and evening (12 hours apart) with 
or without food. The HCQ/placebo dosing schedule may be adjusted 
as needed in order to minimize gastrointestinal side effects (see dose 
modification Section 5.4). 


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5.1.5 
Duration of treatment 
Dabrafenib and trametinib may be continued indefinitely until 
progression of disease. Due to the risk of retinal toxicity HCQ/placebo 
will be administrated for a maximum of 2 years unless there is 
sufficient evidence from a comprehensive retinal exam that there are 
no early signs of retinal toxicity and the treating ophthalmologist 
provides a written plan of monitoring more frequently than yearly for 
treatment beyond 2 years. 
5.1.6 
Concomitant Medication and Procedures 
Because HCQ has known effects on P450 enzymes, patients 
requiring anti-convulsants may be treated with any of the non-enzyme 
inducing anti-convulsants which include: felbamate, valproic acid, 
gabapentin, lamotrigine, tiagibine, topiramate, or levetiracetam. The 
exception is zonisamide which should be avoided, as zonisamide 
accumulates in red blood cells as does HCQ. For nausea, aprepitant 
should be avoided. Radiation therapy to the surgical bed with gamma 
knife radiotherapy while on treatment during the first cycle is allowed 
for small volume surgically resected brain metastases. Gamma knife 
radiotherapy for known active, asymptomatic small volume CNS 
lesions may be performed during the first cycle while on study. If 
radiotherapy is being delivered while the patient is on study, patients 
should hold all three study medications for 2 days prior to radiation 
and resume study medication one day after completion of radiation. 
Radiotherapy for new CNS lesions identified beyond the first cycle is 
not allowed on study. All other concomitant medications are permitted. 
5.2 
Adverse Event Reporting Requirements 
All toxicity grades described throughout this protocol and all reportable 
adverse events will be graded using the NCI Common Terminology Criteria 
for Adverse Events (CTCAE) version 5.0. 
All appropriate treatment areas should have access to a copy of the CTCAE 
version 5.0. A copy of the CTCAE version 5.0 can be downloaded from the 
CTEP website (http://ctep.cancer.gov). 
5.2.1 
Purpose 
Adverse event (AE) data collection and reporting, which are a 
required part of every clinical trial, are done so investigators and 
regulatory agencies can detect and analyze adverse events and risk 
situations to ensure the safety of the patients enrolled, as well as 
those who will enroll in future studies using similar agents.  
5.2.2 
Routine Reporting of Adverse Events (Medidata Rave) 
Adverse events are reported in a routine manner at scheduled times 
during a trial using the Medidata Rave clinical data management 
system. Please refer to Section 0 of the protocol for more information 
on how to access the Medidata Rave system and the EA6191 forms 
packet for instructions on where, when and what adverse events are 
to be reported routinely on this protocol. 


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5.2.3 
Expedited Reporting of Adverse Events (CTEP-AERS) 
In addition to routine reporting, certain adverse events must be also 
reported in an expedited manner for timelier monitoring of patient 
safety and care. The remainder of this section provides information 
and instructions regarding expedited adverse event reporting 
5.2.4 
Terminology 
• 
Adverse Event (AE): Any untoward medical occurrence 
associated with the use of an agent in humans, whether or not 
considered agent related. Therefore, an AE can be ANY 
unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated 
with the use of a medicinal product, whether or not considered 
related to the medicinal product. 
• 
Attribution: An assessment of the relationship between the 
adverse event and the protocol treatment, using the following 
categories. 
ATTRIBUTION 
DESCRIPTION 
Unrelated 
The AE is clearly NOT related to treatment. 
Unlikely 
The AE is doubtfully related to treatment. 
Possible 
The AE may be related to treatment. 
Probable 
The AE is likely related to treatment. 
Definite 
The AE is clearly related to treatment. 
• 
CAEPR (Comprehensive Adverse Events and Potential Risks 
List): An NCI generated list of reported and/or potential AEs 
associated with an agent currently under an NCI IND. Information 
contained in the CAEPR is compiled from the Investigator’s 
Brochure, the Package Insert, as well as company safety reports. 
• 
CTCAE: The NCI Common Terminology Criteria for Adverse 
Events provides a descriptive terminology that is to be utilized for 
AE reporting. A grade (severity) is provided for each AE term.  
• 
Expectedness: Expected events are those that have been 
previously identified as resulting from administration of the agent. 
An adverse event is considered unexpected, for expedited 
reporting purposes, when either the type of event or the severity of 
the event is NOT listed in the protocol or drug package insert. 
5.2.5 
Expedited Adverse Event Reporting Procedure 
Adverse events requiring expedited reporting will use CTEP’s Adverse 
Event Reporting System (CTEP-AERS). CTEP’s guidelines for CTEP-
AERS can be found at http://ctep.cancer.gov.   
A CTEP-AERS report must be submitted electronically via the CTEP-
AERS Web-based application located at http://ctep.cancer.gov., so 
that ECOG-ACRIN and all appropriate regulatory agencies will be 
notified of the event in an expeditious manner. 


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In the rare event when Internet connectivity is disrupted a 24-hour 
notification is to be made by telephone to  
• 
the AE Team at ECOG-ACRIN (857-504-2900) 
• 
the FDA (1-800-FDA-1088) 
An electronic report MUST be submitted via CTEP-AERS immediately 
upon re-establishment of internet connection. 
Supporting and follow up data: Any supporting or follow up 
documentation must be uploaded to the Supplemental Data Folder in 
Medidata Rave within 48-72 hours. In addition, supporting or follow up 
documentation must be faxed to FDA (800-332-0178) in the same 
timeframe. 
CTEP Technical Help Desk: For any technical questions or system 
problems regarding the use of the CTEP-AERS application, please 
contact the NCI Technical Help Desk at ncictephelp@ctep.nci.nih.gov 
or by phone at 1-888-283-7457. 
Many factors determine the requirements for expedited reporting of 
adverse events on each individual protocol. The instructions and 
tables in the following sections have been customized for protocol 
EA6191and outline the specific expedited adverse event reporting 
requirements for study EA6191. 
5.2.6 
Rave-CTEP-AERS integration 
The Rave Cancer Therapy Evaluation Program Adverse Event 
Reporting System (CTEP-AERS) Integration enables evaluation of 
post-baseline Adverse Events (AE) entered in Rave to determine 
whether they require expedited reporting and facilitates entry in 
CTEP-AERS for those AEs requiring expedited reporting.    
All AEs that occur after baseline are collected in Medidata Rave using 
the Adverse Event form, which is available for entry at each treatment 
or reporting period and used to collect AEs that start during the period 
or persist from the previous reporting period. CRA will enter AEs that 
occur prior to the start of treatment on a baseline form that is not 
included in the Rave-CTEP-AERS integration. AEs that occur prior to 
enrollment must begin and end on the baseline Adverse Events form 
and should not be included on the standard Adverse Events form that 
is available at treatment unless there has been an increase in grade. 
Prior to sending AEs through the rules evaluation process, site staff 
should verify the following on the Adverse Event form in Rave: 
• 
The reporting period (course/cycle) is correct; and 
• 
AEs are recorded and complete (no missing fields) and the form is 
query free.  
The CRA reports AEs in Rave at the time the Investigator learns of 
the event. If the CRA modifies an AE, it must be re-submitted for rules 
evaluation. 
Upon completion of AE entry in Medidata Rave, the CRA submits the 
AE for rules evaluation by completing the Expedited Reporting 
Evaluation form. Both NCI and protocol-specific reporting rules 


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evaluate the AEs submitted for expedited reporting. A report is 
initiated in CTEP-AERS using information entered in Medidata Rave 
for AEs that meet reporting requirements. The CRA completes the 
report by accessing CTEP-AERS via a direct link on the Medidata 
Rave Expedited Reporting Evaluation form. 
In the rare occurrence that Internet connectivity is lost, a 24-hour 
notification is to be made to CTEP by telephone at 301-897-7497. 
Once internet connectivity is restored, the 24-hour notification that 
was phoned in must be entered immediately into CTEP-AERS using 
the direct link from Medidata Rave. 
Additional information about the CTEP-AERS integration is available 
on the CTSU website: 
• 
Study specific documents: Protocols > Documents > Education 
and Promotion; and   
• 
Expedited Safety Reporting Rules Evaluation user guide: 
Resources > CTSU Operations Information > User Guides & Help 
Topics. 
NCI requirements for SAE reporting are available on the CTEP 
website:  
• 
NCI Guidelines for Investigators: Adverse Event Reporting 
Requirements is available at 
https://ctep.cancer.gov/protocolDevelopment/electronic_applicatio
ns/docs/aeguidelines.pdf. 
 


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5.2.7 
Steps to determine if an event is to be reported in an expedited 
manner 
 
 
 
Identify the type and grade of the event 
using the CTCAE. 
Determine if the event is related to the 
protocol treatment (attribution). 
With this information, review the chart in 
Section 5.2.8 to determine if the event 
requires expedited reporting. 
Refer to footnote b in 
Section 5.2.8 to 
determine if the event 
meets the protocol 
specific reporting 
requirements for this 
study. If so, report the 
event in CTEP-AERS  
Is the event 
reportable?
No 
Yes 
Report the event in CTEP-AERS 
Determine the expectedness of the 
event. An unexpected event is defined as 
one where the type of severity of the 
event is not listed in the investigator’s 
brochure, package insert or protocol. 


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5.2.8 
Expedited Reporting Requirements for Arm X (Arm A and Arm B) on 
protocol EA6191 
Commercial/IND Exempt Agents: Dabrafenib, Trametinib, and 
Hydroxychloroquine (HCQ)/Placebo 
Expedited reporting requirements for adverse events experienced by patients on arm(s) with 
commercial/IND exempt agents only 
Attribution 
Grade 4c 
Grade 5ac 
ECOG-ACRIN 
and Protocol-
Specific 
Requirements 
Unexpected 
Expected 
Unexpected 
Expected 
See footnote  
(b) for special 
requirements. 
Unrelated or 
Unlikely 
 
 
7 calendar 
days 
7 calendar 
days 
Possible,  
Probable,  
Definite 
7 calendar 
days 
 
7 calendar 
days 
7 calendar 
days 
7 Calendar Days: Indicates a full CTEP-AERS report is to be submitted within 7 calendar days of 
learning of the event. 
a 
A death occurring while on study or within 30 days of the last dose of treatment requires both 
routine and expedited reporting, regardless of causality. Attribution to treatment or other cause 
must be provided. 
NOTE: A death due to progressive disease should be reported as a Grade 5 “Disease 
progression” under the System Organ Class (SOC) “General disorder and 
administration site conditions”. Evidence that the death was a manifestation of 
underlying disease (e.g. radiological changes suggesting tumor growth or 
progression: clinical deterioration associated with a disease process) should be 
submitted. 
NOTE: Any death that occurs > 30 days after the last dose of treatment and is attributed 
possibly, probably, or definitely to the treatment must be reported within 7 calendar 
days of learning of the event.   
b 
Protocol-specific expedited reporting requirements: The adverse events listed below also require 
expedited reporting for this trial: 
Serious Events: Any event following treatment that results in persistent or significant 
disabilities/incapacities, congenital anomalies, or birth defects must be reported 
in CTEP-AERS accessed via Medidata Rave within 7 calendar days of learning 
of the event. For instructions on how to specifically report these events, please 
contact the AEMD Help Desk at aemd@tech-res.com or 301-897-7497. This will 
need to be discussed on a case-by-case basis. 
LVEF Changes: If any of the following circumstances occur, the event(s) must be reported via 
CTEP-AERS within 7 calendar days 
• 
Asymptomatic: Absolute decrease of >10% in LVEF compared to baseline 
and ejection fraction below the institution’s LLN that does not resolve within 4 
weeks (i.e.: defined as LVEF ≥LLN and absolute decrease ≤10% compared to 
baseline) 
• 
Symptomatic: Grade 3-4 LVEF 
Please refer to the dose modification instructions for further information regarding 
Treatment Modification and Management Guidelines for LVEF Decrease. 
Visual Changes: If RPED (retinal pigment epithelial detachments) is suspected or diagnosed or 
RVO (retinal vein occlusion) is diagnosed, the event(s) must be reported via 


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CTEP-AERS within 7 calendar days. Please refer to the dose modification 
instructions for further information regarding Treatment Modification and 
Management Guidelines for Visual Changes. 
Pyrexia:  Any occurrence of pyrexia accompanied by hypotension, or dehydration requiring IV 
fluids, or severe rigors/chills in the absence of an obvious infectious must be reported via 
CTEP-AERS within 7 calendar days. 
Liver Chemistry Changes: If any of the following circumstances occur, the event(s) must be 
reported via CTEP-AERS within 7 calendar days 
• 
ALT ≥ 3xULN and bilirubin ≥ 2x ULN or > 35% direct bilirubin 
• 
ALT ≥ 3xULN and INR ≥ 1.5, if INR measured (INR threshold does 
not apply if patient is on anticoagulant) 
• 
ALT > 5xULN 
• 
ALT > 3xULN persistent for > 4 weeks 
• 
ALT > 3xULN associated with symptoms (new or worsening) 
believe to be related to liver injury of hypersensitivity 
Please refer to the dose modification instructions for further information 
regarding Treatment Modification and Management Guidelines for 
Liver Chemistry Changes. 
c. NOTE: All adverse events meeting the criteria in this table that occurs while the patient is on study 
treatment and for 30 days after the last dose of protocol treatment must be reported in 
CTEP-AERs according to the timeframes outlined. Any adverse event meeting the criteria 
that occurs more than 30 days after the last dose of protocol treatment and is related to 
Hydroxychloroquine/Placebo must be reported in CTEP-AERS according to the timeframes 
outlined. 
5.2.9 
Other recipients of adverse event reports and supplemental data 
A drug supporter representative may call a site for additional or 
supplemental information regarding a serious adverse event. Any 
additional written AE information requested by the drug supporter 
MUST be submitted to BOTH ECOG-ACRIN and the drug supporter. 
Adverse events determined to require expedited reporting must also 
be reported by the institution, according to the local policy and 
procedures, to the Institutional Review Board responsible for oversight 
of the patient. 
5.2.10 
Second Primary Cancer Reporting Requirements 
All cases of second primary cancers, including acute myeloid 
leukemia (AML) and myelodysplastic syndrome (MDS), that occur 
following treatment on NCI-sponsored trials must be reported to 
ECOG-ACRIN using Medidata Rave. 
• 
A second malignancy is a cancer that is UNRELATED to any 
prior anti-cancer treatment (including the treatment on this 
protocol). Second malignancies require ONLY routine reporting 
as follows: 
1. Complete a Second Primary Form in Medidata Rave within 14 
days. 
2. Upload a copy of the pathology report to ECOG-ACRIN via 
Medidata Rave confirming the diagnosis. 


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3. If the patient has been diagnosed with AML/MDS, upload a 
copy of the cytogenetics report (if available) to ECOG-ACRIN 
via Medidata Rave. 
• 
A secondary malignancy is a cancer CAUSED BY any prior anti-
cancer treatment (including the treatment on this protocol). 
Secondary malignancies require both routine and expedited 
reporting as follows: 
1. Complete a Second Primary Form in Medidata Rave within 14 
days. 
2. Report the diagnosis via CTEP-AERS at 
http://ctep.cancer.gov. 
Report under a.) leukemia secondary to oncology 
chemotherapy, b.) myelodysplastic syndrome, or c.) treatment 
related secondary malignancy 
3. Upload a copy of the pathology report to ECOG-ACRIN via 
Medidata Rave and submit a copy to NCI/CTEP confirming the 
diagnosis. 
4. If the patient has been diagnosed with AML/MDS, upload a 
copy of the cytogenetics report (if available) to ECOG-ACRIN 
via Medidata Rave and submit a copy to NCI/CTEP. 
NOTE: 
The ECOG-ACRIN Second Primary Form and the CTEP-
AERS report should not be used to report recurrence or 
development of metastatic disease. 
NOTE: 
If a patient has been enrolled in more than one NCI-
sponsored study, the ECOG-ACRIN Second Primary Form 
must be submitted for the most recent trial. ECOG-ACRIN 
must be provided with a copy of the form and the 
associated pathology report and cytogenetics report (if 
available) even if ECOG-ACRIN was not the patient's most 
recent trial. 
NOTE: 
Once data regarding survival and remission status are no 
longer required by the protocol, no follow-up data should 
be submitted in CTEP-AERS or by the ECOG-ACRIN 
Second Primary Form. 


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5.3 
Comprehensive Adverse Events and Potential Risks lists (CAEPR) 
5.3.1 
Comprehensive Adverse Events and Potential Risks list (CAEPR) for 
Dabrafenib NSC763760 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) 
provides a single list of reported and/or potential adverse events (AE) 
associated with an agent using a uniform presentation of events by 
body system. Frequency is provided based on 1374 patients. Below is 
the CAEPR for Dabrafenib 
Version 2.5, September 30, 20191 
 
 Adverse Events with Possible  
 Relationship to Dabrafenib (GSK2118436B) 
 (CTCAE 5.0 Term) 
[n= 1374] 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
 
Anemia2,3 
 
EYE DISORDERS 
 
 
Eye disorders - Other (iritis)4 
 
 
Uveitis4 
GASTROINTESTINAL DISORDERS 
 
Abdominal pain 
 
 
 
Colitis 
 
 
Colonic perforation 
 
Constipation 
 
 
Diarrhea 
 
Nausea 
 
 
 
 
Pancreatitis 
 
Vomiting 
 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
 
Chills 
 
 
Edema limbs5 
 
Fatigue 
 
 
Fever6 
 
 
 
Flu like symptoms 
 
IMMUNE SYSTEM DISORDERS 
 
 
Allergic reaction7 
INFECTIONS AND INFESTATIONS 
 
Upper respiratory infection 
 
INVESTIGATIONS 
 
Creatinine increased3 
 
 
Neutrophil count decreased3 
 
 
Platelet count decreased3 
 
 
White blood cell decreased3 
 
METABOLISM AND NUTRITION DISORDERS 
 
Anorexia 
 
 
Hyperglycemia3 
 
 
Hypokalemia3 
 
 
Hyponatremia3 
 


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 Adverse Events with Possible  
 Relationship to Dabrafenib (GSK2118436B) 
 (CTCAE 5.0 Term) 
[n= 1374] 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
Hypophosphatemia3 
 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
Arthralgia 
 
 
 
Back pain 
 
 
Myalgia 
 
 
Pain in extremity 
 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) 
 
Neoplasms benign, malignant 
and unspecified (incl cysts and 
polyps) - Other (squamous cell 
carcinoma or keratoacanthoma)8 
 
 
Skin papilloma 
 
 
 
Treatment related secondary 
malignancy (non-SCC)9 
NERVOUS SYSTEM DISORDERS 
 
Dizziness 
 
Headache 
 
 
 
 
Syncope 
RENAL AND URINARY DISORDERS 
 
 
Acute kidney injury 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
 
Cough 
 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
Alopecia 
 
 
 
Dry skin 
 
 
Hair texture abnormal 
 
 
Hyperhidrosis 
 
Hyperkeratosis 
 
 
 
Palmar-plantar 
erythrodysesthesia syndrome 
 
 
Pruritus 
 
Rash10 
 
 
 
 
Skin and subcutaneous tissue 
disorders - Other (drug reaction with 
eosinophilia and systemic symptoms 
[DRESS]) 
 
 
Skin and subcutaneous tissue 
disorders - Other (neutrophilic 
panniculitis)11 
 
 
Stevens-Johnson syndrome 
VASCULAR DISORDERS 
 
Hypertension 
 
 
Thromboembolic event12 
 
 
Vascular disorders - Other 
(hemorrhage)13 
 


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1 This table will be updated as the toxicity profile of the agent is revised. Updates will be distributed to all 
Principal Investigators at the time of revision. The current version can be obtained by contacting 
PIO@CTEP.NCI.NIH.GOV. Your name, the name of the investigator, the protocol and the agent should 
be included in the e-mail. 
2 The incidence of anemia is increased when dabrafenib mesylate (GSK2118436B) is used in 
combination with trametinib dimethyl sulfoxide (GSK1120212B). 
3 The frequencies of these events are based upon laboratory findings rather than being due to patient-
reported outcomes. 
4 Dabrafenib mesylate (GSK2118436B) has been associated with ocular toxicities including 
chorioretinitis, retinitis, iridocyclitis, iritis, and uveitis. 
5 Edema limbs (peripheral edema) is a risk associated when dabrafenib mesylate (GSK2118436B) is 
used in combination with trametinib dimethyl sulfoxide (GSK1120212B) compared to dabrafenib 
mesylate (GSK2118436B) alone. 
6 Fever (pyrexia) can be associated with hypotension and/or (in rare cases) syncope. The frequency of 
fever and serious febrile events is increased when dabrafenib mesylate (GSK2118436B) is used in 
combination with trametinib dimethyl sulfoxide (GSK1120212B). 
7 Manifestations of allergic reactions (hypersensitivity) to dabrafenib mesylate (GSK2118436B) may 
include bullous rash (bullous dermatitis). 
8 Squamous cell carcinoma (SCC), including SCC of the skin, SCC in situ (Bowen’s disease), and 
keratoacanthoma have been observed. 
9 New non-SCC malignancies have been reported including primary melanoma, basal cell carcinoma, 
and non-cutaneous malignancies. 
10 Rash includes the terms: rash, rash acneiform, rash papular, rash maculo-papular, and erythema. 
11 Recurrent neutrophilic panniculitis has been observed in at least one patient treated with dabrafenib 
mesylate (GSK2118436B) in combination with the MEK inhibitor trametinib dimethyl sulfoxide 
(GSK1120212B). 
12 Venous thromboembolic events (including deep vein thrombosis and pulmonary embolism) is a risk 
associated when dabrafenib mesylate (GSK2118436B) is used in combination with trametinib dimethyl 
sulfoxide (GSK1120212B). 
13 Treatment with dabrafenib mesylate (GSK2118436B) in combination with trametinib dimethyl sulfoxide 
(GSK1120212B) resulted in an increased incidence and severity of hemorrhagic events compared to 
patients treated with dabrafenib mesylate (GSK2118436B) as a single agent. Sites of hemorrhage may 
include, but are not limited to, intracranial, reproductive tract, respiratory tract, and gastrointestinal 
hemorrhage. 
Adverse events reported on Dabrafenib mesylate (GSK2118436B) trials, but for which 
there is insufficient evidence to suggest that there was a reasonable possibility that 
Dabrafenib mesylate (GSK2118436B) caused the adverse event: 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Blood and lymphatic system disorders - 
Other (agranulocytosis); Blood and lymphatic system disorders - Other (pancytopenia); 
Disseminated intravascular coagulation; Febrile neutropenia; Hemolysis; Leukocytosis 
CARDIAC DISORDERS - Atrial fibrillation; Atrial flutter; Chest pain - cardiac; Heart failure; Left 
ventricular systolic dysfunction; Mitral valve disease; Myocardial infarction; Pericardial effusion; 
Sinus tachycardia 
EAR AND LABYRINTH DISORDERS - Ear pain 
ENDOCRINE DISORDERS - Hyperthyroidism; Hypothyroidism 
EYE DISORDERS - Blurred vision; Eye disorders - Other (amaurosis fugax); Eye disorders - 
Other (vitreous detachment); Floaters; Photophobia; Retinal detachment; Retinopathy; Vision 
decreased 
GASTROINTESTINAL DISORDERS - Dry mouth; Dyspepsia; Gastritis; Stomach pain 


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GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Death NOS; Disease 
progression; Gait disturbance; Localized edema; Malaise; Non-cardiac chest pain; Pain 
HEPATOBILIARY DISORDERS - Cholecystitis; Hepatic pain 
INFECTIONS AND INFESTATIONS - Bacteremia; Bronchial infection; Catheter related 
infection; Device related infection; Gallbladder infection; Infections and infestations - Other 
(bacterial peritonitis); Infections and infestations - Other (blood culture positive); Infections and 
infestations - Other (croup infectious); Infections and infestations - Other (Epstein-Barr virus 
infection); Infections and infestations - Other (respiratory tract infection); Lung infection; Otitis 
media; Pharyngitis; Rash pustular; Rhinitis infective; Sepsis; Skin infection; Urinary tract 
infection; Viremia 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Bruising; Injury, poisoning 
and procedural complications - Other (complication associated with device); Injury, poisoning 
and procedural complications - Other (device occlusion); Injury, poisoning and procedural 
complications - Other (radiation injury, stroke-like migraine attacks after radiation therapy); 
Seroma 
INVESTIGATIONS - Alanine aminotransferase increased; Alkaline phosphatase increased; 
Aspartate aminotransferase increased; Blood bilirubin increased; CD4 lymphocytes decreased; 
Ejection fraction decreased; Electrocardiogram QT corrected interval prolonged; GGT 
increased; Lipase increased; Lymphocyte count decreased; Weight gain; Weight loss 
METABOLISM AND NUTRITION DISORDERS - Dehydration; Hypercalcemia; Hyperkalemia; 
Hypernatremia; Hyperuricemia; Hypocalcemia; Hypoglycemia; Hypomagnesemia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthritis; Generalized 
muscle weakness; Muscle cramp; Muscle weakness lower limb; Muscle weakness upper limb; 
Neck pain 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - 
Leukemia secondary to oncology chemotherapy; Myelodysplastic syndrome; Neoplasms 
benign, malignant and unspecified (incl cysts and polyps) - Other (acrochordon); Neoplasms 
benign, malignant and unspecified (incl cysts and polyps) - Other (bile duct adenocarcinoma); 
Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other (mycosis 
fungoides) 
NERVOUS SYSTEM DISORDERS - Ataxia; Cognitive disturbance; Depressed level of 
consciousness; Dysgeusia; Dysphasia; Hydrocephalus; Lethargy; Nervous system disorders - 
Other (expressive aphasia); Nervous system disorders - Other (intracranial pressure increased); 
Paresthesia; Seizure; Somnolence; Stroke 
PSYCHIATRIC DISORDERS - Agitation; Anxiety; Confusion; Depression; Hallucinations; 
Insomnia 
RENAL AND URINARY DISORDERS - Proteinuria; Renal calculi; Urinary frequency; Urinary 
retention 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Menorrhagia; Prostatic obstruction; 
Reproductive system and breast disorders - Other (hematospermia) 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Adult respiratory distress 
syndrome; Allergic rhinitis; Dyspnea; Hypoxia; Nasal congestion; Oropharyngeal pain; Pleuritic 
pain; Productive cough; Pulmonary edema; Respiratory failure; Rhinorrhea; Sore throat; Stridor; 
Voice alteration 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Bullous dermatitis7; Eczema; 
Erythroderma; Photosensitivity; Purpura; Skin and subcutaneous tissue disorders - Other 
(palmoplantar keratoderma); Skin and subcutaneous tissue disorders - Other (sunburn); Skin 
hyperpigmentation 
VASCULAR DISORDERS - Flushing; Hot flashes; Hypotension  


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NOTE: 
Dabrafenib (GSK2118436B) in combination with other agents could cause an 
exacerbation of any adverse event currently known to be caused by the other agent, 
or the combination may result in events never previously associated with either 
agent. 
5.3.2 
Comprehensive Adverse Events and Potential Risks list (CAEPR) for 
Trametinib dimethyl sulfoxide (GSK1120212B, NSC 763093) 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) 
provides a single list of reported and/or potential adverse events (AE) 
associated with an agent using a uniform presentation of events by 
body system. Frequency is provided based on 1111 patients. Below is 
the CAEPR for Trametinib (GSK1120212B). 
Version 2.6, October 10, 20191 
 
Adverse Events with Possible 
Relationship to Trametinib (GSK1120212B) 
(CTCAE 5.0 Term) 
[n= 1111] 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
 
 
Anemia 
 
CARDIAC DISORDERS 
 
 
Heart failure 
 
 
Left ventricular systolic dysfunction 
 
Sinus bradycardia 
 
EYE DISORDERS 
 
Blurred vision 
 
 
Dry eye 
 
 
 
Eye disorders - Other 
(chorioretinopathy also known as 
retinal pigment epithelial 
detachment) 
 
 
Eye disorders - Other (retinal vein 
occlusion) 
 
Eye disorders - Other (visual 
disorders)2 
 
 
 
Papilledema 
 
Periorbital edema 
 
GASTROINTESTINAL DISORDERS 
 
Abdominal pain 
 
 
 
Colitis 
 
 
Colonic perforation 
 
Constipation 
 
Diarrhea 
 
 
 
Dry mouth 
 
 
Dyspepsia 
 
 
Mucositis oral 
 
Nausea 
 
 
 
Vomiting 
 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
 
Chills 
 


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Adverse Events with Possible 
Relationship to Trametinib (GSK1120212B) 
(CTCAE 5.0 Term) 
[n= 1111] 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
Edema face 
 
Fatigue 
 
 
 
Fever 
 
Generalized edema3 
 
 
IMMUNE SYSTEM DISORDERS 
 
Allergic reaction4 
 
INFECTIONS AND INFESTATIONS 
 
Folliculitis 
 
 
Lung infection 
 
 
Paronychia 
 
 
Skin infection 
 
INVESTIGATIONS 
 
Alanine aminotransferase 
increased 
 
 
Alkaline phosphatase increased 
 
 
Aspartate aminotransferase 
increased 
 
 
CPK increased 
 
 
Ejection fraction decreased 
 
METABOLISM AND NUTRITION DISORDERS 
 
Anorexia 
 
 
Dehydration 
 
 
Hypoalbuminemia 
 
 
Hypomagnesemia 
 
 
Hyponatremia 
 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
 
Arthralgia 
 
 
Back pain 
 
 
Pain in extremity 
 
 
 
Rhabdomyolysis 
NERVOUS SYSTEM DISORDERS 
 
Dizziness 
 
 
Headache 
 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
 
Cough 
 
 
Dyspnea 
 
 
 
Pneumonitis 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
 
Alopecia 
 
 
Dry skin 
 
 
Nail changes 
 
 
 
Palmar-plantar erythrodysesthesia 
syndrome 
 
Pruritus 
 


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Adverse Events with Possible 
Relationship to Trametinib (GSK1120212B) 
(CTCAE 5.0 Term) 
[n= 1111] 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
Skin and subcutaneous tissue 
disorders - Other (drug reaction 
with eosinophilia and systemic 
symptoms [DRESS]) 
Skin and subcutaneous tissue 
disorders - Other (rash)5 
  
 
 
 
Stevens-Johnson syndrome6 
VASCULAR DISORDERS 
 
Hypertension 
 
 
Thromboembolic event (venous) 
 
Vascular disorders - Other 
(hemorrhage)7 
 
1 This table will be updated as the toxicity profile of the agent is revised. Updates will be distributed to all 
Principal Investigators at the time of revision. The current version can be obtained by contacting 
PIO@CTEP.NCI.NIH.GOV. Your name, the name of the investigator, the protocol and the agent should 
be included in the e-mail. 
2 Visual disorders include visual disturbance that can be associated with conjunctival hemorrhage, 
corneal graft rejection, cyclitis, eye nevus, halo vision, iritis, macular edema, retinal hemorrhage, visual 
acuity reduced, visual impairment, and vitreous detachment. 
3 Generalized edema includes edema, lymphedema, and edema limbs. 
4 Hypersensitivity (allergic reactions) may present with symptoms such as fever, rash, increased liver 
function tests, and visual disturbances. 
5 Skin and subcutaneous tissue disorders - Other (rash) may include rash, rosacea, erythematous rash, 
genital rash, rash macular, exfoliative rash, rash generalized, erythema, rash papular, seborrhoeic 
dermatitis, dermatitis psoriasiform, rash follicular, skin fissures, and skin chapped. 
6 Stevens-Johnson syndrome has been observed in patients treated with trametinib and dabrafenib 
combination. 
7 The majority of hemorrhage events were mild. Major events, defined as symptomatic bleeding in a 
critical area or organ (e.g., eye, GI hemorrhage, GU hemorrhage, respiratory hemorrhage), and fatal 
intracranial hemorrhages have been reported. 
Adverse events reported on trametinib dimethyl sulfoxide (GSK1120212B) trials, but for 
which there is insufficient evidence to suggest that there was a reasonable possibility 
that trametinib dimethyl sulfoxide (GSK1120212B) caused the adverse event: 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Disseminated intravascular coagulation; 
Febrile neutropenia; Leukocytosis 
CARDIAC DISORDERS - Atrial fibrillation; Cardiac arrest; Myocardial infarction; Restrictive 
cardiomyopathy; Sinus tachycardia 
EYE DISORDERS - Corneal ulcer; Eyelid function disorder; Flashing lights; Floaters; Glaucoma; 
Photophobia  
GASTROINTESTINAL DISORDERS - Ascites; Duodenal ulcer; Esophageal necrosis; 
Esophageal ulcer; Esophagitis; Gastric hemorrhage7; Gastric ulcer; Gastritis; Gastrointestinal 
disorders - Other (intestinal obstruction); Gastrointestinal disorders - Other (pneumatosis 
intestinalis); Gastrointestinal fistula; Gingival pain; Hemorrhoidal hemorrhage7; Ileus; 
Obstruction gastric; Pancreatitis; Small intestinal obstruction 


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GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Flu like symptoms; 
General disorders and administration site conditions - Other (axillary pain); Localized edema; 
Malaise; Non-cardiac chest pain; Pain 
HEPATOBILIARY DISORDERS - Cholecystitis; Hepatic failure; Hepatic pain; Hepatobiliary 
disorders - Other (hepatic encephalopathy) 
INFECTIONS AND INFESTATIONS - Biliary tract infection; Catheter related infection; Device 
related infection; Endocarditis infective; Enterocolitis infectious; Hepatitis viral; Infections and 
infestations - Other (abscess limb); Infections and infestations - Other (necrotizing fasciitis); 
Infections and infestations - Other (oral infection); Pharyngitis; Sepsis; Upper respiratory 
infection; Urinary tract infection 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Bruising  
INVESTIGATIONS - Blood bilirubin increased; Blood lactate dehydrogenase increased; 
Creatinine increased; Electrocardiogram QT corrected interval prolonged; GGT increased; 
Lipase increased; Lymphocyte count decreased; Platelet count decreased; Serum amylase 
increased; White blood cell decreased 
METABOLISM AND NUTRITION DISORDERS - Hyperglycemia; Hyperkalemia; 
Hyperphosphatemia; Hyperuricemia; Hypocalcemia; Hypoglycemia; Hypokalemia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Generalized muscle 
weakness; Muscle cramp; Musculoskeletal and connective tissue disorder - Other (compression 
fracture); Myalgia; Neck pain 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - 
Tumor hemorrhage7; Tumor pain 
NERVOUS SYSTEM DISORDERS - Dysgeusia; Encephalopathy; Intracranial hemorrhage7; 
Lethargy; Nervous system disorders - Other (diplopia); Seizure; Somnolence; Stroke; Syncope; 
Transient ischemic attacks 
PSYCHIATRIC DISORDERS - Anxiety; Confusion; Delirium; Depression; Hallucinations; 
Insomnia; Personality change 
RENAL AND URINARY DISORDERS - Acute kidney injury; Cystitis noninfective; Dysuria; 
Hematuria; Proteinuria; Urinary incontinence 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Vaginal fistula; Vaginal hemorrhage7 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Bronchopulmonary 
hemorrhage7; Hypoxia; Laryngeal edema; Oropharyngeal pain; Pleural effusion; Pneumothorax; 
Productive cough; Pulmonary hypertension; Respiratory failure; Sinus disorder 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Bullous dermatitis; Photosensitivity; 
Purpura; Skin and subcutaneous tissue disorders - Other (erythema nodosum); Skin ulceration; 
Urticaria 
VASCULAR DISORDERS - Hematoma; Hot flashes; Hypotension  
NOTE: 
Trametinib (GSK1120212B) in combination with other agents could cause an 
exacerbation of any adverse event currently known to be caused by the other agent, 
or the combination may result in events never previously associated with either 
agent. 
5.4 
Dose Modifications 
5.4.1 
General Instructions 
5.4.1.1 
Dabrafenib/Trametinib Dose Reduction Procedures 
• 
If treatment related toxicities occur when dabrafenib 
and trametinib are used in combination, then both 


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agents should be simultaneously dose reduced, 
interrupted or discontinued with the exception of the 
following: 
• 
Dose modifications are required for dabrafenib 
only (and not trametinib) for these events: pyrexia 
and, RAS mutation positive non-cutaneous 
malignancies 
• 
Dose modifications are required for trametinib only 
(and not dabrafenib) for these events: left 
ventricular rejection fraction (LVEF) reduction, 
retinal vein occlusion (RVO) retinal pigment 
epithelial detachment (RPED) and interstitial lung 
disease (ILD)/pneumonitis (primarily related to 
trametinib). 
NOTE: 
Dose modifications are not 
recommended for adverse reactions of 
cutaneous squamous cell carcinoma 
(cuSCC) or new primary melanoma. 
5.4.1.2 
Dose Level Reduction Tables 
Table 1: Dabrafenib Dose Level Reductions 
Dose Level 
Dose/Schedule 
Starting Dose 
150 mg twice daily 
First Reduction 
100 mg twice daily 
Second Reduction 
75 mg twice daily 
Third Reduction 
50 mg twice daily 
If unable to tolerate 50 mg twice 
daily 
Discontinue dabrafenib 
Trametinib Dose Reductions 
Table 2: Trametinib Dose Reductions 
Dose Level 
Dose/Schedule 
Starting Dose 
2 mg twice daily 
First Reduction 
1.5 mg twice daily 
Second Reduction 
1.0 mg twice daily 
Third Reduction 
0.5 mg twice daily 
If unable to tolerate 0.5 mg once 
daily 
Discontinue trametinib 
Hydroxychloroquine/Placebo Dose Reductions 
Table 3: HCQ/placebo Dose Reductions 
Dose Level 
Dose/Schedule 
Starting Dose 
600 mg twice daily 
First Reduction 
600 mg once daily in the morning and 


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Dose Level 
Dose/Schedule 
400 mg once daily in the evening 
Second Reduction 
400 mg twice daily 
Third Reduction 
A third dose reduction to 400 mg once a 
day (qd) may be pursued in patients 
deemed to be deriving clinical benefit at 
the discretion of the treating physician. 
For any AE with a grade ≥ 3, HCQ/placebo dose will be 
held until the toxicity resolves to ≤ grade 1 before 
restarting, after which HCQ/placebo may be restarted at a 
reduced dose as described in table 3. 
5.4.1.3 
Dose reductions for toxicities that overlap between D+T 
and HCQ/placebo 
Some toxicities overlap between dabrafenib, trametinib 
and HCQ/placebo making it difficult to accurately assign 
association. In these cases table 3 in conjunction with 
table 4 should be used to dose reduce in the appropriate 
fashion. In general HCQ/placebo dose should be reduced 
and if this does not reduce the toxicity to < grade 2 or the 
toxicity returns after being reduced to < grade 2 then dose 
modifications of both dabrafenib and trametinib will be 
made together. Non-hematological toxicities having an 
attribution to trametinib of possible, probable or definite will 
result in dose modifications as described below. 
5.4.1.4 
Dose Delays, Missed Doses, and Dose Reescalation 
Major Events are grade 3 and 4 hematologic and non-
hematologic toxicities that are not treatment related. 
Treatment should be delayed for major events if HCQ may 
further complicate the non-treatment related event. If a 
major event requires a delay of treatment, treatment must 
be delayed until toxicity is resolved (≤ Grade 2 or ≤ 
Baseline). Missed doses do not need to be made up but 
the missed doses should be documented in the diaries. 
Dose reescalation following resolution to ≤ Grade 1 toxicity 
is allowed. 
5.4.2 
General Guidelines for Toxicities and Dose Modifications 
Guidelines for specific toxicities are outlined below, but general 
guidelines for toxicities not listed are provided in Table 5. 
Table 4: General Dose modification guidelines for dabrafenib and 
trametinib for toxicities attributable to only dabrafenib and/or 
trametinib. These are general guidelines but for specific 
toxicities dose modification instructions may be different and are 
provided in the subsequent sections. 
CTCAE Grade 
Action and Dose Modification 
Grade 1 
• Continue dabrafenib, trametinib and HCQ/placebo at current dose level 
• Monitor closely 


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CTCAE Grade 
Action and Dose Modification 
• Provide supportive care according to institutional standards 
Grade 2 
• Interrupt dabrafenib and trametinib if clinically indicated, continue HCQ/placebo 
• Monitor closely 
• Provide supportive care according to institutional standards 
• When toxicity resolves to Grade 1 or baseline, restart dabrafenib and trametinib 
treatment at current dose level 
Grade 3 
• Interrupt dabrafenib and trametinib if clinically indicated, continue HCQ/placebo 
• Monitor closely 
• Provide supportive care according to institutional standards 
• When toxicity resolves to Grade 1 or baseline, restart dabrafenib and trametinib 
both reduced by one dose level 
• If the Grade 3 toxicity recurs, interrupt study treatment 
• When toxicity resolves to Grade 1 or baseline, restart dabrafenib and trametinib 
both reduced by another dose level 
Grade 4 
• Interrupt dabrafenib and trametinib, continue HCQ/placebo 
• Monitor closely 
• Provide supportive care according to institutional standards 
• If event resolves to Grade 1 or baseline patient may continue dabrafenib and 
trametinib both reduced by one dose level 
• If event does not resolve permanently discontinue study treatment 
5.4.3 
Guidelines and Dose Modifications for Specific Toxicities 
5.4.3.1 
Management and Dose Modification Guidelines for Pyrexia 
• 
Pyrexia is defined as a body temperature equal to or 
above 38.5○ Celsius or 101.3° Fahrenheit 
• 
Pyrexia is an adverse event associated with dabrafenib 
and is increased in frequency and severity in patients 
receiving dabrafenib in combination with trametinib. In 
a minority of cases, pyrexia was accompanied by 
symptoms such as severe chills/rigors, dehydration, 
hypotension, dizziness or weakness and required 
hospitalization 
• 
Patients should be instructed on the importance of 
immediately reporting febrile episodes. In the event of 
a fever, the patient should be instructed to take anti-
pyretics (e.g. ibuprofen or 
acetaminophen/paracetamol) as appropriate to control 
fever. The use of oral corticosteroids should be 
considered in those instances in which anti-pyretics are 
insufficient. Monitor serum creatinine and other 
evidence of renal function during and following severe 
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Table 5: Management and Dose Modification 
Guidelines of Dabrafenib only for Pyrexia 
Management and Dose Modification Guidelines of Dabrafenib only for Pyrexia 
Work up: 
• 
Clinical evaluation for infection and hypersensitivity, especially if pyrexia is complicated by rigors, 
severe chills, dehydration, etc.  
• 
Laboratory work-up (should include full-blood-count, electrolytes, creatinine, BUN, CRP, liver-
function tests, blood and urine culture). 
Management:  
• 
Anti-pyretic treatment should be started immediately at the first occurrence. Anti-pyretic treatment 
may include acetaminophen (paracetamol), ibuprofen, or suitable anti-pyretic medication per 
institutional standards.  
• 
Oral hydration is encouraged in patients without evidence of dehydration. Intravenous hydration is 
recommended if pyrexia is complicated by dehydration/hypotension. 
• 
In patients experiencing pyrexia complicated by rigors, severe chills, etc., which cannot be 
controlled with anti-pyretic medication, oral corticosteroids should be started at the 2nd event and 
doses should be gradually increased for subsequent events. 
Prophylactic anti-pyretic treatment is recommended after the 2nd event, or after the 1st event if 
complicated by rigors or severe chills. Prophylactic anti-pyretics may be discontinued after three days 
in absence of pyrexia.  
Notes 
• 
Escalation of dabrafenib is allowed if no episode of pyrexia is observed in the 4 weeks subsequent 
to dose reduction from the dose level you were on before. 
Pyrexia accompanied by hypotension, or dehydration requiring IV fluids, or severe rigors/chills in the 
absence of an obvious infectious cause should be reported as an SAE. 
All Events 
• 
Clinical evaluation for infection and 
hypersensitivity 
• 
Laboratory work-up 
• 
Hydration as required 
 
Event Management 
Action and Dose Modification 
1st Event 
• 
Administer anti-pyretic treatment as 
clinically indicated and initiate 
prophylactic treatment if associated 
with rigors, renal failure, dehydration 
or hypotensionf 
1st Event 
• 
Interrupt dabrafenib 
• 
Continue trametinib and HCQ/placebo 
• 
Once pyrexia resolves to baseline, restart dabrafenib at 
the same dose level 
• 
If fever was associated with rigors, renal failure, 
dehydration or hypotension, reduce dabrafenib to 
100 mg BID 
2nd Event: 
• 
Within 3 days of onset of pyrexia 
• 
Optimize anti-pyretic therapy 
• 
Consider oral corticosteroids 
(i.e., prednisone 10 mg) for at 
least 5 days or as clinically 
indicatede 
2nd Event: 
• 
Interrupt dabrafenib 
• 
Continue trametinib and HCQ/placebo 
• 
Once pyrexia resolves to baseline, restart dabrafenib at 
100 mg BID 
• 
If fever was associated with rigors, renal failure, 
dehydration or hypotension, reduce dabrafenib to 
75 mg BID 


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3rd Event: 
• 
Within 3 days of onset of pyrexia 
• 
Optimize anti-pyretic therapy 
3rd Event: 
• 
Interrupt dabrafenib 
• 
Continue trametinib and HCQ/ placebo; start 
prednisone 20 mg PO qday for at least 5 days or as 
clinically indicated 
• 
Once pyrexia resolves to baseline, restart dabrafenib at 
75 mg BID; continue prednisone 20 mg PO qday as 
clinically indicated 
• 
If fever was associated with rigors, renal failure, 
dehydration or hypotension, reduce dabrafenib to 
50 mg BID. 
4th Eventf 
• 
Within 3 days of onset of pyrexia 
• 
Optimize anti-pyretic therapy 
4th Event: 
• 
Interrupt dabrafenib 
• 
Continue trametinib and HCQ/ placebo; start 
prednisone 20 mg PO qday for at least 5 days or as 
clinically indicated 
• 
Once pyrexia resolves to baseline, restart 
dabrafenib reduced to 50 mg BID; continue with 
prednisone 20 mg PO qday as clinically 
indicated 
5.4.3.2 
Management and Dose Modification Guidelines for Rash 
Rash is a frequent AE observed in patient receiving 
trametinib, dabrafenib, or the combination of both agents. 
HCQ can also cause a rash. 
Table 6: Management and Dose Modification 
Guidelines for Rash 
Management and Dose Modification Guidelines for Rash 
Supportive care: 
Prevention:   
• Avoid unnecessary exposure to sunlight 
• Apply broad-spectrum sunscreen (containing titanium dioxide or zinc oxide) with a skin protection 
factor (SPF) ≥ 15 at least twice daily. 
• Use thick, alcohol-free emollient cream (e.g., glycerine and cetomacrogol cream) on dry areas of the 
body at least twice daily. 
• Topical steroids and antibiotics should be applied at least twice daily starting on Day 1 of study 
treatment, to body areas such as face, chest, and upper back.   
• Use mild-strength topical steroid (hydrocortisone 1% cream) or topical antibiotic (e.g., clindamycin) or 
oral antibiotics (e.g., doxycycline 100 mg BID, minocycline 100 mg BID) 
Symptom management: 
• Pruritic lesions: cool compresses and oral antihistamine therapies  
• Fissuring lesions: Monsel’s solution, silver nitrate, or zinc oxide cream  
• Desquamation: thick emollients and mild soap  
• Paronychia: antiseptic bath, local potent corticosteroids in addition to oral antibiotics; if no 
improvement, consult dermatologist or surgeon 
• Infected lesions: appropriate bacterial/fungal culture-driven systemic or topical antibiotics  
Notes: 
• Rash prophylaxis is recommended for the first 6 weeks of study treatment  
• Subjects who develop rash/skin toxicities should be seen by a qualified physician and should receive 
evaluation for symptomatic/supportive care management  


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5.4.3.3 
Management and Dose Modification Guidelines for Renal 
Insufficiency 
Cases of renal insufficiency have occurred in patients 
receiving dabrafenib and the combination of dabrafenib 
and trametinib. Prior to start of study treatment, 
concomitant medications should be reviewed for the 
potential risk of inducing nephrotoxicity and concomitant 
medications should be modified if clinically possible. 
Table 7: Management and Dose Modification 
Guidelines for Renal Insufficiency 
Serum Creatinine Level 
Adverse Event Management 
Action and Dose Modification 
Serum creatinine 
increase > 0.2 mg/dL (18 
umol/L) but  0.5 mg/dL 
(44 umol/L) above 
baseline 
• 
Recheck serum creatinine within 1 
week 
• 
Serum creatinine increase > 1 
week: contact Study chair. If 
elevation persists beyond 4 weeks, 
recommend evaluation (consider 
renal biopsy) for etiology; consider 
nephrology consultation. 
Continue HCQ/placebo, 
dabrafenib and trametinib at the 
same dose level 
CTCAE 
Grade 
Adverse Event Management 
Action and Dose Modification 
Grade 1 
• Initiate prophylactic and 
symptomatic treatment measures 
• Use moderate strength topical 
steroid.2 
• Reassess after 2 weeks. 
• Continue HCQ/placebo, dabrafenib and trametinib 
• If rash does not recover to baseline within 2 weeks 
despite best supportive care, reduce HCQ/placebo 
by one dose level.2 
Grade 2  
• Initiate prophylactic and 
symptomatic treatment measures. 
• Use moderate strength topical 
steroid.1 
• Reassess after 2 weeks. 
• Continue dabrafenib and trametinib at the same 
dose, but reduce HCQ/placebo by one dose 
level.  
• If rash recovers to ≤ grade 1 within 2 weeks, 
increase HCQ/placebo dose to previous dose level. 
• If no recovery to ≤ grade 1 within 2 weeks, interrupt 
HCQ/placebo until recovery to ≤ grade 1. 
• Restart study treatment with HCQ/placebo at 
reduced dose level.2 
• If no improvement in rash then reduce darbrafenib 
and trametinib by one dose level and restart the 
HCQ/placebo at reduced level. 
Grade ≥ 3  • Use moderate strength topical 
steroids PLUS oral methyl-
prednisolone dose pack.1 
• Consult dermatologist. 
• Interrupt HCQ/placebo, dabrafenib and trametenib 
until rash recovers to ≤ grade 1. 
• Restart with all three study agents reduced by 
one dose level 
• If no recovery to ≤ grade 2 within 2 weeks, 
permanently discontinue study treatment. 
1. Moderate-strength topical steroids: Hydrocortisone 2.5% cream or fluticasone propionate concentration 
0.05% cream. 
2. Study treatment may be escalated to previous dose level if no rash is evident 4 weeks after restarting 
study treatment. 


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Serum Creatinine Level 
Adverse Event Management 
Action and Dose Modification 
• 
If pyrexia is present, treat pyrexia 
as per guidelinesa 
Serum creatinine 
increase 
> 0.5 mg/dL (44 umol/L) 
above baseline or serum 
creatinine  
> 2 mg/dL 
(> 177 umol/L) 
• 
Monitor serum creatinine ≥ 2-times 
per week 
• 
Hospitalization may be necessary if 
serum creatinine cannot be 
monitored frequently 
• 
If pyrexia is present, treat pyrexia 
per guidelinesa 
• 
Consult nephrologist if clinically 
indicated 
• 
Perform renal biopsy if clinically 
indicated, for example: 
• 
Renal insufficiency persists 
despite volume repletion 
• 
Patient has new rash or signs of 
hypersensitivity (such as 
elevated eosinophil count) 
Interrupt HCQ/placebo, 
dabrafenib and trametinib 
• 
until serum creatinine 
recovers to baseline 
• 
Restart with HCQ, 
dabrafenib and trametinibb 
a. NSAIDs can induce renal insufficiency, especially in patients with dehydration; encourage oral fluids 
or consider intravenous fluids as clinically indicated. See guidelines for pyrexia Section 5.4.3.1. 
b. Investigator may restart at either the same or a reduced dose level of dabrafenib. Escalation of study 
treatment to previous dose level is allowed if another episode of renal insufficiency does not occur 
after 4 weeks of dose reduction. Study treatment may not be restarted if there is evidence of 
thrombotic microangiopathy. 
5.4.3.4 
Management and Dose Modification Guidelines for Hepatic 
Insufficiency 
Cases of hepatic insufficiency have occurred in patient 
receiving dabrafenib and the combination of dabrafenib 
and trametinib. Prior to start of study treatment, 
concomitant medications should be reviewed for the 
potential risk of inducing hepatic toxicity and concomitant 
medications should be modified if clinically possible. 
Table 8: Management and Dose Modification 
Guidelines for Hepatic Toxicity 
Criteria – 
Actions 
Follow Up Assessments 
ALT-absolute 
ALT  5xULN 
Immediately discontinue 
dabrafenib, trametinib and 
HCQ/placebo 
Report the event in CTEP-AERS 
within 7 calendar days. 
Perform liver event follow up 
assessments. 
Monitor the patient until liver 
chemistries resolve, stabilize, or 
return to within baseline (see 
MONITORING below). 
Do not restart/rechallenge 
Viral hepatitis serology 
Blood sample for 
pharmacokinetic (PK) analysis, 
obtained within 48 hours after 
last dose. 
Serum creatine 
phosphokinase (CPK) and 
lactate dehydrogenase (LDH). 
Fractionate bilirubin, if total 
bilirubin2xULN 
Obtain complete blood count 
with differential to assess 
ALT Increase 
ALT  3xULN 
persists for  4 
weeks 
Bilirubin 
ALT  3xULN 
and bilirubin  
 2xULN (> 35% 
direct bilirubin) 
INR 
ALT  3xULN 
and INR>1.5, if 
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Criteria – 
Actions 
Follow Up Assessments 
Cannot 
Monitor 
ALT  3xULN 
and cannot be 
monitored weekly 
for 4 weeks 
patient with study treatment 
If restart/rechallenge not allowed 
per protocol or not granted, 
permanently discontinue study 
treatment and may continue 
patient in the study for any 
protocol specified follow up 
assessments. 
MONITORING: 
For bilirubin or INR criteria: 
Repeat liver chemistries (include 
ALT, AST, alkaline phosphatase, 
bilirubin) and perform liver event 
follow up assessments within 24 
hrs. 
A specialist or hepatology 
consultation is recommended. 
Monitor patient twice weekly until 
liver chemistries resolve, 
stabilize or return to within 
baseline. 
For All other criteria: 
Repeat liver chemistries (include 
ALT, AST, alkaline phosphatase, 
bilirubin) and perform liver event 
follow up assessments within 24-
72 hrs 
 
Monitor patient weekly until liver 
chemistries resolve, stabilize or 
return to within baseline 
eosinophilia 
Record the appearance or 
worsening of clinical 
symptoms of liver injury, or 
hypersensitivity, on the AE 
report form. 
Record use of concomitant 
medications on the 
concomitant medications 
report form including 
acetaminophen, herbal 
remedies, other over the 
counter medications. 
Record alcohol use on the liver 
event alcohol intake case 
report form. 
For bilirubin or INR criteria: 
Anti-nuclear antibody, anti-
smooth muscle antibody, Type 
1 anti-liver kidney microsomal 
antibodies, and quantitative 
total immunoglobulin G (IgG or 
gamma globulins). 
Serum acetaminophen adduct 
HPLC assay (quantifies 
potential acetaminophen 
contribution to liver injury in 
patients with definite or likely 
acetaminophen use in the 
preceding week). 
Only in those with underlying 
chronic hepatitis B at study 
entry (identified by positive 
hepatitis B surface antigen): 
quantitative hepatitis B DNA 
and hepatitis delta antibody. 
Liver imaging (ultrasound, 
magnetic resonance, or 
computerized tomography) 
and /or liver biopsy to evaluate 
liver disease; complete Liver 
Imaging and/or Liver Biopsy 
eCRF forms. 
Symptomatic 
ALT  3xULN 
associated with 
symptoms (new 
or worsening) 
believed to be 
related to liver 
injury or 
hypersensitivity 
 
5.4.3.5 
Management and Dose Modification Guidelines for 
Pneumonitis 
Pneumonitis has been observed in patient receiving 
trametinib. To reduce the risk of pneumonitis, patient will 
be monitored closely for symptoms, evaluated with imaging 
and functional tests. 


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Table 9: Management and Dose Modification 
Guidelines for Pneumonitis of Trametinib only 
CTCAE Grade 
Adverse Event Management 
Action and Dose Modification 
Grade 1 
• 
CT scan (high-resolution with lung windows) 
recommended 
• 
Clinical evaluation and laboratory work-up for 
infection 
• 
Monitoring of oxygenation via pulse-oximetry 
recommended 
• 
Consultation with pulmonologist 
recommended 
• 
Continue trametinib at 
current dose 
Grade 2 
• 
CT scan (high-resolution with lung windows) 
• 
Clinical evaluation and laboratory work-up for 
infection 
• 
Consult pulmonologist 
• 
Pulmonary function tests -if  
< normal, repeat every 8 weeks until ≥ normal 
• 
Bronchoscopy with biopsy and/or 
bronchioaveloar lavage (BAL) recommended 
• 
Symptomatic therapy including corticosteroids 
if clinically indicated 
• 
Interrupt trametinib until 
recovery to grade ≤1 
• 
Restart treatment with 
trametinib reduced by one 
dose level 
Grade 3 
• 
CT scan (high-resolution with lung windows) 
• 
Clinical evaluation and laboratory work-up for 
infection 
• 
Consult pulmonologist 
• 
Pulmonary function tests-if < normal, repeat 
every 8 weeks until ≥ normal 
• 
Bronchoscopy with biopsy and/or BAL if 
possible 
• 
Symptomatic therapy including corticosteroids 
as clinically indicated 
• 
Interrupt trametinib until 
recovery to grade ≤1, then 
restart at reduced dose. 
• 
If no recovery to grade ≤1 
within 4 weeks, 
permanently discontinue 
trametinib 
Grade 4 
• 
Same as grade 3 
• 
Permanently discontinue 
trametinib 
• 
Unblinding may be allowed 
to improve medical care. 
See Section 4.5 
5.4.3.6 
Management and Dose Modification Guidelines for 
Reduced Left ventricular ejection fraction (LVEF) 
Decreases in left ventricular ejection fraction have been 
seen with the use of trametinib with an incidence of 9% 
with the combination of trametinib and dabrafenib 
compared to 0% with dabrafenib alone. Therefore, 
transthoracic echo must be performed at baseline and 
repeated every 3 months while on study or as clinically 
indicated. More frequent evaluation is warranted if there 
are signs or symptoms suggestive of clinical CHF. The 
same procedure (either ECHO or MUGA, although ECHO 


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is preferred) should be performed at baseline and at follow-
up visit(s). 
Table 10: Management and Dose Modification 
Guidelines of Trametinib for LVEF Decrease 
Clinic 
LVEF-drop (%) or CTCAE grade 
Action and Dose Modification 
Asymptomatic 
Absolute decrease of > 10% in 
LVEF compared to baseline and 
ejection fraction below the 
institution’s LLN 
Interrupt trametinib and repeat ECHO within 2 
weeksa,b  
If the LVEF recovers within 4 weeks (defined 
as LVEF ≥LLN and absolute decrease ≤10% 
compared to baseline) then restart at a reduced 
dose level of trametinib. 
• 
Repeat ECHO at 2, 4, 8 and 12 weeks after 
re-start; continue in intervals of 12 weeks 
thereafter 
If LVEF does not recover within 4 weeks 
• 
Consult with cardiologist 
• 
Permanently discontinue trametinib 
• 
Report as SAE 
• 
Repeat ECHO after 2, 4, 8, 12, and 16 
weeks or until resolution 
Symptomaticb 
Grade 3: resting LVEF 39-20% or 
>20% absolute reduction from 
baseline 
Permanently discontinue trametinib 
Report as SAE 
Interrupt dabrafenib.c 
Consult with cardiologist 
Repeat ECHO after 2, 4, 8, 12, and 16 weeks 
or until resolution 
Grade 4 toxicity will trigger unblinding per 
Section 4.5 
Grade 4: resting LVEF < 20% 
a. If ECHO does not show LVEF recovery after 2 weeks, repeat ECHO 2 weeks later. 
b. Symptoms may include: dyspnea, orthopnea, and other signs and symptoms of pulmonary 
congestion and edema. 
c. Once LVEF recovers, including resolution of symptoms, restart of dabrafenib monotherapy will be at 
the discretion of the study investigator. 
5.4.3.7 
Management and Dose Modification Guidelines for QTc 
prolongation 
Both dabrafenib and trametinib have been shown to 
prolong the QTc interval. However, to date, there are no 
clinical adverse event reports attributable to QTc interval 
prolongation or manifest cardiac arrhythmias. However, the 
following recommendations have been developed to 
minimize the risk of ventricular tachyarrhythmias in patients 
with metastatic melanoma treated with this regimen: 
• 
Avoid combination with other drugs with potential to 
lead to prolongation of QTc interval, if possible. 
• 
ECG should be monitored at baseline, and each cycle 
(monthly) thereafter. 


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• 
Monitor ECG weekly until the QTc interval decreases 
to < 500 msec, or a cardiologist provides 
documentation that it is safe to resume therapy before 
reinstituting therapy at a reduced dose. 
Table 11: Management and Dose Modification 
Guidelines for QTcB-Prolongation 
(QT interval on electrocardiogram 
corrected using the Bazett’s 
formula) 
QTc-Prolongation a 
Action and Dose Modification 
QTcB ≥501 msec (milliseconds) 
Interrupt all three study agents until QTcB prolongation 
resolves to grade 1 or baseline 
Test serum potassium, calcium, phosphorus and magnesium. 
If abnormal correct per routine clinical practice to within 
normal limits. 
Review concomitant medication usage for agents that prolong 
QTc. 
If event resolves, restart study treatment at current dose levelb 
If event does not resolve, discuss with a cardiologist, if 
deemed clinically significant then discontinue study treatment 
If event recurs, discuss with a cardiologist, if deemed clinically 
significant then permanently discontinue study treatments 
a Based on average QTc value of triplicate ECGs. For example, if an ECG demonstrates a prolonged 
QT interval, obtain two or more ECGs over a brief period, and then use the averaged QTc values of 
the three ECGs to determine if study treatments should be interrupted or discontinued. 
b If the QTc prolongation resolves to grade 1 or baseline, the patient may resume study treatment. 
5.4.3.8 
Management and Dose Modification Guidelines for 
Hypertension 
For patient experiencing an increase in systolic and/or 
diastolic blood pressure that is persistent and may be 
associated with the study treatment, recommendations for 
the clinical management of hypertension are described in 
Table 12. 
Table 12: Management and Dose Modification 
Guidelines for Hypertension 
Hypertension 
Action and Dose Modification 
(Scenario A) 
Asymptomatic and persistenta SBP of  
≥ 140 and < 160 mmHg, or DBP ≥ 90 and 
< 100 mmHg, 
or 
Clinically significant increase in DBP of 20 
mmHg (but DBP still <100 mmHg). 
Continue dabrafenib and trametinib and HCQ/placebo at 
the current dose 
Adjust current or initiate new antihypertensive medication 
Titrate antihypertensive medication(s) during the next 2 
weeks as indicated to achieve well-controlledb BP 
If BP is not well controlled within 2 weeks, consider 
referral to a specialist and go to scenario (B). 
(Scenario B) 
Asymptomatic SBP ≥ 160 mmHg, or DBP 
≥100 mmHg, 
or 
Interrupt dabrafenib and trametinib if clinically indicated 
but continue HCQ/placebo 
Adjust current or initiate new antihypertensive 
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Hypertension 
Action and Dose Modification 
Failure to achieve well-controlled BP 
within 2 weeks in Scenario A 
Titrate antihypertensive medication(s) during the next 2 
weeks to achieve well-controlled BP 
Once BP is well controlledb, restart dabrafenib and 
trametinib reduced by one dose levelc and continue 
HCQ/placebo 
(Scenario C) 
Symptomaticd hypertension 
or 
Persistent SBP ≥160 mmHg, or DBP  
≥ 100 mmHg, despite antihypertensive 
medication and dose reduction of study 
treatment 
Interrupt dabrafenib, trametinib and HCQ/placebo 
treatment 
Adjust current or initiate new antihypertensive 
medication(s) 
Titrate antihypertensive medication during the next 2 
weeks to achieve well-controlled BP 
Referral to a specialist for further evaluation and follow-up 
is recommended 
Once BP is well controlled, restart 3 study treatments 
reduced by one dose levelc 
(Scenario D) 
Refractory hypertension unresponsive to 
above interventions, or having 
hypertensive crisis. 
Permanently discontinue study treatment 
Continue follow-up per protocol. 
a. Hypertension detected in two separate readings during up to three consecutive visits 
b. Well-controlled blood pressure defined as SBP ≤140 mm Hg and DBP ≤90 mm Hg in two separate 
readings during up to three consecutive visits. 
c. Escalation of study treatment to previous dose level can be considered if BPs remain well-controlled 
for 4 weeks after restarting of study treatment. 
Symptomatic hypertension defined as hypertension aggravated by symptoms (e.g., headache, light-
headedness, vertigo, tinnitus, episodes of fainting) that resolve after the blood pressure is controlled 
within the normal range. 
5.4.3.9 
Other dabrafenib-specific adverse events and 
recommended management 
Palmar plantar erythrodysesthesia (PPES) – Measures for 
PPES should include: 
Lifestyle modification: avoidance of hot water, traumatic 
activity, constrictive footwear, or excessive friction on the 
skin and the use of thick cotton socks and gloves, and 
shoes with padded insoles 
• Symptomatic treatments: apply moisturizing creams 
frequently, topical keratolytics (e.g. urea 20-40% cream, 
salicylic acid 6%, tazarotene 0.1% cream, fluorouracil 
5% cream), clobetasol propionate 0.05% ointment for 
erythematous areas, topical lidocaine 2%, and / or 
systemic pain medication such as nonsteroidal anti-
inflammatory drugs, codeine, and pregabalin for pain. 
• Dose modification may also be required. 
Pancreatitis – In the event of abdominal pain or 
suspected pancreatitis, amylase and lipase laboratory 
samples should be collected for confirmation of the 


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diagnosis. Patients should be closely monitored when re-
starting dabrafenib after an episode of pancreatitis. 
Uveitis: Treatment with dabrafenib has been associated 
with the development of uveitis, including iritis. Monitor 
patients for visual signs and symptoms (such as, change in 
vision, photophobia and eye pain) during therapy. 
Hyperglycemia: Hyperglycemia requiring an increase in 
the dose of, or initiation of insulin or oral therapy can occur 
with dabrafenib. Monitor serum glucose levels as clinically 
appropriate during treatment with dabrafenib in patient with 
pre-existing diabetes or hyperglycemia. Advise patients to 
report symptoms of severe hyperglycemia such as 
excessive thirst or any increase in the volume or frequency 
of urination. 
Investigators should always err on the side of caution in 
these settings if treatment-related toxicity is a possibility. 
5.4.3.10 
Ocular Toxicity 
Due to the known ocular toxicities associated with BRAF 
and MEK inhibitors and the potential for toxicity with HCQ, 
an ophthalmic exam at baseline and yearly thereafter is 
required. The standard of care for patients on HCQ is that 
the ophthalmologist performs visual field 10-2 test, plus 
one of the three other highly sensitive screening tests: the 
FAF (fundus autofluorescence imaging), the SD-OCT 
(spectral domain optical coherence), or the multifocal 
electroretinogram (mfERG). Episodes of visual changes 
have been observed in patientreceiving trametinib, 
dabrafenib, and combination therapy. An ophthalmologist 
should be consulted if changes in vision develop. 
However, if the visual changes are clearly unrelated to 
study treatment (e.g., allergic conjunctivitis), then monitor 
closely as it may be reasonable to defer ophthalmic 
examination. Treatment with dabrafenib has been 
associated with the development of uveitis, including iritis. 
Monitor patients for visual signs and symptoms (such as, 
change in vision, photophobia and eye pain) during 
therapy. Special attention should be given to retinal 
findings (e.g., retinal pigment epithelial detachment 
(RPED) or retinovascular abnormalities (i.e., branch or 
central retinal vein occlusions (RVO). 
With particular regard to visual field deficits patients should 
be cautioned to report any visual symptoms, particularly 
difficulty seeing entire words or faces, intolerance to glare, 
decreased night vision, or loss of peripheral vision. These 
symptoms of retinal toxicity or subclinical evidence of 
retinal toxicity on eye exams should prompt drug 
discontinuation and ophthalmologic evaluation. 
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stay on dabrafenib and/or trametinib at the discretion of the 
treating physician in consultation with an ophthalmologist. 
Guidelines regarding management and dose reduction for 
visual changes and/or ophthalmic examination findings 
considered to be related to study treatment are provided in 
Tables 13, 14, and 15. 
Table 13: Management and Dose Modification 
Guidelines for Visual Changes and/or Ophthalmic 
Examination Findings 
CTCAE 
Gradea 
Adverse Event Management 
Action and Dose Modification 
Grade 1b 
• 
Consult ophthalmologist 
within 7 days of onset 
• 
If dilated fundus examination cannot be 
performed within 7 days of onset, interrupt 
trametinib and hydroxychloroquine until RPED, 
RVO, and visual field deficit can be excluded 
by retina specialist/ophthalmologist. 
Dabrafenib may be continued. 
• 
If RPED and RVO excluded, continue (or 
restart) trametinib and HCQ/placebo at same 
dose level 
• 
If RPED suspected or diagnosed: see RPED 
dose modification table 14 below; report as 
SAE if diagnosed. 
• 
If RVO diagnosed: Permanently discontinue 
trametinib and report as SAE. 
Grade 2 and 
Grade 3 
• 
Consult ophthalmologist 
immediately 
• 
Interrupt trametinib and 
HCQ/placebo. Dabrafenib 
may be continued. 
• 
If RPED and RVO excluded, restart trametinib 
and HCQ at same dose level. 
• 
If RPED diagnosed, see RPED dose 
modification table below; report as SAE. 
• 
If RVO diagnosed: Permanently discontinue 
trametinib and report as SAE 
Grade 4 
• 
Consult ophthalmologist 
immediately 
• 
Interrupt trametinib and 
HCQ/placebo. Dabrafenib 
may be continued.  
• 
If RPED and RVO excluded, may consider 
restarting trametinib at same or reduced dose 
• 
If RVO or RPED diagnosed, permanently 
discontinue trametinib and report as SAE. 
Abbreviations: RPED = retinal pigment epithelial detachment; CTCAE = Common Terminology Criteria 
for Adverse Events; RVO= retinal vein occlusion; SAE = serious adverse event 
a Refers to the CTCAE ‘Eye disorders – Other, specify’ 
b If visual changes are clearly unrelated to study treatment (e.g., allergic conjunctivitis), monitor 
closely but ophthalmic examination is not required. 


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Table 14: Recommended dose modifications for 
trametinib for retinal pigment epithelial detachments 
(RPED) 
CTCAE Grade 
Action and Dose Modification 
Grade 1 RPED (Asymptomatic; 
clinical or diagnostic observations 
only) 
• 
Continue treatment with retinal evaluation each cycle 
(monthly) until resolution. If RPED worsens follow instructions 
below  
Grade 2-3 RPED (Symptomatic 
with mild to moderate decrease in 
visual acuity; limiting instrumental 
ADL) 
• 
Interrupt trametinib and hydroxychloroquine/placebo 
• 
Retinal evaluation each cycle (monthly) 
• 
If improved to ≤ Grade 1, restart trametinib at lower dose 
(reduced by 0.5 mg) or discontinue in patients taking 
trametinib 1 mg daily 
Table 15: Management of Ocular Toxicities 
Ocular Toxicity 
Action 
Uveitis, conjunctivitis 
• 
Continue all therapies as long as effective local therapies can 
control inflammation 
Retinal Vein occlusion, retinal 
pigment epithelial detachment 
(RPED), papilledema 
• 
See table 13 and 14 
Visual field deficits 
• 
Discontinue HCQ/placebo 
5.4.3.11 
Cutaneous Squamous Cell Carcinoma (cuSCC) 
Cases of cuSCC (which include those classified as 
keratoacanthoma or mixed keratoacanthoma subtype) 
have been observed in patient treated with dabrafenib. 
Approximately 70% of events occurred within the first 12 
weeks of treatment with a median time to onset of 8 
weeks. Dose modification or interruption of study treatment 
is not required for cuSCC or KA, however cuSCC should 
be reported as an SAE if it meets the reporting 
requirements outline in Section 5.2.10. 
The cuSCC risk management plan includes (at a minimum) 
regular, thorough skin examinations by a dermatologist or 
melanoma oncology specialist trained to diagnose and 
treat these lesions, regular head and neck exams by the 
treating physician, In patients who develop cuSCC or any 
suspicious skin lesions during the trial, definitive treatment 
(i.e., surgical excision) of any SCC/KA or other suspicious 
lesion(s) is required (shave biopsies are not 
recommended), and the excised tissue is to be sent to a 
pathology laboratory. A complete dermatological history of 
prior medications and cuSCC risk factors (i.e., radiation 
therapy, sun exposure, immunosuppression, prior SCC, 
use of tanning beds, precursor lesions and 
photochemotherapy for psoriasis) must be collected. 
• 
A designated dermatologist or the treating medical 
oncologist, if he/she is adept at skin exams will be 
available to perform skin exams to monitor for cuSCC, 


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BCC, actinic keratosis, keratoacanthoma and second 
primary melanomas. Any lesion suspected of being a 
SCC, BCC, actinic keratosis, keratoacanthoma or 
second primary melanoma should be appropriately 
mapped, photographed, with the photos stored digitally 
and made available upon request. 
• 
Any suspicious lesions identified at baseline and while 
on D+T+ placebo or D+T+HCQ must be fully excised 
and sent for pathological examination (shave biopsies 
are not recommended). 
• 
Actinic keratosis, keratoacanthoma or other skin 
conditions should be treated as per local standard of 
care. 
5.4.3.12 
New primary melanoma 
New primary melanomas have been reported in patients 
treated with dabrafenib. These were identified within the 
first 5 months of therapy and did not require treatment 
modification other than excision. Monitoring for skin lesions 
should occur as described for cuSCC. 
5.5 
Drug interactions: 
Table 16: Prohibited medications with CYP3A or CYP2C* Interactions 
PROHIBITED – Strong inducers of CYP3A or CYP2C8, since concentrations of dabrafenib may 
be decreased 
Class 
Drugs 
Antibiotics 
Rifamycin class agents (e.g., rifampin, rifabutin, rifapentine),  
Anticonvulsant 
Carbamazepine, oxcarbazepine, phenobarbital, phenytoin, s-mephenytoin  
Miscellaneous 
bosentan, St-John’s wort 
 
PROHIBITED – Strong inhibitors of CYP3A, or CYP2C8 since concentrations of dabrafenib may 
be increased 
Class/Therapeutic Area 
Drugs/Agents 
Antibiotics 
Clarithromycin, telithromycin, troleandomycin 
Antidepressant 
Nefazodone 
Antifungals 
Itraconazole, ketoconazole, posaconazole, voriconazole 
Hyperlipidemia 
Gemfibrozil  
Antiretroviral 
ritonavir, saquinavir, atazanavir 
Miscellaneous 
Conivaptan  
Table 17: USE WITH CAUTION: Moderate inhibitors of CYP3A, or CYP2C8 
since concentrations of dabrafenib may be increased 
Class/Therapeutic Area 
Moderate CYP3A and CYP2C8 Inhibitors 
Antiarrhythmics 
Diltiazem, verapamil 
Antibiotic 
Erythromycin 


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Class/Therapeutic Area 
Moderate CYP3A and CYP2C8 Inhibitors 
Antifungal 
Fluconazole 
Miscellaneous 
Aprepitant 
USE WITH CAUTION: Co-administration of these drugs with study treatment may result in loss of 
efficacy. Monitor patient for loss of efficacy or substitute with another medication. 
Class/Therapeutic Area 
CYP3A4, CYP2B6, CYP2C8, CYP2C9, CYP2C19 or Transporter 
Substrates that May be Affected by Induction  
Analgesics 
Alfentanil, buprenorphine, celecoxib, codeine, fentanyl, methadone, 
oxycodone 
Antiarrhythmics 
Disopyramide, dronedarone, mexiletine, propafenone, quinidine 
Antibiotics 
Chloramphenicol, doxycycline, erythromycin, moxifloxacin 
Anticoagulants/ 
Antiplatelets 
Cilostazole, warfarin 
Anticonvulsants 
Divalproex, lamotrigine, valproate, zonisamide 
Antidepressants and 
Antipsychotics 
Aripiprazole, bupropion, buspirone, desipramine, haloperidol, mirtazapine, 
pimozide, quetiapine, trazodone, amitriptyline, clomipramine, imipramine 
Antidiabetics 
Glyburide, saxagliptin, tolbutamide, nateglinide, pioglitazone, repaglinide, 
rosiglitazone 
Antifungals 
Caspofungin, fluconazole, terbinafine 
Antihistamines 
Astemizole, chlorpheniramine, ebastine 
Antihypertensives 
Amlodipine, diltiazem, felodipine, nifedipine, nilvadipine, nisoldipine, 
verapamil 
Antimigraine Agents 
Diergotamine, eletriptan, ergotamine 
Corticosteroids 
Dexamethasone, methylprednisolone, oral budesonide 
Erectile Dysfunction 
Agents 
Sildenafil, tadalafil, vardenafil 
HMG-CoA Reductase 
Inhibitors 
Atorvastatin, lovastatin, simvastatin, rosuvastatin, pravastatin 
Hypnotics and Sedatives 
Alprazolam, brotizolam, diazepam, estazolam, midazolam, triazolam, 
zolpidem, zopiclone 
Immunosuppressants 
Everolimus, sirolimus, tacrolimus 
Miscellaneous 
Aprepitant, cisapride, darifenacin, digoxin, disopyramide, leflunomide, 
methohexital, oral contraceptives, quinine, ranitidine, solifenacin, 
sulfasalazine, tramadol, tolvaptan, chloroquine, zopiclone 
Selective Aldosterone 
Blockers 
Eplerenone 
USE WITH CAUTION: Co-administration of drugs that increase gastric pH should be used with 
caution when administered with dabrafenib as exposure to dabrafenib may be decreased 
pH altering agents 
dexlansoprazole. esomeprazole, famotidine, ilaprazole, lansoprazole, 
omeprazole, pantoprazole, rabeprazole, ranitidine 


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5.6 
Supportive Care 
All supportive measures consistent with optimal patient care will be given 
throughout the study. 
5.7 
Duration of Therapy  
Patients will receive protocol therapy unless: 
• 
Extraordinary Medical Circumstances: If at any time the constraints of this 
protocol are detrimental to the patient's health, protocol treatment should be 
discontinued. In this event submit forms according to the instructions in the 
EA6191 Forms Packet. 
• 
Patient withdraws consent. 
• 
Patient experiences unacceptable toxicity. 
• 
Non-protocol therapies are administered. 
• 
Treatment will continue until disease progression. 
5.8 
Duration of Follow-up  
For this protocol, all patients, including those who discontinue the protocol 
therapy early, will be followed for response until progression, even if non-
protocol-therapy is initiated. Patients will be evaluated for at least 6 months after 
discontinuation of study treatment and will be followed for a minimum of one year 
from the start of treatment, unless disease progression is reported prior to one 
year. One year survival information will be extracted from the medical record or 
by phone call for patient who have discontinued protocol treatment and 
completed the 6 month follow-up evaluations prior to one year from the start of 
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Measurement of Effect 
6.1 
Antitumor Effect – Solid Tumors  
For the purposes of this study, patients should be re-evaluated for response 
every 8 (+/-1) weeks. In addition to a baseline scan, confirmatory scans should 
also be obtained not less than 4 weeks following initial documentation of 
objective response. 
Response and progression will be evaluated in this study using the international 
criteria proposed by the revised Response Evaluation Criteria in Solid Tumors 
(RECIST) guideline (version 1.1) [Eur J Ca 45:228-247, 2009]. Changes in the 
largest diameter (unidimensional measurement) of the tumor lesions and the 
shortest diameter in the case of malignant lymph nodes are used in RECIST. 
The following general principles must be followed: 
1. To assess objective response, it is necessary to estimate the overall tumor 
burden at baseline to which subsequent measurements will be compared. All 
baseline evaluations should be performed as closely as possible to the 
beginning of treatment and never more than four weeks before registration. 
2. Measurable disease is defined by the presence of at least one measurable 
lesion. 
3. All measurements should be recorded in metric notation by use of a ruler or 
calipers. 
4. The same method of assessment and the same technique must be used to 
characterize each identified lesion at baseline and during follow-up. 
6.1.1 
Definitions 
Evaluable for Objective Response 
Only those patients who have measurable disease present at 
baseline, have received at least one cycle of therapy, and have had 
their disease re-evaluated will be considered evaluable for response. 
These patients will have their response classified according to the 
definitions stated below. 
NOTE: 
Patients who exhibit objective disease progression prior to 
the end of cycle 1 will also be considered evaluable. 
Evaluable Non-Target Disease Response 
Patients who have lesions present at baseline that are evaluable but 
do not meet the definitions of measurable disease, have received at 
least one cycle of therapy, and have had their disease re-evaluated 
will be considered evaluable for non-target lesion assessment. The 
response assessment is based on the presence, absence, or 
unequivocal progression of the lesions. 
6.1.2 
Disease Parameters 
Measurable Disease 
Measurable lesions are defined as those that can be accurately 
measured in at least one dimension (longest diameter to be recorded) 
as ≥ 20 mm by chest x-ray, as  


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≥ 10 mm with CT scan, or ≥ 10 mm with calipers by clinical exam. All 
tumor measurements must be recorded in millimeters. 
NOTE: 
Tumor lesions that are situated in a previously irradiated 
area might or might not be considered measurable. If the 
investigator thinks it appropriate to include them, the 
conditions under which such lesions should be considered 
must be defined in the protocol. 
Malignant Lymph Nodes 
To be considered pathologically enlarged and measurable, a lymph 
node must be  
≥ 15 mm in short axis when assessed by CT scan (CT scan slice 
thickness recommended to be no greater than 5 mm). At baseline and 
in follow-up, only the short axis will be measured and followed. 
Non-measurable Disease 
All other lesions (or sites of disease), including small lesions (longest 
diameter < 10 mm or pathological lymph nodes with ≥ 10 to < 15 mm 
short axis), are considered non-measurable disease. Bone lesions, 
leptomeningeal disease, ascites, pleural/pericardial effusions, 
lymphangitis cutis/pulmonitis, inflammatory breast disease, and 
abdominal masses (not followed by CT or MRI), are considered as 
non-measurable. Non-measurable also includes lesions that are < 20 
mm by chest x-ray. 
NOTE: 
Cystic lesions that meet the criteria for radiographically 
defined simple cysts should not be considered as 
malignant lesions (neither measurable nor non-
measurable) since they are, by definition, simple cysts. 
‘Cystic lesions’ thought to represent cystic metastases can be 
considered as measurable lesions, if they meet the definition of 
measurability described above. However, if non-cystic lesions are 
present in the same patient, these are preferred for selection as target 
lesions. 
Target Lesions 
All measurable lesions up to a maximum of 2 lesions per organ and 5 
lesions in total, representative of all involved organs, should be 
identified as target lesions and recorded and measured at baseline. 
Target lesions should be selected on the basis of their size (lesions 
with the longest diameter), be representative of all involved organs, 
but in addition should be those that lend themselves to reproducible 
repeated measurements. It may be the case that, on occasion, the 
largest lesion does not lend itself to reproducible measurement in 
which circumstance the next largest lesion which can be measured 
reproducibly should be selected. 
A sum of the diameters (longest for non-nodal lesions, short axis for 
nodal lesions) for all target lesions will be calculated and reported as 
the baseline sum diameters. If lymph nodes are to be included in the 
sum, then only the short axis is added into the sum. The baseline sum 


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of the diameters will be used as reference to further characterize any 
objective tumor regression in the measurable dimension of the 
disease. 
Non-target Lesions 
All other lesions (or sites of disease) including any measurable lesions 
over and above the 5 target lesions should be identified as non-target 
lesions and should also be recorded at baseline. Measurements of 
these lesions are not required, but the presence or absence of 
unequivocal progression of each should be noted throughout follow-
up.  
6.1.3 
Methods for Evaluation of Disease 
All measurements should be taken and recorded in metric notation 
using a ruler or calipers. All baseline evaluations should be performed 
as closely as possible to the beginning of treatment and never more 
than 4 weeks before registration. 
The same method of assessment and the same technique must be 
used to characterize each identified and reported lesion at baseline 
and during follow-up. Imaging-based evaluation is preferred to 
evaluation by clinical examination unless the lesion(s) being followed 
cannot be imaged but are assessable by clinical exam. 
Clinical Lesions 
Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes) and ≥ 10 
mm in diameter as assessed using calipers (e.g., skin nodules). In the 
case of skin lesions, documentation by color photography, including a 
ruler to estimate the size of the lesion, is recommended.  
Conventional CT and MRI  
This guideline has defined measurability of lesions on CT scan based 
on the assumption that CT slice thickness is 5 mm or less. If 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).  
Use of MRI remains a complex issue. MRI has excellent contrast, 
spatial, and temporal resolution; however, there are many image 
acquisition variables involved in MRI which greatly impact image 
quality, lesion conspicuity, and measurement. Furthermore, the 
availability of MRI is variable globally. As with CT, if an MRI is 
performed, the technical specifications of the scanning sequences 
used should be optimized for the evaluation of the type and site of 
disease. Furthermore, as with CT, the modality used at follow-up must 
be the same as was used at baseline and the lesions should be 
measured/assessed on the same pulse sequence. It is beyond the 
scope of the RECIST guidelines to prescribe specific MRI pulse 
sequence parameters for all scanners, body parts, and diseases. 
Ideally, the same type of scanner should be used and the image 
acquisition protocol should be followed as closely as possible to prior 


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scans. Body scans should be performed with breath-hold scanning 
techniques, if possible. 
PET-CT 
At present, the low dose or attenuation correction CT portion of a 
combined PET-CT is not always of optimal diagnostic CT quality for 
use with RECIST measurements. However, if the site can document 
that the CT performed as part of a PET-CT is of identical diagnostic 
quality to a diagnostic CT (with IV and oral contrast), then the CT 
portion of the PET-CT can be used for RECIST measurements and 
can be used interchangeably with conventional CT in accurately 
measuring cancer lesions over time. Note, however, that the PET 
portion of the CT introduces additional data which may bias an 
investigator if it is not routinely or serially performed. 
Ultrasound 
Ultrasound is not useful in assessment of lesion size and should not 
be used as a method of measurement. Ultrasound examinations 
cannot be reproduced in their entirety for independent review at a 
later 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, such techniques may be useful to confirm 
complete pathological response when biopsies are obtained or to 
determine relapse in trials where recurrence following complete 
response (CR) or surgical resection is an endpoint. 
Tumor Markers 
Tumor markers alone cannot be used to assess response. If markers 
are initially above the upper normal limit, they must normalize for a 
patient to be considered in complete clinical response. Specific 
guidelines for both CA-125 response (in recurrent ovarian cancer) and 
PSA response (in recurrent prostate cancer) have been published 
[JNCI 96:487-488, 2004; J Clin Oncol 17, 3461-3467, 1999; J Clin 
Oncol 26:1148-1159, 2008]. In addition, the Gynecologic Cancer 
Intergroup has developed CA-125 progression criteria which are to be 
integrated with objective tumor assessment for use in first-line trials in 
ovarian cancer [JNCI 92:1534-1535, 2000]. 
Cytology, Histology 
These techniques can be used to differentiate between partial 
responses (PR) and complete responses (CR) in rare cases (e.g., 
residual lesions in tumor types, such as germ cell tumors, where 
known residual benign tumors can remain). 


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The cytological confirmation of the neoplastic origin of any effusion 
that appears or worsens during treatment when the measurable tumor 
has met criteria for response or stable disease is mandatory to 
differentiate between response or stable disease (an effusion may be 
a side effect of the treatment) and progressive disease. 
6.1.4 
Response Criteria 
6.1.4.1 
Evaluation of Target Lesions 
Complete Response (CR) 
Disappearance of all target lesions. Any pathological lymph 
nodes (whether target or non-target) must have reduction 
in short axis to < 10 mm. 
Partial Response (PR) 
At least a 30% decrease in the sum of the diameters of 
target lesions, taking as reference the baseline sum 
diameters 
Progressive Disease (PD) 
At least a 20% increase in the sum of the diameters of 
target lesions, taking as reference the smallest sum on 
study (this includes the baseline sum if that is the smallest 
on study). In addition to the relative increase of 20%, the 
sum must also demonstrate an absolute increase of at 
least 5 mm. 
NOTE: 
The appearance of one or more new lesions is 
also considered progression, See Section 
6.1.4.3. 
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. (Note: a change of 20% or 
more that does not increase the sum of the diameters by 5 
mm or more is coded as stable disease) 
To be assigned a status of stable disease, measurements 
must have met the stable disease criteria at least once 
after study entry at a minimum interval of 8 weeks. 
6.1.4.2 
Evaluation of Non-Target Lesions 
Complete Response (CR) 
Disappearance of all non-target lesions. All lymph nodes 
must be non-pathological in size (< 10 mm short axis) 
Non-CR/Non-PD 
Persistence of one or more non-target lesion(s). 
Progressive Disease (PD) 
Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target lesions (see 


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Section 6.1.4.3). Unequivocal progression should not 
normally trump target lesion status. It must be 
representative of overall disease status change, not a 
single lesion increase. 
When the patient also has measurable disease, there must 
be an overall level of substantial worsening in non-target 
disease such that, even in the 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 qualify 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 only has non-measurable disease, the 
increase in overall disease burden should be comparable 
in magnitude to the increase that would be required to 
declare PD for measurable disease: i.e., an increase in 
tumor burden from “trace” to “large”, an increase in nodal 
disease from “localized” to “widespread”, or an increase 
sufficient to require a change in therapy. 
Although a clear progression of “non-target” lesions only is 
exceptional, the opinion of the treating physician should 
prevail in such circumstances, and the progression status 
should be confirmed at a later time by the review panel (or 
Principal Investigator). 
6.1.4.3 
Evaluation of New Lesions 
The appearance of new lesions constitutes Progressive 
Disease (PD). 
A growing lymph node that did not meet the criteria for 
reporting as a measurable or non-measurable lymph node 
at baseline should only be reported as a new lesion (and 
therefore progressive disease) if it:  
a) increases in size to ≥ 15 mm in the short axis, or  
b) there is new pathological confirmation that it is disease 
(regardless of size). 
New effusion or ascites that appears during treatment 
should only be reported as a new lesion (and therefore 
progressive disease) if it has cytological confirmation of 
malignancy. 
6.1.4.4 
Evaluation of Best Overall Response 
The best overall response is the best response recorded 
from the start of the treatment until disease 
progression/recurrence or non-protocol therapy (taking as 
reference for progressive disease the smallest 
measurements recorded since the treatment started). The 


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patient’s best response assignment will depend on the 
achievement of both measurement and confirmation 
criteria. 
For Patients with Measurable Disease (i.e., Target 
Disease) 
Target 
Lesions 
Non-Target  
Lesions 
New 
Lesions* 
Best Overall 
Response 
Remarks  
CR 
CR 
No 
CR 
 
CR 
Non-CR/Non-PD*** 
No 
PR 
 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD***/not evaluated 
No 
PR 
SD 
Non-PD***/not evaluated 
No 
SD 
Documented at least once 
≥ 8 weeks from 
randomization 
PD 
Any 
Yes or No 
PD 
No prior SD, PR or CR 
Any 
PD** 
Yes or No 
PD*** 
Any 
Any 
Yes 
PD 
* 
See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
** In exceptional circumstances, unequivocal progression in non-target lesions may be accepted as 
disease progression. 
*** PD in non-target lesions should not normally trump target lesion status. It must be representative of 
overall disease status change, not a single lesion increase. Please refer to the Evaluation of Non-
Target Lesions – Progressive Disease section for further explanation. 
NOTE: 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 the objective 
progression even after discontinuation of treatment. 
6.1.4.5 
Duration of Response 
Duration of Overall Response 
The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is 
first recorded) until the first date that recurrent or 
progressive disease is objectively documented (taking as 
reference for progressive disease the smallest 
measurements recorded since the treatment started). 
The duration of overall CR is measured from the time 
measurement criteria are first met for CR until the first date 
that progressive disease is objectively documented. 
Duration of Stable Disease 
Stable disease is measured from the start of the treatment 
until the criteria for progression are met, taking as 
reference the smallest measurements recorded since the 
treatment started, including the baseline measurements.  


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To be assigned a status of stable disease, measurements 
must have met the stable disease criteria at least once 
after study entry at a minimum interval 8 weeks. 
 


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Study Parameters 
7.1 
Therapeutic Parameters  
1. Prestudy CXR and/or scans should be done ≤ 3 weeks prior to randomization. 
2. Prestudy CBC (with differential and platelet count) should be done ≤ 14 days prior to randomization. 
3. All required prestudy chemistries, as outlined in Section 0, should be done ≤ 14 days prior to randomization. 
Assessment 
Baseline 
X= Each 28-day Cycle (Monthly)1 
/alternative interval 
End of treatment7 (for 
any reason) or 
disease progression 
Post Treatment/ Follow-
up6 
History and physical 
examination 
X 
X 
 
 
Vital Signs (including BP) 
X 
X 
 
 
EKG 
X 
X 
 
 
LVEF 
X 
 
 
 
Standard ophthalmological 
exam10 
X 
Yearly or as clinically indicated  
 
 
Transthoracic echo8 
X 
Every 3 months or as clinically 
indicated 
As clinically indicated 
As clinically indicated 
Brain CT or MRI 
X 
Every 4 cycles if brain metastases 
are present on baseline scan, or 
more often as clinically indicated 
As clinically indicated 
As clinically indicated 
Chest CT2 
X 
Every 2 cycles or more often as 
clinically indicated. 
Confirmatory scans at least 4 weeks 
following initial documentation of 
objective response9 
As clinically indicated 
Every 2 months until 6 
months after 
completion of study 
treatment and as 
clinically indicated per 
protocol Section 
5.4.3.11 for cuSCC risk 
management 
Abdomen/pelvis CT or MRI2 
X 
Every 2 cycles and as clinically 
indicated 
Confirmatory scans at least 4 weeks 
As clinically indicated 
As clinically indicated 


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Assessment 
Baseline 
X= Each 28-day Cycle (Monthly)1 
/alternative interval 
End of treatment7 (for 
any reason) or 
disease progression 
Post Treatment/ Follow-
up6 
following initial documentation of 
objective response9 
CBC with differential4 
X 
X 
X 
 
Serum chemistry5 
X 
X 
X 
 
PT/PTT9 
X 
X 
 
 
Serum or Urine Pregnancy 
Test3 
X 
 
 
 
Biological Sample Submissions 
See Sections 7.2 and 0 
1. Day 1 of cycle 1 begins the first day of treatment. A cycle constitutes 28 days or 4 weeks of D+T+HCQ/ placebo therapy. Monthly tests and 
procedures should be done on Day 1 of each cycle, however, account for major holidays and unforeseen events such as inclement weather, 
scheduled visits and testing can occur +/- 1 week from the start of each cycle, as long as there is documentation as to why they did not occur 
according to intended schedule. 
2. Standard of care imaging will be utilized for tumor measurements while on study. The preferred type of imaging is high resolution CT scans of 
the chest abdomen and pelvis with contrast. In cases of elevated creatinine or anaphylactic reaction to contrast dye, CT scans without contrast 
or MRI with gadolinium may be substituted for the abdomen and non-contrast CT for the chest. PET/CT scans may not be substituted unless the 
CT portion of the PET/CT is a high resolution scan with contrast. 
NOTE: 
All visceral areas originally involved by tumor should be re-imaged every 2 cycles. 
3. All females of childbearing potential must have a negative [blood test or urine test] within 14 days prior to study randomization to rule out 
pregnancy. 
4. CBCs (with differential and platelet count) which includes WBC, ANC, Platelets, Hgb, and Hct. 
5. Serum chemistries include: sodium, potassium, BUN, serum creatinine, glucose, SGOT (AST), SGPT (ALT), total bilirubin, alkaline 
phosphatase, LDH, albumin. 
6. Follow-up: all patient will be evaluated for at least 6 months after discontinuation of study treatment and will be followed for a minimum of one 
year from the start of treatment, unless disease progression is reported prior to one year. One year survival information will be extracted from the 
medical record or by phone call for patient who have discontinued protocol treatment and completed the 6 month follow-up evaluations prior to 
one year from the start of treatment. 
7. An End of Treatment (EOT) visits should occur 30 days (+/- 7 days) from the last dose for all patients. For patients experiencing toxicities, EOT 
visits should occur every 2 weeks (+/-3 days) until toxicities resolve. 
8. Transthoracic echocardiogram must be completed within 28 days before starting therapy. They should be repeated every 3 months or as 
clinically indicated 


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9. As clinically indicated, with documentation of the medical necessity. 
10. Any abnormalities found on standard of care eye exams will be graded and attributed to study medication by the investigator. NO additional data 
from routine eye exams needs to be captured. 
7.2 
Biological Sample Submissions 
1. Specimens are to be submitted as outlined in Section 0. 
2. All specimens submitted must be entered and tracked via the online ECOG-ACRIN Sample Tracking System (STS). 
Biological Materials 
Prior to Start of 
Treatment 
Cycle 1, 
Day 7 
(+/- 2 days) 
Cycle 2, 
prior to start of 
treatment 
(+/-1 week) 
Cycle 3, 
prior to start of 
treatment 
(+/-1 week) 
Progression 
Submit from patients who answer ‘Yes’ to ‘I agree that my tissue and blood samples and related health 
information may be kept in a Biobank for use in future health research.’5 
Archival Tumor Tissue 
Biopsy1 
X 
 
 
 
 
Plasma (one 10mL 
EDTA purple top tube)2 
X 
X6 
X6,7 
X7 
 
Submit from patients who answer ‘Yes’ to ‘I agree biopsies may be done to obtain research samples.’ 
Serial Tumor Tissue 
Biopsy1,4 
X 
X3 
 
X 
1. Tumor tissue and related pathology reports are to be submitted within one month of randomization or collection. 
2. Kits are being provided for the collection and shipment of the plasma specimens. See Appendix VI for instructions. Kit orders will 
on average be delivered within three (3) business days from when the order was placed. 
3. Either week 1 +/- 2 days or week 4 +/-1 week or both. The investigator will use clinical judgement to choose time points for the 
second on-treatment biopsy and whether both may be collected.  
4. Serial biopsies are to be obtained from patients that have easily accessible lesions. 
5. As outlined in the Informed Consent patient participation in tumor tissue and plasma submissions is optional. Institutions must 
offer participation in these optional studies to all patients. 
6. For patients submitting tumor tissue from serial research biopsies plasma collection will be prior to start of treatment, Cycle 1 
Day 7 (+/- 2 days, and prior to start of Cycle 2 treatment (+/-1 week). 
7. For patients not submitting tumor tissue from serial research biopsies plasma collection will be prior to start of treatment, prior to 
start of Cycle 2 treatment (+/- 1 week), and prior to Cycle 3 treatment (+/- 1 week). 
Rev Add2 


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Drug Formulation and Procurement 
8.1 
Dabrafenib mesylate (NSC 763760) 
8.1.1 
Chemical Name  
N-{3-[5-(2-Amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-
2-fluorophenyl}-2,6-difluorobenzene sulfonamide, methanesulfonate 
salt 
8.1.2 
Other Names 
GSK2118436B, GSK2118436A (free base), Tafinlar® 
8.1.3 
Classification 
BRAF inhibitor 
8.1.4 
CAS Registry Number 
1195768-06-9 
8.1.5 
Molecular Formula 
C23H20F3N5O2S2 ·CH4O3S 
8.1.6 
M.W. 
615.68 (mesylate salt) 
8.1.7 
Mode of Action: Dabrafenib mesylate is a potent and selective BRAF 
kinase inhibitor. This inhibition suppresses downstream activity of 
pERK, a biomarker, and has antiproliferative activity against BRAF 
mutant tumors. The mode of action is consistent with ATP-competitive 
inhibition. 
8.1.8 
How Supplied 
Commercially available as capsules.  
50 mg capsules: Dark red capsule imprinted with ‘GSTEW’ and 
‘50mg’ available in bottles of 120 (NDC 0078-0682-66). Each bottle 
contains a silica gel desiccant. 
75 mg capsules: Dark pink capsule imprinted with ‘GSLHF’ and 
‘75mg’ available in bottles of 120 (NDC 0078-0681-66). Each bottle 
contains a silica gel desiccant. 
8.1.9 
Storage 
Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 
86°F) 
8.1.10 
Stability 
Refer to the package label for expiration. 
8.1.11 
Route and Method of Administration 
Oral administration. Take dabrafenib mesylate can be taken on an 
empty stomach either 1 hour before or 2 hours after a meal. If a dose 
is missed, it should not be taken later. 


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8.1.12 
Potential Drug Interactions 
In vivo data shows that metabolism of dabrafenib mesylate and its 
metabolites is mediated by CYP3A4 and CYP2C8 with minor 
contributions by CYP 2C9 and 2C19. Use caution if strong inducers or 
inhibitors of CYP2C8 or 3A4 are co-administered with dabrafenib. 
Although in vitro studies indicate dabrafenib mesylate and its 
metabolites are substrates for P-glycoprotein (P-gp) and BCRP 
transporters, the apparent high oral bioavailability and permeability 
indicate modulation of efflux transporters will have minimal impact on 
dabrafenib pharmacokinetics. 
Dabrafenib mesylate and its metabolites showed moderate inhibition 
of CYP 2C8, 2C9, 2C19 and 3A4 in human liver microsomes. Use 
caution in patients who are taking sensitive substrates of these 
enzymes. Additionally, dabrafenib and its metabolites showed 
inhibition of OATP1B1, OATP1B3, OAT1, OAT3 and OCT2 
transporter systems; however, the drug-drug interaction risk is 
believed to be low based on clinical exposures. 
Neither dabrafenib nor its metabolites show inhibition of P-gp in vitro, 
but are moderate inhibitors of BCRP. Dabrafenib may affect the 
pharmacokinetics of co-medications with narrow therapeutic index 
whose absorption or clearance depends on BCRP-mediated 
transport. 
In vitro, dabrafenib mesylate induces CYP 2B6 and 3A4 and possibly 
CYP 2C8, 2C9 2C19, UDP glucuronosyltransferase and P-gp.; 
although in vivo, the overall effect of dabrafenib induction is as a mild 
inducer of CYP2C9 and moderate inducer of CYP3A4. Use caution in 
patients who are taking substrates of these pathways, such as 
warfarin or hormonal contraceptives and monitor for loss of efficacy. 
Dabrafenib solubility is pH-dependent but is not expected to be 
reduced when co-administered with pH elevating agents like proton 
pump inhibitors. 
8.1.13 
Patient Care Implications 
In the case of overdose, patients should be treated symptomatically 
since there is no specific antidote. Hemodialysis is likely to be 
ineffective since dabrafenib mesylate is highly bound to plasma 
proteins. 
Advise women study participants of reproductive potential to use 
effective non-hormonal contraception methods while receiving study 
treatment and for 2 weeks after the last dose of dabrafenib. Hormonal 
contraceptives can be ineffective when taken concurrently with 
dabrafenib. Male study participants (including those who have had a 
vasectomy) must use a condom during intercourse while taking 
dabrafenib and for 2 weeks after the last dose and should not father a 
child during this period. 
Patients should be instructed on the importance of immediately 
reporting febrile episodes. In the event of a fever, the patient should 
be instructed to take anti-pyretics (e.g. ibuprofen or 


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acetaminophen/paracetamol) as appropriate to control fever. The use 
of oral corticosteroids should be considered in those instances in 
which anti-pyretics are insufficient. Monitor serum creatinine and other 
evidence of renal function during and following severe events of 
pyrexia. 
8.1.14 
Side effects 
See Section 5.3.1 
8.2 
Trametinib dimethyl sulfoxide (NSC 763093) 
8.2.1 
Chemical Name (IUPAC) 
equimolecular combination of N-(3-{3-cyclopropyl-5-[(2-fluoro- 4-
iodophenyl)amino]-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-
tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl}phenyl)acetamide with 
(methylsulfinyl)methane 
8.2.2 
Other Names 
trametinib, GSK1120212B, TMT212-NXA, JTP-74057, JTP-78296, 
JTP-75303, Mekinist® 
8.2.3 
CAS Registry Number 
1187431-43-1 
8.2.4 
Classification 
MEK inhibitor 
8.2.5 
Molecular Formula 
C26H23FIN5O4  •  C2H6OS 
8.2.6 
M.W. 
693.53 (DMSO solvate form) 
8.2.7 
Approximate Solubility 
Trametinib dimethyl sulfoxide is almost insoluble in aqueous media at 
pH range of 2-8. 
8.2.8 
Mode of Action 
Trametinib dimethyl sulfoxide is a reversible, highly selective, 
allosteric inhibitor of mitogen-activated extracellular signal regulated 
kinase 1 (MEK1) and MEK2. Tumor cells commonly have 
hyperactivated extracellular signal-related kinase (ERK) pathways in 
which MEK is a critical component. Trametinib dimethyl sulfoxide 
inhibits activation of MEK by RAF kinases and MEK kinases. 
8.2.9 
Description 
Trametinib dimethyl sulfoxide is a white to almost white powder. 
8.2.10 
How Supplied 
Commercially available 


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The tablet core contains mannitol, microcrystalline cellulose, 
hypromellose, croscarmellose sodium, magnesium stearate (non-
animal), colloidal silicon dioxide and sodium lauryl sulfate. 
0.5 mg tablets are yellow, modified oval, biconvex and film-coated 
with ‘GS’ debossed on one face and ‘TFC’ on the opposing face. 
Aqueous film coating consists of hypromellose, titanium dioxide, 
polyethylene glycol, iron oxide yellow. 
2 mg tablets are pink, round, biconvex and film-coated with ‘GS’ 
debossed on one face and ‘HMJ’ on the opposing face. Aqueous film 
coating consists of hypromellose, titanium dioxide, polyethylene 
glycol, polysorbate 80, iron oxide red. 
8.2.11 
Storage 
Store tablets at 2°C -8°C (36° F to 46° F) in the original bottle. Do not 
repackage tablets or remove desiccant. Bottles should be protected 
from light and moisture. 
8.2.12 
Stability 
Refer to the package label for expiration. 
8.2.13 
Route of Administration 
Oral. Take by mouth on an empty stomach, either 1 hour before or 2 
hours after a meal. If a dose of trametinib is missed, it should not be 
taken later. 
8.2.14 
Potential Drug Interactions 
In vitro studies suggest that trametinib is not a substrate of CYP 
enzymes or of human BCRP, MRP2, OATP1B1, OATP1B3, 
OATP2B1, OCT1 or MATE1 transporters. Trametinib elimination by 
deacetylation to metabolite M5 is dependent on carboxylesterases 
(CES1b, CES1c and CES2). Trametinib is a substrate for P-gp and 
BSEP, but this is not expected to be clinically relevant due to 
trametinib’s high permeability. 
Trametinib is an in vitro inhibitor of CYP 2C8 and is anticipated to 
have overall low potential for drug interactions as a perpetrator. It is 
also a weak CYP 2B6 and 3A4 inducer and expected to have little 
clinical effect on sensitive substrates. Trametinib is not an inhibitor of 
CYP 1A2, 2A6, 2B6, 2C9, 2C19, 2D6 and 3A4 and not an inhibitor of 
MRP2 or BSEP, but an in vitro inhibitor of P-gp, BCRP, OATP1B1, 
OATP1B3, OAT1, OAT3, OCT2 and MATE1 at systemic 
concentrations that are not clinically relevant. No clinically relevant 
inhibition by trametinib is predicted in the liver or kidney and a low risk 
of intestinal drug-drug interaction is possible with BCRP. 
Trametinib is highly bound to plasma proteins (97.3%) and has the 
potential to interfere with other highly protein-bound drugs. Use 
caution in patients taking concomitant drugs that are highly protein-
bound and have narrow therapeutic ranges. 


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8.2.15 
Patient Care Implications 
Advise women study participants of reproductive potential to use 
effective contraception while receiving study treatment and for 4 
months after the last dose of trametinib. Advise women not to 
breastfeed while receiving study treatment and for 4 months after the 
last dose of trametinib. Advise men study participants to use barrier 
contraception and not to father a child while taking study treatment 
and for 4 months after the last dose of trametinib. Patients should be 
instructed on the importance of immediately reporting febrile 
episodes. In the event of a fever, the patient should be instructed to 
take anti-pyretics (e.g. ibuprofen or acetaminophen/paracetamol) as 
appropriate to control fever. The use of oral corticosteroids should be 
considered in those instances in which anti-pyretics are insufficient. 
Monitor serum creatinine and other evidence of renal function during 
and following severe events of pyrexia. 
8.2.16 
Side Effects 
See Section 0 
8.3 
Hydroxychloroquine and Matching Placebo 
All orders for HCQ and placebo must be placed using the EA6191 Drug Request 
Form and submitted to EA Drug team at DrugOrder@ecog-acrin.org. 
8.3.1 
Chemical name 
Hydroxychloroquine sulfate 
8.3.2 
Other names 
PLAQUENIL® 
8.3.3 
Molecular Formula 
C18H26ClN3O.H2SO4 
8.3.4 
Molecular weight 
433.95 
8.3.5 
Mode of Action 
Chloroquine has been shown to be a catalytic inhibitor of DNA repair 
enzymes (topoisomerase II). 
8.3.6 
Storage and stability 
Store at room temperature [20° to 25°C (68° to 77°F), allows 
excursions between 15° and 30°C (59° to 86°F) 
8.3.7 
Route of administration 
Oral. Take three (3) tablets by mouth that contains 200 mg of 
hydroxychloroquine sulfate/placebo (600 mg total). Take with or 
without food. 
8.3.8 
Potential Drug Interactions  
Drug Interactions Digoxin: Concomitant HCQ/placebo and digoxin 
therapy may result in increased serum digoxin levels: serum digoxin 


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levels should be closely monitored in patients receiving combined 
therapy. 
Insulin or antidiabetic drugs: As HCQ/placebo may enhance the 
effects of a hypoglycemic treatment, a decrease in doses of insulin or 
antidiabetic drugs may be required. 
Drugs that prolong QT interval and other arrhythmogenic drugs: 
HCQ/placebo prolongs the QT interval and should not be 
administered with other drugs that have the potential to induce cardiac 
arrhythmias. Also, there may be an increased risk of inducing 
ventricular arrhythmias if HCQ/placebo is used concomitantly with 
other arrhythmogenic drugs. 
Mefloquine and other drugs known to lower the convulsive threshold: 
HCQ/placebo can lower the convulsive threshold. Co-administration of 
HCQ/placebo with other antimalarials known to lower the convulsion 
threshold (e.g., mefloquine) may increase the risk of convulsions. 
Antiepileptics: The activity of antiepileptic drugs might be impaired if 
co-administered with HCQ/placebo. 
Methotrexate: Combined use of methotrexate with HCQ/placebo has 
not been studied and may increase the incidence of adverse effects. 
Cyclosporin: An increased plasma cyclosporin level was reported 
when cyclosporin and HCQ/placebo were co-administered. 
The following interactions have been observed on treatment with the 
structurally related substance chloroquine phosphate, and therefore 
cannot be ruled out for hydroxychloroquine. 
Praziquantel: Chloroquine has been reported to reduce the 
bioavailability of praziquantel. 
Antacids and kaolin: Antacids and kaolin can reduce absorption of 
chloroquine; an interval of at least 4 hours between intake of these 
agents and chloroquine should be observed. 
Cimetidine: Cimetidine can inhibit the metabolism of chloroquine, 
increasing its plasma level. Concomitant use of cimetidine should be 
avoided. 
Ampicillin: In a study of healthy volunteers, chloroquine significantly 
reduced the bioavailability of ampicillin. 
8.3.9 
Patient Care Implications:  
Patients should be informed of the early signs and symptoms of 
toxicity such as rash or visual changes. Patients must see their 
physicians promptly in case of the appearance of these or of any 
unusual effects. Periodic laboratory tests may be recommended in 
some patients. Patients should be fully informed of the potential risks 
of the use ofHCQ/placebo, especially in pregnancy and in children. 
Teratogenic Effects: Human pregnancies resulting in live births have 
been reported in the literature and no increase in the rate of birth 
defects has been demonstrated. Embryonic deaths and malformations 


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of anophthalmia and microphthalmia in the offspring have been 
reported when pregnant rats received large doses of chloroquine. 
Nursing Mothers: Caution should be exercised when administering 
HCQ/placebo to nursing women. It has been demonstrated that 
hydroxychloroquine administered to nursing women is excreted in 
human milk and it is known that infants are extremely sensitive to the 
toxic effects of 4-aminoquinolines. 
Pediatric Use: Safety and efficacy have not been established in the 
chronic use of HCQ/placebo for systemic lupus erythematosus and 
juvenile idiopathic arthritis in children. Children are especially 
sensitive to the 4-aminoquinoline compounds. Most reported fatalities 
followed the accidental ingestion of chloroquine, sometimes in small 
doses (0.75 g or 1 g in one 3-year-old child). Patients should be 
strongly warned to keep these drugs out of the reach of children. 
Geriatric Use: Clinical studies of HCQ/placebo did not include 
sufficient numbers of subjects aged 65 and over to determine whether 
they respond differently from younger subjects. However, this drug is 
known to be substantially excreted by the kidney, and the risk of toxic 
reactions to this drug may be greater in patients with impaired renal 
function. Because elderly patients are more likely to have decreased 
renal function, care should be taken in dose selection and it may be 
useful to monitor renal function. 
8.3.10 
Side Effects  
The following adverse events have been identified during post-
approval use of HCQ/placebo or other 4-aminoqunoline compounds. 
Because these reactions are reported voluntarily from a population of 
uncertain size, it is not always possible to reliably estimate their 
frequency or establish a causal relationship to drug exposure. 
Blood and lymphatic system disorders: Bone marrow failure, anemia, 
aplastic anemia, agranulocytosis, leukopenia, and thrombocytopenia. 
Hemolysis reported in individuals with glucose-6-phosphate 
dehydrogenase (G-6-PD) deficiency. 
Cardiac disorders: Cardiomyopathy which may result in cardiac failure 
and in some cases a fatal outcome. PLAQUENIL prolongs the QT 
interval. Ventricular arrhythmias and torsade de pointes have been 
reported in patients taking HCQ/placebo. 
Ear and labyrinth disorders: Vertigo, tinnitus, nystagmus, nerve 
deafness, deafness. 
Eye disorders: Irreversible retinopathy with retinal pigmentation 
changes (bull’s eye appearance), visual field defects (paracentral 
scotomas) and visual disturbances (visual acuity), maculopathies 
(macular degeneration), decreased dark adaptation, color vision 
abnormalities, corneal changes (edema and opacities) including 
corneal deposition of drug with or without accompanying symptoms 
(halo around lights, photophobia, blurred vision). 
Gastrointestinal disorders: Nausea, vomiting, diarrhea, and abdominal 
pain. 


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General disorders and administration site conditions: Fatigue. 
Hepatobiliary disorders: Liver function tests abnormal, hepatic failure 
acute. 
Immune system disorders: Urticaria, angioedema, bronchospasm. 
Metabolism and nutrition disorders: Decreased appetite, 
hypoglycemia, porphyria, weight decreased. 
Musculoskeletal and connective tissue disorders: Sensorimotor 
disorder, skeletal muscle myopathy or neuromyopathy leading to 
progressive weakness and atrophy of proximal muscle groups, 
depression of tendon reflexes and abnormal nerve conduction. 
Nervous system disorders: Headache, dizziness, seizure, ataxia and 
extrapyramidal disorders such as dystonia, dyskinesia, and tremor 
have been reported with this class of drugs. 
Psychiatric disorders: Affect/emotional lability, nervousness, irritability, 
nightmares, psychosis, suicidal behavior. 
Skin and subcutaneous tissue disorders: Rash, pruritus, pigmentation 
disorders in skin and mucous membranes, hair color changes, 
alopecia. Dermatitis bullous eruptions including erythema multiforme, 
Stevens-Johnson syndrome, and toxic epidermal necrolysis, drug 
reaction with eosinophilia and systemic symptoms (DRESS 
syndrome), photosensitivity, dermatitis exfoliative, acute generalized 
exanthematous pustulosis (AGEP). AGEP has to be distinguished 
from psoriasis, although HCQ/placebo may precipitate attacks of 
psoriasis. It may be associated with pyrexia and hyperleukocytosis. 
8.3.11 
Drug Orders/How Supplied 
HCQ and matching placebo are being provided free of charge for this 
study by Sandoz Inc. a division of Novartis, and distributed by Patwell 
Pharmaceutical Solutions LLC. Each capsule contains 200 mg of 
HCQ or placebo and will be packaged in 100 count bottles. Each 
shipment will contain 6 bottles of either HCQ or matching placebo for 
3 months of treatment. The label will include: 
• 
Study Number 
• 
Med ID # 
• 
The Number of Tablets 
• 
Administration instructions (i.e. ‘Administer as Directed per 
Protocol’) 
• 
IND caution statement and/or local regulatory statements 
• 
Expiration Date 
• 
Storage instructions  
8.3.12 
IND Status 
When used in this protocol, HCQ/placebo are each classified as an 
“unapproved use of an approved agent” and by definition considered 
investigational agents. However, while it is not an indication currently 
approved by the FDA, the use of HCQ/placebo in this protocol is 


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exempt from the requirements of an IND and described under Title 21 
CFR 312.2(b). 
8.3.13 
Initial Orders 
Following submission of the required regulatory documents and 
patient randomization, a supply of HCQ and matching placebo may be 
ordered from the ECOG-ACRIN Drug Team. Institutions must email 
the completed EA6191 Drug Request Form to the ECOG-ACRIN Drug 
Team at DrugOrder@ecog-acrin.org. The drug order form is available 
for download on the CTSU website under the protocol specific 
Pharmacy tab. If email is not available, the completed form may be 
faxed to ATTN: ECOG-ACRIN Drug Team at 617-589-0919. No 
blinded starter supplies are available for this protocol. 
8.3.14 
Important Information for Drug Orders 
At the time of randomization each patient will be assigned a patient 
specific Blinded Drug ID number, example DR1117. The Blinded Drug 
ID number will appear on the patient’s Confirmation of Registration 
Form. 
The EA6191 Drug Request Form must include the patient specific 
Blinded Drug ID number with each drug request in order for the drug 
order to be processed. Failure to provide this information on the drug 
order form will result in a delay of the drug order being processed and 
shipped. 
This study is a double-blinded treatment protocol. Blinded 100 
count bottles of HCQ and matching placebo MAY NOT be 
transferred from one patient to another patient. 
Each shipment will contain 6 bottles for a 3-month supply of HCQ and 
matching placebo. Study drug is provided in 100 count bottles. Each 
capsule contains 200 mg of HCQ or placebo. 
8.3.15 
Reorders 
Once it is determined that the patient will continue treatment, reorders 
should be made by submitting the EA6191 Drug Request Form should 
be emailed to the ECOG-ACRIN Drug Team at DrugOrder@ecog-
acrin.org. 
Each shipment will contain 6 bottles for a 3-month supply of 
HCQ/placebo. Study drug is provided in 200 mg capsules of 100 
capsules/bottle. 
For both initial orders and reorders, Patwell will ship orders 
received prior to 2 pm ET Monday-Thursday the same day for 
next day delivery. Patwell will ship orders received after 2 pm ET 
Monday-Thursday or on Friday will be shipped the following 
business day for next day delivery. There will be no weekend or 
holiday deliveries. 
8.3.16 
Drug Inventory Records 
Investigational Product Records at Investigational Site(s): It is the 
responsibility of the Investigator to ensure that a current record of 


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investigational product disposition is maintained at each study site 
where investigational product is inventoried and disposed. Records or 
logs must comply with applicable regulations and guidelines. 
8.3.17 
Drug Destruction and Return 
At the completion of the patient’s treatment at your institution, all 
unused drugs, partially used, or empty blister packs must be 
destroyed at the site according to the institution’s policy for drug 
destruction. Please maintain appropriate records of the disposal, 
including dates and quantities. 
8.3.18 
Emergency Unblinding 
See Section 4.5. 
 


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Statistical Considerations 
9.1 
Study Design and Objectives 
In this randomized phase II study, 84 patients with advanced BRAF V600E/K 
melanoma and serum LDH > ULN will be randomized to: dabrafenib + trametinib 
+ HCQ (Arm A) and dabrafenib + trametinib + placebo (Arm B). The primary 
objective is to compare the rate of one-year progression-free survival (PFS) 
between the two arms. It is hypothesized that HCQ will overcome resistance and 
significantly improve the rate of one year PFS. 
Secondary objectives are to evaluate: PFS, best overall response rate, complete 
response rate, treatment duration, adverse event rate and overall survival (OS) 
by treatment arms. 
9.2 
Study Endpoints 
PFS is defined as the time from randomization to progression or death 
(whichever occurs first). Patients who have not had an event will be censored at 
the date of last disease assessment documenting the patient was free of 
progression. Progression will be evaluated based on international criteria 
proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) 
guideline (version 1.1) as described in Section 0. One-year PFS rate in each arm 
will be estimated from the Kaplan-Meier PFS curve. 
Response will be defined by the RECIST guidelines (version 1.1) as described in 
Section 0. Treatment duration will be measured from treatment start to treatment 
end dates on protocol. For patients who have progressed, information on 
treatment type and duration on off-protocol therapies will be collected in the long-
term follow up. Adverse events will be graded using the National Cancer Institute 
(NCI) Common Terminology Criteria for Adverse Events (CTCAE). Overall 
Survival (OS) will be defined as the time from randomization to death from any 
cause. Patients who have not died will be censored at the date last known to be 
alive. 
9.3 
Sample Size Considerations and Monitoring Plan 
In patients with elevated LDH, the null hypothesis is a 1-year PFS rate of 20% in 
the control arm and the targeted effect size is 25% improvement in the treatment 
arm (i.e. alternate hypothesis is 45% 1-year PFS rate).  
Eighty-four patients (for 80 eligible and evaluable) will be equally randomized to 
HCQ vs. placebo arms. It is expected to accrue 84 patients in 28 months (target 
accrual 3 patients per month). We expect the number of patients who will be 
censored before one-year will be very small (less than 4 out of 84 accrued). The 
sample size of 80 eligible and evaluable patients will provide 81.7% power for the 
comparison of one-year PFS rate of 20% to 45%. To be conservative, we used 
the power calculation based on the Fisher’s exact test, assuming 80 patients with 
one-year PFS assessed. One-sided type I error rate of 0.10 was used. It is likely 
PFS follows a cure rate model with a mixture of patients who have progression 
and cured. As there is limited data to evaluate the cure rate model parameters, a 
landmark analysis based on the one-year PFS rate was used for the sample size 
calculation. 
Rev Add2 
Rev Add2 


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One interim analysis for futility will be conducted when one-year PFS rate is 
assessed in the first 40 patients at 50% information time. We will adopt a 
stopping rule proposed by Wieand et al. (Statistics in Medicine vol 13: 1453-
1458, 1994). That is, if one-year PFS rate in the HCQ arm is lower than the one-
year PFS rate in the placebo arm, an early stopping will be considered. 
Conditional power will be also estimated. 
9.4 
Statistical Analysis Plan 
As a primary analysis, one-year PFS rates estimated from the Kaplan-Meier 
curves will be compared by treatment arm. A test statistic of the difference in 
one-year PFS rates divided by the square root or the sum of the variances will be 
used with a normal approximation. As a secondary analysis, PFS distribution will 
be estimated using the method of Kaplan-Meier by treatment arm and compared 
using the log-rank test. In this analysis, all cases with PFS assessed (including 
cases with censored < one-year) will be included. 
For the secondary endpoints, overall response and complete response rates will 
be estimated by treatment arm and 95% CIs will be provided. Overall survival will 
be described using the method of Kaplan-Meier by treatment arm. Adverse 
events will be monitored carefully throughout the study and will be summarized 
by treatment arm. Treatment duration will be estimated by treatment arm. 
9.5 
Gender and Ethnicity  
Based on previous data from E1608, E3611, the anticipated accrual in subgroups 
defined by gender and race is: 
EXAMPLE 
PLANNED ENROLLMENT REPORT 
Racial Categories 
Ethnic Categories 
Total 
Not Hispanic or Latino 
Hispanic or Latino 
Female 
Male 
Female 
Male 
American Indian/ 
Alaska Native 
1 
0 
1 
1 
3 
Asian 
3 
2 
0 
0 
5 
Native Hawaiian or 
Other Pacific Islander 
1 
0 
0 
0 
1 
Black or African 
American 
6 
5 
0 
0 
11 
White 
40 
25 
1 
1 
67 
More Than One Race 
4 
3 
3 
3 
13 
Total 
55  
35 
5 
5 
100 
9.6 
Study Monitoring 
This study will be monitored by the ECOG-ACRIN Data Safety Monitoring 
Committee (DSMC). The DSMC meets twice each year. For each meeting, all 
monitored studies are reviewed for safety and progress toward completion. When 
appropriate, the DSMC will also review interim analyses of outcome data. Copies 
of the toxicity reports prepared for the DSMC meetings are included in the study 


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reports prepared for the ECOG-ACRIN group meeting (except that for double 
blind studies, the DSMC may review unblinded toxicity data, while only pooled or 
blinded data will be made public). These group meeting reports are made 
available to the local investigators, who may provide them to their IRBs. Only the 
study statistician and the DSMC members will have access to interim analyses of 
outcome data. Prior to completion of this study, any use of outcome data will 
require approval of the DSMC. Any DSMC recommendations for changes to this 
study will be circulated to the local investigators in the form of addenda to this 
protocol document. A complete copy of the ECOG-ACRIN DSMC Policy can be 
obtained from the ECOG-ACRIN Operations Office – Boston. 


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Specimen Submissions 
Representative archival tumor tissue, serial tumor tissue research biopsies and plasma 
specimens are to be submitted per patient consent for future undefined research studies. 
All specimens must be clearly labeled with the ECOG-ACRIN protocol number EA6191, 
the patient’s initials and ECOG-ACRIN patient sequence number, the collection date, 
and specimen type. For pathology materials, it is strongly recommended that full patient 
names be provided. 
It is required that all specimens submitted on this trial be entered and tracked via the 
ECOG-ACRIN Sample Tracking System (STS) Section 10.5. An STS shipping manifest 
form is to be included with every submission. 
10.1 
Submissions to ECOG-ACRIN Central Biorepository and Pathology Facility 
(CBPF) 
If you have any questions concerning tumor tissue and peripheral blood 
submissions please contact the ECOG-ACRIN CBPF at (844) 744-2420 or 
eacbpf@mdanderson.org 
10.1.1 
Pathology Material Submissions 
Guidelines for pathologists are provided in Appendix I. 
Submit per patient consent within one month of randomization or 
collection. Tissue requested is archival diagnostic tumor tissue and 
tumor tissue from serial research biopsies collected at: 
• 
Baseline 
• 
Cycle 1 Day 7 (+/- 2 days) and/or Cycle 2 prior to treatment (+/-1 
week) 
• 
Progression 
NOTE: 
Information regarding the reimbursements associated with 
the research biopsies is provided in Appendix VI. 
Submitting pathologist and clinical research associate may refer to 
Appendix I which outlines the Pathology Submission Guidelines. 
The tumor tissue specimens are to be labeled with the institution’s 
assigned pathology ID number as well as the information above. 
10.1.1.1 
Required Forms: 
The following forms must be submitted with all pathology 
submissions: 
• 
STS generated Shipping Manifest Form 
• 
Copy of the institutional pathology reports 
• 
Immunological study reports, if available 
10.1.1.2 
Tumor Tissue Submissions (archival and research 
biopsies): 
• 
Representative formalin-fixed paraffin-embedded 
(FFPE) tumor tissue blocks 
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NOTE: 
Reimbursement guidelines for research 
biopsies are outlined in Appendix VII. Biopsies 
to obtain specimens for research must be 
determined to be minimal risk prior to 
performance. 
NOTE: 
Only blocks will be accepted from serial 
research biopsies eligible for 
reimbursement, though institutions are allowed 
to keep an H&E slide. 
NOTE: 
If archival blocks are unavailable for 
submission, cores and slides are to be 
submitted. All cores and slides must be 
adequately labeled, with slides numbered 
sequentially in the order cut. Alternative 
submission requirements: 
• 
One (1) H&E slide 
• 
Twenty (20) 5 µm and five (5) 4 µm 
unstained, positively charged, air-dried plus 
slides from the thickest part of the tumor. 
• 
One (1) or more core punches (minimum of 
4mm diameter). If core punch tool is 
unavailable, request core punch kit from the 
ECOG-ACRIN CBPF (844) 744-2420. 
Adequately label every slide and core 
submitted. 
If these criteria cannot be met, please contact the 
ECOG-ACRIN CBPF (eacbpf@mdanderson.org) to 
obtain alternative submission requirements. 
10.1.2 
Plasma Submissions 
Kits for the collection and shipment of the plasma specimens are 
ordered online from Cenetron Central Laboratories. Instructions are 
provided in Appendix VI. Questions regarding kits can be directed to 
projectmanagement@cenetron.com or call the Cenetron Clinical 
Trials Group at (512) 439-2000. Kits must be ordered after the patient 
has been randomized to the trial and will generally arrive within three 
(3) business days from when the order was placed. 
10.1.2.1 
Plasma Collection Time Points: 
• 
Prior to Start of Treatment 
• 
Cycle 1, Day 7 (+/- 2 days) (from patients submitting 
tumor tissue from serial research biopsies) 
• 
Cycle 2, prior to treatment (+/-1 week) 
• 
Cycle 3, prior to treatment (+/-1 week) (from patients 
not submitting tumor tissue from serial research 
biopsies) 
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10.1.2.2 
Plasma Preparation Guidelines 
• 
Collect 10mL of whole blood into one (1) EDTA Purple 
Top tube   
• 
Invert tube gently 8-10 times to ensure proper mixing 
• 
Centrifuge within 20 minutes of collection at 1000-
1500g (approximately 3000 rpm) for 15 minutes or 
longer at 4˚C 
• 
Carefully pipette the top plasma layer and aliquot into 
each of four (4) cryovials 
• 
Replace the stopper on the EDTA tube containing the 
residual cells 
• 
Place plasma and residual cells upright in -70°C 
freezer and ship overnight on dry ice (at least five 
pounds) or batch for subsequent shipping. If -70°C 
freezer is not available, store blood at -20°C and ship 
with 24 hours. If dry ice is not available, please contact 
the ECOG-ACRIN CBPF at (844) 744-2420 for 
shipping alternatives. 
10.2 
Shipping Procedures  
Tumor tissue specimens (both archival and research biopsies) are to be shipped 
overnight at ambient temperature (cool pack in warm weather) within one (1) 
month following randomization or collection. 
Batch ship plasma specimens overnight frozen on dry ice. 
The laboratory is open Monday through Friday to receive specimens. Do not ship 
on Fridays or Saturdays, or the day before legal holidays. 
Friday shipments are ill advised, similarly shipping before holidays is often 
problematic. The laboratory is closed Saturday, Sunday, and holidays. 
Ship using the CBPF’s FedEx account using the FedEx on-line ship manager. 
Access to the FedEx shipping account for specimen shipments to the ECOG-
ACRIN CBPF at MD Anderson Cancer Center can only be obtained by logging 
into fedex.com with an account issued by the ECOG-ACRIN CBPF. For security 
reasons, the account number will no longer be given out in protocols, over the 
phone, or via email. If your institution needs to have an account created, please 
contact the ECOG-ACRIN CBPF by email at eacbpf@mdanderson.org 
Ship to: 
MD Anderson Cancer Center CBPF 
Mike Balco 
Life Science Plaza - Suite 910 
2130 West Holcombe Boulevard, LSP9.4227 
Houston, TX 77030 
Phone: Toll Free (844) 744-2420 (713-745-4440 Local or International Sites) 
Fax: (713)-563-6506 
An STS Shipping Manifest Form must be generated and shipped with all 
specimen submissions. 
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10.3 
Use of Specimens in Research 
An amendment or proposal for any additional correlative science studies to be 
performed on biological specimens will be submitted to CTEP/NCI for review and 
approval according to NCTN guidelines. Amendments to the protocol and/or 
proposals for use of biological specimens will include the appropriate 
background, experimental plans with assay details, and detailed statistical 
section. Specimens for testing will not be released until the appropriate NCI 
approvals have been obtained. 
The proposed future studies will assess the biological effects of the triple drug 
regimen, and generate candidate predictive markers of efficacy. 
Specimens submitted will be processed to maximize their utility for current and 
future research projects and may include, but not limited to, extraction of plasma, 
serum, DNA and RNA. 
Specimens from patients who consented to allow their specimens to be used for 
future approved research studies will be retained in an ECOG-ACRIN designated 
central repository. For this trial, specimens will be retained at the ECOG-ACRIN 
Central Biorepository and Pathology Facility. Specimens will be de–identified 
prior to distribution for any approved research projects. 
If future use is denied or withdrawn by the patient, the specimens will be 
removed from consideration for use in any future study. Pathology materials may 
be retained for documentation purposes or returned to the institution. All other 
specimens will be destroyed per guidelines of the respective repository. 
10.4 
ECOG-ACRIN Sample Tracking System 
It is required (barring special circumstances) that all specimens submitted on 
this trial be entered and tracked using the ECOG-ACRIN Sample Tracking 
System (STS). As of June 2007, the software will allow the use of either 1) an 
ECOG-ACRIN username and password previously assigned (for those already 
using STS), or 2) CTSU username and password. 
When you are ready to log the collection and/or shipment of the specimens 
required for this study, please access the Sample Tracking System software by 
clicking https://webapps.ecog.org/Tst.  
Important: Please note that the STS software creates pop-up windows, so you 
will need to enable pop-ups within your web browser while using the software. A 
user manual and interactive demo are available by clicking this link: 
http://www.ecog.org/general/stsinfo.html. Please take a moment to familiarize 
yourself with the software prior to using the system. 
An STS generated Shipping Manifest must be generated and shipped with all 
specimen submissions. 
Please direct your questions or comments pertaining to the STS to 
ecog.tst@jimmy.harvard.edu. 
Study Specific Notes 
Generic Specimen Submission Form (#2981v3) will be required only if STS is 
unavailable at time of specimen submission. Notify the laboratory of the shipment 
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Retroactively enter all specimen collection and shipping information when STS is 
available. 
10.5 
Sample Inventory Submission Guidelines  
Inventories of all specimens submitted will be tracked via the ECOG-ACRIN STS 
and receipt and usability verified by the receiving laboratory. Inventories of 
specimens forwarded and utilized will be submitted by the investigating 
laboratories to the ECOG-ACRIN Operations Office - Boston on a monthly basis 
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Electronic Data Capture 
Please refer to the EA6191 Forms Completion Guidelines for the forms submission 
schedule. Data collection will be performed exclusively in Medidata Rave 
This study will be monitored by the Clinical Data Update System (CDUS) Version 3.0. 
Cumulative protocol- and patient-specific CDUS data will be submitted electronically to 
CTEP on a quarterly basis by FTP burst of data. Reports are due January 31, April 30, 
July 31, and October 31. Instructions for submitting data using the CDUS can be found 
on the CTEP Web site (http://ctep.cancer.gov/reporting/cdus.html). 
For studies assigned Demography monitoring and enrolling patients via OPEN: 
Required submission of patient demographic data for this study will be submitted 
automatically via OPEN. 
NOTE: 
Serious adverse events must be submitted via CTEP-AERS per protocol 
guidelines. 
Patient Consent and Peer Judgment 
Current FDA, NCI, state, federal and institutional regulations concerning informed 
consent will be followed. 
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MJ, Mirsky DM, Handler MH, Foreman NK, Thorburn A. Autophagy inhibition 
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9. Goulielmaki M, Koustas E, Moysidou E, Vlassi M, Sasazuki T, Shirasawa S, 
Zografos G, Oikonomou E, Pintzas A. BRAF associated autophagy exploitation: 
BRAF and autophagy inhibitors synergise to efficiently overcome resistance of BRAF 
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CI, Murugan S, Fennelly C, Noguera-Ortega E, Chu CT, Liu S, Xu X, Krepler C, Xiao 
M, Xu W, Wei Z, Frederick DT, Boland G, Mitchell TC, Karakousis GC, Schuchter 
LM, Flaherty KT, Zhang G, Herlyn M, Koumenis C, Amaravadi RK. ER Translocation 
of the MAPK Pathway Drives Therapy Resistance in BRAF-Mutant Melanoma. 
Cancer Discov. 2019;9(3):396-415. Epub 2018/12/20. doi: 10.1158/2159-8290.CD-
18-0348. PubMed PMID: 30563872; PMCID: PMC6397701. 
11. Vogl DT, Stadtmauer EA, Tan KS, Heitjan DF, Davis LE, Pontiggia L, Rangwala R, 
Piao S, Chang YC, Scott EC, Paul TM, Nichols CW, Porter DL, Kaplan J, Mallon G, 
Bradner JE, Amaravadi RK. Combined autophagy and proteasome inhibition: a 
phase 1 trial of hydroxychloroquine and bortezomib in patients with 
relapsed/refractory myeloma. Autophagy. 2014;10(8):1380-90. Epub 2014/07/06. 
doi: 10.4161/auto.29264. PubMed PMID: 24991834; PMCID: PMC4203515. 
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Torigian DA, Panosian JT, Troxel AB, Tan KS, Heitjan DF, DeMichele AM, Vaughn 
DJ, Redlinger M, Alavi A, Kaiser J, Pontiggia L, Davis LE, O'Dwyer PJ, Amaravadi 
RK. Combined MTOR and autophagy inhibition: phase I trial of hydroxychloroquine 
and temsirolimus in patients with advanced solid tumors and melanoma. Autophagy. 
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24991838; PMCID: PMC4203516. 
13. Rangwala R, Leone R, Chang YC, Fecher LA, Schuchter LM, Kramer A, Tan KS, 
Heitjan DF, Rodgers G, Gallagher M, Piao S, Troxel AB, Evans TL, DeMichele AM, 
Nathanson KL, O'Dwyer PJ, Kaiser J, Pontiggia L, Davis LE, Amaravadi RK. Phase I 
trial of hydroxychloroquine with dose-intense temozolomide in patients with 
advanced solid tumors and melanoma. Autophagy. 2014;10(8):1369-79. Epub 
2014/07/06. doi: 10.4161/auto.29118. PubMed PMID: 24991839; PMCID: 
PMC4203514. 
14. Rosenfeld MR, Ye X, Supko JG, Desideri S, Grossman SA, Brem S, Mikkelson T, 
Wang D, Chang YC, Hu J, McAfee Q, Fisher J, Troxel AB, Piao S, Heitjan DF, Tan 
KS, Pontiggia L, O'Dwyer PJ, Davis LE, Amaravadi RK. A phase I/II trial of 
hydroxychloroquine in conjunction with radiation therapy and concurrent and 
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PubMed PMID: 24991840; PMCID: PMC4203513. 
15. Mahalingam D, Mita M, Sarantopoulos J, Wood L, Amaravadi RK, Davis LE, Mita 
AC, Curiel TJ, Espitia CM, Nawrocki ST, Giles FJ, Carew JS. Combined autophagy 
and HDAC inhibition: a phase I safety, tolerability, pharmacokinetic, and 
pharmacodynamic analysis of hydroxychloroquine in combination with the HDAC 
inhibitor vorinostat in patients with advanced solid tumors. Autophagy. 
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M, Lim CY, Witze E, Chude CI, Zhang G, Alicea GM, Piao S, Murugan S, Ojha R, 
Levi SM, Wei Z, Barber-Rotenberg JS, Murphy ME, Mills GB, Lu Y, Rabinowitz J, 
Marmorstein R, Liu Q, Liu S, Xu X, Herlyn M, Zoncu R, Brady DC, Speicher DW, 
Winkler JD, Amaravadi RK. A Unified Approach to Targeting the Lysosome's 
Degradative and Growth Signaling Roles. Cancer Discov. 2017;7(11):1266-83. Epub 
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McAfee Q, McLaughlin NP, Zhang G, Goldman AR, Ojha R, Piao S, Noguera-Ortega 
E, Martorella A, Alicea GM, Lee JJ, Schuchter LM, Xu X, Herlyn M, Marmorstein R, 
Gimotty PA, Speicher DW, Winkler JD, Amaravadi RK. PPT1 Promotes Tumor 
Growth and Is the Molecular Target of Chloroquine Derivatives in Cancer. Cancer 
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18. Robert C, Karaszewska B, Schachter J, Rutkowski P, Mackiewicz A, Stroiakovski D, 
Lichinitser M, Dummer R, Grange F, Mortier L, Chiarion-Sileni V, Drucis K, Krajsova 
I, Hauschild A, Lorigan P, Wolter P, Long GV, Flaherty K, Nathan P, Ribas A, Martin 
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Song D, Gangadhar TC, Schuchter LM, Mitnick S, Huang A, Nichols CW, Amaravadi 
RK, Kim BJ, Aleman TS. FREQUENT SUBCLINICAL MACULAR CHANGES IN 
COMBINED BRAF/MEK INHIBITION WITH HIGH-DOSE 
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phosphorylation in advanced melanoma. Mol Cancer 11, 76 (2012). 
 
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Appendix I 
 
Pathology Submission Guidelines 
The following items are included in Appendix I: 
1. Guidelines for Submission of Pathology Materials  
(instructional sheet for Clinical Research Associates [CRAs]) 
2. Instructional memo to submitting pathologists 
3. ECOG-ACRIN Generic Specimen Submission Form (#2981v3) 
 


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Guidelines for Submission of Pathology Materials 
The following pathology materials are to be submitted within one (1) month of 
randomization or collection. 
Pathology Submissions 
1. Representative formalin-fixed paraffin-embedded (FFPE) from the archival 
pretreatment tumor tissue biopsy and serial tumor tissue research biopsies from 
baseline, weeks one and/or four, and progression 
NOTE: 
Reimbursement guidelines for research biopsies are outlined in Appendix VII. 
Biopsies to obtain specimens for research must be determined to be minimal 
risk prior to performance. 
NOTE: 
Only blocks will be accepted from research biopsies eligible for 
reimbursement, though institutions are allowed to keep an H&E slide. 
NOTE: 
If blocks are unavailable for submission, cores and slides are to be submitted. 
All cores and slides must be adequately labeled, with slides numbered 
sequentially in the order cut. Alternative submission requirements: 
• 
One (1) H&E slide 
• 
Twenty (20) 5 µm and five (5) 4 µm unstained, positively charged, air-
dried plus slides from the thickest part of the tumor 
• 
One (1) or more core punches (minimum of 4mm diameter). If core punch 
tool is unavailable, request core punch kit from the ECOG-ACRIN CBPF 
(844) 744-2420. Adequately label every slide and core submitted. 
If these criteria cannot be met, please contact the ECOG-ACRIN CBPF 
(eacbpf@mdanderson.org) to obtain alternative submission requirements. 
2. Forms and Reports 
Adequate patient identifying information must be included with every submission to 
retain chain of custody. It is strongly recommended that full patient names be provided. 
The information will be used only to identify patient materials and will expedite any 
required communications with the institution (including pathologists). 
The following items are to be included with the pathology materials: 
• 
Institutional Pathology Report 
• 
ECOG-ACRIN Generic Specimen Submission Form (#2981v3) [If STS is 
unavailable] 
• 
Sample Tracking System (STS) Shipping Manifest Form 
• 
Immunological study reports, if available 
3. Mail pathology materials to: 
MD Anderson Cancer Center CBPF 
Mike Balco 
Life Science Plaza - Suite 910 
2130 West Holcombe Boulevard, LSP9.4227 
Houston, TX 77030 
Phone: Toll Free (844) 744-2420 (713-745-4440 Local or International Sites) 
Fax: (713) 563-6506 
Email: eacbpf@mdanderson.org 
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If you have any questions concerning the above instructions, contact the Pathology 
Coordinator at the ECOG-ACRIN Central Biorepository and Pathology Facility by 
telephone: (844) 744-2420 or email: eacbpf@mdanderson.org 


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MEMORANDUM 
TO:  
__________________________________________________ 
 
(Submitting Pathologist) 
FROM: 
Stanley Hamilton, M.D., Chair 
 
ECOG-ACRIN Laboratory Science and Pathology Committee 
DATE:  
____________________________________ 
SUBJECT: 
Submission of Pathology Materials for EA6191: The BAMM2 (BRAF, 
Autophagy, MEK inhibition in Melanoma) Study: A Randomized Double 
Blind Phase II Study of Dabrafenib and Trametinib with or without 
hydroxychloroquine in Advanced BRAF V600E/K Melanoma 
 
The patient named on the attached request has been entered onto an ECOG-ACRIN 
protocol by _____________________________ (ECOG-ACRIN Investigator). This 
protocol requires the submission of pathology materials for future undefined research 
studies. 
Please return the pathology reports, the slides and/or blocks and any other required 
materials to the Clinical Research Associate (CRA). The CRA will forward all required 
pathology materials to the ECOG-ACRIN Central Biorepository and Pathology Facility. 
Blocks and/or slides submitted for this study will be retained at the ECOG-ACRIN 
Central Biorepository and Pathology Facility for undefined future research studies. 
Paraffin blocks will be returned upon written request for purposes of patient 
management. 
If you have any questions regarding this request, please contact the ECOG-ACRIN 
Central Biorepository and Pathology Facility at (844) -744-2420 (713-745-4440 Local or 
International Sites) or email: eacbpf@mdanderson.org 
The ECOG-ACRIN CRA at your institution is: 
Name: ___________________________________  
Address: _________________________________  
Phone: __________________________________  
Thank you. 
 


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ECOG-ACRIN Generic Specimen Submission Form  
Form No. 2981v3 
Page 1 of 1 
Institution Instructions: This form is to be completed and submitted with all specimens ONLY if the Sample Tracking System (STS) is not available. Use one form per 
patient, per time- point. All specimens shipped to the laboratory must be listed on this form. Enter all dates as MM/DD/YY. Keep a copy for your files. Retroactively log all 
specimens into STS once the system is available. Contact the receiving lab to inform them of shipments that will be sent with this form. 
Protocol Number    
 
Patient ID     
 
Patient Initials   Last  
 First     
 
Date Shipped    
 
Courier     
 Courier Tracking Number   
 
Shipped To (Laboratory Name)   
 
Date CRA will log into STS    
 
FORMS AND REPORTS: Include all forms and reports as directed per protocol, e.g., pathology, cytogenetics, flow cytometry, patient consult, etc. 
Required fields for all samples 
Additional fields for tissue submissions 
Completed by  
Receiving Lab 
Protocol Specified Timepoint: 
Sample Type  
(fluid or fresh tissue, 
include collection tube type) 
Quantity 
Collection  
Date and Time 24 HR 
Surgical or  
Sample ID 
Anatomic  
Site 
Disease Status  
(e.g., primary, mets, 
normal) 
Stain or 
Fixative 
Lab ID 
 
Fields to be completed if requested per protocol. Refer to the protocol-specific sample submissions for additional fields that may be required. 
Leukemia/Myeloma 
Studies: 
Diagnosis 
Intended Treatment Trial 
Peripheral WBC Count (x1000) 
Peripheral Blasts % 
Lymphocytes % 
 
 
 
 
Study Drug 
Information: 
Therapy Drug Name 
Date Drug Administered 
Start Time 24 HR 
Stop Time 24HR 
 
 
 
 
Caloric Intake: 
Date of Last Caloric Intake 
Time of Last Caloric Intake 24HR 
 
CRA Name   
 
CRA Phone   
 
CRA Email   
 
Comments 
 
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Appendix II 
 
Patient Thank You Letter 
We ask that the physician use the template contained in this appendix to prepare a letter 
thanking the patient for enrolling in this trial. The template is intended as a guide and can 
be downloaded from the web site at http://www.ecog.org. As this is a personal letter, 
physicians may elect to further tailor the text to their situation. 
This small gesture is a part of a broader program being undertaken by ECOG-ACRIN 
and the NCI to increase awareness of the importance of clinical trials and improve 
accrual and follow-through. We appreciate your help in this effort. 
 ______________________________________________________________________  
 
[PATIENT NAME] 
[DATE] 
[PATIENT ADDRESS] 
 
 
Dear [PATIENT SALUTATION], 
 
Thank you for agreeing to take part in this important research study. Many questions 
remain unanswered in cancer. With the participation of people like you in clinical trials, 
we hope to improve treatment and quality of life for those with your type of cancer. 
We believe you will receive high quality, complete care. I and my research staff will 
maintain very close contact with you. This will allow me to provide you with the best care 
while learning as much as possible to help you and other patients. 
On behalf of [INSTITUTION] and ECOG-ACRIN, we thank you again and look forward to 
helping you. 
 
 
Sincerely, 
 
 
 
 
[PHYSICIAN NAME] 
 
 


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Appendix III 
 
Patient Pill Calendar 
 
Pill Calendar Directions 
1. Take your scheduled dose of each pill. 
• 
Dabrafenib should be taken twice daily, about 12 hours apart on an empty 
stomach (1 hour before or 2 hours after meals) 
• 
Trametinib should be taken once daily, on an empty stomach (1 hour before or 2 
hours after a meal) 
• 
Hydroxchloroquine (HCQ or placebo) should be taken twice daily, about 12 hours 
apart (in the morning and evening). It can be taken with or without food. 
2. If you forget, the missed pills will not be taken later. 
3. Please bring the empty bottles or any leftover capsules/ tablets and your pill calendar 
to your next clinic visit. 
 
 


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Patient Pill Calendar 
This is a calendar on which you are to record the time and number of tablets you take each day. You should take your scheduled dose 
of each pill. Note the times and the number of tablets that you take each day. If you develop any side effects, please record them 
and anything you would like to tell the doctor in the space provided. Bring any unused tablets and your completed pill calendar to your 
doctor’s visits. 
DAY 
Date 
 
 
Month   Day   Year 
Drug Name  
Time pills 
taken 
 
 
AM       PM 
Number of 
pills taken 
 
 
AM      PM 
Use the space below to make notes about 
things you would like to tell the doctor 
(including unusual symptoms you 
experience, other medicine you have 
taken and anything else you think would 
be of interest.) 
1 
 
 
 
Dabrafenib (twice daily) 
 
 
 
 
 
 
 
 
Trametinib (once daily) 
 
 
 
 
 
 
 
 
HCQ or placebo (twice daily) 
 
 
 
 
 
 
2 
 
 
 
Dabrafenib (twice daily) 
 
 
 
 
 
 
 
 
Trametinib (once daily) 
 
 
 
 
 
 
 
 
HCQ or placebo (twice daily) 
 
 
 
 
 
 
3 
 
 
 
Dabrafenib (twice daily) 
 
 
 
 
 
 
 
 
Trametinib (once daily) 
 
 
 
 
 
 
 
 
HCQ or placebo (twice daily) 
 
 
 
 
 
 
4 
 
 
 
Dabrafenib (twice daily) 
 
 
 
 
 
 
 
 
Trametinib (once daily) 
 
 
 
 
 
 
 
 
HCQ or placebo (twice daily) 
 
 
 
 
 
 
5 
 
 
 
Dabrafenib (twice daily) 
 
 
 
 
 
 
 
 
Trametinib (once daily) 
 
 
 
 
 
 
 
 
HCQ or placebo (twice daily) 
 
 
 
 
 
 


ECOG-ACRIN 
EA6191 
Cancer Research Group 
Version Date: January 19, 2023 
105 
DAY 
Date 
 
 
Month   Day   Year 
Drug Name  
Time pills 
taken 
 
 
AM       PM 
Number of 
pills taken 
 
 
AM      PM 
Use the space below to make notes about 
things you would like to tell the doctor 
(including unusual symptoms you 
experience, other medicine you have 
taken and anything else you think would 
be of interest.) 
6 
 
 
 
Dabrafenib (twice daily) 
 
 
 
 
 
 
 
 
Trametinib (once daily) 
 
 
 
 
 
 
 
 
HCQ or placebo (twice daily) 
 
 
 
 
 
 
7 
 
 
 
Dabrafenib (twice daily) 
 
 
 
 
 
 
 
 
Trametinib (once daily) 
 
 
 
 
 
 
 
 
HCQ or placebo (twice daily) 
 
 
 
 
 
 
8 
 
 
 
Dabrafenib (twice daily) 
 
 
 
 
 
 
 
 
Trametinib (once daily) 
 
 
 
 
 
 
 
 
HCQ or placebo (twice daily) 
 
 
 
 
 
 
9 
 
 
 
Dabrafenib (twice daily) 
 
 
 
 
 
 
 
 
Trametinib (once daily) 
 
 
 
 
 
 
 
 
HCQ or placebo (twice daily) 
 
 
 
 
 
 
10 
 
 
 
Dabrafenib (twice daily) 
 
 
 
 
 
 
 
 
Trametinib (once daily) 
 
 
 
 
 
 
 
 
HCQ or placebo (twice daily) 
 
 
 
 
 
 
11 
 
 
 
Dabrafenib (twice daily) 
 
 
 
 
 
 
 
 
Trametinib (once daily) 
 
 
 
 
 
 
 
 
HCQ or placebo (twice daily) 
 
 
 
 
 
 


ECOG-ACRIN 
EA6191 
Cancer Research Group 
Version Date: January 19, 2023 
106 
DAY 
Date 
 
 
Month   Day   Year 
Drug Name  
Time pills 
taken 
 
 
AM       PM 
Number of 
pills taken 
 
 
AM      PM 
Use the space below to make notes about 
things you would like to tell the doctor 
(including unusual symptoms you 
experience, other medicine you have 
taken and anything else you think would 
be of interest.) 
12 
 
 
 
Dabrafenib (twice daily) 
 
 
 
 
 
 
 
 
Trametinib (once daily) 
 
 
 
 
 
 
 
 
HCQ or placebo (twice daily) 
 
 
 
 
 
 
13 
 
 
 
Dabrafenib (twice daily) 
 
 
 
 
 
 
 
 
Trametinib (once daily) 
 
 
 
 
 
 
 
 
HCQ or placebo (twice daily) 
 
 
 
 
 
 
14 
 
 
 
Dabrafenib (twice daily) 
 
 
 
 
 
 
 
 
Trametinib (once daily) 
 
 
 
 
 
 
 
 
HCQ or placebo (twice daily) 
 
 
 
 
 
 
15 
 
 
 
Dabrafenib (twice daily) 
 
 
 
 
 
 
 
 
Trametinib (once daily) 
 
 
 
 
 
 
 
 
HCQ or placebo (twice daily) 
 
 
 
 
 
 
16 
 
 
 
Dabrafenib (twice daily) 
 
 
 
 
 
 
 
 
Trametinib (once daily) 
 
 
 
 
 
 
 
 
HCQ or placebo (twice daily) 
 
 
 
 
 
 


ECOG-ACRIN 
EA6191 
Cancer Research Group 
Version Date: January 19, 2023 
107 
DAY 
Date 
 
 
Month   Day   Year 
Drug Name  
Time pills 
taken 
 
 
AM       PM 
Number of 
pills taken 
 
 
AM      PM 
Use the space below to make notes about 
things you would like to tell the doctor 
(including unusual symptoms you 
experience, other medicine you have 
taken and anything else you think would 
be of interest.) 
17 
 
 
 
Dabrafenib (twice daily) 
 
 
 
 
 
 
 
 
Trametinib (once daily) 
 
 
 
 
 
 
 
 
HCQ or placebo (twice daily) 
 
 
 
 
 
 
18 
 
 
 
Dabrafenib (twice daily) 
 
 
 
 
 
 
 
 
Trametinib (once daily) 
 
 
 
 
 
 
 
 
HCQ or placebo (twice daily) 
 
 
 
 
 
 
19 
 
 
 
Dabrafenib (twice daily) 
 
 
 
 
 
 
 
 
Trametinib (once daily) 
 
 
 
 
 
 
 
 
HCQ or placebo (twice daily) 
 
 
 
 
 
 
20 
 
 
 
Dabrafenib (twice daily) 
 
 
 
 
 
 
 
 
Trametinib (once daily) 
 
 
 
 
 
 
 
 
HCQ or placebo (twice daily) 
 
 
 
 
 
 
21 
 
 
 
Dabrafenib (twice daily) 
 
 
 
 
 
 
 
 
Trametinib (once daily) 
 
 
 
 
 
 
 
 
HCQ or placebo (twice daily) 
 
 
 
 
 
 
22 
 
 
 
Dabrafenib (twice daily) 
 
 
 
 
 
 
 
 
Trametinib (once daily) 
 
 
 
 
 
 
 
 
HCQ or placebo (twice daily) 
 
 
 
 
 
 


ECOG-ACRIN 
EA6191 
Cancer Research Group 
Version Date: January 19, 2023 
108 
DAY 
Date 
 
 
Month   Day   Year 
Drug Name  
Time pills 
taken 
 
 
AM       PM 
Number of 
pills taken 
 
 
AM      PM 
Use the space below to make notes about 
things you would like to tell the doctor 
(including unusual symptoms you 
experience, other medicine you have 
taken and anything else you think would 
be of interest.) 
23 
 
 
 
Dabrafenib (twice daily) 
 
 
 
 
 
 
 
 
Trametinib (once daily) 
 
 
 
 
 
 
 
 
HCQ or placebo (twice daily) 
 
 
 
 
 
 
24 
 
 
 
Dabrafenib (twice daily) 
 
 
 
 
 
 
 
 
Trametinib (once daily) 
 
 
 
 
 
 
 
 
HCQ or placebo (twice daily) 
 
 
 
 
 
 
25 
 
 
 
Dabrafenib (twice daily) 
 
 
 
 
 
 
 
 
Trametinib (once daily) 
 
 
 
 
 
 
 
 
HCQ or placebo (twice daily) 
 
 
 
 
 
 
26 
 
 
 
Dabrafenib (twice daily) 
 
 
 
 
 
 
 
 
Trametinib (once daily) 
 
 
 
 
 
 
 
 
HCQ or placebo (twice daily) 
 
 
 
 
 
 
27 
 
 
 
Dabrafenib (twice daily) 
 
 
 
 
 
 
 
 
Trametinib (once daily) 
 
 
 
 
 
 
 
 
HCQ or placebo (twice daily) 
 
 
 
 
 
 
28 
 
 
 
Dabrafenib (twice daily) 
 
 
 
 
 
 
 
 
Trametinib (once daily) 
 
 
 
 
 
 
 
 
HCQ or placebo (twice daily) 
 
 
 
 
 
 


ECOG-ACRIN 
EA6191 
Cancer Research Group 
Version Date: January 19, 2023 
109 
The BAMM2 (BRAF, Autophagy, MEK inhibition in Melanoma) Study: A Randomized 
Double Blind Phase II Study of Dabrafenib and Trametinib with or without 
Hydroxychloroquine in Advanced BRAFV600E/K Melanoma with elevated LDH 
Appendix IV 
 
ECOG Performance Status 
PS 0 
Fully active, able to carry on all pre-disease performance without restriction 
PS 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. 
PS 2 
Ambulatory and capable of all self-care but unable to carry out any work 
activities. Up and about more than 50% of waking hours. 
PS 3 
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours. 
PS 4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or 
chair. 
 


ECOG-ACRIN 
EA6191 
Cancer Research Group 
Version Date: January 19, 2023 
110 
The BAMM2 (BRAF, Autophagy, MEK inhibition in Melanoma) Study: A Randomized 
Double Blind Phase II Study of Dabrafenib and Trametinib with or without 
Hydroxychloroquine in Advanced BRAFV600E/K Melanoma with elevated LDH 
Appendix V 
 
EA6191 Collection and Shipping Kit Order Instructions 
Specimen Collection/Shipping Kits are being provided by CENETRON CENTRAL 
LABORATORIES and are to be ordered ONLINE. 
Starter kits are not available. Kit requests are to be made after patient randomization. 
Questions regarding kits can be directed to projectmanagement@cenetron.com or call the 
Cenetron Clinical Trials Group at (512) 439-2000. 
Ordering Process: 
• 
Following randomization of the patient to the trial, go to the website www.cenetron.com 
and click on the ‘Order Kits’ button at the top right. It is recommended that kits be 
ordered same day as patient randomization. 
• 
The order form is not study specific and can be used for any study. Complete the online 
form as follows: 
• 
Sponsor (REQUIRED): ECOG-ACRIN 
• 
Contact Name (REQUIRED): Name of the institution kit contact 
• 
Protocol Number (REQUIRED): EA6191 
• 
Phone Number (REQUIRED): Phone number of the kit contact. Please ensure that 
this is a number that can be reached from an external caller 
• 
FAX Number: Fax number of the kit contact 
• 
Investigator: Last name of the kit contact is adequate 
• 
Email (REQUIRED): Email of the institution kit contact. Must be entered twice to 
confirm 
• 
Date Supplies Needed (REQUIRED): Add three (3) business days or more to order 
date. (Reminder that weekends and holidays must also be considered in this 
timeline) 
• 
KIT NAME (REQUIRED): Type in the kit type needed 
• 
EA6191 Collection Kit 
• 
Quantity: 1 
• 
Comments: Provide EA6191 Patient Case ID# and Full Shipping Address 
• 
Patient Case ID = ##### 
• 
‘Ship Kit to’ name of the individual to whom the kit is being shipped. (May be different 
than the kit contact provided above) 
• 
Full street address, town, state and zip code 
• 
Answer the security question 
Please complete this form correctly, including the valid ECOG-ACRIN patient case 
number and complete shipping address. If information is missing the kit processing 
will be delayed. 


ECOG-ACRIN 
EA6191 
Cancer Research Group 
Version Date: January 19, 2023 
111 
The BAMM2 (BRAF, Autophagy, MEK inhibition in Melanoma) Study: A Randomized 
Double Blind Phase II Study of Dabrafenib and Trametinib with or without 
Hydroxychloroquine in Advanced BRAFV600E/K Melanoma with elevated LDH 
Appendix VI 
 
Tumor Tissue Research Biopsy Reimbursement Instructions 
Biopsies performed to obtain research specimens from patients who answer ‘Yes’ to ‘I agree 
biopsies may be done to obtain research samples’ at: 
• 
Baseline (following registration, prior to start of treatment) 
• 
Cycle 1 Day 7 (+/- 2 days) and/or prior to start of treatment on Cycle 2 (+/- 1 week) 
• 
Progression 
Biopsies are reimbursable at the following research rates per biopsy: 
• 
Radiology Assisted = $4,000 
Biopsies that are performed as part of the patient’s standard of care are not eligible for 
reimbursement. 
All institutions are eligible for the reimbursement for applicable research biopsies regardless 
of cooperative group. 
Prior to performing the research biopsies, the following conditions must be met: 
a. The research rates outlined above are deemed acceptable by the institution’s central 
research office. Costs above these reimbursement rates are not to be billed to the 
patient or patient’s insurance. 
b. The research rate is reported to the institution’s financial office and an account 
established under the designated Investigator’s name. 
Reminder that the institution must set up the mechanism for the ‘billing’ of these 
research biopsies. ECOG-ACRIN recommends billing the cooperative group Principal 
Investigator (PI) of the institution. Contact your coordinating group’s operations office 
and ask to whom this account should be named. 
Expenses for research biopsies will be paid only to participating institutions, not to any other 
persons or entities, at the above stated research rates. 
Distribution of the reimbursements requires: 
• 
Submission and receipt of the research biopsies via the ECOG-ACRIN Sample Tracking 
System (STS) 
• 
Completion and submission of the EA6191 Biopsy Reimbursement Form to the ECOG-
ACRIN Operations Office - Boston 
• 
Supporting documentation, if requested 
 
 
Rev Add2 


ECOG-ACRIN 
EA6191 
Cancer Research Group 
Version Date: January 19, 2023 
112 
EA6191 Biopsy Reimbursement Form 
This form is to be used to request reimbursement for the performance and submission of the 
tumor tissue biopsies at baseline, weeks one and/or four, and progression as outlined in 
Section 0. Reimbursements are NOT applicable for biopsies performed as part of standard 
of care, and thus billed to the patient or their insurance. 
If you have questions about the reimbursement process, 
please contact the EA funding team at 
ea.fundingsheet@jimmy.harvard.edu 
Please fax the completed form to the  
ECOG-ACRIN Translational Science Team (TST), FAX: 
(617) 589-0914 
 
Payee Address 
 
 Payee/W-9 Name: 
 
 
 
Payee Tax ID #: 
 
Attention To: 
 
 
 
 
Institution CTEP ID: 
 
Street Address: 
 
 
Name of Investigator: 
 
 City, State, Zip: 
 
 
NCI Investigator ID: 
 
 Any Requested Reference on 
Payment (i.e. Invoice #): 
 
 
 
ECOG-
ACRIN 
Case ID 
Date of 
Service 
Time  
Point 
Service Performed 
Amount 
Requested 
#1 
 
 
Baseline 
Radiology Assisted 
$4,000 
#2 
 
 
C1 D7 
Radiology Assisted 
$4,000 
#3 
 
 
Prior to C2 
Radiology Assisted 
$4,000 
#4 
 
 
Progression 
Radiology Assisted 
$4,000 
 
I confirm that these patients are registered to the protocol referenced above, the patient numbers and 
procedure dates are correct, and the biopsies were performed for the purposes of the trial only, following 
registration of the patient to the lowest step of the trial, and that the biopsy was NOT standard of care and 
was NOT billed to insurance or the patient. 
Signature:  ______________________________________________ Date: _____________ 
 
If there are problems with this invoice, please contact:  
 
Name 
 
Phone 
 
Fax 
 
Email 
 
 
 
 
 
 
ECOG-Operations Office Use Only:      TST Reviewer: ____________________  Date: _____________ 
Patient 
#1 
#2 
#3 
#4 
Date of Registration to Step 1 
 
 
 
 
Registering/Tracking Institution 
 
 
 
 
Data in STS indicates ‘Not billed to insurance’ 
 
 
 
 
Performed post-registration & per protocol 
 
 
 
 
Specimen received by CBPF 
 
 
 
 
Approved 
 
 
 
 
 
Rev Add2