Clinical trial NCT03898908
Conditions: Metastatic Melanoma Brain Metastases
Keywords: metastases melanoma encorafenib binimetinib
Sponsor: Grupo Español Multidisciplinar de Melanoma
Start date: 2019-07-18; Completion date: 2023-07-31
Enrollment: 48 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Phase II clinical trial, with two cohorts of patients included in parallel, all with melanoma BRAF mutated and brain metastases without previous local treatment in the brain. Cohort 1 will include patients with asymptomatic brain metastases and cohort 2 will include patients with symptomatic brain metastasis.

Detailed description:

Arms: arm 1: Encorafenib - Orally, 75 mg and 50 mg capsules Binimetinib - Orally, 15 mg tablets

In each cohort, patients will be treated with encorafenib 450 mg once daily and binimetinib 45 mg twice daily until PD or death.
Interventions: intervention 1: encorafenib intervention 2: binimetinib intervention 3: Whole brain radiation therapy intervention 4: Radiosurgery/stereotactic radiosurgery
Intervention descriptions: intervention 1: Encorafenib 75mg and 50mg (capsules) for a 450mg daily for oral administration during 56 days and after local radiation treatment.

If no progression of disease progression (PD) is reported, treatment will continue until PD, unacceptable toxicity or death. intervention 2: Binimetinib 15mg (tablets) for a 45mg/12 hours for oral administration during 56 days and after local radiation treatment. intervention 3: The whole brain planning target volume (PTV) will receive 30 Gy in 10 fractions.

Treatment will be delivered once daily, 5 fractions per week, over 2 to 2.5 weeks. intervention 4: Dose selection must be based on previously published Radiation Therapy Oncology Group (RTOG) data, with dose modification left up to the treating physician. The total dose will depend on the size of the metastatic lesion(s) and proximity to critical structures.

Suggested doses are as follow: 1 fraction x 15-25 Gy; 3 fractions x 9-11 Gy; 5 fractions x 6-7 Gy; or 6 fractions x 5-6 Gy.

For GTV \> 20 mm hypofractionated stereotactic radiotherapy could be preferred. Treatment will be delivered once daily, alternate-day, 3 fractions per week.

Protocol documents:
Prot_SAP_000.pdf: 
 Title: 
 MULTICENTRE PHASE II CLINICAL TRIAL TO EVALUATE THE ACTIVITY OF 
 ENCORAFENIB AND BINIMETINIB BEFORE LOCAL TREATMENT IN PATIENTS 
 WITH BRAF MUTATED MELANOMA WITH METASTASIS TO THE BRAIN. 
 Protocol Number: 
 GEM-1802 
 EudraCT: 
 2018-002530-20 
 Acronym: 
 EBRAIN-MEL 
 Sponsor: 
 Grupo Español Multidisciplinar de Melanoma - GEM 
 MULTIDISCIPLINARY SPANISH MELANOMA RESEARCH GROUP 
 Scientific Coordinators: 
 Iván Márquez Rodas, M.D., Ph.D. 
 Hospital General Universitario Gregorio Marañón, Madrid 
 Alfonso Berrocal Jaime, M.D., Ph.D. 
 Hospital General Universitario de Valencia, Valencia. 


 S  PONSOR  S  IGNATURE  P  AGE 
 Protocol Number:  GEM-1802 
 Title:  Phase  II,  multicentre  clinical  trial  to  evaluate  the  activity  of  encorafenib  and  binimetinib 
 administered  before  local  treatment  in  patients  with  BRAF  mutant  melanoma  metastatic  to  the 
 brain. 
 EudraCT Number:  2018-002530-20 
 Version number and date: 5.0 4JUL2022 
 I  have  received  and  read  the  Investigator’s  Brochure  for  encorafenib  and  binimetinib.  I  have  read 
 the  GEM-1802  protocol  and  agree  to  conduct  the  study  as  outlined.  I  agree  to  maintain  the 
 confidentiality  of  all  information  received  or  developed  in  connection  with  this  protocol  and  I  agree 
 to  conduct  this  trial  in  accordance  with  all  provisions  of  the  protocol,  GCPs  and  the  Declaration  of 
 Helsinki. 
 __________________________________________ 
 ____________________________ 
 Sponsor's signature 
 Signature date 
 __________________________________________ 
 ____________________________ 
 Scientific coordinator’s signature 
 Signature date 
 GEM 1802 - Protocol version 5.0, 4. JUL. 2022 
 Page  2  of  94 


 I  NVESTIGATOR ’  S  A  GREEMENT 
 Protocol Number:  GEM-1802 
 Title:  Phase  II,  multicentre  clinical  trial  to  evaluate  the  activity  of  encorafenib  and  binimetinib 
 administered  before  local  treatment  in  patients  with  BRAF  mutant  melanoma  metastatic  to  the 
 brain. 
 EudraCT Number:  2018-002530-20 
 Version number and date:  5.0; 4 of JUL 2022 
 I  have  received  and  read  the  Investigator’s  Brochure  of  encorafenib  and  binimetinib.  I  have  read 
 the  GEM-1802  protocol  and  agree  to  conduct  the  study  as  outlined.  I  agree  to  maintain  the 
 confidentiality  of  all  information  received  or  developed  in  connection  with  this  protocol  and  I  agree 
 to  conduct  this  trial  in  accordance  with  all  provisions  of  the  protocol,  GCPs  and  the  Declaration  of 
 Helsinki. 
 Investigator Printed Name 
 Investigator Signature 
 Date 
 GEM 1802 - Protocol version 5.0, 4. JUL. 2022 
 Page  3  of  94 


 1. 
 S  YNOPSIS 
 Sponsor:  Grupo Español Multidisciplinar en Melanoma  - GEM 
 Investigational Products:  Encorafenib and binimetinib 
 Active Ingredients:  Encorafenib and binimetinib 
 Title  of  Study:  Phase  II,  multicentre  clinical  trial  to  evaluate  the  activity  of  encorafenib  and 
 binimetinib  administered  before  local  treatment  in  patients  with  BRAF  mutant  melanoma 
 metastatic to the brain. 
 Protocol number:  GEM-1802 
 EudraCT:  2018-002530-20 
 Study center(s):  21 sites in Spain. In attached document 
 Coordinating Investigators: 
 Dr. Iván Márquez Rodas - Hospital General Universitario Gregorio Marañón, Madrid. 
 Dr. Alfonso Berrocal Jaime - Hospital General Universitario de Valencia, Valencia. 
 Principal Investigators:  In attached document 
 Studied period (years): 
 Estimated date first patient enrolled: 3Q 2019 (19.JUL.2019) 
 Estimated end of enrolment: 3Q 2022 
 Estimated date last patient completed: 3Q 2024 
 Phase of 
 development: 
 II 
 Objectives: 
 1.  Primary objective: 
 Intracranial  objective  response  rate  assessed  by  the  investigators  using  modified  RECIST 
 criteria before local treatment in cohort 1 and in cohort 2. 
 2.  Secondary objectives: 
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 a. Intracranial  objective  response  rate  assessed  by  the  investigators  using  modified 
 RECIST criteria. before local treatment in cohort 2. 
 b.  Intracranial  objective  response  rate  assessed  by  the  investigators  using  modified 
 RECIST criteria. before local treatment in cohort 1. 
 c.The  duration  of  the  intracranial  response  in  both  cohorts  assessed  by  the  investigators 
 using modified RECIST criteria. 
 d.  The 
 intracranial  progression  free  survival  assessed  by  the  investigators  using 
 modified RECIST criteria in both cohorts. 
 e.  Percentage  of  patients  free  of  intracranial  progression  according  to  modified  RECIST 
 criteria at 6 (week 24), 12 (week 48) and 24 months (week 96) in both cohorts 
 f.  Percentage  of  patients  free  of  extracraneal  progression  according  to  RECIST  criteria 
 at 6 (week 24), 12 (week 48) and 24 months (week 96) in both cohorts 
 g. Overall survival in both cohorts 
 h.Percentage of alive patients at 6, 12 and 24 months in both cohorts 
 i. Toxicity of the combination until local treatment in both cohorts 
 I.Toxicity of the combination after local treatment in both cohorts 
 II. Quality of life in both cohorts 
 Methodology: 
 This  is  a  phase  II  clinical  trial,  with  two  cohorts  of  patients  included  in  parallel,  all  with  melanoma 
 BRAF  mutated  and  brain  metastases  without  previous  local  treatment  in  the  brain.  Cohort  1  will 
 include  patients  with  asymptomatic  brain  metastases  and  cohort  2  will  include  patients  with 
 symptomatic brain metastasis. 
 BRAF  mutation  status  will  be  tested  locally  using  a  validated  test  before  patient  inclusion, 
 patients  will  receive  both  encorafenib  450  mg/day  and  binimetinib  45  mg/12  h  (twice  a  day) 
 (COMBO450)  until  progression  disease  (PD),  toxicity  or  death.  After  56  days  of  treatment,  a 
 contrast  enhanced  brain  MRI  and  body  CT  scan  will  be  performed  as  the  first  tumour 
 assessment.  Depending  on  the  outcome  of  this  image  test,  patients  undergo  local  radiation 
 treatment  (radiosurgery  or  whole  brain  radiotherapy  (WBRT)  as  per  local  radiotherapy 
 oncologist.  Encorafenib  and  binimetinib  will  be  interrupted  24h  before  radiotherapy  and  restart 
 24h  after  the  last  dose  of  radiotherapy.  After  local  treatment  encorafenib  and  binimetinib  will  be 
 administered  at  same  doses  until  PD,  toxicity  or  death.  After  progression,  patients  will  be 
 followed  only  for  overall  survival.  In  the  case  of  COMBO450  is  providing  a  clinical  benefit  to  any 
 patient, treatment could be continued, after agreement with Sponsor. 
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 This  study  will  be  carried  out  following  good  clinical  practices  (GCP)  guidelines  as  per  European 
 and Spanish regulations for clinical investigations. 
 Number of patients (planned):  At least 63 patients. 
 Cohort 1: N=48;  Cohort 2: N=15. 
 Main eligibility criteria: 
 ●  Patients 18 years old 
 ●  Patients with a metastatic BRAF V600 mutated melanoma 
 ●  ECOG 0-1 in asymptomatic patients (cohort 1), 0-2 in symptomatic patients (cohort 2) 
 ●  Previous  administration  of  BRAF  and/or  MEK  inhibitors  in  the  metastatic  setting  is  not 
 allowed.  These  treatments  would  be  allowed  if  they  were  administered  in  the  adjuvant 
 setting,  providing  relapse  does  not  occur  on  treatment  or  within  12  months  of  ending 
 adjuvant  treatment  and/or  during  adjuvant  treatment,  moreover,  any  grade  3-4  prior 
 toxicity must be resolved to grade 0 or at baseline levels. 
 ●  Previous  immunotherapy  treatments  are  allowed  in  any  metastatic  and  adjuvant  setting, 
 regardless of when the patient has relapsed. 
 ●  At least one brain metastasis with 5 to 50 mm, measured by MRI 
 ●  Steroids  or  anticonvulsants  are  allowed  if  clinically  needed  and  are  not  being 
 administered in an increasing dose 
 Full list of eligibility criteria is detailed in section 6 of this protocol 
 Investigational products, dosage and mode of administration: 
 COMBO450: 
 ●  Encorafenib - Orally, 75 mg and 50 mg capsules 
 ●  Binimetinib - Orally, 15 mg tablets 
 In  each  cohort,  patients  will  be  treated  with  encorafenib  450  mg  once  daily  and  binimetinib  (Bini) 
 45 mg twice daily until PD or death. 
 Duration of treatment: 
 All  patients  receiving  COMBO450  for  at  least  56  days  of  treatment,  will  be  evaluated  with  a 
 contrast enhanced brain MRI and CT body scan, as the first tumour assessment: 
 ●  Patients  with  PD  at  first  evaluation  in  brain  MRI  (per  RECIST  modified  criteria)  and  /or 
 body  CT  scan  (per  RECIST  1.1  criteria)  will  discontinue  study  drugs  and  will  be  followed 
 for overall survival. 
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 ●  Patients  with  intracranial  complete  response  (CR)  and  no  systemic  PD,  will  be  followed 
 every  two  months  with  brain  MRI  and  body  CT  scan  up  to  12  months.  If  no  PD  after  one 
 year,  patients  will  be  followed  as  per  institutional  criteria,  and  continue  with  the  study 
 treatment 
 ○  Whenever  is  considered  by  the  investigator,  local  treatment  can  be  administered 
 to patients with an intracranial CR. 
 ●  Patients  with  no  CR  nor  PD  in  brain  MRI  per  modified  RECIST  1.1  criteria,  and  no 
 systemic  PD  per  RECIST  1.1,  will  be  treated  with  local  radiotherapy  (RT)  (radiosurgery 
 or  WBRT),  and  then  they  will  continue  COMBO  450.  The  first  3  patients  with  indication  to 
 be  treated  with  radiotherapy  will  be  treated  in  an  initial  running  phase.  These  three  first 
 patients  are  going  to  be  treated  sequentially  or  at  the  same  time  depending  on  when 
 radiotherapy  treatment  is  needed.  If  no  safety  concerns  appear,  the  rest  of  the  patients 
 will continue receiving local treatment when it will be medically indicated: 
 ○  Encorafenib  and  binimetinib  will  be  interrupted  24h  before  radiotherapy  and 
 restart  24h  after  the  last  dose  of  radiotherapy.  The  local  radiation  technique  will 
 be  defined  and  indicated  by  the  radiotherapy  oncologist  (local  co-investigator) 
 following  the  criteria  defined  below,  regarding  how  to  treat  patients  with  the 
 different  techniques  depending  on  the  number  of  lesions  and  its  maximum  size  in 
 the  last  tumour  assessment  done  during  the  treatment  with  encorafenib  and 
 binimetinib: 
 ■  *Radiosurgery (RS) or Stereotactic radiosurgery (SRS): 
 ●  1 brain metastases < 4 cm 
 ●  ≤ 3 brain metastases ≤ 3 cm 
 ●  ≤ 4 brain metastases ≤ 2.5 cm 
 ■  Whole brain radiotherapy (WBRT): 
 ●  ≥ 4 brain metastases 
 ●  Almost one brain metastasis of ≥ 4 cm 
 ●  ≤ 4 brain metastases not eligible for RS or SRS 
 ●  Metastases located at brain stem, midbrain, pons, and medulla or 
 within 10 mm of the optic nerves and chiasm. 
 *Radiosurgery: for patients who do not meet criteria for radiosurgery (RS) or (SRS), exceptional 
 cases are allowed after prior detailed consultation with the trial coordinators. 
 ●  After  the  first  evaluation  of  the  patient's  intracranial  response,  patients  without 
 progression  who  received  a  local  treatment,  could  receive  other  local  treatments  at  the 
 discretion of the investigator, if this is considered beneficial for the patient. 
 ●  Surgery can be done if, as per investigator criteria, is necessary for the patient's health. 
 ●  Patients  with  an  intracranial  CR  not  treated  with  radiation,  if  during  follow  up  an  only 
 intracranial  PD  occurs,  local  treatment  will  be  carried  out  as  per  protocol  criteria.  These 
 patients  can  continue  encorafenib  and  binimetinib  treatment  after  local  treatment  if 
 clinical benefit is considered by investigator. 
 ●  All  patients  progressing  by  RECIST  1.1  criteria  in  body  CT  scan  and/or  by  modified 
 RECIST  1.1.  criteria  in  contrast  enhanced  brain  MRI,  after  having  received  local 
 radiation therapy  will discontinue systemic treatment  with COMBO 450. 
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 Criteria for evaluation: 
 Efficacy  assessment  will  be  performed  according  to  modified  RECIST  1.1  criteria  by  contrast 
 enhanced  MRI  for  evaluating  intracranial  disease  and  according  to  RECIST  1.1  criteria  by  CT 
 scan  (PET-CT  is  also  allowed)  for  evaluating  systemic  disease,  every  8  weeks  (+/-1  week)  up  to 
 12  months.  If  no  PD  during  the  first  year,  patients  will  be  followed  as  per  institutional  criteria. 
 Image  technique  should  be  consistent  throughout  the  study.  If  no  PD  is  observed  after  one  year 
 of  follow  up,  patients  will  be  followed  as  per  institutional  criteria,  maintaining  the  treatment  when 
 clinical benefit is observed. 
 Pharmacokinetics: 
 No pharmacokinetic study will be performed. 
 Safety: 
 Assessment  of  adverse  events,  safety,  and  toxicity  will  be  performed  according  to  the  Common 
 Terminology  Criteria  for  Adverse  Events  (CTCAE  -  version  4.03)  at  each  patient  visit  from  the 
 time of Informed Consent is signed until the end of the study. 
 Quality of Life: 
 EORTC QLQ 30 administered at baseline, at week 8 and week 24. 
 Statistical methods: 
 The  sample  calculation  has  been  done  for  the  primary  endpoint  (cohort  1)  and  it’s  based  on  a 
 Fleming’s Single Stage Procedure: 
 We  want  to  show  that  the  Intracranial  response  rate  by  modified  RECIST  1.1  before  local 
 treatment  is  superior  or  equal  to  the  reference  value,  say,  ϑ0=40%.  Under  the  hypothesis  to 
 have  a  response  rate  under  new  treatment  (π1)  of  60%  with  α  risk  =  5%  in  one-sided  test  and  a 
 power of 80%, the required sample size is 38 patients. 
 Finally,  if  20%  of  patients  will  be  lost  of  follow  up,  die  or  progress  before  day  56  without  doing 
 the  first  tumour  assessment  (according  data  published  in  COMBI-MB  study),  the  initial  sample 
 size will be 48 patients, to obtain 38 evaluable patients . 
 Data of study will be analysed in the following populations: 
 ●  ITT: All patients that has been enrolled in the trial 
 ●  Evaluable  population  (PP):  All  patients  fulfilling  all  eligibility  criteria  and  having  at  least 
 two  valid  tumour  assessments  (baseline  and  one  evaluation  MRI  or  CT-scan)  without 
 any protocol deviation that makes the patient invalid for the primary endpoint evaluation. 
 ●  Safety population: All patients receiving at least one dose of treatment. 
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 Cohort  2  (N=15)  is  exploratory  and  no  formal  sample  calculation  has  been  performed,  a 
 descriptive  analysis  will  be  performed  on  the  same  variables  and  population  as  cohort  1  (N=48). 
 The  only  difference  is  that  the  population  included  will  be  symptomatic.  The  efficacy  and  safety 
 as an overall of both cohorts in conjunction will be also addressed. 
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 INDEX 
 Sponsor Signature Page 
 2 
 Investigator’s Agreement 
 3 
 1. Synopsis 
 4 
 List of Abbreviations and Definitions of Terms 
 13 
 2. Introduction 
 18 
 2.1. Disease background 
 18 
 2.2. BRAF in Melanoma 
 18 
 2.3. Melanoma with brain metastasis 
 19 
 2.3.1. Management of patients with melanoma metastatic to the brain with favourable 
 prognosis 
 21 
 2.3.2. Management of patients with melanoma metastatic to the brain with intermediate and 
 poor prognosis 
 21 
 2.4. Systemic therapy for melanoma patients with brain metastases 
 21 
 2.4.1. Immunotherapies 
 22 
 2.4.2. Targeted Therapies 
 22 
 2.4.3. Mitogen-activated protein kinase kinase inhibitors (MEK) 
 23 
 2.4.4. Combination of BRAF Inhibitor and MEK Inhibitor 
 23 
 3. Trial rationale 
 24 
 3 .0.1.  Rationale for primary endpoint 
 2 5 
 3.1. Rationale for dose selection 
 25 
 4. Hypothesis and Objectives 
 26 
 4.1. Study Hypothesis 
 25 
 4.2. Study Objectives 
 25 
 5. Study Design 
 27 
 5.1. Overall Study Design 
 27 
 5.2. Patient Screening 
 28 
 5.3. Patient Inclusion and Cohort Assignment 
 30 
 6. Eligibility Criteria 
 32 
 6.1. Inclusion criteria 
 32 
 6.2. Exclusion criteria 
 33 
 7. Treatment of Subjects 
 35 
 7.1. Description of Study Drug 
 35 
 7.1.1. Encorafenib 
 35 
 7.1.2. Binimetinib 
 35 
 7.1.3. COMBO 450 administration instructions 
 35 
 7.1.4. Radiation therapy 57-60 
 36 
 7.1.4.1 Whole Brain Radiation Therapy 
 36 
 7.1.4.2. Radiosurgery/Stereotactic radiosurgery 
 37 
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 7.2. Dose modifications 
 40 
 7.2.1. Dose modification and dose delay for encorafenib (as monotherapy) and combination 
 (encorafenib and binimetinib) 
 42 
 7.2.2. Follow-up for toxicities 
 49 
 7.2.2.1. Management of hand foot skin reaction (HFSR) 
 49 
 7.2.2.2. Follow up evaluations for appearance of keratoacanthoma (KA) and/or 
 squamous cell carcinoma (SCC) 
 49 
 7.2.2.3. Management of nausea and/or vomiting 
 50 
 7.2.2.4 Monitoring of blood pressure 
 50 
 7.3. Concomitant Medications 
 51 
 7.3.1. Permitted concomitant treatment 
 51 
 7.3.2. Permitted concomitant therapy requiring caution and/or action 
 51 
 7.3.3. Prohibited concomitant treatment 
 52 
 7.4. Treatment Compliance 
 52 
 7.5. Randomization and Blinding 
 53 
 7.6. Study Drug Supply, labelling, dispensing and handling 
 53 
 7.6.1. Study Drug Supply 
 53 
 7.6.2. Study drug labelling 
 54 
 7.6.3. Study drug storage 
 54 
 7.7. End of treatment 
 54 
 8. Study Assessments 
 55 
 8.1. Schedule for tests and determinations 
 55 
 Protocol specifications for trial determinations 
 56 
 8.2. Schedule of Assessments 
 58 
 8.3. Study timetable and end of study 
 61 
 8.3.1.  End of Study Declaration 
 62 
 8.3.2. Early study termination 
 62 
 9. Assessment of Safety 
 63 
 9.1. Safety Parameters 
 63 
 9.1.1. Demographic/Medical History 
 63 
 9.1.2. Prior Medications 
 63 
 9.1.3. Vital Signs 
 63 
 9.1.4. Physical Examination 
 63 
 9.1.5. Electrocardiogram (ECG) 
 63 
 9.1.6. Laboratory Assessments 
 64 
 9.1.6.1. Pregnancy Screening 
 64 
 9.1.6.2. Eastern Cooperative Oncology Group (ECOG) Performance Status 
 64 
 9.2. Adverse and Serious Adverse Events 
 64 
 9.2.1. Definitions 
 64 
 9.2.1.1. Adverse Event (AE) 
 64 
 9.2.1.2. Serious Adverse Event (SAE) 
 65 
 9.2.1.3. Suspected unexpected serious adverse reaction (SUSAR) 
 65 
 9.2.1.4. Adverse drug reaction (ADR) 
 65 
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 9.2.1.5. Serious adverse reaction (SAR) 
 65 
 9.3. Assessment 
 66 
 9.3.1. Causality Assessment 
 66 
 9.3.2. Expectedness assessment by the sponsors 
 66 
 9.3.3. Severity assessment 
 66 
 9.3.4. Action taken 
 67 
 9.3.5. Outcome 
 67 
 9.4. Reporting 
 67 
 9.4.1. Reporting an Adverse Event 
 67 
 9.4.2. Reporting a Serious Adverse Event 
 67 
 9.4.3. Reporting Pregnancy 
 68 
 9.5. Reporting of individual SAEs and SUSARs by the Sponsor 
 69 
 9.6. Periodic reporting on safety to principal investigators 
 69 
 10.  Statistics 
 70 
 10.1. Sample size calculation 
 70 
 10.2. Study endpoints 
 70 
 10.3. Efficacy assessment 
 72 
 10.3.1 Time-point efficacy assessment 
 72 
 10.4. Safety assessment 
 73 
 10.5. Definition of study populations 
 73 
 10.6. Statistical analysis 
 74 
 10.7. Statistical Methods 
 74 
 11. Direct access to source data/documents 
 75 
 11.1. Source data definition 
 75 
 11.2. Study Monitoring 
 75 
 11.3. Audits and Inspections 
 76 
 11.4. Independent Ethical Committee (IEC) or Institutional Review Board (IRB) Review 
 76 
 11.5. Ethical Conduct of the Study 
 76 
 11.6. Written Informed Consent 
 77 
 12. Quality control and quality assurance 
 78 
 13. Data handling and record keeping 
 79 
 13.1. Inspection of Records 
 79 
 13.2. Retention of Records 
 79 
 14. Publication Policy 
 81 
 15. List of References 
 83 
 16. Appendix 1:  EORTC QLQ-C30                                                                                               88 
 17. Appendix 2: Barthel Index 
 92 
 95 
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 L  IST  OF  A  BBREVIATIONS  AND  D  EFINITIONS  OF  T  ERMS 
 The following abbreviations and specialist terms are used in this study protocol. 
 Abbreviation or Specialist Term 
 Explanation 
 ADL 
 Activities of Daily Living 
 ADR 
 Adverse drug reaction 
 AE 
 Adverse event 
 AP 
 Anatomic pathology 
 ASCO 
 American Society of Clinical Oncology 
 AUC 
 Area Under Curve 
 beta-hCG 
 Beta-human chorionic gonadotropin 
 BID 
 bis in die, (Latin for "twice daily") 
 BRAF 
 v-raf murine sarcoma viral oncogene homolog B1 
 CIs 
 Confidence intervals 
 CK 
 Creatine  kinase  (CK),  also  known  as  creatine  phosphokinase  (CPK) 
 or phosphocreatine kinase 
 Cmax 
 Maximum (or peak) serum concentration 
 COMBO 450 
 Encorafenib 450 mg once daily and binimetinib 45 mg twice daily 
 CB 
 Clinical benefit 
 CDR 
 Control disease rate 
 CR 
 Complete Response 
 CSR 
 Central Serous Retinopathy 
 CTCAE 
 Common Terminology Criteria for Adverse Events 
 CT Scan 
 Computed Tomography Scan 
 DBP 
 Diastolic Blood Pressure 
 DLT 
 Dose Limiting Toxicity 
 DM 
 Distant metastasis 
 DR 
 Duration of response 
 DVP 
 Data Validation Plan 
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 ECG 
 Electrocardiogram 
 ECOG 
 Eastern Cooperative Oncology Group 
 eCRF 
 Electronic Case Report Form 
 EDC 
 Electronic Data Capture 
 ECG 
 Electrocardiogram 
 EMA 
 European Medicines Agency 
 ESMO 
 European society of Medical Oncology 
 FDA 
 US Food and Drug Administration 
 FFPE 
 Formalin-fixed paraffin-embedded 
 FISH 
 Fluorescence in situ hybridization 
 FU 
 Follow-up 
 GCP 
 Good Clinical Practice 
 Hb 
 Haemoglobin 
 H/E 
 Haematoxylin/eosin 
 HFSR 
 Hand Foot Skin Reaction 
 IB 
 Investigator Brochure 
 ICF 
 Informed Consent Form 
 ICH 
 International Conference on Harmonization 
 IEC 
 Independent Ethics Committee 
 IFN 
 Interferon 
 IMP 
 Investigational Medicinal Product 
 IRB 
 Institutional Review Board 
 ISF 
 Investigator Site File 
 ITT 
 Intention To Treat 
 KA 
 Keratoacanthoma 
 KPS 
 Karnofsky Performance Status 
 LLN 
 Lower Limit of Normality 
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 LVEF 
 Left Ventricular Ejection Fraction 
 LOCF 
 Last Observation  Carried Forward 
 MAP 
 Mitogen-Activated Protein 
 MASCC 
 Multinational Association of Supportive Care 
 MDM2 
 Mouse double minute 2 homolog 
 MedDRA 
 Medical Dictionary for Regulatory Activities 
 MEK 
 Mitogen-activated protein kinase kinase 
 MLPA 
 Multiplex ligation-dependent probe amplification 
 Modified RECIST 
 Modified Response Evaluation Criteria In Solid Tumours 
 MRI 
 Magnetic Resonance Imaging 
 MTD 
 Maximum Tolerated Dose 
 MUGA 
 Multigated Acquisition Scan 
 OAE 
 Other significant adverse event 
 ORR 
 Overall response rate 
 OS 
 Overall Survival 
 OTEL 
 Open To Enrolment Letter 
 PCR 
 Polymerase Chain Reaction 
 PD 
 Progression disease 
 PET-CT 
 Positron emission tomography–computed tomography 
 PFS 
 Progression Free Survival 
 PI 
 Principal Investigator 
 PK 
 Pharmacokinetics 
 PLGA 
 Poly (lactic-co-glycolic acid) 
 PP 
 Per Protocol 
 PR 
 Partial Response 
 PRT 
 Primary retroperitoneal tumours 
 PS 
 Performance Status 
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 QD 
 Quaque die, every day “once daily” 
 QLQ 30 
 Quality of Life Questionnaire Core 30 
 QoL 
 Quality of Life 
 RDD 
 Retinal Degenerative Disease 
 RECIST 
 Response Evaluation Criteria In Solid Tumours 
 REEC 
 Registro Español de Estudios Clínicos (Spanish Registry of Clinical 
 Studies) 
 RLS 
 Retroperitoneal Liposarcoma 
 RP 
 Retroperitoneum 
 RP2D 
 Recommended Phase II dose 
 RVO 
 Retinal Vein Occlusion 
 Rx 
 Radiography 
 SAE 
 Serious adverse event 
 SAP 
 Statistical Analysis Plan 
 SAR 
 Serious adverse reaction 
 SBP 
 Systolic Blood Pressure 
 SCC 
 Squamous Cell Carcinoma 
 SD 
 Stable disease 
 SDV 
 Source Data Verification 
 SP 
 Safety Population 
 SRS 
 Stereotactic Radiosurgery 
 SUSAR 
 Suspected unexpected serious adverse reaction 
 Sx 
 Surgery 
 Tmax 
 Time of the sample identified as Cmax 
 TR 
 Translational Research 
 TTLR 
 Time to Local Relapse 
 ULN 
 Upper Limit of Normality 
 VMAT 
 Volumetric Modulated Arc Therapy 
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 WBC 
 White Blood Count 
 WBRT 
 Whole Brain Radiotherapy 
 WHO 
 World Health Organization 
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 2. 
 I  NTRODUCTION 
 2.1. 
 Disease background 
 Melanoma  accounts  for  4%  of  incident  cancers  and  its  mortality  rate  is  increasing  1  .  Surgical 
 excision  remains  the  treatment  of  choice  for  early  disease,  and  adjuvant  therapy  with  interferon 
 alfa  has  shown  benefit  in  some  stage  II  and  III  cases  2  .  Recently,  adjuvant  treatment  with 
 checkpoint inhibitors  3-6  and targeted therapies (BRAF  and MEK inhibitors) have been approved  7-10  . 
 However,  advanced  melanoma  is  an  aggressive  disease  for  which  there  are  few  therapies,  and 
 which portends a poor prognosis. 
 Previously  approved  drugs  like  interleukin-2  and  dacarbazine  in  this  setting;  in  clinical  trials,  each 
 had  response  rates  of  10-20%  and  neither  showed  an  overall  survival  benefit  11,12  .  More  recently, 
 ipilimumab  (Yervoy),  a  fully  humanized  antibody  that  binds  to  cytotoxic  T-lymphocyte-associated 
 antigen  4  (CTLA-4)  and  sustains  an  immune  attack  on  neoplastic  cells,  was  approved  by  the  FDA 
 and  EMA  for  use  in  the  metastatic  setting.  Approval  was  based  on  a  randomized  study  showing 
 that  ipilimumab  improved  survival  from  6  months  to  10  months  compared  with  an  experimental 
 vaccine  13  .  This  advance  promised  new  effective  treatment  for  what  was  once  a  treatment-refractory 
 disease  and  more  research  is  underway  to  investigate  other  molecular  pathways  that  may  be 
 targeted in an effort to produce further significant results. 
 The  use  of  immune  checkpoint  inhibitors  for  the  treatment  of  advanced  melanoma  has  evolved 
 beyond  monotherapies  to  combination  strategies.  This  combination  approach  results  in  response 
 rates  around  60%  and  superior  progression-free  survival  compared  with  ipilimumab  monotherapy 
 (median 11.5 versus 2.9 months)  14  . 
 2.2. 
 BRAF in Melanoma 
 One  potential  advance  that  showed  a  lot  of  promise  in  the  preclinical,  and  now  in  the  clinical 
 setting,  is  the  targeting  of  the  BRAF  kinase  in  melanoma.  Vemurafenib,  dabrafenib  and 
 encorafenib  are  BRAF  kinase  inhibitors  available  in  Europe  and  the  United  States.  Trametinib, 
 cobimetinib  and  binimetinib,  a  mitogen-activated  extracellular  signal  regulated  kinase  (MEK) 
 inhibitors, are also approved. 
 The  mitogen-activated  protein  (MAP)  kinase  pathway  is  an  important  driver  in  melanoma  and  is 
 made  up  of  several  potential  targets  providing  therapeutic  options  14  .  In  this  pathway,  the  activation 
 of  RAS  proteins  stimulates  the  RAF  kinases  ARAF,  BRAF,  and  RAF1.  This  process  causes  the 
 phosphorylation  of  the  MEK  kinases,  which  phosphorylate  the  ERK  kinases.  Activated  ERK 
 regulates  cyclin  D1,  which,  in  turn,  regulates  multiple  cellular  processes  involved  in  cell  division 
 (see Figure 1). 
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 Figure 1. The mitogen-activated protein (MAP) kinase pathway. 
 Approximately  40-60%  of  melanomas  contain  a  mutation  in  the  gene  that  encodes  BRAF  that 
 leads  to  constitutive  activation  of  downstream  signalling  in  the  MAP  kinase  pathway.  In  80-90%  of 
 these  cases,  the  activating  mutation  consists  of  the  substitution  of  glutamic  acid  for  valine  at  amino 
 acid 600 (V600E)  15,16  . 
 BRAF-mutated  melanoma  tends  to  exhibit  distinctive  clinical  features  and  is  characterized  by  more 
 aggressive  biological  behaviour  than  BRAF  wild-type  (WT)  melanoma  17  .  Compared  with  patients 
 with  BRAF  WT  melanoma,  those  with  BRAF-mutated  melanoma  are  more  often  younger  and  have 
 tumours  with  superficial  spreading  or  nodular  histology  and/or  in  anatomical  regions  without 
 chronic  sun  damage  18  .  Furthermore,  BRAF-mutant  tumours  are  more  likely  to  metastasize  to  the 
 brain  than  BRAF  WT  tumours  19  .  BRAF-mutated  melanoma  has  also  been  linked  to  shorter  overall 
 survival in patients with stage IV cancer than in those with BRAF WT disease  18-20  . 
 2.3. 
 Melanoma with brain metastasis 
 Brain  metastases  in  patients  with  advanced  and  metastatic  melanoma  are  a  frequent  complication 
 and  a  significant  cause  of  morbidity  and  mortality  in  this  patient  population.  As  the  incidence  of 
 brain  metastases  continues  to  increase  in  patients  with  metastatic  melanoma,  it  is  urgent  that  we 
 identify  effective  therapies.  During  the  past  decade,  management  of  melanoma  has  continued  to 
 evolve.  In  the  era  of  whole-exome  and  next-generation  sequencing,  there  is  a  requisite  role  for 
 identification  of  driver  mutations,  specifically,  BRAF,  given  the  possibility  for  targeted  therapies  and 
 the  opportunity  for  improved  survival.  Moving  forward,  trials  that  investigate  multimodal  treatment 
 regimens—combinations  of  targeted  or  immunotherapies  with  surgery  or  radiation—will  answer 
 additional questions regarding the optimization of management in this growing patient population  21  . 
 Recent  data  have  shown  an  incidence  of  brain  metastases  in  ≤  50%  of  patients  with  metastatic 
 melanoma  22  .  Because  this  is  typically  a  late  complication  of  systemic  disease,  melanoma-related 
 brain  metastases  have  been  associated  with  significant  neurologic  morbidity  and  a  poor  median 
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 overall  survival,  with  treatment,  of  approximately  9  months  23  .  Factors  that  predict  survival  include 
 age,  performance  status,  and  the  number  of  brain  metastases,  which  are  summarized  as  the 
 melanoma-specific graded prognostic assessment  24  . 
 Table  1.  Prognostic  groups  for  outcome  after  palliative  treatment  of  brain  metastases  by  recursive 
 partitioning analysis  25  . 
 Class 
 Prognostic Factors 
 Median survival, 
 months 
 I 
 KPS ≥70 percent 
 7.1 
 Age <65 years 
 Controlled primary site 
 No extracranial metastases 
 III 
 KPS <70 
 2.3 
 II 
 All others 
 4.2 
 KPS: Karnofsky performance status. 
 Table 2. Graded prognostic assessment for brain metastases from melanoma  26  . 
 Prognostic factor 
 Scoring criteria 
 Median survival (months) by 
 score: 
 0-1.0 = 3.4 
 1.5-2.0 = 4.7 
 2.5-3.0 = 8.8 
 3.5-4.0 = 13.2 
 0 
 1.0 
 2.0 
 Karnofsky PS 
 <70 
 70-80 
 90-100 
 Number of brain metastases 
 >3 
 2-3 
 1 
 Until  recently,  management  of  brain  metastases  has  primarily  focused  on  local,  intracranial  control 
 of  disease.  In  cases  of  single  metastatic  lesions  or  large,  symptomatic  lesions  in  oligometastatic 
 disease,  resection  is  typically  advised.  For  patients  with  more  than  a  single  brain  metastasis, 
 radiation  therapy,  including  stereotactic  radiosurgery  and  whole-brain  radiation  therapy,  has  been 
 the  mainstay  of  treatment  27  .  As  long-term  data  from  post–whole-brain  radiation  therapy  outcomes 
 have  emerged,  this  modality  is  used  less  frequently  because  of  the  risk  of  neurocognitive  decline. 
 Historically,  systemic  or  cytotoxic  therapies  have  not  played  a  prominent  role  mainly  because  of  the 
 challenges  of  penetrating  the  blood-brain  barrier  and  of  achieving  activity  within  the  central  nervous 
 system  (CNS).  Recently,  emergence  of  novel  genomic  techniques  —whole-exome  and 
 next-generation  sequencing—  has  enabled  the  identification  of  driver  mutations  in  melanoma. 
 Such  specific  targets  as  the  neuroblastoma  RAS  viral  oncogene  homolog  (NRAS)  and  v-RAF 
 murine  sarcoma  viral  oncogene  homolog  B  (BRAF)  have  been  exploited  for  therapeutic  use  21  . 
 Furthermore,  immunotherapy  has  revolutionized  the  management  of  melanoma,  specifically,  with 
 inhibition  of  cytotoxic  T-lymphocyte  antigen-4  (CTLA-4),  programmed  death-1  (PD-1),  which  is 
 expressed on lymphocytes, and programmed death ligand-1, which is expressed on tumour cells  28  . 
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 2.3.1.  Management  of  patients  with  melanoma  metastatic  to  the  brain  with  favourable 
 prognosis 
 In  favourable  prognosis  patients  (i.e.,  limited  or  no  extracranial  disease,  a  good  performance 
 status,  and  a  single  or  limited  number  of  brain  metastases),  aggressive  treatment  to  eradicate 
 metastases  in  the  brain  is  associated  with  an  improved  outcome.  Surgery  traditionally  was  used  to 
 treat  patients  with  a  single  or  limited  number  of  lesions,  often  supplemented  with  WBRT. 
 Subsequent  advances  have  made  stereotactic  radiosurgery  (SRS)  an  alternative,  particularly  when 
 lesions are not surgically accessible or when multiple lesions are present. 
 2.3.2. Management of patients with melanoma metastatic to the brain with intermediate and 
 poor prognosis 
 Patients  with  less  favourable  prognosis  ( Table  1 )  are  generally  treated  with  WBRT  rather  than 
 surgery  or  SRS.  However,  surgery  might  be  occasionally  performed  to  resect  a  large  symptomatic 
 or life-threatening lesion. 
 WBRT  is  widely  used  as  the  treatment  for  intermediate/poor  prognosis  patients  with  melanoma 
 metastatic  to  the  brain.  Even  with  treatment,  the  prognosis  for  these  patients  is  poor  (3-4 
 months)  29-32  .  The  Radiation  Therapy  Oncology  Group  (RTOG)  conducted  a  series  of  randomized 
 trials  to  determine  the  optimal  dose  and  fractionation  schedule  for  WBRT  in  patients  with  brain 
 metastases.  Patients  were  assigned  to  40  Gy  in  four  weeks,  40  Gy  in  three  weeks,  30  Gy  in  three 
 weeks,  30  Gy  in  two  weeks,  or  20  Gy  in  one  week.  The  overall  response  rate  (75  to  80  percent  for 
 symptom  palliation)  and  median  survival  (15  to  18  weeks)  were  equivalent  in  all  arms  of  these 
 studies.  Patients  treated  with  larger  fractions  over  a  shorter  time  responded  more  quickly,  but  the 
 duration  of  the  clinical  response  and  the  time  to  progression  were  similar  in  all  treatment  arms. 
 Brain metastases caused death in 40 percent of patients. 
 Subsequent  RTOG  trials  exploring  the  use  of  ultra-rapid  fractionation  schedules,  dose  escalation  in 
 favourable  prognosis  subgroups,  accelerated  fractionation,  and  the  use  of  radio  sensitizers,  failed 
 to show any benefit over conventional radiation therapy. 
 2.4. 
 Systemic therapy for melanoma patients with brain metastases 
 Until  recently,  there  were  few  treatment  options  for  patients  with  advanced  or  metastatic  melanoma 
 associated  with  significant  increases  in  overall  survival.  Of  these,  patients  with  disease  that  has 
 metastasized  to  the  brain  have  a  particularly  poor  prognosis  and  generally  ineffective  treatment 
 options.  Recent  advances  have  led  to  the  approval  of  ipilimumab,  an  antibody  that  blocks  cytotoxic 
 T-lymphocyte  antigen-4  to  augment  antitumour  T-cell  responses,  and  vemurafenib,  a  BRAF  kinase 
 inhibitor. 
 Although  improved  understanding  of  the  brain  microenvironment  and  the  blood–brain  barrier  in 
 metastatic  disease  is  required,  data  indicating  both  ipilimumab  and  vemurafenib  also  have  activity 
 against  brain  metastases  are  most  encouraging.  The  next  step  is  to  investigate  the  optimal 
 sequence,  as  well  as  combination  treatment  regimens,  which  will  allow  for  further  improved 
 long-term survival without compromising safety  33  . 
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 2.4.1. 
 Immunotherapies 
 As  in  other  solid  tumours,  the  role  of  immunotherapies  has  increased  in  the  management  of 
 metastatic  melanoma  34  .  Interleukin-2  was  the  earliest  immunotherapy  agent  to  be  used  in 
 melanoma.  Unfortunately,  whereas  it  demonstrated  some  efficacy,  it  was  associated  with  severe 
 toxicity,  notably,  fluid  retention  and  capillary  leak  syndrome,  which  led  to  increased  peritumoural 
 edema  28  .  Subsequently,  high-dose  interleukin-2  (HDIL-2)  treatment  was  studied;  however,  there 
 are little data to report on the outcome of patients with brain metastases who received HDIL-2  21  . 
 The  next  generation  of  immunotherapy  agents  have  focused  on  immune  checkpoint  inhibitors, 
 such  as  CTLA-4,  PD-1,  and  programmed  death  ligand-1  antibodies.  Ipilimumab,  a  CTLA-4 
 monoclonal  antibody,  has  demonstrated  improved  survival  in  metastatic  melanoma  and  in  patients 
 with melanoma brain metastases. 
 A  phase  II  trial  of  ipilimumab  in  patients  with  small  and  asymptomatic  brain  metastases—that  did 
 not  require  corticosteroids—demonstrated  that  24%  of  patients  achieved  a  partial  response  or 
 stable  disease  29  .  In  the  NIBIT-M1  study,  there  was  demonstrated  clinical  activity  in  patients  with 
 advanced  melanoma  who  were  treated  with  ipilimumab  and  fotemustine,  including  in  patients  with 
 brain  metastases  30  .  A  subsequent  3-year  analysis  demonstrated  the  efficacy  of  this  combination 
 without impairment of the immunologic activity of ipilimumab  38  . 
 The  NIBIT-M2  study,  a  randomized,  phase  III  trial,  will  compare  overall  survival  in  treatment  with 
 fotemustine  alone  versus  ipilimumab  plus  fotemustine  versus  ipilimumab  plus  nivolumab  (a  PD-1 
 inhibitor)  as  first-line  therapy  in  patients  with  symptomatic  brain  metastases.  In  addition,  the  role  of 
 pembrolizumab,  a  PD-1  blocking  antibody,  is  being  investigated  in  patients  with  melanoma  and 
 brain metastases  39  . 
 Although  rare,  there  have  been  reports  of  neurologic  toxicities  associated  with  immune  checkpoint 
 blockade.  Among  those  reported  as  immune-related  adverse  events  are  transient  peripheral 
 neuropathies,  which  have  been  reported  in  <  1%  of  patients  who  received  ipilimumab  40  . 
 Recommended  management  in  the  event  of  grade  2  neuropathy—no  interference  in  daily 
 activities—is  an  oral  steroid  taper  and  to  continue  at  the  same  dose  of  ipilimumab  41  .  For  more 
 severe  grade  3  or  4  neuropathy,  systemic  corticosteroids  and  discontinuation  of  ipilimumab  are 
 recommended  41  .  Other  case  reports  of  neurologic  disease  have  described  optic  neuritis,  aseptic 
 meningitis, myasthenia gravis, and Guillain-Barre syndrome  42  . 
 Data  presented  in  ASCO  2018  data  from  our  GEM-1202  clinical  trial  (NCT02115139),  phase  II 
 study  of  Ipilimumab  (IPI)  and  radiation  (WBRT)  in  patients  with  unresectable  melanoma  and  brain 
 metastases  43  ,  showed  that  concomitant  IPI+WBRT  is  feasible,  there  were  no  unexpected  safety 
 issues, being one-year OS rate in this trial, higher than the historical results. 
 2.4.2. 
 Targeted Therapies 
 BRAF  mutations  are  present  in  ≤  50%  of  patients  with  advanced  melanoma  and  should  be 
 investigated  if  a  patient  presents  at  this  stage.  Approximately  90%  of  the  BRAF  mutations  in 
 cutaneous  melanoma  are  valine  to  glutamic  acid  substitution  (Val600Glu,  V600E);  there  are  other 
 known  activating  mutations,  including  valine  to  lysine  (Val600Lys,  V600K),  which  constitute  a 
 smaller  percentage  44  .  Introduction  of  BRAF-targeted  agents  in  patients  who  harbour  these 
 mutations  has  led  to  rapid  systemic  disease  responses  within  weeks  of  initiation  of  therapy,  which 
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 has  prompted  the  same  investigations  in  the  management  of  intracranial  disease.  Currently,  there 
 are  three  approved  BRAF  inhibitors  available  for  clinical  use:  vemurafenib,  the  first  agent  licensed 
 for  treatment  of  BRAF-mutant  metastatic  melanoma,  dabrafenib  and  encorafenib.  It  is  not  yet  clear 
 whether  these  agents  have  a  differential  effect  on  disease  according  to  the  specific  mutation  type 
 (V600E v V600K)  44  . 
 2.4.3. 
 Mitogen-activated protein kinase kinase inhibitors (MEK) 
 Selective  mitogen-activated  protein  kinase  kinase  (MEK)  inhibition  has  also  been  explored  as  a 
 potential  therapeutic  target  in  melanoma  and  has  been  combined  with  BRAF  inhibitors.  Results 
 suggest  an  additional  survival  benefit  compared  with  BRAF  inhibitor  therapy  alone.  MEK  exists 
 downstream  of  BRAF  in  the  mitogen-activated  protein  kinase  signalling  pathway,  which  makes  the 
 combination  of  inhibitors  an  attractive  therapeutic  option  because  resistance  to  BRAF  inhibitor 
 monotherapy  may  be  reduced  with  the  addition  of  MEK  inhibition.  In  phase  I  and  II  trials  in  BRAF 
 V600–mutant  metastatic  melanoma,  combination  of  dabrafenib  and  trametinib,  an  MEK  inhibitor, 
 resulted  in  a  median  overall  survival  of  2  years  and  a  progression-free  survival  of  3  years 
 compared  with  vemurafenib  monotherapy.  As  expected,  patients  with  a  favourable  prognostic 
 profile  experienced  a  more  durable  response  45  .  In  addition,  there  were  similarities  in  the  incidences 
 of  grade  3  or  4  toxic  effects  and  adverse  effects,  which  led  to  dose  reduction.  Skin-related  adverse 
 effects  were  less  frequent  in  the  dabrafenib  and  trametinib  arm  46  .Thus  far,  no  data  exist  for  use  of 
 MEK inhibitor monotherapy in patients with melanoma-related brain metastases. 
 2.4.4. 
 Combination of BRAF Inhibitor and MEK Inhibitor 
 COMBI-MB  is  the  first  study  to  communicate,  in  a  prospective  manner  (phase  II  clinical  trial)  the 
 activity  of  the  combination  of  a  BRAF  inhibitor  (dabrafenib)  and  an  MEK  inhibitor  (trametinib)  in 
 patients  with  brain  metastases  47,48  ,  providing  preliminary  evidence  of  clinical  benefit  with  the 
 combination of BRAF/MEK inhibitors in patients with melanoma and brain metastases. 
 COLUMBUS  trial  49  is  the  first  phase  3  study  demonstrating  that  COMBO450  (ENCO  450  mg  once 
 daily  (QD)  +  BINI  45  mg  twice  daily  (BID)  significantly  improved  OS,  this  promising  approach  need 
 to be studied in patients with brain metastases. 
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 3. 
 T  RIAL  RATIONALE 
 As  previously  stated,  brain  metastases  accounts  for  approximately  20%  of  patients  with  melanoma, 
 being its frequency presumably higher in BRAF mutant melanoma  50  . 
 Most  pivotal  clinical  trials  with  both  targeted  therapy  and  immunotherapy  excluded  patients  with 
 active and/or untreated brain metastasis, leading to an unmet clinical need in real world practice. 
 In  the  targeted  therapy  field,  the  study  COMBI-MB  is  the  first  study  to  communicate,  in  a 
 prospective  manner  (phase  II  clinical  trial)  the  activity  of  the  combination  of  a  BRAF  inhibitor 
 (dabrafenib)  and  an  MEK  inhibitor  (trametinib)  in  patients  with  brain  metastases.  Briefly,  in  this 
 study,  the  primary  endpoint  was  an  intracranial  response  of  the  combination  in  four  different 
 cohorts (being cohort A the main objective), showing these results  51  . 
 ●  A)  BRAFV600E-positive,  asymptomatic  melanoma  brain  metastases,  with  no  previous 
 local  brain  therapy,  and  an  Eastern  Cooperative  Oncology  Group  (ECOG) 
 performance status of 0 or 1:  intracranial ORR 58%. 
 ●  B)  BRAFV600E-positive,  asymptomatic  melanoma  brain  metastases,  with  previous 
 local  brain  therapy,  and  an  ECOG  performance  status  of  0  or  1:  intracranial  ORR 
 56%. 
 ●  C)  BRAFV600D/K/R-positive,  asymptomatic  melanoma  brain  metastases,  with  or 
 without  previous  local  brain  therapy,  and  an  ECOG  performance  status  of  0  or  1: 
 intracranial ORR 44%. 
 ●  D)  BRAFV600D/E/K/R-positive,  symptomatic  melanoma  brain  metastases,  with  or 
 without  previous  local  brain  therapy,  and  an  ECOG  performance  status  of  0,  1,  or  2: 
 intracranial ORR 59%. 
 These  results,  although  in  an  indirect  comparison,  are  better  in  terms  of  response  than  treating 
 these  patients  only  with  dabrafenib,  according  to  the  study  BREAK-MB  (39%  in  patients  without 
 previous local treatment)  52  . 
 Thus,  COMBI-MB  supports  the  use  of  dabrafenib  and  trametinib  also  in  BRAF  mutant  melanoma 
 patients  with  brain  metastases.  However,  one  of  the  main  critics  to  this  study,  is  the  apparently 
 short  progression  free  survival  in  the  main  cohort  (cohort  A,  patients  asymptomatic)  in  comparison 
 with  patients  treated  in  other  clinical  trials  with  the  same  combination  and  no  brain  metastases:  5.6 
 months  in  COMBI  MB  51  versus  11  months  in  COMBI-D  53  .  One  of  the  reasons  could  be  the 
 well-known  poorer  prognosis  of  these  patients,  but  another  one  could  be  the  fact  that  patients  in 
 this  clinical  trial,  were  not  allowed  by  protocol  to  be  treated  with  a  local  therapy  (except  for 
 previously  treated  ones  in  cohort  B,  C  and  D,  but  always  before  the  dabrafenib  and  trametinib).  For 
 those  patients  achieving  a  non-complete  response,  it  is  unknown  if  further  local  therapy  (radiation, 
 radiosurgery, surgery) could improve the duration of the responses. 
 Combination  or  sequencing  of  systemic  (targeted)  and  local  treatment  with  radiation  has 
 demonstrated  a  manageable  toxicity  profile,  with  some  concerns  regarding  radio  necrosis  and 
 increase in dermatitis. Most of these data, however, come from retrospective case series  54  . 
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 Finally,  although  encorafenib  in  combination  with  binimetinib  is  indicated  for  the  treatment  of  adult 
 patients  with  unresectable  or  metastatic  melanoma  with  a  BRAF  V600  mutation,  it  is  unknown  the 
 activity in patients with BRAF mutant melanoma and brain metastases. 
 3.0.1. 
 Rationale for primary endpoint 
 COMBI-MB  reported  similar  treatment  activity  of  BRAF/MEK  inhibitors  in  BRAF  V600  mutated 
 melanoma  with  brain  metastasis  regardless  of  symptomatology51.  Moreover,  recent  studies  on 
 proposed setting are reporting iORR regardless of symptoms at diagnosis55,56. 
 We  sought  to  determine  as  the  primary  endpoint  for  this  trial  the  intracranial  ORR  (iORR) 
 regardless  of  symptomatology.  iORR  will  be  also  calculated  as  initially  proposed  by  cohort, 
 depending on symptomatology. 
 3.1. 
 Rationale for dose selection 
 The  dose  selected  in  this  trial  is  COMBO450  (ENCO  450  mg  once  daily  (QD)  +  BINI  45  mg  twice 
 daily (BID) administered to patients in phase III COLUMBUS trial (NCT01909453)  7  . 
 Local  treatment  could  be  radiation  therapy  or  focused  hypofractionated  image  guided  VMAT 
 (volumetric  modulated  arc  therapy)  for  patients  with  ≤  4  brain  metastases  of  ≤  3  cm  in  diameter,  or 
 whole  brain  radiation  if  patient  has  >  4  brain  metastases  and/or  any  lesion  of  >  3cm),  according  to 
 local radiotherapy oncologist criteria. 
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 4. 
 H  YPOTHESIS  AND  O  BJECTIVES 
 Taking  all  into  account,  the  present  project  will  try  to  evaluate  the  role  of  the  combination  of 
 encorafenib and binimetinib administered before local treatment that will follow, after response. 
 4.1. 
 Study Hypothesis 
 The main hypothesis is that: 
 ●  Intracranial  response  rate  by  modified  RECIST  1.1  before  local  treatment  will  be  ≥ 40%  in 
 cohort 1 and 2. 
 Study will be considered positive if the main hypothesis is achieved. 
 4.2. 
 Study Objectives 
 1.  Primary objective: 
 a.  Intracranial  objective  response  rate  by  modified  RECIST  1.1  before  local 
 treatment in cohort 1 and in cohort 2. 
 2.  Secondary objectives : 
 a.  Intracranial  objective  response  rate  assessed  by  the  investigators  using 
 modified RECIST 1.1 before local treatment in cohort 2. 
 b.  Intracranial  objective  response  rate  assessed  by  the  investigators  using 
 modified RECIST 1.1 before local treatment in cohort 1. 
 c.  The  duration  of  the  intracranial  response  in  both  cohorts  assessed  by  the 
 investigators using modified RECIST 1.1. 
 d.  The  intracranial progression free survival by modified RECIST in both cohorts 
 e.  Percentage  of  patients  free  of  intracranial  progression  according  to  modified 
 RECIST  at  6  (week  24),  12  (week  48)  and  24  months  (week  96)  in  both 
 cohorts. 
 f. 
 Percentage  of  patients  free  of  extracraneal  progression  according  to  RECIST 
 1.1 () at 6 (week 24), 12 (week 48) and 24 months (week 96) in both cohorts. 
 g.  Overall survival in both cohorts. 
 h.  Percentage of alive patients at 6, 12 and 24 months in both cohorts. 
 i. 
 Toxicity of the combination until local treatment in both cohorts: 
 ●  Toxicity of the combination after local treatment in both cohorts. 
 ●  Quality of life in both cohorts. 
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 5. 
 S  TUDY  D  ESIGN 
 5.1. 
 Overall Study Design 
 This  is  a  phase  II  clinical  trial  with  two  cohorts  of  patients,  all  with  melanoma  BRAF  mutant  and 
 brain metastases: 
 ●  Cohort  1:  patients  with  asymptomatic  brain  metastases  and  without  previous 
 radiotherapy (previous surgery is allowed) treatment in the brain. N=48 
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 ●  Cohort  2:  patients  with  symptomatic  brain  metastasis  and  without  previous 
 radiotherapy (previous surgery is allowed)treatment in the brain. N=15 
 The  design  includes  local  confirmation  of  BRAF  mutation,  screening  phase,  systemic  treatment 
 phase,  radiotherapy  or  radiosurgery  (according  to  the  radiotherapist  criteria,  following  the 
 indications included in the protocol), and quality of life assessment. 
 5.2. 
 Patient Screening 
 Once  completed  all  regulatory  and  Sponsor  requirements  and  after  received  the  “ O pen  T o 
 E nrolment  L etter”  ( OTEL ),  confirming  that  study  is  fully  active  in  the  corresponding  site,  the  trial 
 (informed consent) can be offered to potential patients. 
 Informed  consent  will  be  obtained  prior  to  start  of  the  specified  screening  window.  Procedures 
 conducted  as  part  of  the  subject’s  routine  clinical  management  (e.g.,  blood  count  determinations 
 and  imaging  studies  such  as  bone  scans)  prior  to  signing  of  informed  consent  may  be  used  for 
 screening  or  for  defining  baseline  data,  provided  these  procedures  are  conducted  as  specified  in 
 the  protocol.  Once  informed  consent  form  (ICFs)  is  signed,  a  trial  screening  number  will  be 
 assigned  to  each  patient  after  registering  at  Electronic  Data  Capture  (EDC)  platform.  Each  site  will 
 receive  access  to  the  EDC  platform  to  register  each  screened  case,  since  as  per  GCP  guidelines  it 
 is mandatory to register every patient who signs a consent form. 
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 Furthermore,  within  the  Investigator  Site  File  (ISF),  a  Patient  Identification  List  will  be  included  in 
 order  to  identify  patients  according  to  local  normal  practice.  This  document  will  allow  for  immediate 
 and  unequivocal  identification  of  patients  participating  in  this  clinical  trial.  This  document  will 
 always  be  stored  under  Investigator  staff  custody  at  the  site.  The  screening  number  will  identify 
 patients  throughout  the  screening  period  while  procedures  needed  to  confirm  the  subjects’ 
 suitability for the trial protocol, such as clinical laboratory tests, imaging, and others are performed. 
 Screening  determinations  include  obtaining  informed  consent,  signature  and  registration,  patient 
 record  review,  local  BRAF  mutation  status,  clinical  consultation,  imaging  procedures,  and 
 laboratory  analyses  including  haematology,  biochemistry,  and  urine  tests.  Additional  information 
 about screening procedures can be found in section 8 of this protocol. 
 5.3. 
 Patient Inclusion and Cohort Assignment 
 During  the  screening  (28  days  before  day  1  cycle  1)  it  should  be  assessed  whether  the  patient  is 
 symptomatic (cohort 2) or asymptomatic (cohort 1). 
 Definition  of  Asymptomatic  (cohort  1):.Patients  without  active  symptoms  secondary  to  brain 
 metastases at the moment of inclusion. 
 After  confirming  that  a  patient  fulfils  all  eligibility  criteria  of  the  study  (inclusion/exclusion  criteria), 
 site staff will initiate the eCRF registration procedure. 
 Once  procedure  is  fulfilled  the  site  staff  will  receive  the  “Inclusion  confirmation  communication”, 
 and protocol-specific treatment can be initiated. 
 This  is  an  open  label,  single  arm  study  including  two  cohorts  of  patients,  in  each  cohort,  patients 
 will be treated with encorafenib 450 mg once daily and binimetinib 45 mg twice daily. 
 After  56  days  of  treatment,  a  contrast  enhanced  brain  MRI  and  CT  body  scan  will  be  performed  as 
 first tumour assessment: 
 - 
 Patients  with  PD  at  first  evaluation  in  brain  MRI  (modified  RECIST  1.1  criteria)  and  /or 
 body  CT  scan  (RECIST  1.1  criteria)  will  discontinue  study  treatment  and  will  continue 
 in the study for OS follow-up. 
 - 
 Patients  with  CR  in  brain  (modified  RECIST  1.1)  and  no  PD  in  the  body  (RECIST  1.1), 
 will  continue  study  treatment  and  will  be  followed  every  two  months  with  contrast 
 enhanced  brain  MRI  and  body  CT  scan  up  to  12  months.  If  no  PD  after  one  year, 
 patients will be followed as per institutional criteria, and continue with the treatment. 
 o 
 If  considered  by  the  investigator,  local  treatment  can  be  done  for  brain  CR 
 patients,  but  only  after  confirming  no  safety  concerns  (defined  as  substantial 
 deterioration  of  vital  signs  (including  ECOG  PS),  physical  examination,  ECG, 
 Lab.  Values  that  do  not  recommend  RT)  with  the  three  first  patients  treated 
 with  radiation  therapy  in  the  running  phase  (for  more  information,  please  see 
 section 9.1). 
 - 
 Patients  with  no  CR  and  no  PD  in  brain  MRI  per  modified  RECIST  1.1  criteria,  and  no 
 PD  in  body  per  RECIST  1.1  criteria,  will  be  treated  with  local  RT  and/or  radiosurgery, 
 and  then  will  continue  Enco  and  Bini.  The  first  3  patients  will  be  treated  in  a  running 
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 phase.  These  three  first  patients,  that  have  achieved  non-CR,  non-PD  in  brain  and  no 
 PD  in  body,  are  going  to  be  treated  sequentially  or  at  the  same  time  depending  on 
 when  radiotherapy  treatment  is  needed.  If  no  safety  concerns  appear  (defined  as 
 substantial  deterioration  of  vital  signs  (including  ECOG  PS),  physical  examination, 
 ECG,  Lab.  Values  that  do  not  recommend  RT),  the  rest  of  patients  that  have  achieved 
 non-CR,  non-PD  in  brain  will  begin  local  treatment  when  it  will  be  indicated  under 
 medical criteria: 
 ●  Encorafenib  and  binimetinib  will  be  interrupted  24h  before  radiotherapy 
 and restart 24h after the last dose of radiotherapy. 
 ●  The  local  radiation  technique  will  be  defined  and  indicated  by  the 
 radiotherapy  oncologist  (local  co-investigator)  criteria,  depending  on 
 the  number  of  lesions  and  its  maximum  size  in  the  last  tumour 
 assessment  done  during  the  treatment  with  encorafenib  and 
 binimetinib: 
 ●  *Radiosurgery (RS) or Stereotactic radiosurgery (SRS): 
 ●  1 brain metastases < 4 cm 
 ●  ≤ 3 brain metastases ≤ 3 cm 
 ●  ≤ 4 brain metastases ≤ 2.5 cm 
 *Radiosurgery: for patients who do not meet criteria for radiosurgery (RS) or (SRS), exceptional 
 cases could be allowed after prior detailed consultation with the trial coordinators. 
 ●  Whole brain radiotherapy (WBRT): 
 ●  ≥ 4 brain metastases 
 ●  Almost one brain metastasis of ≥ 4 cm 
 ●  ≤ 4 brain metastases not eligible for RS or SRS 
 Location  metastases:  brain  stem,  midbrain,  pons,  medulla  or  within  10  mm  of  the  optic  nerves  and 
 chiasm. 
 - 
 After  the  first  evaluation  of  the  patient's  intracranial  response,  patients  without 
 progression  who  received  a  local  treatment,  could  receive  other  local  treatments  at 
 the discretion of the investigator, if this is considered beneficial for the patient. 
 - 
 Surgery  can  be  done  if,  as  per  investigator  criteria,  is  necessary  for  the  patient's 
 health. 
 - 
 For  patients  in  CR  in  the  first  assessment,  if  they  were  not  treated  with  radiation,  and 
 in  follow  up  a  PD  occurs  only  in  the  brain ,  brain  local  treatment  will  be  carried  out  as 
 per  protocol.  These  patients  can  continue  encorafenib  and  binimetinib  treatment  after 
 local treatment. 
 - 
 Every  patient  with  a  stable  disease  or  response  in  both,  brain  and  body,  in  the  first 
 assessment,  when  presenting  a  DP  after  local  treatment  in  the  body  CT  scan  by 
 RECIST  1.1.  and/or  brain  MRI,  by  modified  RECIST  1.1,  they  will  discontinue  the 
 systemic treatment with encorafenib and binimetinib. 
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 - 
 After progression, patients will be followed only for overall survival. 
 o 
 In  case  of  encorafenib  and  binimetinib  are  providing  a  clinical  benefit  to  any 
 patient,  treatment  could  be  continued  after  discussion  with  Sponsor 
 ( investigacion@mfar.net ),  if  it  agrees  on  that.  In  this  case,  follow  up  will  be 
 done  as  per  institutional  criteria.  In  the  study,  these  patients  will  be  followed 
 only for overall survival. 
 - 
 Study  assessments:  in  each  monthly  visit,  adverse  events  will  be  registered,  blood 
 samples  will  be  collected  for  blood  cell  counts  and  general  biochemistry  (including 
 magnesium,  potassium  and  creatinine-kinases);  an  ECG  will  be  performed  at 
 baseline,  after  one  month  of  treatment,  and  every  3  months  thereafter;  a  left 
 ventricular  ejection  fraction  (LVEF)  evaluation  will  be  performed  by  as  per  institutional 
 guidelines  at  baseline  and  every  3  months  thereafter  ophthalmologic  anamnesis  and 
 evaluation  will  be  performed  by  oncologist  at  baseline  and  in  every  monthly  visit,  if 
 there’s  any  alarm  symptom  or  sign,  patient  will  be  evaluated  by  Ophthalmologist.  Body 
 CT-scan  and  contrast  enhanced  brain  MRI  will  be  performed  baseline  and  every  8 
 weeks  up  to  12  months  and  according  to  normal  practise  thereafter.  More  information 
 regarding study determination is provided in section 8 of this protocol. 
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 6. 
 E  LIGIBILITY  C  RITERIA 
 6.1. 
 Inclusion criteria 
 Patients eligible for inclusion in this study must meet all the following criteria: 
 1.  Written  informed  consent  of  approved  by  the  investigator’s  Institutional  Review  Board 
 (IRB)/Independent Ethics Committee (IEC), prior to the performance of any trial activities. 
 2.  Histologically  confirmed  diagnosis  of  unresectable  metastatic  cutaneous  melanoma,  or 
 unknown  primary  melanoma  with  one  or  more  brain  metastasis  with  a  diameter  of  5  t o  50 
 mm, measured by contrast enhanced MRI. 
 3.  A documented mutation in BRAFV600 in the tumour tissue. 
 4.  Modified Barthel Index of Activities of Daily Living > 10 (see appendix 2). 
 5.  Subjects aged ≥ 18 years. 
 6.  ECOG 0-1 in asymptomatic patients (cohort 1), 0-2 in symptomatic patients (cohort 2). 
 7.  Adequate hematologic function: 
 a.  Haemoglobin ≥ 9 g/dL (may have been transfused). 
 b.  Platelet count ≥ 100 × 10 9/L. 
 c.  Absolute neutrophil count (ANC) ≥ 1.5 × 10 9/L. 
 8.  Adequate  hepatic  function  defined  by  a  total  bilirubin  level  ≤  2.0  ×  the  upper  limit  of 
 normality  (ULN)  and  AST  and  ALT  levels  ≤  2.5  ×  ULN  or  AST  and  ALT  levels  ≤  5  x  ULN  (for 
 subjects with documented metastatic disease to the liver). 
 9.  Serum  Creatinine  ≤  2.0  x  ULN  or  estimated  creatinine  clearance  ≥  30  mL/min  according  to 
 the Cockcroft-Gault formula (or local institutional standard method). 
 10.  Have  evidence  of  at  least  one  measurable  lesion  as  detected  by  radiological  or 
 photographic  methods  according  tto  guidelines  by  modified  RECIST  1.1.Patients  with 
 unresectable  locally  advanced  or  metastatic  melanoma  untreated  or  having  progressed  on 
 or  after  a  prior  first  line  with  antiPD1  +/-  antiCTLA-4  (patients  could  have  had  brain 
 metastasis  when  treated  with  immunotherapy).  Prior  immunotherapy  must  have  ended  at 
 least  3  weeks  (anti-PD1  monotherapy)  or  4  weeks  (anti-PD1  +  anti-CTLA4)  before  to  the 
 cohort  assignment  (in  case  that  this  premise  is  not  met,  please,  contact  with  the  sponsor: 
 investigación@mfar.net). 
 11.  Patients  relapsing  to  a  prior  adjuvant  therapy  (e.g.  IFN,  IL-2  therapy,  any  other 
 immunotherapy,  radiotherapy  or  chemotherapy)  are  allowed.  When  patients  received  BRAF 
 +/-  MEK  inhibitors  as  adjuvant  treatment,  relapse  must  have  occurred  ≥  12  months  after  the 
 end  of  it.  Moreover,  patient  mustn’t  present  any  residual  grade  3-4  toxicity,  including 
 medically  serious  and  reversible/controlled  toxicities  (e.g.:  GGT  elevation,  CPK  elevation, 
 vomiting) 
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 12.  Steroids  or  anticonvulsants  are  allowed  if  clinically  needed  and  once  the  patient  is  included 
 in the trial are not being administered in an increasing dose. 
 13.  Female  subjects  must  either  be  of  non-reproductive  potential  (e.g.,  post-menopausal  by 
 history:  ≥60  years  old  and  no  menses  for  ≥1  year  without  an  alternative  medical  cause;  OR 
 history  of  hysterectomy,  OR  history  of  bilateral  tubal  ligation,  OR  history  of  bilateral 
 oophorectomy)  or  must  have  a  negative  urine  pregnancy  test  upon  study  entry.  If  the  result 
 in  the  urine  pregnancy  test  is  positive,  a  serum  pregnancy  test  should  be  done  to  confirm 
 pregnancy. 
 14.  Normal functioning of daily living activities. 
 15.  Willingness  and  ability  to  attend  scheduled  visits,  follow  the  treatment  schedule  and 
 undergo clinical tests and other study procedures. 
 6.2. 
 Exclusion criteria 
 Patients meeting any of the following criteria are excluded from the study: 
 1.  Uveal or mucosal melanoma. 
 2.  History  of  leptomeningeal  metastases,  with  the  exception  that  they  are  only  seen  in  brain 
 MRI  and  the  patient  has  ECOG  0-1  and  no  neurological  symptoms  (except  for  cohort  2, 
 where symptomatic patients will be allowed if ECOG is 0-2). 
 3.  Another  cancer  in  the  last  two  years,  except  for  in  situ  carcinoma  of  the  cervix  or  squamous 
 cell  carcinoma  of  the  skin  adequately  treated  or  limited  basal  cell  skin  cancer  adequately 
 controlled.  If  another  cancer  was  diagnosed  in  the  two  previous  years,  it  should  be  in 
 complete  remission  and  without  the  need  for  any  other  maintenance  treatment  (i.e 
 hormonotherapy,  chemotherapy,  targeted  therapy  including  monoclonal  antibodies  and 
 immunotherapy) 
 4.  History  of  or  current  evidence  of  central  serous  retinopathy  (CSR),  retinal  vein  occlusion 
 (RVO) or history of retinal degenerative disease (RDD). 
 5.  Any  previous  systemic  chemotherapy  treatment,  brain  radiotherapy,  targeted  therapy  based 
 on BRAF and/or MEK inhibitors for locally advanced unresectable or metastatic melanoma. 
 6.  History of Gilbert's syndrome. 
 7.  Previous  treatment  with  a  BRAF  or  MEK  inhibitor  in  metastatic  setting.  This  treatment  will 
 be  allowed  in  the  adjuvant  setting  (see  above).  Previous  treatments  with  immunotherapy 
 will be allowed in both the metastatic and adjuvant setting. 
 8.  Known  positive  serology  for  human  immunodeficiency  virus,  or  an  active  hepatitis  B  or 
 hepatitis C infection, or both; 
 9.  Impaired  cardiovascular  function  or  clinically  significant  cardiovascular  diseases  “Clinically 
 significant  (i.e.,  active)  cardiovascular  disease:  cerebrovascular  accident/stroke  (<  6 
 months  prior  to  enrolment),  myocardial  infarction  (<  6  months  prior  to  enrolment),  unstable 
 angina,  congestive  heart  failure  (≥  New  York  Heart  Association  Classification  Class  II),  a 
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 LVEF  <  50%  evaluated  as  per  institutional  guidelines,  or  serious  cardiac  arrhythmia 
 requiring medication or a triplicate average baseline QTc interval > 500 ms.” 
 10.  Uncontrolled arterial hypertension despite medical treatment. 
 11.  Moderate (Child Pugh Class B) or severe (Child Pugh Class C) hepatic impairment. 
 12.  Impairment of gastrointestinal function. 
 13.  Neuromuscular disorders associated with high concentrations of creatine kinase. 
 14.  Medical,  psychiatric,  cognitive  or  other  conditions  that  may  compromise  the  patient's  ability 
 to  understand  the  patient  information,  give  informed  consent,  comply  with  the  study 
 protocol or complete the study. 
 15.  Known hypersensitivity to encorafenib, binimetinib or their components. 
 16.  Persisting  toxicity  related  to  prior  therapy  of  Grade  >1  NCI-CTCAE  v  4.03;  however, 
 alopecia and sensory neuropathy Grade ≤ 2 is acceptable. 
 17.  Female  patients  who  are  pregnant  or  breastfeeding  or  male  or  female  patients  of 
 reproductive  potential  who  are  not  willing  to  employ  highly  effective  birth  control  from 
 screening to 180 days after the last dose of study treatment. 
 18.  Known alcohol or drug abuse. 
 19.  Inability to swallow tablets or capsules. 
 20.  Total lactase deficiency or glucose-galactose malabsorption. 
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 7. 
 T  REATMENT  OF  S  UBJECTS 
 7.1. 
 Description of Study Drug 
 7.1.1. Encorafenib 
 Pharmaceutical form and route of administration:  Capsules  for oral use. 
 Strength : provided as 75 mg and 50 mg capsules. 
 Presentation:  The  encorafenib  drug  product  is  supplied  as  a  capsule  formulation  in  dosage 
 strengths  of  50  mg  and  75  mg  the  dosage  forms  for  each  strength  have  identical  formulations 
 which  are  packaged  into  blisters  in  different  coloured  capsules  per  strength.  Sites  will  provide 
 patients  enough blisters to cover the treatment until  next patient’s visit 
 7.1.2. Binimetinib 
 Pharmaceutical form and route of administration:  Tablets  for oral use. 
 Strength:  Provided as 15 mg tablets. 
 Presentation:  Binimetinib  15  mg  will  be  provided  as  film-coated  tablets  and  packaged  into 
 high-density  polyethylene  blisters.  Sites  will  provide  patients  enough  bottles  to  cover  the  treatment 
 until the next patient visit. 
 7.1.3. COMBO 450 administration instructions 
 Encorafenib  and  binimetinib  will  be  administered  orally  on  a  daily  schedule  as  a  flat  fixed  dose  (not 
 by body weight or body surface area). 
 Patients  will  be  supplied  during  the  control  visit  with  enough  number  of  tablets  and/or  capsules  for 
 all  doses  to  be  taken  prior  to  the  next  scheduled  visit.  In  addition,  patients  will  be  provided  a  dosing 
 diary and should document in this diary each prescribed dose, and whether it was taken or not. 
 If a patient vomits at any time after dosing, the dose of study drug should not be re-administered. 
 Doses  of  binimetinib  that  are  omitted  for  any  reason  should  not  be  made  up  later  if  it  is  less  than  6 
 hours  until  the  next  dose  is  due.  Doses  of  encorafenib  that  are  omitted  any  reason  can  be  taken  up 
 to 12 hours prior to the next dose. 
 Patients  must  avoid  consumption  of  grapefruit  or  grapefruit  juice  during  the  entire  study  and 
 preferably  7  days  before  the  first  dose  of  study  medications,  due  to  potential  CYP3A4  interaction 
 with  the  study  medications.  Orange  juice  is  allowed.  Complete  dosing  instructions  will  be  provided 
 to  study  patients  and  will  include  the  minimum  times  between  doses  and  instructions  for  missed 
 doses.  Patients  will  also  be  instructed  not  to  chew,  crush,  or  dissolve  tablets  and/or  capsules  of 
 study  drugs.  The  investigator  or  responsible  site  personnel  should  instruct  the  patient  to  take  the 
 study  drugs  as  per  protocol  (Sponsor  compliance).  All  dosages  prescribed  and  dispensed  to  the 
 patient  and  all  dose  changes  and  all  missed  doses  during  the  study  must  be  recorded  on  the 
 eCRF.  Drug  accountability  must  be  performed  on  a  regular  basis.  Patients  will  be  instructed  to 
 return  unused  study  drugs  to  the  site  at  the  end  of  each  cycle.  The  site  personnel  will  ensure  that 
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 the  appropriate  dose  of  each  study  drug  is  administered  at  each  visit  and  will  provide  the  patient 
 with the correct number of drugs for subsequent dosing. 
 Patients  should  be  instructed  to  take  with  a  large  glass  of  water  (~250  ml)  daily  in  the  morning  at 
 approximately  the  same  time  every  day  the  Combination  of  450  mg  of  encorafenib  and  45  mg  of 
 binimetinib  (Combo  450)  together.  Twelve  hours  later,  patients  should  take  again  45  mg  of 
 binimetinib  with  a  large  glass  of  water  (~250  ml).  In  total,  patients  should  take  90  mg  of  binimetinib 
 every  day,  if  the  dose  has  not  been  modified.  All  dose  administrations  may  be  taken  with  or  without 
 food,  but  the  same  method  should  be  used  consistently  throughout  the  study.  Despite  this,  the 
 concomitant administration of encorafenib with grapefruit juice should be avoided. 
 The prescribed doses for binimetinib should be taken twice daily, approximately 12 hours apart. 
 On  visit  days  when  the  patient  is  scheduled  to  be  at  the  clinic,  patients  will  take  encorafenib  and 
 binimetinib  (as  applicable)  in  the  clinic  under  the  supervision  of  the  investigator  or  designee  on  the 
 morning.  On  the  evening  of  the  visit  day  patients  will  take  binimetinib  (as  applicable)  at  home.  On 
 all  other  days,  patients  will  take  encorafenib  and  binimetinib  (as  applicable)  at  home.  If  a  patient 
 temporarily  interrupts  treatment  with  binimetinib,  the  patient  may  continue  treatment  with 
 encorafenib  as  monotherapy  at  a  maximum  dose  of  300  mg  QD .  If  binimetinib  is  permanently 
 discontinued,  encorafenib  should  be  discontinued.  If  a  patient  permanently  discontinues  treatment 
 with  encorafenib,  the  patient  must  discontinue  treatment  with  binimetinib,  complete  the  end  of 
 treatment visit and continue to be followed until disease progression. 
 7.1.4. 
 Radiation therapy  59-62 
 7.1.4.1 Whole Brain Radiation Therapy 
 1. Total Dose: 
 ●  The whole brain planning target volume (PTV) will receive 30 Gy in 10 fractions. 
 ●  Treatment will be delivered once daily, 5 fractions per week, over 2 to 2.5 weeks. 
 2. Immobilization, Simulation, Localization: 
 ●  Patients  will  be  treated  in  the  supine  position  using  an  adequate  immobilization 
 (aquaplast mask). 
 ●  A  treatment-planning  CT  scan  of  the  whole  head  region  must  be  acquired  with  the 
 patient  in  the  same  position  and  immobilization  device  as  for  treatment.  Axial  slice 
 thickness  not  exceeding  3-5  mm  will  be  required.  Contrast  IV  and  MRI-CT  fusion  are 
 not necessary. 
 3. Target volumes: 
 ●  It is not necessary to define the Gross Tumour Volume (GTV). 
 ●  The  Clinical  Target  Volume  (CTV)  is  defined  as  the  whole  brain  parenchyma  to  C1 
 (if  no  posterior  fossa  metastasis)  or  C2  (if  MRI  evidence  of  posterior  fossa 
 metastasis). 
 ●  The PTV is defined as the CTV + 0.5 cm with clip at patient surface. 
 4. Treatment Planning: 
 ●  Treatments  must  be  delivered  with  3-D  planning  through  parallel  opposed  fields  that 
 cover  the  entire  cranial  contents  (also  it  is  allowed  static  or  dynamic  intensity 
 modulation). 
 ●  All portals will be treated daily. 
 ●  Treatment  will  be  delivered  using  megavoltage  machines  with  photon  beams 
 ranging from 4 to 8 MV. Electron, particle, or implant therapy is not permissible. 
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 5. Dose Specification: 
 ●  Doses will be specified at the central axis at midplane on the brain. 
 90% of the whole brain PTV must be covered by the prescription dose. 
 ●  Maximum  dose  to  2%  of  the  PTV  (D2%)  37.5  Gy,  and  minimum  dose  to  98%  of  the 
 PTV (D98%) 25 Gy. 
 ●  If  treatment  is  delivered  with  Helical  Tomotherapy  96%  of  the  whole  brain  PTV  must 
 be covered by the prescription dose. Max dose 30 Gy, 30 Gy to >=96%. 
 ●  If  LINAC-based  IMRT  is  delivered,  92%  of  the  whole  brain  PTV  must  be  covered  by 
 the prescription dose. Max Dose 34 Gy. Min Dose:  27,6 Gy. 
 6. Critical Structures: 
 ●  The lenses, orbits, optic nerves, optic chiasm and brain will be contoured. 
 ●  Hippocampus  protection  is  allowed  in  patients  who  do  not  present  any  nearby 
 lesion, enabling the possibility of protecting said area. 
 ●  Minimize  the  dose  to  the  lens  and  orbits.  Dose  to  any  point  within  the  optic  nerves 
 or optic chiasm cannot exceed 37.5 Gy. 
 ●  If  treatment  is  delivery  with  Helical  Tomotherapy  Eyes:  Max  Dose  8  Gy,  5  Gy 
 <=20%. Lenses: Max Dose 3 Gy. 
 ●  If  LINAC-based  IMRT  Involving  Static  Gantry  Angles:  Eyes:  Max  Dose  7  Gy,  5  Gy 
 <=20%. Lenses: Max Dose 5 Gy. 
 7. Documentation: 
 ●  Verification  of  orthogonal  films  or  portal  images  that  localize  the  isocenter  placement 
 must be obtained. 
 7.1.4.2. 
 Radiosurgery/Stereotactic radiosurgery 
 1.  All  participating  institutions  must  use  approved  stereotactic  localization  procedures  for 
 imaging and treatment delivery. 
 2.  Devices:  Gamma  Knife  or  Accelerator  Linac-Based  Systems  (IMRT,  Rapid  Arc, 
 VMAT), Cyberknife, or Tomotherapy Hi-Art system. 
 3.  Total Dose: 
 a.  Dose  selection  must  be  based  on  previously  published  Radiation  Therapy 
 Oncology  Group  (RTOG)  data,  with  dose  modification  left  up  to  the  treating 
 physician.  The  total  dose  will  depend  on  the  size  of  the  metastatic  lesion(s) 
 and proximity to critical structures. 
 b.  Suggested  doses  are  as  follows:  1  fraction  x  15-25  Gy;  3  fractions  x  9-11  Gy;  5 
 fractions x 6-7 Gy; or 6 fractions x 5-6 Gy. 
 c.  For  GTV  >  20  mm  hypofractionated  stereotactic  radiotherapy  could  be 
 prefered. 
 d.  Treatment will be delivered once daily, alternate-day, 3 fractions per week. 
 4.  Immobilization, Simulation, Localization: 
 a.  Patients  will  be  treated  in  the  supine  position  using  an  adequate  immobilization 
 facemask/stereotactic frame. 
 b.  A  treatment-planning  CT  scan  of  the  whole  head  region  must  be  acquired  with 
 the  patient  in  the  same  position  and  immobilization  device  as  for  treatment. 
 Axial  slice  thickness  not  exceeding  2-3  mm  will  be  required  to  define  gross 
 tumour volumes. 
 c.  Administration IV contrast increases the diagnostic accuracy of CT. 
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 d.  The MRI planning and treatment-planning CT should be fused. 
 5.  Target volumes: 
 a.  GTV  will  be  delineated  on  axial  T1-weighted  gadolinium-enhanced  MRI.  Areas 
 of edema will not be considered part of the target volume. 
 b.  PTV will be defined as expanding GTV 1-2 mm. 
 6.  Treatment Planning: 
 a.  Treatments  must  be  delivered  with  Intensity-Modulated  RT.  Acceptable  IMRT 
 modalities  include  helical  tomotherapy  or  LINAC-based  IMRT  involving  static 
 gantry  angles  or  volumetric  arc  therapy  (VMAT).  It  is  also  possible  to  use 
 Gamma Knife. 
 7.  Dose Specification: 
 a.  The  Dose  will  be  prescribed  to  the  isodose  surface  (50-90%  [maximum  = 
 100%]),  which  encompasses  the  target,  to  ensure  at  least  95%  coverage  of 
 the  PTV  with  the  prescription  dose.  The  100%  (maximum)  dose  and  minimum 
 dose will be recorded for each patient. 
 b.  Three  isodose  lines  should  be  submitted:  the  prescription  isodose  line,  90%  of 
 the  prescription  isodose  line  (not  90%  of  total  dose)  and  80%  of  the 
 prescription isodose line. 
 ●  Acceptable variation: 80% isodose line covers the target 
 ●  Unacceptable deviation: 80% isodose line does not cover target 
 c.  Dose  Homogeneity  QA:  The  ratio  of  the  maximum  dose  to  the  prescribed  dose 
 (MD/PD) will be: 
 ●  Per protocol if <2 
 ●  Acceptable variation if >2 but <2.5 
 ●  Unacceptable deviation if >2.5 
 d.  Dose  Conformity  QA:  The  ratio  of  prescription  isodose  volume  to  the  target 
 volume (PI/TV) is: 
 ●  Per protocol if between 1.0 and 2.0 
 ●  Acceptable variation if >0.9 but <1.0 or >2.0 but <3.5 
 ●  Unacceptable deviation if >3.5 
 8.  Critical Structures: 
 a.  The lenses, orbits, optic nerves, optic chiasm and brain, will be contoured. 
 b.  There  are  no  clear  dose  limits  established  for  organs  at  risk  for  SR  or  HBRT. 
 Gerard et al. has just published a recent compilation about dose-constraints. 
 9.  Documentation: 
 a.  For  all  forms  of  dose  delivery,  immediately  before  treatment,  images  that 
 localize  the  isocenter  placement  shall  be  obtained,  with  appropriate 
 adjustment  to  ensure  a  translational  position  deviation  less  than  1  mm  in  any 
 direction and minimal rotational deviation. 
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 7.2. 
 Dose modifications 
 Patients  will  be  monitored  for  adverse  events  at  each  visit  with  the  NCI  CTCAE  version  4.03  used 
 for  all  grading.  If  a  patient  develops  a  toxicity,  the  dose  may  be  adjusted  as  outlined  in  Table  8-9 
 and  Table  10,  which  include  criteria  for  interruption  and  re-initiation  of  encorafenib  and  binimetinib. 
 All  dose  modifications  should  be  based  on  the  worst  preceding  toxicity  (CTCAE  version  4.03).  All 
 dosing  interruptions  and  changes  must  be  recorded  on  the  Dosage  Administration  Record  at 
 eCRF. 
 Eye disorders should be graded according to CTCAE version 4.03 as described below in Table 3. 
 Table 3. CTCAE grading for eye disorders 
 Grade 
 Description 
 1 
 Asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated; 
 no change in vision 
 2 
 Moderate; minimal, local or non-invasive intervention indicated; limiting instrumental ADL; best 
 corrected visual acuity 20/40 and better or 3 lines or less decreased vision from known baseline 
 3 
 Severe or medically significant but not immediately sight threatening; limiting self-care ADL; decrease 
 in visual acuity (best corrected visual acuity worse than 20/40 or more than 3 lines of decreased vision 
 from known baseline, up to 20/200) 
 4 
 Sight-threatening consequences; urgent intervention indicated; best corrected visual acuity of 20/200 
 or worse in the affected eye 
 ADL = Activities of Daily Living 
 Retinal  detachment  should  be  graded  according  to  the  CTCAE  version  4.03  as  described  below  in 
 Table 4. 
 Table 4. CTCAE grading for retinal detachment 
 Grade 
 Description 
 1 
 - 
 2 
 Exudative and visual acuity 20/40 or better 
 3 
 Rhegmatogenous or exudative detachment; operative intervention indicated; decline in vision (worse 
 than 20/40 but better than 20/200 
 4 
 Blindness (20/200 or worse) in the affected eye 
 Definition: A disorder characterized by the separation of the inner retina layers from the underlying pigment epithelium. 
 Uveitis should be graded according to the CTCAE version 4.03 as described below in Table 5 
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 Table 5. CTCAE grading for uveitis 
 Grade 
 Description 
 1 
 Anterior uveitis with trace cells 
 2 
 Anterior uveitis with 1+ or 2+ cells 
 3 
 Anterior uveitis with 3+ or greater cells; intermediate posterior or panuveitis 
 4 
 Best corrected visual acuity of 20/200 or worse in the affected eye 
 Definition: A disorder characterized by inflammation to the uvea of the eye. 
 Palmar-plantar  erythrodysesthesia  syndrome  should  be  graded  according  to  the  CTCAE  version 
 4.03 as described below in Table 6. 
 Table 6. CTCAE grading for Palmar-plantar erythrodysesthesia syndrome 
 Grade 
 Description 
 1 
 Minimal skin changes or dermatitis (e.g., erythema, edema, or hyperkeratosis) without pain 
 2 
 Skin changes (e.g., peeling, blisters, bleeding, fissures, edema, or hyperkeratosis) with pain; limiting 
 instrumental ADL 
 3 
 Severe skin changes (e.g., peeling, blisters, bleeding, fissures, edema, or hyperkeratosis) with pain; 
 limiting self-care ADL 
 4 
 - 
 Definition: A disorder characterized by redness, marked discomfort, swelling, and tingling in the palms of the hands or 
 the soles of the feet. Also known as Hand-Foot Syndrome. 
 Diarrhea should be graded according to CTCAE version 4.03 as described below in Table 7. 
 Table 7. CTCAE grading for Diarrhea 
 Grade 
 Description 
 1 
 Increase of <4 stools per day over baseline; mild increase in ostomy output compared to baseline 
 2 
 Increase of 4 - 6 stools per day over baseline; moderate increase in ostomy output compared to 
 baseline; limiting instrumental ADL 
 3 
 Increase of >=7 stools per day over baseline; hospitalization indicated; severe increase in ostomy 
 output compared to baseline; limiting self-care ADL 
 4 
 Life-threatening consequences; urgent intervention indicated 
 5 
 Death 
 Definition: A disorder characterized by an increase in frequency and/or loose or watery bowel movements. 
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 7.2.1.  Dose  modification  and  dose  delay  for  encorafenib  (as  monotherapy)  and  combination 
 (encorafenib and binimetinib) 
 For  patients  who  do  not  tolerate  encorafenib  and/or  binimetinib  initial  dosing  schedule,  dose 
 adjustment  is  permitted  to  allow  the  patient  to  continue  study  drug  (see  Table  8  for  encorafenib  and 
 Table 9 for binimetinib). 
 A  dose  reduction  below  100  mg  QD  for  encorafenib  and  below  30  mg  BID  for  binimetinib  is  not 
 allowed.  Dose  interruptions  of  more  than  28  consecutive  days  are  not  allowed  unless  approved  by 
 the Sponsor ( investigacion@mfar.net ). 
 Table 8. Dose reduction for encorafenib 
 Dose reduction based on the highest AE grade 
 Dose level 
 Encorafenib* 
 0 (starting dose) 
 450 mg QD (6 capsules of 75 mg) 
 -1 (monotherapy dose) 
 300 mg QD** (4 capsules of 75 mg) 
 -2 
 200 mg QD (2 capsules of 75 mg and 1 capsule of 
 50 mg) 
 -3 
 100 mg QD*** (2 capsules of 50 mg) 
 *If binimetinib is permanently discontinued, encorafenib should be discontinued 
 **The  maximum  dose  of  encorafenib  if  it  is  administered  as  monotherapy  while 
 binimetinib is temporarily interrupted 
 ***Dose reduction below 100 mg is not allowed 
 Table 9. Dose reduction for binimetinib 
 Dose reduction based on the highest AE grade 
 Dose level 
 Binimetinib 
 0 (starting dose) 
 45 mg BID (3 pills of 15 mg) 
 -1 
 30 mg BID* (2 pills of 15 mg) 
 *Dose reduction below 30 mg is not allowed 
 Doses  of  binimetinib  that  are  omitted  for  any  reason  should  not  be  made  up  later  if  it  is  less  than 
 6 hours  until  the  next  dose  is  due.  Doses  of  encorafenib  that  are  omitted  for  any  reason  can  be 
 taken  up  to  12  hours  prior  to  the  next  dose.  For  both  encorafenib  and  binimetinib,  when  the  toxicity 
 that  resulted  in  a  dose  reduction  improves  to  Grade  1  or  less,  the  dose  should  be  re-escalated  at 
 the investigators discretion provided there are no other concomitant toxicities. 
 If  binimetinib  is  dose  reduced  due  to  left  ventricular  dysfunction,  prolonged  QTcF  >  500  msec  or 
 any  grade  4  toxicity  related  to  the  drug,  no  dose  re-escalation  is  allowed.  If  encorafenib  is  dose 
 reduced  due  to  prolonged  QTcF  >  500  msec  or  any  grade  4  toxicity  related  to  the  drug,  no  dose 
 re-escalation  is  allowed.  Dose  reduction/interruption/discontinuation  decisions  should  be  based  on 
 the  CTCAE  grade  of  the  toxicity  and  the  guidelines  provided  below  (Table  8).  In  general,  doses 
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 should  not  be  reduced  or  interrupted  for  Grade  1  toxicities,  but  treatment  to  control  symptoms 
 should  be  provided  as  appropriate.  All  AEs  should  be  followed  weekly  or  as  clinically  appropriate 
 until stabilization or resolution. 
 If  a  patient  temporarily  interrupts  treatment  with  binimetinib,  the  patient  must  continue  treatment 
 reducing  encorafenib  at  dose  of  300  mg  QD,  if  patient  was  receiving  450  mg  QD  of  encorafenib  in 
 combination  with  binimetinib  (see  Table  8  for  encorafenib  dose  reductions).  However,  if  a  patient 
 discontinues  treatment  with  encorafenib,  they  must  discontinue  treatment  with  binimetinib, 
 complete  the  end  of  treatment  visit  and  continue  to  be  followed  until  disease  progression.  Please 
 refer  to  table  10  for  dose  adjustment  recommendations  for  encorafenib  and/or  binimetinib  induced 
 toxicities. 
 Table  10.  Encorafenib  and  binimetinib  –  Recommended  dose  modifications  associated  with 
 treatment-related adverse events 
 Worst toxicity CTCAE v 4.03 Grade 
 (unless otherwise specified) 
 Dose adjustments of both drugs 
 Cutaneous reactions 
 Encorafenib 
 Binimetinib 
 Grade 2 
 Encorafenib and binimetinib should be maintained. 
 If  rash  worsens  or  does  not  improve  within  2  weeks  with  treatment, 
 encorafenib  and  binimetinib  should  be  withheld  until  being  Grade  0  or  1 
 toxicity. Then: 
 ● 
 If  it  is  the  first  occurrence  of  Grade  2,  both  drugs  can  be  resumed 
 at the same dose. 
 ● 
 If  it  is  a  recurrent  Grade  2  toxicity,  both  drugs  should  be  resumed 
 at a reduced dose. 
 Grade 3 
 Encorafenib  and  binimetinib  should  be  withheld  until  improvement  to 
 Grade 0 or 1 toxicity. Then: 
 ● 
 If  it  is  the  first  occurrence  of  Grade  3,  both  drugs  can  be  resumed 
 at the same dose. 
 ● 
 If  it  is  a  recurrent  Grade  3  toxicity,  both  drugs  should  be  resumed 
 at a reduced dose. 
 Grade 4 
 Encorafenib and binimetinib should be permanently discontinued. 
 Squamous  Cell  Carcinoma  (SCC), 
 Keratoacanthoma  (KA)  or  any  other 
 suspicious skin lesion 
 Encorafenib 
 Binimetinib 
 Grade 3-4 
 Encorafenib  and  binimetinib  should  be  maintained  at  same  dose  and  local 
 treatment  of  lesion  (e.g.  new  primary  melanoma)  should  be  done  based 
 upon institutional practice. 
 Palmar-plantar 
 erythrodysaesthesia 
 syndrome (PPES) 
 Encorafenib 
 Binimetinib 
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 Grade 2 
 Encorafenib  and  binimetinib  should  be  maintained  and  supportive 
 measures such as topical therapy should be instituted. 
 If  not  improvement  despite  supportive  therapy  within  2 weeks,  encorafenib 
 and  binimetinib  should  be  withheld  until  improvement  to  Grade 0  or  1 
 toxicity.  Then,  treatment  should  be  resumed  at  the  same  dose  level  or  at  a 
 reduced dose of encorafenib. 
 Grade 3 
 Encorafenib  and  binimetinib  should  be  withheld,  supportive  measures  such 
 as  topical  therapy  should  be  instituted,  and  patients  should  be  reassessed 
 weekly  until  improvement  to  Grade 0  or  1  toxicity.  Then,  treatment  should 
 be resumed at the same dose level or at a reduced dose of encorafenib. 
 Liver laboratory abnormalities 
 Encorafenib 
 Binimetinib 
 Grade 2 
 Aspartate 
 aminotransferase 
 (AST) 
 or 
 Alanine 
 aminotransferase 
 (ALT)  >3x  -  ≤5x  upper 
 limit of normal (ULN) 
 Encorafenib and binimetinib should be maintained. 
 If  no  improvement  within  2 weeks,  binimetinib  should  be  withheld  until 
 improved  to  Grade 0 or 1  or  to  baseline  levels.  At  same  time,  encorafenib 
 should  be  reduced  to  300mg  QD  if  the  patient  was  receiving  450mg  of 
 encorafenib QD with binimetinib. 
 If  no  improvement  within  4 weeks,  encorafenib  should  be  withheld  until 
 improved to Grade 0 or 1 or to baseline levels. 
 Then, both drugs should be resumed at the same dose. 
 Grade 3, first 
 occurrence 
 AST  or  ALT  >5x  ULN  + 
 blood bilirubin >2x ULN 
 Encorafenib and binimetinib should be withheld for up to 4 weeks. 
 ● 
 If  toxicity  improves  to  Grade 0  or  1  or  to  baseline  levels,  both 
 drugs should be resumed at a reduced dose. 
 ● 
 If  toxicity  doesn’t  improve  both  drugs  should  be  permanently 
 discontinued. 
 Grade 3, 
 recurrent 
 It  should  be  considered  to  permanently  discontinue  encorafenib  and 
 binimetinib. 
 Grade 4, first 
 occurrence 
 AST or ALT >20x ULN 
 Encorafenib and binimetinib should be withheld for up to 4 weeks. 
 ● 
 If  toxicity  improves  to  Grade 0  or  1  or  to  baseline  levels,  both 
 drugs should be resumed at a reduced dose level. 
 ● 
 If  toxicity  doesn’t  improve  both  drugs  should  be  permanently 
 discontinued. 
 Or, encorafenib and binimetinib should be permanently discontinued. 
 Grade 4, 
 recurrent 
 Encorafenib and binimetinib should be permanently discontinued. 
 QTc prolongation 
 Encorafenib 
 Binimetinib 
 QTcF  >  500  ms  and  has  changed  ≤60 
 ms from pre-treatment value 
 Encorafenib  and  binimetinib  should  be  withheld  and  all  abnormal 
 electrolytes and risk factors had to be controlled. 
 When  QTcF  is  ≤500 ms,  encorafenib  and  binimetinib  should  be  resumed  at 
 a reduced dose of encorafenib. 
 Encorafenib  and  binimetinib  should  be  discontinued  if  more  than  one 
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 recurrence happens. 
 QTcF  >  500  ms  and  has  changed  >60 
 ms from pre-treatment value 
 Encorafenib  and  binimetinib  should  be  permanently  discontinued  and  all 
 abnormal electrolytes and risk factors had to be controlled. 
 Left 
 ventricular 
 ejection 
 fraction 
 (LVEF) decrease 
 Encorafenib 
 Binimetinib 
 Grade 2 
 Asymptomatic 
 and 
 an 
 absolute 
 decrease 
 >10% 
 from  baseline,  that  is 
 below  the  lower  limit 
 of normal (LLN) 
 See table 8. 
 If  a  patient  temporarily  interrupts 
 (withheld) 
 treatment 
 with 
 binimetinib, 
 the  patient  may 
 continue 
 treatment 
 with 
 encorafenib  as  monotherapy  at 
 a maximum dose of 300 mg QD. 
 Binimetinib  should  be  withheld  for  up  to 
 4 
 weeks 
 and 
 LVEF 
 should 
 be 
 evaluated every 2 weeks. 
 Binimetinib  should  be  resumed  at  a 
 reduced  dose  if  all  the  following  are 
 present within 4 weeks: 
 - 
 LVEF is at or above the LLN 
 - 
 Absolute 
 decrease 
 from 
 baseline is ≤ 10%. 
 If  the  LVEF  does  not  recover  within 
 4 weeks,  binimetinib  and  encorafenib 
 should be permanently discontinued. 
 Grade 3 or 4 
 Symptomatic 
 left 
 ventricular 
 dysfunction (LVD) 
 See  table  8. 
 If  binimetinib  is 
 permanently 
 discontinued, 
 encorafenib 
 should 
 be 
 discontinued 
 Binimetinib  should  be  permanently 
 discontinued  and  LVEF  should  be 
 evaluated 
 every 
 2 
 weeks 
 until 
 recovery. 
 Hypertension 
 Encorafenib 
 Binimetinib 
 Severe  and  uncontrolled  despite  specific 
 treatment 
 See 
 table 
 8. 
 If 
 a 
 patient 
 temporarily  interrupts  (withheld) 
 treatment  with  binimetinib,  the 
 patient  may  continue  treatment 
 with 
 encorafenib 
 as 
 monotherapy  at  a  maximum 
 dose of 300 mg QD. 
 Binimetinib  should  be  withheld  until 
 hypertension  is  controlled.  Then,  follow 
 indications  of  dose  adjustments  for 
 other adverse reactions. 
 Venous thromboembolism (VTE) 
 Encorafenib 
 Binimetinib 
 Uncomplicated deep vein thrombosis 
 (DVT) or pulmonary embolism (PE) ≤ 
 grade 3 
 See 
 table 
 8. 
 If 
 a 
 patient 
 temporarily  interrupts  (withheld) 
 treatment  with  binimetinib,  the 
 patient  may  continue  treatment 
 with 
 encorafenib 
 as 
 monotherapy  at  a  maximum 
 dose of 300 mg QD. 
 Binimetinib  should  be  withheld  for  up  to 
 4 weeks. 
 ●  If 
 improved 
 to 
 Grade 0 or 1, 
 binimetinib  should  be  resumed  at 
 reduced dose. 
 ●  If  it  is  not  improved  within 
 4 weeks,  binimetinib  should  be 
 permanently discontinued. 
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 Grade 4 pulmonary embolism 
 See  table  8.  If  binimetinib  is 
 permanently 
 discontinued, 
 encorafenib 
 should 
 be 
 discontinued. 
 Binimetinib  should  be  permanently 
 discontinued. 
 Interstitial 
 lung 
 disease 
 (ILD)/Pneumonitis 
 Encorafenib 
 Binimetinib 
 Grade 2 
 See 
 table 
 8. 
 If 
 a 
 patient 
 temporarily  interrupts  (withheld) 
 treatment  with  binimetinib,  the 
 patient  may  continue  treatment 
 with 
 encorafenib 
 as 
 monotherapy  at  a  maximum 
 dose of 300 mg QD. 
 Binimetinib  should  be  withheld  for  up  to 
 4 weeks. 
 ●  If 
 improved 
 to 
 Grade 0 or 1, 
 binimetinib  should  be  resumed  at 
 reduced dose. 
 ●  If 
 it 
 is  not  resolved  within 
 4 weeks,  binimetinib  should  be 
 permanently discontinued. 
 Grade 3 or 4 
 See  table  8.  If  binimetinib  is 
 permanently 
 discontinued, 
 encorafenib 
 should 
 be 
 discontinued. 
 Binimetinib  should  be  permanently 
 discontinued. 
 Diarrhea 
 Encorafenib 
 Binimetinib 
 Grade 1-2 
 Uncomplicated 
 See 
 table 
 8. 
 If 
 a 
 patient 
 temporarily  interrupts  (withheld) 
 treatment  with  binimetinib,  the 
 patient  may  continue  treatment 
 with 
 encorafenib 
 as 
 monotherapy  at  a  maximum 
 dose of 300 mg QD. 
 Binimetinib should be withheld for up to 
 4 weeks. 
 ● 
 If improved to Grade 0 or 1, 
 binimetinib should be 
 resumed at same dose. 
 Complicated 
 Encorafenib should be withheld 
 for up to 4 weeks. 
 ● 
 If improved to Grade 0 
 or 1, encorafenib 
 should be resumed at 
 same dose. 
 Binimetinib should be withheld for up to 
 4 weeks. 
 ● 
 If improved to Grade 0 or 1, 
 binimetinib should be 
 resumed at reduced dose. 
 Grade 3-4 
 Encorafenib should be withheld 
 for up to 4 weeks. 
 ● 
 If improved to Grade 0 
 or 1, encorafenib 
 should be resumed at 
 same dose, if in the 
 judgment of the 
 investigator the toxicity 
 is unrelated to 
 encorafenib, or at one 
 reduced dose. 
 Binimetinib should be withheld for up to 
 4 weeks. 
 ● 
 If improved to Grade 0 or 1, 
 binimetinib should be 
 resumed at reduced dose. 
 Nausea/Vomiting 
 Encorafenib 
 Binimetinib 
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 Grade 1-2 
 Treatment  with  encorafenib  and  binimetinib  should  be  maintained  at  the 
 current dose. Promptly institute antiemetic measures. 
 Grade 3 
 Encorafenib  should  be  withheld 
 for up to 4 weeks. 
 ● 
 If  improved  to  Grade  0 
 or 
 1, 
 encorafenib 
 should  be  resumed  at 
 reduced dose. 
 Binimetinib should be withheld for up to 
 4 weeks. 
 ● 
 If  improved  to  Grade 0 or 1, 
 binimetinib 
 should 
 be 
 resumed  at  the  same  dose  if, 
 in 
 the 
 judgment 
 of 
 the 
 investigator,  the  toxicity  is 
 unrelated  to  binimetinib,  or  at 
 one reduced dose. 
 Grade 4 
 Encorafenib and/or binimetinib should be permanently discontinued. 
 Note:  Interrupt  dose  for  ≥  grade  3  vomiting  or  grade  3  nausea  only  if  the  vomiting  or  nausea  cannot  be 
 controlled with optimal antiemetics (as per local practice). 
 Rhabdomyolysis/Creatine 
 phosphokinase (CK) increase 
 Encorafenib 
 Binimetinib 
 Asymptomatic 
 grade 3 
 CK >5 – 10x ULN 
 Encorafenib  and  binimetinib  should  be  maintained  and  it  should  be 
 ensured that the patient has an adequate hydration. 
 Asymptomatic 
 grade 4 
 CK >10x ULN 
 See 
 table 
 8. 
 If 
 a 
 patient 
 temporarily  interrupts  (withheld) 
 treatment  with  binimetinib,  the 
 patient  may  continue  treatment 
 with 
 encorafenib 
 as 
 monotherapy  at  a  maximum 
 dose of 300 mg QD. 
 Binimetinib  should  be  withheld  until 
 improved  to  Grade  0  or  1,  moreover, 
 an  adequate  hydration  of  the  patient 
 should be ensured. 
 Grade  3  or  4  with  renal  impairment  or 
 muscle symptoms 
 See 
 table 
 8. 
 If 
 a 
 patient 
 temporarily  interrupts  (withheld) 
 treatment  with  binimetinib,  the 
 patient  may  continue  treatment 
 with 
 encorafenib 
 as 
 monotherapy  at  a  maximum 
 dose of 300 mg QD 
 Binimetinib  should  be  withheld  until 
 improved  to  Grade  0  or  1,  moreover, 
 an  adequate  hydration  of  the  patient 
 should be ensured. 
 If  resolved  within  4  weeks,  binimetinib 
 should  be  resumed  at  reduced  dose  or 
 permanently discontinued. 
 Retinal pigment epithelial 
 detachment (RPED)  a 
 Encorafenib 
 Binimetinib 
 Grade 2 
 Symptomatic 
 See 
 table 
 8. 
 If 
 a 
 patient 
 temporarily  interrupts  (withheld) 
 treatment  with  binimetinib,  the 
 patient  may  continue  treatment 
 with 
 encorafenib 
 as 
 monotherapy  at  a  maximum 
 Binimetinib  should  be  withheld  for  up  to 
 2 weeks  and  ophthalmic  monitoring 
 should  be  repeated  including  visual 
 acuity assessment. 
 ●  If 
 improved 
 to 
 Grade 0 or 1, 
 GEM 1802 - Protocol version 5.0, 4. JUL. 2022 
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 dose of 300 mg QD 
 binimetinib  should  be  resumed  at 
 the same dose. 
 ●  If  not  improved  to  Grade 0  or  1, 
 binimetinib  should  be  resumed  at 
 a lower dose. 
 Grade 3 
 Symptomatic 
 See 
 table 
 8. 
 If 
 a 
 patient 
 temporarily  interrupts  (withheld) 
 treatment  with  binimetinib,  the 
 patient  may  continue  treatment 
 with 
 encorafenib 
 as 
 monotherapy  at  a  maximum 
 dose of 300 mg QD 
 Binimetinib  should  be  withheld  for  up  to 
 2 weeks  and  ophthalmic  monitoring 
 should  be  repeated  including  visual 
 acuity assessment. 
 ●  If 
 improved 
 to 
 Grade 0 or 1, 
 binimetinib  should  be  resumed  at 
 same dose. 
 ●  If 
 improved 
 to 
 Grade 2, 
 binimetinib  should  be  resumed  at 
 a lower dose. 
 If  not  improved  to  Grade 2,  binimetinib 
 should be permanently discontinued. 
 Grade 4 
 Symptomatic 
 with 
 reduced visual acuity 
 See  table  8.  If  binimetinib  is 
 permanently 
 discontinued, 
 encorafenib 
 should 
 be 
 discontinued 
 Binimetinib  should  be  permanently 
 discontinued. 
 Retinal vein occlusion (RVO)  a 
 Encorafenib 
 Binimetinib 
 Any grade 
 See  table  8.  If  binimetinib  is 
 permanently 
 discontinued, 
 encorafenib 
 should 
 be 
 discontinued 
 Binimetinib  should  be  permanently 
 discontinued. 
 Uveitis, iritis and/or iridocyclitis  a 
 Encorafenib 
 Binimetinib 
 Grade 1 or 2 
 Initiate specific ocular therapy (e.g. topical). 
 If  Grade 1  or  2  uveitis  does  not  respond  to  specific  ocular  therapy, 
 encorafenib  and  binimetinib  should  be  withheld  and  ophthalmic  monitoring 
 should be repeated within 2 weeks. 
 ● 
 If  Grade 1  and  improves  to  Grade 0,  then  treatment  should  be 
 resumed at the same dose. 
 ● 
 If  Grade 2  improves  to  Grade 0  or  1,  then  treatment  should  be 
 resumed at a reduced dose. 
 Grade 3 
 Encorafenib  and  binimetinib  should  be  withheld  and  ophthalmic  monitoring 
 should be repeated within 2 weeks. 
 ● 
 If  Grade 3  improves  to  Grade 0  or  1,  then  treatment  should  be 
 resumed at a reduced dose. 
 If  not  improved  within  6  weeks,  encorafenib  and  binimetinib  should  be 
 permanently  discontinued  and  an  ophthalmologic  monitoring  should  be 
 performed until resolution. 
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 Grade 4 
 Encorafenib  and  binimetinib  should  be  permanently  discontinued  and  an 
 ophthalmologic monitoring should be performed until resolution. 
 a  NOTE:  Any  visual  acuity  impairment  at  screening  should  be  documented  and  should  be  considered  as 
 baseline 
 Other adverse reactions 
 Encorafenib 
 Binimetinib 
 Recurrent or intolerable Grade 2 
 or 
 First occurrence Grade 3 
 Encorafenib  and/or  binimetinib  should  be  withheld  for  up  to  4 weeks  (see 
 table  8  to  adjust  encorafenib  dose  as  monotherapy  if  it  was  not 
 interrupted). 
 ● 
 If  improved  to  Grade 0  or  1  or  to  baseline  levels,  then,  encorafenib 
 and/or binimetinib should be resumed at a reduced dose. 
 If  not  improved,  encorafenib  and/or  binimetinib  should  be  permanently 
 discontinued. 
 Recurrent Grade 3 
 It  should  be  considered  to  permanently  discontinue  encorafenib  and 
 binimetinib. 
 First occurrence Grade 4 
 Encorafenib  and/or  binimetinib  should  be  withheld  for  up  to  4 weeks  (see 
 table  8  to  adjust  encorafenib  dose  as  monotherapy  if  it  was  not  interrupted 
 too). 
 ● 
 If  improved  to  Grade 0  or  1  or  to  baseline  levels,  then  encorafenib 
 and/or binimetinib should be resumed at a reduced dose level. 
 ● 
 If  not  improved,  encorafenib  and  binimetinib  should  be  permanently 
 discontinued. 
 Or, encorafenib and/or binimetinib should be permanently discontinued. 
 Recurrent Grade 4 
 Encorafenib and binimetinib should be permanently discontinued. 
 7.2.2. Follow-up for toxicities 
 Patients  whose  treatment  is  interrupted  or  permanently  discontinued  due  to  an  adverse  event  or 
 clinically  significant  laboratory  value,  must  be  followed  up  at  least  once  a  week  (or  more  frequently 
 if  required  by  institutional  practices,  or  if  clinically  indicated)  for  4  weeks,  and  subsequently  at 
 approximately 4-week intervals, until resolution or stabilization of the event, whichever comes first. 
 Appropriate  clinical  experts  such  as  an  Ophthalmologist,  cardiologist  or  dermatologist  should  be 
 consulted  as  deemed  necessary.  Further  guidelines  and  recommendations  for  the  management  of 
 specific study drug Combination induced toxicities are provided in table 10. 
 7.2.2.1. Management of hand foot skin reaction (HFSR) 
 Because  HFSR  has  been  reported  for  encorafenib,  it  is  recommended  that  patients  are  educated 
 prior  to  starting  study  treatment  to  avoid  activities  that  can  cause  friction  on  hands  and  feet.  In 
 addition, supportive measures for prevention and/or management of HFSR should be instituted. 
 Clinical  judgment  and  experience  of  the  treating  physician  should  guide  the  management  plan  of 
 each patient. 
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 Dose  reduction/interruption/discontinuation  decisions  for  HFSR  should  be  based  on  the  CTCAE 
 grade  of  the  toxicity  (Section  6.4)  and  the  guidelines  provided  in  table  10.  A  visit  at  a  podiatrist  may 
 also be recommended at the discretion of the investigator. 
 7.2.2.2.  Follow  up  evaluations  for  appearance  of  keratoacanthoma  (KA)  and/or  squamous  cell 
 carcinoma (SCC) 
 The  skin  of  patients  will  be  examined  regularly  to  monitor  for  the  possible  development  of  KA 
 and/or  SCC,  as  these  have  been  reported  to  occur  under  selective  BRAF  inhibitor  treatment 
 (Flaherty  et  al  2010;  Kefford  et  al  2010;  Robert  et  al  2011).  Patients  should  be  instructed  to  inform 
 their  physicians  upon  the  occurrence  of  any  skin  changes.  In  case  of  occurrence  of  KA  and/or 
 SCC, treatment of these lesions will follow institutional standards. 
 7.2.2.3. Management of nausea and/or vomiting 
 Because  nausea  and  vomiting  have  been  reported  for  encorafenib  and  binimetinib,  it  is 
 recommended  that  patients  are  educated  on  the  possibility  of  occurrence  of  these  side  effects  prior 
 to  starting  study  treatment.  Patient  education  as  well  as  proper  management  of  nausea  and/or 
 vomiting  at  the  first  sign  is  important.  Clinical  judgment  and  experience  of  the  treating  physician 
 should  guide  the  management  plan  of  each  patient.  Patients  experiencing  nausea  and/or  vomiting 
 CTCAE  ≥1  will  receive  antiemetics  at  the  discretion  of  the  treating  physician  (as  per  local 
 guideline).  It  is  recommended  that  patients  be  provided  a  prescription  for  antiemetics  and  are 
 instructed  on  the  use  of  antiemetics  on  the  first  day  of  study  drug  treatment.  Prophylactic 
 antiemetics  such  as  dexamethasone  8  mg,  prochlorperazine,  or  metoclopramide  may  be 
 administered to patients on an "as needed" basis. 
 Dose  interruption/reduction  decisions  for  nausea  and/or  vomiting  should  be  based  on  the  CTCAE 
 grade of the toxicity and the guidelines provided in table 10. 
 As  a  guidance  for  recommendations  on  supportive  measures  for  the  prevention  and/or 
 management  of  nausea  and/or  vomiting,  the  published  recommendation  from  American  Society  of 
 Clinical  Oncology  (ASCO)  57  ,  the  European  society  of  Medical  Oncology  (ESMO)  and  Multinational 
 Association of supportive Care (MASCC)  58  can be used. 
 7.2.2.4 Monitoring of blood pressure 
 All  patients  must  monitor  their  blood  pressure  at  home  at  Days  14  and  42  after  randomization  if 
 they meet at least one of the following criteria: 
 ●  Patients with history of hypertension and/or 
 ●  Patients receiving antihypertensive drugs before onset of study treatment and/or 
 ●  Patients with a screening systolic blood pressure of ≥140 mmHg and/or 
 ●  Patients with a screening diastolic blood pressure of ≥90 mmHg. 
 The  investigator  is  to  educate  the  patient  on  the  signs  and  symptoms  of  hypertension  and  to 
 evaluate  the  tension  after  taking  any  hypertensive  drug  and  resting  for  5  minutes  in  a  sitting 
 position  if  they  use  a  home  blood  pressure  monitor.  More  frequent  assessments  during  the  study 
 drug  treatment  period  may  also  be  performed  at  the  discretion  of  the  investigator  and  if  medically 
 indicated. 
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 Measurements  are  to  be  taken  at  the  same  time  in  the  morning  on  Study  Days  14  and  42,  after 
 taking  any  hypertensive  medications  and  after  being  at  rest  for  5  minutes  in  a  sitting  position.  If 
 SBP  ≥160  mmHg,  or  DBP  ≥  100  mmHg,  the  patient  should  contact  his/her  investigator  to  have  an 
 unscheduled  visit.  At  this  unscheduled  visit,  the  patient’s  blood  pressure  should  be  assessed,  and 
 these  measurements  must  be  documented  in  the  eCRF  page.  Early  initiation  of  treatment  and 
 aggressive management of emergent hypertension must be implemented after its diagnosis. 
 A  diary  will  be  provided  for  the  patients  to  record  their  self-assessed  blood  pressure  measurements 
 and  present  the  collected  data  to  the  investigator  for  evaluation  and  appropriate  management.  This 
 diary must be maintained in the patient’s source documentation. 
 7.3. 
 Concomitant Medications 
 All  concomitant  medications  taken  by  the  subject  during  the  trial,  starting  from  the  date  of  signature 
 of  informed  consent,  will  be  recorded.  The  indication,  dose,  frequency,  and  dates  of  treatment  will 
 be recorded in the patient’s medical records and in the appropriate section of the eCRF. 
 All  medications  (prescriptions  or  over-the-counter  medications)  on-going  at  the  start  of  the  trial  or 
 started  during  the  study  or  until  30  days  from  the  end  of  the  last  protocol  treatment  and  different 
 from the study medication will be documented. 
 7.3.1. 
 Permitted concomitant treatment 
 The  patient  must  notify  the  investigational  site  about  any  new  medications  he/she  takes  after  the 
 start  of  the  study  drug.  All  medications  (other  than  study  drug)  and  significant  non-drug  therapies 
 (including  physical  therapy,  herbal/natural  medications  and  blood  transfusions)  administered  during 
 the  study  must  be  listed  on  the  Concomitant  Medications  or  the  Surgical  and  Medical  Procedures 
 eCRF.  Patients  taking  concomitant  medications  chronically  should  maintain  the  same  dose  and 
 dose schedule throughout the study if medically feasible. 
 Any  medications  that  are  considered  necessary  to  protect  subject  welfare  and  will  not  interfere  with 
 the trial medication may be given at the Investigator’s discretion. 
 Rescue  medications  may  be  administered  to  address  anticipated  adverse  reactions  or  anticipated 
 emergency situations. 
 7.3.2. 
 Permitted concomitant therapy requiring caution and/or action 
 Encorafenib  is  a  reversible  inhibitor  of  CYP2B6,  CYP2C9,  CYP3A4  and  UGT1A1.  It  is  also  a  time 
 dependent  inhibitor  of  CYP3A4.  Binimetinib  is  also  a  reversible  inhibitor  of  CYP2B6.  Permitted 
 medications  to  be  used  with  caution  in  this  study  include  those  that  are  sensitive  substrates  of 
 CYP2B6,  CYP2C9,  CYP3A4,  and  UGT1A1  or  those  substrates  that  have  a  narrow  therapeutic 
 index  (NTI).  Substrates  of  CYP3A4  are  allowed  based  on  a  lack  of  interaction  with  midazolam. 
 There  is  a  potential  for  encorafenib  to  induce  CYP3A4  at  concentrations  >10-50  uM,  which  may 
 reduce  the  effectiveness  of  hormonal  contraception  methods.  Therefore,  the  use  of  at  least  one 
 form  of  non-hormonal  contraception  will  be  needed  during  the  participation  in  this  study.  Please 
 see  Section  6.2  exclusion  criterion  18  for  use  of  contraception  methods  required  for  this  study. 
 Caution  should  be  used  in  patients  receiving  concomitant  treatment  with  other  drugs  that  are 
 substrates  of  CYP3A4  as  the  efficacy  of  these  drugs  could  be  reduced  when  administered  with 
 encorafenib. 
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 Encorafenib  has  been  identified  to  be  primarily  metabolized  by  CYP3A4  and  to  a  lesser  extent  by 
 CYP2C19  in  vitro.  The  use  of  strong  inhibitors  of  CYP3A4  are  prohibited,  please  see  section 
 below.  Moderate  inhibitors  of  CYP3A4  and  strong  inhibitors  of  CYP2C19  should  be  taken  with 
 caution  when  co-administered  with  encorafenib.  Patients  should  be  closely  monitored  for  the 
 occurrence  of  adverse  events.  Regular  assessments  will  be  performed  as  described  in  Table  11.  If 
 a  patient  develops  a  toxicity,  encorafenib  dose  may  be  adjusted  as  outlined  in  the  dose 
 modification Table 8. 
 Binimetinib  has  been  identified  to  be  primarily  metabolized  by  glucuronidation.  It  is  advised  that 
 strong  inhibitors  of  UGT1A1  should  be  taken  with  caution  when  co-administered  with  binimetinib. 
 Patients  should  be  closely  monitored  for  the  occurrence  of  adverse  events.  Regular  assessments 
 will  be  performed  as  described  in  Table  11.  If  a  patient  develops  a  toxicity,  binimetinib  dose  may  be 
 adjusted  as  outlined  in  the  dose  modification  Table  9.  In  vitro  data  showed  that  both  binimetinib 
 and  encorafenib  are  substrates  of  P-gp.  Binimetinib  is  also  a  substrate  of  BCRP.  Thus,  the  use  of 
 drugs  that  are  known  to  inhibit  or  induce  P-gp  and  BCRP  should  be  used  with  caution.  Encorafenib 
 is  a  BCRP  inhibitor.  It  is  also  a  potent  inhibitor  of  the  renal  transporters  OAT1,  OAT3  and  OCT2 
 and  the  hepatic  transporters  OATP1B1  and  OATP1B3.  Therefore,  the  co-administration  of  drugs 
 that  are  known  to  be  sensitive  or  NTI  substrate  of  BCRP,  OAT1,  OAT3,  OCT2,  OATP1B1  and 
 OATP1B3 should be used with caution. 
 The  solubility  of  binimetinib  and  encorafenib  is  pH  dependent  and  a  10-fold  decrease  in  solubility  is 
 observed  between  pH  1  and  2.  Patients  receiving  concomitant  treatments  that  could  potentially 
 modify  the  gastric  pH  (i.e.  PPI)  should  be  instructed  to  take  them  at  least  two  hours  after  the 
 administration of binimetinib. 
 7.3.3. Prohibited concomitant treatment 
 Any  other  investigational  treatment  within  the  past  30  days  of  treatment  initiation  and  during  the 
 trial is disallowed. 
 Anticancer  therapies  (including  chemo-  or  biologic-therapy  or  radiation  therapy,  covering  >30%  of 
 the  red  bone  marrow  reserve,  and  surgery)  are  prohibited  while  the  patients  are  receiving  study 
 treatment.  If  such  therapeutic  measures  are  required  for  a  patient,  then  the  patient  must  be 
 discontinued  from  study  treatment.  If  local  treatment,  radiotherapy  or  surgery,  is  indicated  by  the 
 protocol  of  this  study,  it  is  allowed  but  following  the  next  indication  regarding  the  study  treatment. 
 To  reduce  possible  skin  toxicity  during  and  after  radiotherapy,  encorafenib  and  binimetinib  will  be 
 interrupted 24h before radiotherapy and restart 24h after the last dose of radiotherapy. 
 The  concomitant  use  of  strong  CYP3A4  inhibitors  would  likely  significantly  increase  the  exposure 
 of encorafenib and thus should not be used during this study. 
 7.4. 
 Treatment Compliance 
 Study  drug  compliance  will  be  assessed  by  the  Investigator  and/or  study  personnel  at  each  patient 
 visit  for  encorafenib  and  binimetinib  and  information  provided  by  the  patient  and/or  caregiver  will  be 
 captured  in  the  patient  records  as  part  of  source  documentation  at  each  patient  visit. 
 Corresponding drug administration information will be reported also in the eCRF. 
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 A  patient  medication  diary  will  be  provided  for  each  patient.  Patients  or  caregivers  should  complete 
 this diary during the entire study. 
 The  investigator  or  designee  must  maintain  an  accurate  record  of  the  shipment  and  dispensing  of 
 study  treatments  in  the  IWRS  system  designed  for  this  trial  (access  to  IWRS  system  will  be  created 
 by study monitors during site initiation visit or can be asked by email to: investigacion@mfar.net). 
 Patients  will  be  asked  to  return  all  unused  study  treatment  and  packaging  on  a  regular  basis,  at  the 
 end of the study or at the time of study treatment discontinuation. 
 Compliance  with  the  IMP  schema  is  critical  for  patients  and  trial  outcomes,  and  any  deviation  from 
 the  IMP  schema  may  jeopardize  trial  results  or  may  affect  patient  safety;  for  these  reasons, 
 non-compliance  may  be  considered  as  a  protocol  deviation.  When  an  investigational  product  is 
 dispensed  in  a  clinical  trial,  the  investigator  or  a  person  designated  by  the  investigator  will  ensure 
 high level of compliance with the investigational product administration procedures. 
 All  stages  from  IMP  since  will  be  documented  in  the  corresponding  forms  to  guarantee  traceability 
 during the procedure. 
 For  this  trial,  IMP  compliance  will  be  assessed  by  reviewing  the  consistency  of  information  in  the 
 IWRS, the eCRF, patient records, nurse sheets, and in the pharmacy source documentation. 
 At  study  close-out,  and,  as  appropriate  during  the  study,  the  investigator  will  return  all  used  and 
 unused  study  treatment,  packaging,  drug  labels  to  the  Sponsor  or  designee’s  monitor  or  to  the 
 Sponsor address provided in the investigator folder at each site. 
 Upon  approval  from  the  Sponsor  personnel  and  after  accountability  has  been  confirmed  by  the 
 Sponsor  or  designee’s  monitor,  the  study  drug  supply  can  be  destroyed  by  the  clinical  site, 
 according  their  normal  practise,  or,  when  destruction  in  site  is  not  possible,  destroyed  at  Sponsor 
 supply vendor, as appropriate. 
 7.5. 
 Randomization and Blinding 
 Not applicable. 
 7.6. 
 Study Drug Supply, labelling, dispensing and handling 
 7.6.1. Study Drug Supply 
 The  Sponsor  will  supply  encorafenib  and  binimetinib  throughout  the  study  period  and  once  ended 
 the  trial  to  those  patients  who  are  benefiting  of  study  treatment,  as  long  as,  medication  be  available 
 for  this  trial  by  the  manufacturer  of  the  IMPs.  In  case  that  the  study  is  suspended  or  completed 
 while  there  are  still  patients  under  treatment  with  COMBO  450,  the  investigator  or  responsible 
 should  evaluate  both  patient’s  clinical  status  to  confirm  that  disease  is  controlled  and  then  inform  to 
 the  sponsor  who  will  make  sure  that  based  on  the  available  information  of  the  efficacy  of  the 
 treatment,  current  availability  of  the  investigational  medical  product  and  the  potential  benefit  for  the 
 patient,  will  ensure  that  the  patient  continues  with  treatment  as  long  as  there  is  clinical  benefit  from 
 it. 
 The  Investigator  or  responsible  site  personnel  must  instruct  the  patient  or  caregiver  to  take  the 
 study  drug  as  per  protocol.  Study  drug(s)  will  be  dispensed  to  the  patient  by  authorized  site 
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 personnel  only.  All  dosages  prescribed  to  the  patient  and  all  dose  changes  during  the  study  must 
 be recorded on the patient record and the eCRF. 
 7.6.2. Study drug labelling 
 All  drugs  (encorafenib  and  binimetinib)  will  be  open  label.  Medication  labels  will  be  in  the  local 
 language  and  comply  with  the  legal  requirements  of  each  country,  including  storage  conditions  for 
 the  drugs,  batch  number  and  expiration  date,  among  others.  The  patient  number  should  be 
 hand-written by the investigator or its staff at the drug delivery time. 
 7.6.3. Study drug storage 
 Study  treatments  must  be  received  by  designated  personnel  at  the  study  site,  handled  and  stored 
 safely  and  properly,  and  kept  in  a  secured  location  to  which  only  the  Investigator  and  designated 
 site personnel have access. 
 Upon  receipt,  the  study  drugs  should  be  stored  according  to  the  instructions  specified  on  the  drug 
 labels  and  Investigator’s  Brochure  for  encorafenib  and  binimetinib.  Study  medication  is  to  be  stored 
 in  a  secure  locked  area  while  under  the  responsibility  of  the  Investigator.  Receipt  and  dispensing  of 
 study medication must be recorded by an authorized person at the Investigator’s site. 
 Records  of  drug  formulation,  batch  number,  and  number  of  blisters  dispensed  must  be  recorded  in 
 the IWRS system elaborated for this trial and in pharmacy source records. 
 7.7. 
 End of treatment 
 End  of  treatment  is  defined  as  the  last  visit  where  the  decision  is  made  to  discontinue  treatment.  All 
 required  procedures  of  the  Final  Visit  schedule  may  be  completed  within  ±7  days  of  the  end  of 
 treatment  visit.  Repeat  disease  assessment  is  not  required  if  performed  within  28  days  prior  to  the 
 end of treatment visit. 
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 8. 
 S  TUDY  A  SSESSMENTS 
 8.1. 
 Schedule for tests and determinations 
 Table 11. Schedule for tests and determinations 
 Visit 
 Baseline 
 (D-28 to 
 D-1) 
 w4 
 w8 
 (D-56) 
 Every 
 4w 
 Every 
 8w 
 Every 
 12 w 
 End of 
 treatment 
 (28 +/-4d) 
 FU 
 before 
 DP 
 FU 
 after 
 DP for 
 OS 
 Informed consent 
 X 
 Screening registration 
 X 
 Histology confirmation of 
 disease 
 X 
 BRAF Status 
 X 
 Anamnesis 
 X 
 Demographics 
 X 
 Physical examination / vital 
 signs 
 X 
 X 
 X 
 X 
 X 
 ECOG PS 
 X 
 X 
 X 
 X 
 X 
 X 
 Basic neurologic examination 
 and Modified Barthel Index 
 X 
 X 
 X 
 X 
 X 
 X 
 Ophthalmologic anamnesis an 
 evaluation by Oncologist 
 X 
 X 
 X 
 X 
 X 
 Ophthalmologist exploration 
 If clinical suspicion 
 ECG 
 X 
 X 
 X 
 X 
 LVEF 
 (as per institutional guidelines) 
 X 
 X 
 Concomitant medications 
 X 
 X 
 X 
 X 
 X 
 Inclusion/exclusion criteria 
 X 
 QoL 
 X 
 at weeks 8 and 24 
 Analytical tests 
 Clinical laboratory test 
 X 
 X 
 X 
 X 
 X 
 X 
 Pregnancy test 
 X 
 X 
 X 
 Disease evaluation 
 Abdominopelvic CT Scan (  1  ) 
 X 
 X 
 X (  3  ) 
 X 
 (every 
 8w) (  3  ) 
 Brain MRI (  1,2  ) 
 X 
 X 
 X (  3  ) 
 X 
 (every 
 8w) (  3  ) 
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 Colour Digital Photography 
 (including a metric ruler) of 
 skin lesions (  1  ) 
 X 
 X 
 X (  3  ) 
 X 
 (every 
 8w) (  3  ) 
 Safety evaluation 
 Adverse events and Serious 
 Adverse events 
 Every 4 weeks throughout all the study 
 (From ICF signature up to EoT visit) 
 Study Treatment 
 COMBO450 follow-up and 
 dispensing 
 X 
 X 
 Dose reduction 
 Throughout all the study, when applicable 
 Dose delay 
 Throughout all the study, when applicable 
 Long term FU 
 OS Follow-up 
 X 
 New anti-cancer therapy 
 X 
 (  1  ) Out of the assessments indicated by protocol,  patients can be assessed whenever the investigator considers it indicated. 
 (  2  ) Contrast enhanced MRI. 
 (  3  ) Assessments will be done every two months up to  12 months, thereafter, patients will be assessed as per institutional criteria. 
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 Protocol specifications for trial determinations 
 Informed  Consent  Form  (ICF):  Determinations  performed  by  routine  clinical  practice  before  signing  the 
 informed  consent  will  be  valid,  provided  they  are  carried  out  following  from  this  protocol,  if  they  have  been 
 performed during the period included in the table 11. 
 Screening  registration:  Any  patient  that  sign  ICF  should  be  registered  in  the  EDC  system  and  have 
 assigned a unique screening number. 
 Anamnesis:  to  be  performed  during  the  baseline  period  in  the  2  weeks  prior  to  inclusion.  Medical  history  will 
 include  all  active  conditions  and  any  condition  diagnosed  considered  to  be  clinically  significant  by  the 
 investigator. Melanoma history will be recorded separately and not listed as Medical History. 
 Demographics:  Date of birth, race, and sex. 
 Physical  examination/vital  signs:  Complete  physical  examination,  weight,  height,  and  vital  signs  (pulse, 
 respiratory rate,  blood pressure  and body temperature). 
 ECOG-PS:  Functional status will be assessed using  the ECOG score. 
 Neurological  examination:  Basic  neurological  assessment  according  to  normal  practice  and  Modified 
 Barthel Index according to “Guidelines for the Modified Barthel Index of Activities of Daily Living” 
 Ophthalmologic  anamnesis  and  evaluation  by  Oncologist:  ophthalmologic  anamnesis  and  evaluation 
 performed  by  oncologist  as  a  part  of  physical  examination  and  it  will  be  performed  at  baseline  and  in  every 
 monthly  visit.  Only  if  there’s  any  alarm  symptom  or  sign  or  previous  ocular  antecedents,  patient  will  be 
 evaluated by Ophthalmologist. 
 Ophthalmologist  examination:  Patient  will  be  evaluated  by  Ophthalmologist  if  there’s  any  alarm  symptom 
 or sign or previous ocular antecedents. 
 ECG:  Standard  12-lead  ECG  at  baseline,  after  4  weeks  of  treatment,  after  every  12  weeks  and  in  the  end  of 
 treatment visit. Additional ECGs may be performed at the discretion of the investigator. 
 Concomitant  medication:  All  drugs  taken  within  30  days  before  starting  the  trial  and  concomitantly  during 
 the  study  will  be  recorded  in  medical  records  and  in  eCRF  with  indication,  dose  information  and 
 administration dates. 
 Inclusion and Exclusion Criteria:  Verification that  patients meet all inclusion criteria and none of exclusion. 
 Quality of Life:  EORTC QLQ 30 administered at baseline,  at week 8 and week 24. 
 Clinical laboratory test: 
 ● 
 Complete  haematology:  Complete  blood  count  that  includes  total  white  blood  cell  count  with 
 leukocyte formula, haemoglobin, and platelet count. 
 ● 
 Complete 
 serum 
 biochemistry 
 and 
 urinalysis: 
 including 
 LDH, 
 CK 
 (CPK), 
 gamma-glutamyltransferase  (GGT),  creatinine,  creatinine  clearance, 
 ,  total  bilirubin,  alkaline 
 phosphatase,  aspartate  aminotransferase  (AST)  or  GOT,  alanine  aminotransferase  (ALT)  or  GPT, 
 Calcium (Ca), Potassium (K), and Magnesium (Mg). 
 The  analytical  studies  may  be  performed  up  to  72  hours  before  the  scheduled  visits  to  have  the  results  at  the 
 time  of  the  patient’s  visit.  Liver  function  tests,  including  GGT,  ALT,  AST  and  total  bilirubin  should  be 
 performed  following  the  indications  of  “schedule  of  determinations”  and  when  clinically  indicated,  with  more 
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 frequent determinations in case of increases toxicities grade 2, 3 or 4. 
 ● 
 Coagulation  tests:  Coagulation  monitoring  will  be  performed  in  patients  on  anticoagulant  drugs 
 treatment.  During  the  treatment  at  the  discretion  of  the  investigator  or  if  the  patient  is  receiving 
 anticoagulants. 
 Pregnancy test: 
 All  women  with  reproductive  capacity  MUST  have  a  negative  urine  pregnancy  test  within  72  hours  before 
 receiving  study  treatment.  The  minimum  sensitivity  of  the  pregnancy  test  should  be  25  IU/L  or  equivalent 
 units  of  HCG.  If  the  urine  pregnancy  test  is  positive,  a  blood  test  should  be  done  and  if  this  pregnancy  test  in 
 serum is positive, the patient should not receive study treatment and should not be included in the study. 
 Disease evaluation 
 ● 
 Radiological Assessment of Tumour Lesions 
 Body  CT-scan  and  contrast  enhanced  brain  MRI  will  be  performed  baseline  and  every  8  weeks  (+/-1  week) 
 up to 12 months and according to normal practise thereafter. 
 In  addition,  CT/MRI  scans  must  be  obtained  of  anatomic  regions  not  covered  by  the  chest  and  abdomen 
 scans,  in  subjects  where  there  is  clinical  suspicion  for  deep  soft  tissue  metastases  (e.g.,  lesions  in  the  thigh). 
 Such  additional  CT/MRIs  will  be  required  at  Screening  only  when  deep  soft  tissue  disease  is  and  must  be 
 consistently  repeated  at  all  tumour  assessment  visits  if  a  deep  soft  tissue  lesion  is  identified  during 
 Screening. In cases without suspicion for deep soft tissue disease, no such CT/MRIs are required. 
 Similar  methods  of  tumour  assessment  and  similar  techniques  must  be  used  to  characterize  each  identified 
 and  reported  lesion  at  Screening  during  the  treatment  evaluation  phases.  Imaging-based  evaluation  is 
 preferred  to  clinical  examination.  Helical  (spiral)  CT  scans  of  chest  and  abdomen  are  preferred.  If  not 
 available,  conventional  (non-spiral  CT)  should  be  used.  If  not  contraindicated,  IV  contrast  should  be  used  for 
 all  studies.  If  IV  contrast  is  contraindicated,  MRI  should  be  used  at  the  Screening  exam  and  at  all  tumour 
 assessment time points. Oral contrast should be used for all applicable imaging unless contraindicated. 
 A  reference  measurement  ruler  must  be  printed  on  every  image  for  scale  determination.  Sections  should  be 
 contiguous,  similarly  sized  and  consistent  from  visit-to-visit.  Section  thickness  must  be  based  on  institutional 
 standards  (e.g.,  from  5  to  8  mm,  10  mm  cuts  are  not  recommended).  Chest  x-rays  and  ultrasound  are  not 
 acceptable  methods  to  measure  disease.  Response  and  progression  of  disease  must  be  documented  by  CT 
 or MRI like the methods used at Screening. 
 Screening  bone  scans  are  not  mandatory  and  should  be  performed  as  clinically  indicated.  Abnormal  findings 
 on  Screening  bone  scans,  consistent  with  malignant  disease,  require  follow-up  bone  scans  in  specified 
 intervals.  Normal  bone  scans  at  Screening  do  not  require  follow-up  bone  scans,  except  when  clinically 
 indicated.  Abnormal  bone  scans  should  be  confirmed  with  radiographic  plain  films,  CT  or  MRI.  Similarly, 
 progressive  disease  based  only  on  new  lesion(s)  found  on  bone  scans  must  be  supported  with  plain  films, 
 CT  or  MRI  imaging  studies  of  the  bone  lesion(s)  to  confirm  their  malignant  nature.  Increased  intensity  of 
 uptake  in  previously  abnormal  areas  on  bone  scans  is  not  considered  progressive  disease,  unless  the 
 lesions  seen  on  the  correlative  imaging  studies  confirm  the  finding  of  disease  progression.  New  areas  of 
 abnormal uptake on a bone scan represent disease progression. 
 Out  of  the  assessments  indicated  by  protocol,  patients  can  be  assessed  whenever  the  investigator  considers 
 it indicated. 
 ● 
 Intracranial  tumour  response  evaluation  of  brain  lesions  will  be  conducted,  according  to  modified 
 RECIST 1.1 criteria until disease progression, more information is detailed in section 10.3. 
 ● 
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 ● 
 Non-radiological Assessments 
 Visible  cutaneous  lesions  must  be  measured  clinically.  Digital  and  standardized  photographic  images 
 including  a  ruler  for  scale  as  part  of  the  image  are  recommended  for  documentation.  All  clinical  assessments 
 must be performed within proximity (± 7 days) of any protocol specified radiographic assessments 
 Safety  evaluation:  Safety  assessments  and  adverse  events  include  tumour-related,  unrelated  and 
 treatment-related  signs  and  symptoms.  Adverse  events  will  be  documented  and  recorded  in  the  CRF  upon 
 patient  notification.  AEs  will  be  collected  from  the  signing  of  Informed  Consent  until  the  end  of  treatment  visit 
 (30  days  after  end  of  treatment)  or  up  to  resolution.  Classification  of  toxicity  will  be  done  according  to  the 
 common  terminology  criteria  for  adverse  events  of  the  National  Cancer  Institute,  version  4.03  (NCI  CTCAE  v. 
 4.03). 
 PFS  follow-up:  Body  CT-scan  and  contrast  enhanced  brain  MRI  will  be  performed  baseline  and  every  8 
 weeks  (+/-1  week)  up  to  12  months  and  according  to  normal  practice  thereafter  until  disease  progression, 
 independently of the end of treatment reason if it was not the documentation of disease progression. 
 OS  Follow-up:  After  disease  progression  all  patients  will  be  monitored  to  determine  subsequent 
 antineoplastic  treatments  and  survival.  It  is  recommended  to  maintain  contacts  by  phone  or  by  other 
 methods every 4 weeks to carry out timely follow-up (up to 24 months or study closure). 
 New  anti-cancer  therapy:  Information  on  subsequent  treatments  should  include  the  list  of  post-treatment 
 treatments,  the  drugs  administered,  and  the  date  of  initiation  and  discontinuation  of  each  drug.  All  data  will 
 be recorded in the medical record and in the eCRF. 
 8.2. 
 Schedule of Assessments 
 Prior  to  performing  any  trial  assessments  that  are  not  part  of  routine  medical  care  for  the  subject, 
 the Investigator will obtain written informed consent as described in Section 5.2. 
 a) Baseline Assessments 
 The  following  assessments  and  procedures  should  be  performed  within  28  days  before  inclusion, 
 and when applicable, as close as possible to the start of study treatment: 
 ●  Informed consent 
 ●  Screening registration 
 ●  Inclusion /exclusion criteria 
 ●  Medical history including previous cancers treatments 
 ●  Histology confirmation of disease 
 ●  BRAF mutation status (local) 
 ●  Anamnesis 
 ●  Demographics 
 ●  Physical examination and vital signs 
 ●  ECOG performance status 
 ●  Neurologic examination and Modified Barthel Index 
 ●  Ophthalmologic  anamnesis  and  evaluation  by  Oncologist  (if  there’s  any  alarm 
 symptom or sign, patient will be evaluated by Ophthalmologist) 
 ●  ECG 
 ●  Concomitant medications 
 ●  Quality of Life questionnaires (QoL) 
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 ●  Haematology,  coagulation,  serum  biochemistry  including  CK  and  LDH 
 determination (within 72 h before). 
 ●  Urine  pregnancy  test  for  woman  of  childbearing  potential  (within  72  h  before), 
 and in case this test be positive, a serum pregnancy test should be done. 
 ●  LVEF 
 ●  CT Scan 
 ●  Contrast enhanced brain MRI 
 ●  Colour Digital Photography (including a metric ruler) of the skin lesions 
 b) Prior treatment administration  (≤7 days before  day 1 (D1) of cycle 1 (C1)): 
 The  following  assessments  and  procedures  should  be  performed  within  7  days  before  start  of 
 study  treatment  (determination  performed  during  “baseline  assessments”  can  be  used  for  the 
 purposes  of  “prior  treatment  determination”  if  they  are  performed  within  7  days  before  start  of 
 treatment): 
 ●  Physical examination and vital signs 
 ●  ECOG performance status 
 ●  SAEs  related  to  study  procedures  (e.g.  blood  sampling)  must  be  reported 
 including screening failures (and reason for screening failure) 
 ●  Concomitant medications 
 ●  Urine  pregnancy  test  for  women  of  childbearing  potential  (within  72  h  before) 
 and in case this test be positive, a serum pregnancy test should be done 
 ●  Haematology,  coagulation,  serum  biochemistry  including  CK  and  LDH 
 determination (within 72 h before). 
 c) On treatment visits 
 1. - On week 4 
 ●  Physical examination 
 ●  Vital signs 
 ●  ECOG performance status 
 ●  Neurologic examination and Modified Barthel Index 
 ●  Ophthalmologic  anamnesis  and  evaluation  by  Oncologist  (if  there’s  any  alarm 
 symptom or sign, patient will be evaluated by Ophthalmologist) 
 ●  ECG 
 ●  Adverse events follow-up 
 ●  Concomitant medications 
 ●  Haematology,  coagulation,  serum  biochemistry,  pregnancy  test  (urine  test,  and 
 in  case  this  test  be  positive,  a  serum  pregnancy  test  should  be  done  to  confirm 
 no pregnancy). 
 ●  COMBO450 follow up and dispensing 
 2. - On week 8 
 ●  Physical examination 
 ●  Vital signs 
 ●  ECOG performance status 
 ●  Neurologic examination and Modified Barthel Index 
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 ●  Ophthalmologic  anamnesis  and  evaluation  by  Oncologist  (if  there’s  any  alarm 
 symptom or sign, patient will be evaluated by Ophthalmologist) 
 ●  Adverse events follow-up 
 ●  Concomitant medications 
 ●  Haematology, coagulation, serum biochemistry, 
 ●  CT Scan 
 ●  Contrast enhanced brain MRI 
 ●  Colour Digital Photography (including a metric ruler) of the skin lesions 
 ●  QoL 
 3. - Every 4 weeks until disease progression 
 ●  Physical examination 
 ●  Vital signs 
 ●  ECOG performance status 
 ●  Neurologic examination and Modified Barthel Index 
 ●  Ophthalmologic  anamnesis  and  evaluation  by  Oncologist  (if  there’s  any  alarm 
 symptom or sign, patient will be evaluated by Ophthalmologist) 
 ●  Adverse events follow-up 
 ●  Concomitant medications 
 ●  Haematology, coagulation, serum biochemistry 
 ●  Pregnancy  test  (  urine  test,  and  in  case  this  test  be  positive,  a  serum  pregnancy 
 test should be done to confirm no pregnancy.) 
 ●  COMBO450 follow up and dispensing 
 4. - Every 8 weeks until disease progression 
 ●  CT Scan 
 ●  Contrast enhanced brain MRI 
 ●  Colour Digital Photography (including a metric ruler) of the skin lesions 
 ●  QoL (on week 24) 
 5. - Every 12 weeks until disease progression 
 ●  ECG 
 ●  LVEF 
 d) End of treatment - Safety visit (after 28 days of end of treatment) 
 Safety  visit  will  be  performed  at  day  28±4d  after  the  end  of  treatment  to  determine  patient  general 
 status  and  clearly  identify  adverse  events  that  persists  and  could  be  related  to  study  drug.  After 
 this  visit,  only  SAEs  that  could  be  related  to  study  drug  should  be  expedited  reported  to  the 
 Sponsor. 
 ●  Physical examination 
 ●  Vital signs 
 ●  ECOG performance status 
 ●  Neurologic examination and Modified Barthel Index 
 ●  Ophthalmologic  anamnesis  and  evaluation  by  Oncologist  (if  there’s  any  alarm 
 symptom or sign, patient will be evaluated by Ophthalmologist) 
 ●  ECG 
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 ●  Adverse events follow-up 
 ●  Concomitant medications 
 ●  Haematology, coagulation, serum biochemistry, 
 ●  Pregnancy  test  (urine  test  and  in  case  this  test  be  positive,  a  serum  pregnancy 
 test should be done to confirm no pregnancy. 
 e) Follow-up before progression disease 
 ●  ECOG performance status 
 ●  Neurologic examination and Modified Barthel Index 
 ●  Haematology,  coagulation,  serum  biochemistry,  and  pregnancy  test  (urine  test 
 and  in  case  this  test  be  positive,  a  serum  pregnancy  test  should  be  done  to 
 confirm no pregnancy.), (only if patient it’s on treatment) 
 ●  CT  Scan  (every  two  months  up  to  12  months,  thereafter  patients  will  be 
 assessed as per institutional criteria) 
 ●  Contrast  enhanced  brain  MRI  (every  two  months  up  to  12  months,  thereafter 
 patients will be assessed as per institutional criteria) 
 ●  Colour  Digital  Photography  (including  a  metric  ruler)  of  the  skin  lesions  (every 
 two  months  up  to  12  months,  thereafter  patients  will  be  assessed  as  per 
 institutional criteria). 
 After one year of 1st day of treatment, follow up will be performed according local normal practise. 
 f) Follow-up before progression disease after ending treatment: 
 ●  Subjects  who  no  longer  receive  study  treatment  due  to  progression  should  remain  in 
 follow-up until their death or until the closure of the study (whichever comes first). 
 ●  Subjects  who  no  longer  receive  study  treatment  due  to  unacceptable  toxicity  or  at  the 
 discretion  of  the  investigator  should  remain  in  follow  up  until  progression.  Visits  will  be 
 scheduled  every  8  weeks  and  tumor  evaluation  should  be  performed  every  8  weeks  until 
 tumor  progression  the  fist  year,  and  after  12  months,  the  tumor  evaluation  can  be  done  as 
 per  institutional  criteria.The  tests  and  questionnaires  can  be  done  according  to  the  normal 
 practise too. 
 ●  Subjects  who  have  switched  to  an  alternative  treatment  do  not  perform  a  formal  follow-up, 
 except to record the date of the death. 
 g ) OS Long term follow-up 
 ●  New anticancer therapy 
 Follow-up  after  disease  progression  will  be  made  according  to  local  practice.  Survival  information 
 may  be  obtained  via  telephone  contact  with  the  patient,  patient’s  family  or  by  contact  with  the 
 patient’s  current  physician.  Survival  data  will  be  collected  up  to  the  time  of  the  final  overall  survival 
 (OS)  analysis.  At  this  point  Investigators  will  be  notified  that  no  further  data  collection  for  the  study 
 is required. 
 The  status  of  ongoing,  withdrawn  (from  the  study)  and  lost  to  follow  up  patients  at  the  time  of  an 
 overall  survival  analysis  should  be  obtained  by  the  site  personnel  by  checking  the  patient  notes, 
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 hospital  records,  contacting  the  patient’s  general  practitioner  and  checking  publicly  available  death 
 registries. 
 8.3. 
 Study timetable and end of study 
 ●  Expected recruitment period: 36 months 
 ●  Expected follow-up: 24 months 
 8.3.1.  End of Study Declaration 
 Last  Patient  Last  Visit,  expected  on  1Q  2024.  The  study  will  be  considered  closed  from  a  normative 
 point  of  view  after  data  on  primary  and  secondary  variables  are  sufficiently  prepared  for  its  initial 
 publication. 
 8.3.2. Early study termination 
 This  study  can  be  terminated  prematurely  if  in  the  opinion  of  the  sponsor  there  is  a  reasonable  and 
 sufficient  cause.  The  investigator  will  receive  a  written  notification  in  which  the  sponsor  motivates 
 the interruption of the study. 
 Reasonsthat justify are as follows, but not limited to: 
 • Finding of unforeseen, considerable or unacceptable risks for the patients. 
 • Impossibility to include an acceptable number of patients. 
 • Insufficient compliance with protocol requisites. 
 • Plans to modify, halt or discontinue the development of study drug. 
 • In case of early termination of the study, all the study material must be returned to Sponsor. 
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 9. 
 A  SSESSMENT  OF  S  AFETY 
 The  safety  population  (SP)  consists  of  all  enrolled  subjects  who  received  at  least  one  dose  of  study 
 treatment.  Patients  will  be  monitored  for  safety  during  all  stages  of  the  study.  All  safety  and 
 tolerability assessments will be done at pre-dose unless otherwise specified. 
 Assessment  of  adverse  events,  safety,  and  toxicity  will  be  performed  according  to  the  National 
 Cancer  Institute  Common  Toxicity  Criteria  (version  4.03)  from  the  time  of  Informed  Consent  for  the 
 pre-registration  phase  until  the  end  of  study.  The  safety  of  study  treatment  will  be  assessed 
 through  the  recording,  reporting  and  analysing  of  baseline  medical  conditions,  adverse  events,  and 
 physical examination findings including vital signs, ECGs and laboratory tests. 
 9.1. 
 Safety Parameters 
 9.1.1.  Demographic/Medical History 
 All  clinically  relevant  demographic  and  medical  history  data  will  be  obtained  from  all  patients 
 enrolled  in  the  study,  by  the  investigator  or  qualified  designee.  Medical  history  will  include  all  active 
 conditions,  and  any  condition  diagnosed  that  are  considered  clinically  significant  by  the 
 Investigator. Melanoma history will be recorded separately and not listed as Medical History. 
 9.1.2.  Prior Medications 
 The  investigator  or  qualified  designee  will  review  prior  medication  use,  including  any 
 protocol-specified  washout  requirement,  and  record  prior  medication  taken  by  the  subject  within  30 
 days before starting the trial. Prior treatments for melanoma will be recorded. 
 9.1.3.  Vital Signs 
 The  investigator  or  qualified  designee  will  take  vital  signs  at  screening,  prior  to  the  administration  of 
 COMBO  450  and  as  specified  in  the  Table  of  Schedule  of  Assessments.  Vital  signs  include 
 temperature,  pulse,  respiratory  rate,  weight  and  blood  pressure  (after  sitting  for  5  minutes).  Height 
 will be measured at screening only. 
 9.1.4.  Physical Examination 
 A  standard  physical  examination  will  be  performed  to  all  patients  treated  with  COMBO  450  as 
 specified in the Table of Schedule of Assessments. 
 9.1.5.  Electrocardiogram (ECG) 
 A  standard  12-lead  ECG  will  be  performed  using  local  standard  procedures  once  at  baseline  and 
 as  specified  in  the  Table  of  Schedule  of  Assessments.  Clinically  significant  abnormal  findings 
 should be recorded as medical history. 
 9.1.6.  Laboratory Assessments 
 Laboratory  tests  for  haematology,  chemistry  and  urinalysis  will  be  performed  as  specified  in  the 
 Table of Schedule of Assessments. 
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 9.1.6.1. 
 Pregnancy Screening 
 In  any  woman  of  childbearing  potential,  i.e.  not  >  1  year  postmenopausal  or  surgically  sterilized,  a 
 urine  dipstick  pregnancy  test  will  be  performed  at  both  screening,  and  then  (urine  test)  every  4 
 weeks  and  end-of-study.  If  the  dipstick  test  indicates  a  positive  result,  an  hCG  laboratory  blood  test 
 will be performed to confirm the pregnancy. 
 A woman of childbearing potential cannot be included in the study if any of the following occurs: 
 • 
 The  urine  dipstick  pregnancy  test  indicates  a  positive  result  and  the  pregnancy  has  been  not  yet 
 been ruled out by the following β-HCG blood test 
 • 
 No urine dipstick pregnancy test has been performed at screening 
 • 
 The  urine  dipstick  pregnancy  test  indicates  a  negative  result,  but  early  pregnancy  (≤  2  weeks 
 from conception) is suspected by the Investigator based on anamnestic elements 
 • 
 The  urine  dipstick  pregnancy  test  indicates  a  negative  result,  but  a  pregnancy  is  suspected  by 
 the Investigator based on clinical elements and cannot be ruled out by further investigation. 
 If  a  positive  urine  dipstick  pregnancy  test  occurs  at  end-of-study,  or  if  a  pregnancy  is  suspected  at 
 any time during the study, an hCG blood test will be performed to confirm the pregnancy. 
 9.1.6.2. 
 Eastern Cooperative Oncology Group (ECOG) Performance Status 
 The  investigator  or  qualified  designee  will  assess  ECOG  status  at  screening,  prior  to  the 
 administration  of  each  dose  of  trial  treatment  and  as  specified  in  the  Table  of  Schedule  of 
 Assessments. 
 9.2. 
 Adverse and Serious Adverse Events 
 9.2.1.  Definitions 
 Definitions regarding safety and pharmacovigilance to be applied in this study are defined below. 
 9.2.1.1. 
 Adverse Event (AE) 
 An  AE  is  defined  as  any  untoward  medical  occurrence  in  a  patient  or  clinical  investigation  subject 
 administered  a  pharmaceutical  product  and  which  does  not  necessarily  have  to  have  a  causal 
 relationship  with  this  treatment.  An  adverse  event  (AE)  can  therefore  be  any  unfavourable  and 
 unintended  sign  (including  an  abnormal  laboratory  finding,  for  example),  symptom,  or  disease 
 temporally  associated  with  the  use  of  a  medicinal  product,  whether  considered  related  to  the 
 medicinal product. 
 9.2.1.2. 
 Serious Adverse Event (SAE) 
 A  serious  adverse  event  is  an  AE  occurring  during  any  study  phase  (ie,  screening,  treatment,  or 
 follow-up), that fulfils one or more of the following: 
 • 
 Results in death. 
 • 
 It is immediately life-threatening. 
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 • 
 It  requires  in-patient  hospitalization  or  prolongation  of  existing  hospitalization  (hospitalization 
 should  not  be  considered  as  an  AE  (therefore  also  not  an  SAE)  when  it  is  due  to:  medical  or 
 surgical procedures planned before study entry or due to social or economic reasons. 
 • 
 It results in persistent or significant disability or incapacity. 
 • 
 Results in a congenital abnormality or birth defect. 
 • 
 It  is  a  new  cancer  (that  is  not  a  condition  of  the  study).  Although  new  cancer  is  not  always 
 serious  as  per  regulatory  definitions,  these  should  be  considered  and  reported  as  such,  with 
 the seriousness criterion “important medical event”. 
 • 
 It  is  an  important  medical  event  that  may  jeopardize  the  patient  or  may  require  medical 
 intervention  to  prevent  one  of  the  outcomes  listed  above.  Medical  and  scientific  judgement 
 should  be  exercised  in  deciding  whether  expedited  reporting  is  appropriate  in  other  situations, 
 such  as  important  medical  events  that  may  not  be  immediately  life-threatening  or  result  in 
 death  or  hospitalization  but  may  jeopardize  the  patient  or  may  require  intervention  to  prevent 
 one  of  the  other  outcomes  listed  in  the  definition  above.  These  should  also  usually  be 
 considered  serious.  Examples  of  such  events  are  intensive  treatment  in  an  emergency  room  or 
 at  home  for  allergic  bronchospasm;  blood  dyscrasias  or  convulsions  that  do  not  result  in 
 hospitalization; or development of drug dependence or drug abuse. 
 9.2.1.3. 
 Suspected unexpected serious adverse reaction (SUSAR) 
 SUSARs  are  serious  adverse  reactions  that  could  be  related  to  the  IMP  and  assessed  as 
 unexpected based on the applicable encorafenib and binimetinib Investigator’s Brochure (IB). 
 9.2.1.4. 
 Adverse drug reaction (ADR) 
 All  noxious  and  unintended  responses  to  a  medicinal  product  related  to  any  dose  should  be 
 considered  adverse  drug  reactions.  The  phrase  "responses  to  a  medicinal  products"  means  that  a 
 causal  relationship  between  a  medicinal  product  and  an  adverse  event  is  at  least  a  reasonable 
 possibility, i.e., the relationship cannot be ruled out. 
 9.2.1.5. 
 Serious adverse reaction (SAR) 
 A  Serious  Adverse  Reaction  is  any  adverse  reaction  that  fulfils  the  criteria  of  seriousness  as 
 defined  above,  therefore  is  an  adverse  reaction  which  results  in  death,  is  life-threatening,  requires 
 inpatient  hospitalization  or  prolongation  of  existing  hospitalization,  results  in  persistent  or  significant 
 disability  or  incapacity,  is  a  congenital  anomaly/birth  defect,  is  a  new  cancer  (that  is  not  a  condition 
 of  the  study)  or  it  is  an  important  medical  event  that  might  not  be  immediately  life-threatening  or 
 result  in  death  or  hospitalisation  but  might  jeopardise  the  patient  or  might  require  intervention  to 
 prevent one of the other outcomes listed in the definition above. 
 9.3. 
 Assessment 
 All  assessments  of  AEs  (serious  and  non-serious)  listed  below  should  be  recorded  on  the  Adverse 
 Event page of the CRF/eCRF or in the SAE form as appropriate. 
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 9.3.1.  Causality Assessment 
 An  Investigator  who  is  qualified  in  medicine  must  make  the  determination  of  relationship  to  the 
 investigational  product  for  each  AE  (Related  or  Unrelated).  The  Investigator  should  decide 
 whether,  in  his  or  her  medical  judgment,  there  is  a  reasonable  possibility  that  the  event  may  have 
 been  caused  by  the  investigational  product.  If  no  valid  reason  exists  for  suggesting  a  relationship, 
 then  the  AE  should  be  classified  as  “unrelated.”  If  there  is  any  valid  reason,  even  if  undetermined, 
 for  suspecting  a  possible  cause-and-effect  relationship  between  the  investigational  product  and  the 
 occurrence of the AE, then the AE should be considered “related.” 
 9.3.2.  Expectedness assessment by the sponsors 
 The  ‘expectedness’  of  a  serious  adverse  reaction  is  assessed  in  the  light  of  the  encorafenib  and  or 
 binimetinib  IB.  The  expectedness  assessment  will  be  performed  by  Sponsor  according  the 
 information  available  in  last  version  of  study  treatment  IB.  If  information  on  the  expectedness  has 
 been  made  available  by  the  reporting  investigator,  this  should  be  taken  into  consideration  by 
 Sponsor.  If  Sponsor  disagrees  with  the  investigator’s  expectedness  assessment,  both,  the  opinion 
 of the investigator and the sponsor should be provided with the report. 
 9.3.3.  Severity assessment 
 Severity  of  AEs  will  be  assessed  according  to  the  CTCAE  which  provides  a  descriptive 
 terminology,  which  can  be  utilized,  for  Adverse  Event  (AE)  reporting.  A  grading  (severity)  scale  is 
 provided for each AE as follows: 
 Grades:  Grade  refers  to  the  severity  of  the  AE.  The  CTCAE  displays  Grades  1  through  5  with 
 unique clinical descriptions of severity for each AE based on this guideline: 
 • 
 Grade  1  Mild;  asymptomatic  or  mild  symptoms;  clinical  or  diagnostic  observations  only; 
 intervention not indicated 
 • 
 Grade 
 2 
 Moderate; 
 minimal,  local  or  non-invasive  intervention  indicated;  limiting 
 age-appropriate instrumental Activities of Daily Living (ADL)* 
 • 
 Grade  3  Severe  or  medically  significant  but  not  immediately  life-threatening;  hospitalization  or 
 prolongation of hospitalization indicated; disabling; limiting self-care ADL** 
 • 
 Grade 4 Life-threatening consequences; urgent intervention indicated 
 • 
 Grade 5 Death related to AE 
 *Instrumental  ADL  refer  to  preparing  meals,  shopping  for  groceries  or  clothes,  using  the  telephone, 
 managing money, etc. 
 **Self-care  ADL  refer  to  bathing,  dressing  and  undressing,  feeding  self,  using  the  toilet,  taking 
 medications, and not bedridden. 
 9.3.4.  Action taken 
 All  AEs  should  be  treated  appropriately.  Treatment  may  include  one  or  more  of  the  following:  no 
 action  taken  (i.e.  further  observation  only);  study  medication  temporarily  interrupted;  study 
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 medication  permanently  discontinued  due  to  this  AE;  drug  therapy  given;  non-drug  therapy  given, 
 surgery, hospitalization, unknown, other. 
 9.3.5.  Outcome 
 Investigators  should  follow-up  AEs  until  resolution.  The  outcome  of  the  AEs  should  be  assessed  as 
 follows: 
 • 
 Recovered/Resolved 
 • 
 Recovering/Resolving 
 • 
 Not recovered/Not resolved 
 • 
 Recovered/Resolved with sequelae 
 • 
 Fatal 
 • 
 Unknown 
 9.4. 
 Reporting 
 9.4.1.  Reporting an Adverse Event 
 Adverse  events  (serious  and  non-serious)  spontaneously  reported  by  the  patient  and/or  in 
 response  to  an  open  question  from  the  study  personnel  or  revealed  by  observation  will  be  recorded 
 during  the  study  at  the  investigational  site.  Information  about  AEs  (including  SAEs)  will  be  collected 
 from  the  signing  of  Informed  Consent  at  least  until  the  end  of  treatment  visit  or  up  to  resolution.  For 
 each  AE,  the  investigator  will  evaluate  and  report  the  onset  (date  and  time),  resolution  (date  and 
 time),  severity,  causality,  action  taken,  outcome,  and  whether  it  caused  the  patient  to  discontinue 
 the study. 
 9.4.2.  Reporting a Serious Adverse Event 
 Any  SAEs  considered  related  to  the  investigational  product  and  discovered  by  the  Investigator  at 
 any time after the study should be reported. 
 Any  SAE  must  be  reported  by  submitting  the  completed  initial  report  section  of  the  trial-specific 
 SAE  form  within  24  hours  of  becoming  aware  of  the  event.  Submission  is  done  by  sending  the  SAE 
 form by fax or e-mail to MFAR Clinical Research: 
 Serious Adverse Events 
 All serious adverse events must be reported by fax within 24 h to MFAR, S.L. 
 by fax (+ 34 93 253 11 68) or e-mail to  investigacion@mfar.net 
 The  SAE  outcome  must  be  reported  within  2  weeks  after  initial  report  by  submitting  the  follow-up 
 report  (e.g.  initial  SAE  form,  updated  with  follow-up  information)  to  the  Pharmacovigilance  as 
 above.  In  case  the  SAE  is  reported  as  ongoing  after  14  days,  the  follow-up  report  must  be 
 submitted  again  with  the  final  outcome.  The  originals  of  the  SAE  forms  (both  initial  and  follow-up 
 reports)  are  kept  at  the  sites  in  the  Investigator’s  file.  The  Pharmacovigilance  will  forward  each 
 individual  SAE  to  the  coordinating  investigator,  supporting  coordinating  investigators  and  to 
 Sponsor  within  one  working  day.  Wherever  possible  copy  of  summary  of  hospitalization,  autopsy 
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 reports,  and  relevant  laboratory  examinations  should  be  provided.  Additional  follow-up  information, 
 if  required  or  available,  should  all  be  faxed  to  Sponsor  within  one  business  day  of  receipt  and  this 
 should  be  completed  on  a  follow-up  SAE  form  and  placed  with  the  original  SAE  information  and 
 kept with the appropriate section of the CRF and/or study file. 
 The  Sponsor  is  responsible  for  notifying  the  relevant  regulatory  authorities  of  certain  events. 
 Investigators  will  also  be  notified  of  all  unexpected,  serious,  drug-related  events  (7/15  Day  Safety 
 Reports) that occur during the clinical study. 
 All  SAEs  that  occur  after  any  patient  has  signed  the  first  Informed  Consent,  until  end  of  treatment 
 visit, whether they are related to the study, must be recorded on forms provided by the Sponsor 
 9.4.3. 
 Reporting Pregnancy 
 In  case  of  a  pregnancy  notified  after  the  first  dose  was  received,  the  patient  will  not  receive  the 
 following  dose  and  will  be  followed  after  delivery  of  her  child.  All  initial  reports  of  pregnancies  in  a 
 patient  and  pregnancies  in  partners  of  male  patients  included  in  the  study  from  the  screening  visit 
 must  be  reported  to  the  Pharmacovigilance  by  the  Investigator  within  24  hours  of  knowledge  of  the 
 event, using a Pregnancy Form. 
 Should  a  pregnancy  occur,  it  must  be  reported  and  recorded  on  pregnancy  form.  Pregnancy  in 
 itself  is  not  regarded  as  an  AE  unless  there  is  a  suspicion  that  an  investigational  product  may  have 
 interfered with the effectiveness of a contraceptive medication. 
 Any  pregnancy-related  SAE  (e.g.  spontaneous  abortion)  or  any  other  SAE  experienced  during 
 pregnancy  must  be  recorded  on  a  separate  SAE  Report  Form  provided  by  Pharmacovigilance  and 
 reported to Pharmacovigilance as per SAE reporting procedures. 
 Abnormal  pregnancy  outcomes  are  considered  SAEs  and  must  be  reported  using  the  SAE  Form. 
 Investigators  must  actively  follow-up,  document  and  report  to  Sponsor  the  progress  of  the 
 pregnancies  until  an  outcome  is  reached.  At  the  end  of  pregnancy,  the  Investigator  will  complete  an 
 End of Pregnancy Form provided by Pharmacovigilance and report it to Pharmacovigilance. 
 The  outcome  of  all  pregnancies  (spontaneous  miscarriage,  elective  termination,  normal  birth  or 
 congenital  abnormality)  must  be  followed  up  and  documented  even  if  the  patient  was  discontinued 
 from the study. 
 All  reports  of  congenital  abnormalities/birth  defects  are  SAEs.  Spontaneous  miscarriages  should 
 also  be  reported  and  handled  as  SAEs.  Elective  abortions  without  complications  should  not  be 
 handled as AEs. 
 9.5. 
 Reporting of individual SAEs and SUSARs by the Sponsor 
 Sponsor  ensures  that  all  reporting  requirements  and  timelines  for  reporting,  as  defined  in  the 
 applicable  national  law  will  be  followed.  MFAR  will  distribute  all  SUSAR  to  all  principal 
 Investigators,  and  to  each  Regulatory  Agency.  MFAR  will  forward  each  individual  SAE  to  the 
 coordinating investigator. 
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 9.6. 
 Periodic reporting on safety to principal investigators 
 The  Sponsor  through  MFAR  ensures  that  the  reporting  requirements  and  timelines  for  reporting,  as 
 defined  in  the  respective  applicable  laws,  are  followed.  A  Development  Safety  Update  Report 
 (DSUR)  will  be  provided  to  the  local  investigators  for  filing  into  the  investigator’s  file.  MFAR  will 
 submit the DSUR to the involved ECs and involved Regulatory Agencies. 
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 10. 
 S  TATISTICS 
 10.1.  Sample size calculation 
 Sample size calculation: 
 The  sample  calculation  has  been  done  for  the  initially  proposed  primary  endpoint  (cohort  1) 
 and it’s based on a Fleming’s Single Stage Procedure: 
 We  want  to  show  that  the  Intracranial  response  rate  by  modified  RECIST  1.1  before  local  treatment 
 is  superior  or  equal  to  the  reference  value,  say,  ϑ0=40%.  Under  the  hypothesis  to  have  a  response 
 rate  under  new  treatment  (π1)  of  60%  with  α  risk  =  5%  in  one-sided  test  and  a  power  of  80%,  the 
 required sample size is 38 patients. 
 Finally,  assuming  that,  20%  of  patients  will  be  lost  of  follow  up,  die  or  progress  before  day  56 
 without  doing  the  first  tumour  assessment  (according  data  published  in  COMBI-MB  study),  the 
 initial sample size will be 48 patients, to obtain 38 evaluable patients . 
 10.2.  Study endpoints 
 Intracranial  objective  response  (iORR)  rate  by  modified  RECIST  1.1  before  local  treatment  in 
 cohort  1  and  2:  iORR  calculated  as  the  proportion  of  patient  with  a  best  overall  intracranial 
 response  of  complete  response  (CR)  or  partial  response  (PR)  before  local  treatment  in  cohort  1 
 and  2.  The  final  statistical  analysis  of  this  endpoint  is  expected  to  be  performed  within  3  months 
 after  the  local  treatment  of  the  last  patient  in  any  cohort.  iORR  will  be  also  reported  separately  for 
 both cohorts. 
 Duration  of  intracranial  response  in  both  cohorts  (iDOR):  Calculated  as  the  time  from  the  date 
 of  first  documented  CR  or  PR  to  the  first  documented  intracranial  progression  or  death  due  to 
 underlying  cancer,  in  patients  with  documented  intracranial  CR  or  PR  before  local  treatment.  The 
 final  statistical  analysis  of  this  endpoint  is  expected  to  be  performed  within  6  months  after  database 
 closure  expected  at  24  months  after  last  patient  inclusion,  however  interim  analysis  might  be 
 performed when analysing other primary variables. 
 The  intracranial  progression  free  survival  (iPFS)  by  modified  RECIST  in  both  cohorts:  iPFS 
 is  defined  as  the  time  from  the  date  of  inclusion  to  the  date  of  the  first  documented  intracranial 
 disease  progression  or  death  due  to  any  cause,  whichever  occurs  first.  PFS  will  be  determined 
 based  on  tumour  assessment  (modified  RECIST  version  1.1  criteria).  The  local  Investigator's 
 assessments  will  be  used  for  analyses.  Those  patients  who  are  alive  and  have  not  progressed  at 
 the  last  follow-up,  date  of  progression  will  be  censored  at  the  date  of  the  last  follow-up.  Patient  with 
 no  additional  image  test  other  than  baseline  will  be  censored  to  the  day  after  to  inclusion.  The  final 
 statistical  analysis  of  this  endpoint  is  expected  to  be  performed  within  6  months  after  database 
 closure  expected  at  24  months  after  last  patient  inclusion,  however  interim  analysis  might  be 
 performed when analysing other primary variables. 
 Percentage  of  patients  free  of  intracranial  progression  at  6  (week  24),  12  (week  48)  and  24 
 months  (week  96)  in  both  cohorts:  percentage  of  patients  free  of  intracranial  progression 
 assessed  by  modified  RECIST  at  6  months  (week  24),  12  months  (week  48)  and  24-month  (week 
 96)  considering  date  of  inclusion.  The  final  statistical  analysis  of  this  endpoint  is  expected  to  be 
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 performed  within  6  months  after  database  closure  expected  at  24  months  after  last  patient 
 inclusion, however interim analysis might be performed when analysing other primary variables 
 Percentage  of  patients  (%)  free  of  extracraneal  progression  at  6  (week  24),  12  (week  28)  and 
 24  months  (week  96):  percentage  of  patients  free  of  progression  by  RECIST  1.1  at  6  months 
 (week  24),  12  months  (week  48)  and  24-month  (week  96)  considering  date  of  inclusion.  The  final 
 statistical  analysis  of  this  endpoint  is  expected  to  be  performed  within  6  months  after  database 
 closure  expected  at  24  months  after  last  patient  inclusion,  however  interim  analysis  might  be 
 performed when analysing other primary variables. 
 Overall  Survival  in  both  cohorts  (OS):  OS  is  calculated  as  the  time  from  date  of  inclusion  to  date 
 of  death  due  to  any  cause.  The  final  statistical  analysis  of  this  endpoint  is  expected  to  be 
 performed  within  6  months  after  database  closure  expected  at  24  months  after  last  patient 
 inclusion, however interim analysis might be performed when analysing other primary variables. 
 Percentage  of  patients  (%)  alive  at  6,  12  and  24  months  in  both  cohorts:  percentage  of 
 patients  alive  at  6  months,  12  month  and  24-month  considering  date  of  inclusion.  The  final 
 statistical  analysis  of  this  endpoint  is  expected  to  be  performed  within  6  months  after  database 
 closure  expected  at  24  months  after  last  patient  inclusion,  however  interim  analysis  might  be 
 performed when analysing other primary variables. 
 Toxicity  of  the  combination  until  local  treatment:  Number  of  patients  with  adverse  events  and 
 serious  adverse  events,  changes  in  laboratory  values,  vital  signs,  electrocardiograms  (ECGs), 
 LVEF  (MUGA  (Multigated  Acquisition  Scan)  /  echocardiogram)  and  assessment  of  physician, 
 dermatological  and  ocular  examinations  graded  according  to  the  National  Cancer  Institute  (NCI) 
 Common  Terminology  Criteria  for  Adverse  Events  (CTCAE)  v  4.03  until  local  treatment  (local 
 treatment  D1).  It  will  be  studied  using  descriptive  statistics  techniques,  such  as  frequency  tables 
 and  contingency  tables.  The  final  statistical  analysis  of  this  endpoint  is  expected  to  be  performed 
 within  6  months  after  database  closure  expected  at  24  months  after  last  patient  inclusion,  however 
 interim analysis might be performed when analysing other primary variables. 
 Toxicity  of  the  combination  after  local  treatment:  Number  of  patients  with  adverse  events  and 
 serious  adverse  events,  changes  in  laboratory  values,  vital  signs,  electrocardiograms  (ECGs), 
 LVEF  (MUGA  (Multigated  Acquisition  Scan)  /  echocardiogram)  and  assessment  of  physician, 
 dermatological  and  ocular  examinations  graded  according  to  the  National  Cancer  Institute  (NCI) 
 Common  Terminology  Criteria  for  Adverse  Events  (CTCAE)  v  4.03  after  local  treatment  (after  end 
 of  local  treatment  date).  It  will  be  studied  using  descriptive  statistics  techniques,  such  as  frequency 
 tables  and  contingency  tables.  The  final  statistical  analysis  of  this  endpoint  is  expected  to  be 
 performed  within  6  months  after  database  closure  expected  at  24  months  after  last  patient 
 inclusion, however interim analysis might be performed when analysing other primary variables. 
 Quality  of  life:  Change  from  baseline  in  the  global  health  status  score  of  the  EORTC  QLQ-C30. 
 The  final  statistical  analysis  of  this  endpoint  is  expected  to  be  performed  within  6  months  after 
 database  closure  expected  at  24  months  after  last  patient  inclusion,  however  interim  analysis  might 
 be performed when analysing other primary variables. 
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 10.3.  Efficacy assessment 
 Magnetic  contrast  enhanced  brain  resonance  imaging  (MRI)  and  body  CT  scan  will  be  performed 
 at  baseline  and  every  8  weeks  up  to  12  months  and  according  to  normal  practise  thereafter.  All 
 lesions  selected  as  target  and  non-target  lesions  in  the  initial  evaluation  will  be  measured 
 according  to  the  aforementioned  timeline,  until  disease  progression.  Imaging  tests  will  be 
 performed using the same method each time. 
 After  local  treatment,  intracranial  lesions  (both  target  and  non-target  lesions)  will  be  considered  as 
 non-evaluable  (NE),  brain  MRI  be  performed  as  per  protocol  (every  8  weeks  until  first  year  and 
 according  to  normal  practise  thereafter)  however  disease  will  be  followed  only  to  determine  iPFS 
 (unequivocal disease progression or new lesions). 
 10.3.1 Assessment of response guidelines 
 Table 12. Criteria for disease evaluation for target lesions 
 CR 
 Disappearance  of  all  target  lesions.  Any  pathological  lymph  nodes  (whether  target  or  non-target)  must 
 have reduction in short axis to <10 mm 
 PR 
 At  least  a  30%  decrease  in  the  sum  of  diameters  of  target  lesions,  taking  as  reference  the  baseline  sum 
 diameters. 
 PD 
 At  least  a  20%  increase  in  the  sum  of  diameters  of  target  lesions,  taking  as  reference  the  smallest  sum 
 on  study  (this  includes  the  baseline  sum  if  that  is  the  smallest  on  study).  In  addition  to  the  relative 
 increase  of  20%,  the  sum  must  also  demonstrate  an  absolute  increase  of  at  least  5  mm.  (Note:  the 
 appearance of one or more new lesions is also considered progression). 
 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. 
 Table 13. Criteria for disease evaluation for non-target lesions 
 CR 
 Disappearance  of  all  non-target  lesions  and  normalisation  of  tumour  marker  level.  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)  and/or  maintenance  of  tumour  marker  level 
 above the normal limits. 
 PD 
 Unequivocal  progression  (see  comments  below)  of  existing  non-target  lesions.  (Note:  the 
 appearance of one or more new lesions is also considered progression). 
 Table 14: Overall Response Assessment (RECIST) 
 Target Lesions 
 Non-target Lesions 
 New Lesions 
 Overall Response 
 CR 
 CR 
 No 
 CR 
 CR 
 Non-CR/non-PD 
 No 
 PR 
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 CR 
 Not evaluated 
 No 
 PR 
 PR 
 Non-PD or not all evaluated 
 No 
 PR 
 SD 
 Non-PD or not all evaluated 
 No 
 SD 
 Not all evaluated 
 Non-PD 
 No 
 NE 
 PD 
 Any 
 Yes or No 
 PD 
 Any 
 PD 
 Yes or No 
 PD 
 Any 
 Any 
 Yes 
 PD 
 CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, and NE = not 
 evaluable 
 Disease  progression  and  response  evaluations  for  intracranial  and  extracranial  disease  will  be 
 determined  according  to  the  definitions  established  in  the  Response  Evaluation  Criteria  in  Solid 
 Tumours  (RECIST  1.  1);  Minor  modifications  will  be  applied  to  the  assessment  of  intracranial 
 lesions: 
 Intracranial  response  assessment:  The  Investigator  modified  RECIST  1.1  criteria  will  be  used  to 
 evaluate  the  intracranial  response.  The  modifications  to  RECIST  1.1  impact  the  number  and  the 
 minimal  size  of  the  target  lesions  selected  at  baseline.  Up  to  5  intracranial  lesions  should  be 
 selected  as  target;  based  on  size  and  evaluation/tracking  feasibility.  All  the  remaining  brain  lesions 
 different  from  these  5  target  lesions  must  be  considered  as  non-target  lesions  (independently  of 
 their  size).  The  size  of  target  and  non-target  lesions  must  be  measured.  Measurable  lesions  are 
 defined  as  those  that  can  be  accurately  measured  in  at  least  one  dimension  with  the  longest 
 diameter ≥ 5 mm when evaluated by contrast-enhanced MRI. 
 For  intracranial  response,  target  lesions  as  small  as  5  mm  may  be  selected,  however  the  scanning 
 should  be  in  accordance  with  modified  RECIST  1.1  (contiguous  slices  of  maximum  thickness 
 corresponding to half the size of the lesion. 
 Contrast-enhanced  MRI  is  the  only  modality  accepted  for  the  assessment  of  intracranial  lesions 
 For justified exceptions please, contact with the sponsor: investigación@mfar.net). 
 10.3.2 Measurable and non-measurable definitions for response assessment 
 ●  RECIST 1.1 standard definitions will be used 
 10.3.3 Measurable and non-measurable definitions for intracranial response assessment 
 ●  Measurable intracranial lesion: a measure that can be accurately measured at least in one 
 dimension with the longest diameter ≥ 5 mm when evaluated by contrast-enhanced MRI. 
 ●  Non-measurable intracranial lesion: all other lesions, including those too small to be 
 considered measurable (longest diameter < 5 mm). 
 ●  Measurable intracranial disease: The presence of at least one measurable lesion. 
 ●  Non-measurable intracranial (only) disease: The presence of only non-measurable lesions, 
 which at baseline excludes the patient for participation in the study. 
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 10.4.  Safety assessment 
 All  patients  included  in  the  trial  and  have  received  at  least  one  dose  of  study  medication  will  be 
 evaluable for safety analysis. 
 Safety  and  tolerability  of  study  medication  will  be  determined  by  evaluating  the  type,  incidence, 
 frequency,  severity  and  relation  to  the  treatment  of  reported  adverse  events,  physical  examinations 
 and  laboratory  tests.  Any  signs  and/or  symptoms  associated  with  the  existing  tumour  at  baseline 
 worsening  (in  severity  or  frequency)  during  the  trial  should  be  reported  as  an  adverse  event.  They 
 should record all adverse events according to the NCI-CTCAE version 4.03 in each study visit. 
 10.5.  Definition of study populations 
 Data of study will be analysed in the following populations: 
 1.  ITT:  All patients that have been enrolled in the trial. 
 2.  Evaluable  population  per  protocol  (PP) :  All  patients  fulfilling  all  eligibility  criteria  and 
 having  at  least  two  valid  tumour  assessments  (baseline  and  one  evaluation  MRI  or 
 CT-scan)  without  any  protocol  deviation  that  makes  the  patient  invalid  for  the 
 primary endpoint evaluation. 
 3.  Safety population : All patients receiving at least  one dose of treatment. 
 10.6.  Statistical analysis 
 For  each  categorical  variable,  the  results  will  be  summarized  by  frequencies  and  percentages.  For 
 each  continuous  variable,  the  results  will  be  summarized  by  descriptive  statistics  such  as  median, 
 range,  and  interquartile  range  or  by  means,  standard  deviations  and  95%  confidence  intervals 
 (CIs).  For  proportions,  point  estimates  and  exact  95%  confidence  intervals  will  be  calculated.  For 
 time  to  event  endpoints,  Kaplan-Meier  estimates  at  selected  time  points  and  corresponding  curves 
 will  be  presented.  Time  to  event  is  derived  relative  to  the  first  study  treatment  administration. 
 Laboratory  values  will  be  expressed  as  the  absolute  values  and  as  grading  (ordinal  categorical 
 variables) according to NCI CTCAE v 4.03. 
 Treatment-emergent  AE  (AEs  starting  after  the  administration  of  study  treatment  and  up  to  study 
 completion)  will  be  summarized  by  system  organ  class  and  preferred  term.  Grading  will  be 
 presented  by  type  and  grade  in  tables  showing  frequency  and  percentage  of  the  within-patient 
 worst  grades.  In  addition,  grade  ≥3  AEs  will  be  summarized  separately.  Full  analysis  details  will  be 
 outlined in the statistical analysis plan (SAP). 
 10.7.  Statistical Methods 
 Analysis  will  be  based  on  observed  data,  and  missing  data  for  dropouts  are  not  replaced  by 
 methods like LOCF (last option carried forward). 
 Continuous  data  will  be  presented  with  the  number  of  observations,  mean  value  +  standard 
 deviation,  median  value  +  minimum  and  maximum.  Categorical  data  will  be  presented  as  counts 
 and percentages. Individual subject data will be listed. 
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 Individual  and  summary  vital  signs,  ECG  parameters,  clinical  laboratory  data  (haematology,  serum 
 biochemistry  and  urinalysis)  will  be  presented  in  tabular  form.  For  the  values  outside  the  reference 
 range  will  be  flagged  and  for  the  clinically  significantly  abnormal  values  will  be  listed  in  tabular 
 form.  Adverse  events  will  be  tabulated  by  system  organ  class  and  preferred  term  after  medical 
 coding using the NCI CTCAE v 4.03. 
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 11. 
 D  IRECT  ACCESS  TO  SOURCE  DATA /  DOCUMENTS 
 11.1. 
 Source data definition 
 Source  data  is  defined  as  all  data  in  original  records  and  certified  copies  of  original  records  of 
 clinical  findings,  observations,  or  other  activities  in  a  clinical  trial  that  are  necessary  for  the 
 reconstruction and evaluation of the trial. 
 The  Investigator  must  keep  a  file  (medical  file,  original  medical  records)  on  paper  or  electronically 
 for  every  subject  in  the  trial.  It  must  be  possible  to  identify  each  subject  by  using  this  subject  file. 
 This  file  will  contain  the  demographic  and  medical  information  for  the  subject  listed  below  and 
 should be as complete as possible. 
 ●  Subject’s full name, date of birth, sex, height, weight 
 ●  Medical history and concomitant diseases 
 ●  Prior and concomitant therapies (including changes during the trial) 
 ●  Trial  identification,  that  is,  the  Sponsor  trial  number  for  this  clinical  trial,  and  subject 
 number 
 ●  Dates for entry into the trial (informed consent) and visits to the site 
 ●  Any medical examinations and clinical findings predefined in this clinical trial protocol 
 ●  All AEs 
 ●  Date  that  the  subject  left  the  trial  including  any  reason  for  early  withdrawal  from  the  trial 
 or IMP (if applicable). 
 All  documents  containing  source  data  must  be  filed,  including,  but  not  limited  to  CT  or  MRI  scan 
 images,  ECG  recordings,  and  laboratory  results.  Such  documents  must  bear  the  subject  number 
 and  the  date  of  the  procedure.  If  possible,  this  information  should  be  printed  by  the  instrument 
 used  to  perform  the  assessment  or  measurement.  Medical  evaluation  of  such  records  will  be 
 performed as necessary; all evaluations will be documented, signed, and dated by the Investigator. 
 Electronic  subject  files  will  be  printed  whenever  the  Monitor  performs  source  data  verification. 
 Printouts  will  be  signed  and  dated  by  the  Investigator,  countersigned  by  the  Monitor,  and  will  be 
 secured in a safe place at the site. 
 11.2. 
 Study Monitoring 
 During  the  study,  according  to  monitoring  plan,  a  monitor  from  MFAR  or  a  representative  will  have 
 regular contact with the investigational site, for the following: 
 ●  Provide information and support to the investigator(s) 
 ●  Confirm that facilities remain acceptable 
 ●  Confirm  that  the  investigational  team  is  adhering  to  the  protocol,  data  are  being 
 accurately  recorded  in  the  case  report  forms,  and  that  investigational  product 
 accountability checks are being performed 
 ●  Perform  source  data  verification.  This  includes  a  comparison  of  the  data  in  the  case 
 report  forms  with  the  patient’s  medical  records  at  the  hospital  or  practice,  and  other 
 records  relevant  to  the  study.  This  will  require  direct  access  to  all  original  records  for 
 each patient (e.g. clinic charts). 
 ●  Record and report any protocol deviations not previously sent to MFAR 
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 ●  Confirm  that  AEs  and  SAEs  have  been  properly  documented  on  CRFs  and  confirm  that 
 all  SAEs  have  been  forwarded  to  MFAR,  additionally,  confirm  that  all  the  SAEs  that  met 
 criteria for reporting have been forwarded to the IRB 
 The  monitor  will  be  available  between  visits  if  the  investigator(s)  or  other  staff  members  need 
 information or advice. 
 11.3. 
 Audits and Inspections 
 Authorized  representatives  of  Sponsor,  a  regulatory  authority,  an  Independent  Ethics  Committee  or 
 an  Institutional  Review  Board  may  visit  the  site  to  perform  audits  or  inspections,  including  source 
 data  verification.  The  purpose  of  a  Sponsor  audit  or  inspection  is  to  systematically  and 
 independently  examine  all  study-related  activities  and  documents  to  determine  whether  these 
 activities  were  conducted,  and  data  were  recorded,  analysed,  and  accurately  reported  according  to 
 the  protocol,  Good  Clinical  Practice  guidelines  of  the  International  Conference  on  Harmonization, 
 and  any  applicable  regulatory  requirements.  The  investigator  should  contact  Sponsor  through 
 MFAR immediately if contacted by a regulatory agency about an inspection. 
 11.4. 
 Independent  Ethical  Committee  (IEC)  or  Institutional  Review  Board  (IRB) 
 Review 
 Prior  to  commencement  of  the  trial  at  a  given  site,  this  clinical  trial  protocol  will  be  submitted 
 together  with  its  associated  documents  to  the  Central  IEC  for  its  favourable  opinion,  which  will  be 
 filed in the Investigator Site File. A copy will be filed in the Sponsor Trial Master File. 
 The  IEC  will  be  asked  to  document  the  date  of  the  meeting  at  which  the  favourable  opinion  or 
 approval  was  given  and  the  members  and  voting  members  present.  Written  evidence  of  favourable 
 opinion  or  approval  that  clearly  identifies  the  trial,  the  clinical  trial  protocol  version  and  the  Subject 
 Information and Informed Consent Form version reviewed should be provided. 
 Amendments  to  this  clinical  trial  protocol  will  also  be  submitted  to  the  concerned  IEC  or  IRB,  before 
 implementation  of  substantial  changes.  Relevant  safety  information  will  be  submitted  to  the  IEC 
 during the course of the trial in accordance with national regulations and requirements. 
 Initial  IEC  positive  vote,  and  all  materials  approved  by  the  IEC  for  this  study  including  the  patient 
 consent  form  and  recruitment  materials  must  be  maintained  by  the  Investigator  and  made  available 
 for inspection. 
 11.5. 
 Ethical Conduct of the Study 
 The  study  will  be  performed  in  accordance  with  ethical  principles  that  have  their  origin  in  the 
 Declaration  of  Helsinki  and  are  consistent  with  ICH/Good  Clinical  Practice,  applicable  regulatory 
 requirements. 
 11.6. 
 Written Informed Consent 
 The  Principal  Investigator(s)  at  each  centre  will  ensure  that  the  patient  is  given  full  and  adequate 
 oral  and  written  information  about  the  nature,  purpose,  possible  risk  and  benefit  of  the  study. 
 Patients  must  also  be  notified  that  they  are  free  to  discontinue  from  the  study  at  any  time.  The 
 patient  should  be  given  the  opportunity  to  ask  questions  and  allowed  time  to  consider  the 
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 information  provided.  The  patient’s  signed  and  dated  informed  consent  must  be  obtained  before 
 conducting any study procedures. 
 The  Principal  Investigator(s)  will  retain  the  original,  signed  ICF;  this  form  will  be  made  available  for 
 reviewing  during  monitoring  visits.  A  copy  of  the  signed  ICF  will  be  provided  to  the  patient.  The 
 Principal Investigator will document the informed consent procedure in the patient medical records. 
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 12. 
 Q  UALITY  CONTROL  AND  QUALITY  ASSURANCE 
 To  ensure  compliance  with  Good  Clinical  Practices  and  all  applicable  regulatory  requirements,  the 
 Sponsor may conduct a quality assurance audit. 
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 13. 
 D  ATA  HANDLING  AND  RECORD  KEEPING 
 The  data  will  be  recorded  using  the  Electronic  Data  Capture  software  property  of  MFAR,  SL  which 
 is  developed  and  maintained  with  strict  observance  of  the  regulatory  standards  for  Clinical  EDC 
 systems, with special observance of the guidelines specified at: 
 ● 
 CPMP/ICH/135/95. ICH E6. Note for Guidance on Good Clinical Practice. 
 ● 
 Good  Clinical  Data  Management  Practice,  Version  4,  Society  for  Clinical  Data 
 Management (SCDM), October 2005. 
 ● 
 EMEA.  Reflection  on  expectations  for  electronic  source  documents  used  in  clinical  trials. 
 London, 17 October 2007. 
 ● 
 Directive  9  Guidance  for  Industry.  Part  11,  Electronic  Records;  Electronic  Signatures  – 
 Scope and Application (August 2003). 
 ● 
 FDA.  Guidance  for  Industry.  Computerized  Systems  Used  in  Clinical  Investigations  (May 
 2007). 
 ● 
 FDA.  Guidance  for  Industry.  Part  11,  Electronic  Records;  Electronic  Signatures  –  Scope 
 and Application (August 2003) 
 The  EDC  database  is  hosted  at  data  server  located  at  the  Data  Center  maintained  by  Claranet 
 SAU  located  at  “ Calle  Juan  Gris,  10-18,  08014  Barcelona ” .  The  physical  access  to  the  Data  Center 
 is  restricted  to  authorized  Claranet  personnel,  and  the  logical  access  to  the  database  is  restricted 
 to named MFAR personnel. 
 All  the  EDC  users  are  uniquely  identified  by  name,  all  the  access  to  the  software  are  made  through 
 a secure, encrypted connection and all the activity is logged and audited. 
 All  the  EDC  forms  are  built  according  to  the  CRF  defined  by  the  study  protocol  and  is  validated 
 according the DVP (Data Validation Plan) associated. 
 13.1.  Inspection of Records 
 The  Sponsor  will  be  allowed  to  conduct  site  visits  to  the  investigation  facilities  for  the  purpose  of 
 monitoring  any  aspect  of  the  study.  The  Investigator  agrees  to  allow  the  monitor  to  inspect  the  drug 
 storage  area,  study  drug  stocks,  drug  accountability  records,  subject  charts  and  study  source 
 documents, and other records relative to study conduct. 
 13.2.  Retention of Records 
 Upon  initiation  of  the  trial,  the  Investigator  will  be  provided  with  an  Investigator  Site  File  containing 
 all  necessary  trial  documents,  which  will  be  completed  throughout  the  trial  and  updated  as 
 necessary.  The  file  must  be  available  for  review  by  the  Monitor  during  Sponsor  audits,  and  for 
 inspection  by  Health  Authorities  during  and  after  the  trial.  Moreover,  the  file  must  be  safely 
 archived  for  at  least  25  years  (as  per  local  requirements)  after  the  end  of  the  trial.  The  documents 
 to  be  archived  include  the  Subject  Identification  List  and  the  signed  subject  Informed  Consent 
 Forms.  If  archiving  of  the  Investigator  Site  File  is  no  longer  possible  at  the  site,  the  Investigator 
 must notify the Sponsor/designee. 
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 All  original  subject  files  (medical  records)  must  be  stored  at  the  site  (hospital,  research  institution, 
 or  practice)  for  the  longest  possible  time  permitted  by  the  applicable  regulations,  and/or  as  per  ICH 
 GCP  guidelines,  whichever  is  longer  (In  Spain  25  years).  In  any  case,  the  Investigator  should 
 ensure  that  no  destruction  of  medical  records  is  performed  without  the  written  approval  of  the 
 Sponsor. 
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 14. 
 P  UBLICATION  P  OLICY 
 As  stated  in  article  42  of  RD  1090/2015  of  clinical  trials,  the  Sponsor  is  obliged  to  publish  both 
 positive  and  negative  results  of  the  authorized  clinical  trials  in  scientific  journals  and  with  mention 
 to the Ethical Committee of Clinical Research that approved the study. 
 After  completion  of  the  trial,  the  clinical  publication  will  be  carried  out  by  the  Coordinating 
 Investigator  in  collaboration  and  Principal  Investigators,  however  interim  analysis  of  preliminary 
 data  of  primary/secondary  endpoints  may  be  published  by  the  Sponsor  in  scientific  meetings 
 and/or  Congresses.  The  order  of  authors  will  strictly  depend  on  the  number  of  eligible  patients 
 included  by  the  Investigators.  Coordinating  investigators  will  be  first  and  last  authors,  and  the 
 number  of  the  rest  of  the  authors  will  depend  on  the  above  rule  and  the  requirements  of  the 
 congresses and/or journals. 
 The  results  will  be  published  in  two  publications.  It  is  estimated  that  the  first  publication  will  include 
 the  results  of  the  analysis  of  the  primary/secondary  endpoints  and  will  include  data  from  the 
 symptomatic  cohort.  The  second  publication  will  include  the  results  of  the  analysis  of  the 
 primary/secondary  endpoints  from  the  asymptomatic  cohort  and  potential  comparisons  between 
 both  cohorts.  The  Investigator  will  inform  the  Sponsor  in  advance  about  any  plans  to  publish  or 
 present  data  from  the  trial.  Any  publications  and  presentations  of  the  results  (abstracts  in  journals 
 or  newspapers,  oral  presentations,  etc.),  either  in  whole  or  in  part,  by  Investigators  or  their 
 representatives will require written authorization by the Sponsor before submission. 
 The  anonymity  of  the  source  subjects  of  the  data  and  biological  samples  will  be  maintained  at  all 
 times.  The  results  or  conclusions  of  the  study  will  be  communicated  primarily  in  scientific 
 publications  before  being  released  to  the  non-health  public.  No  efficacy  study  outcome  will  be 
 reported  prematurely  or  in  a  sensationalistic  way.  Participating  investigators  should  not  publish  any 
 patient data that is directly related to the study objectives until the trial report is published. 
 The  trial  will  be  registered  in  the  Spanish  Registry  of  Clinical  Studies  (REEC  -  Registro  Español  de 
 Estudios Clínicos ) and  Clinical trials.gov  before  including the first patient. 
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 15. 
 L  IST  OF  R  EFERENCES 
 1. 
 Jemal  A,  Siegel  R,  Xu  J,  Ward  E.  Cancer  statistics,  2010.  CA  Cancer  J  Clin.  2010  Sep-Oct. 
 60(5):277-300. [Medline]. 
 2. 
 Kirkwood  JM,  Strawderman  MH,  Ernstoff  MS,  Smith  TJ,  Borden  EC,  Blum  RH.  Interferon 
 alfa-2b  adjuvant  therapy  of  high-risk  resected  cutaneous  melanoma:  the  Eastern  Cooperative 
 Oncology Group Trial EST 1684. J Clin Oncol. 1996 Jan. 14(1):7-17. [Medline]. 
 3. 
 Weber  J  Adjuvant  Nivolumab  versus  Ipilimumab  in  Resected  Stage  III  or  IV  Melanoma.  N 
 Engl  J  Med.  2017  Nov  9;377(19):1824-1835.  doi:  10.1056/NEJMoa1709030.  Epub  2017  Sep 
 10. https://doi.org/10.1056/NEJMoa1302369. 
 4. 
 Hodi  FS,  O’Day  SJ,  McDermott  DF,  Weber  RW,  Sosman  JA,  Haanen  JB,  et  al.  Improved 
 survival  with  Ipilimumab  in  patients  with  metastatic  melanoma.  N  Engl  J  Med. 
 2010;363:711–23. https://doi.org/10.1056/NEJMoa1003466. 
 5. 
 Robert  C,  Schachter  J,  Long  GV,  Arance  A,  Grob  JJ,  Mortier  L,  et  al.  Pembrolizumab  versus 
 Ipilimumab 
 in 
 Advanced 
 Melanoma. 
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 Engl 
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 Med. 
 2015;372:2521–32. 
 https://doi.org/10.1056/NEJMoa1503093. 
 6. 
 FDA 
 website: 
 https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm590004.htm 
 7. 
 Dummer  R1,  Ascierto  PA2,  et  al.  Encorafenib  plus  binimetinib  versus  vemurafenib  or 
 encorafenib  in  patients  with  BRAF-mutant  melanoma  (COLUMBUS):  a  multicentre, 
 open-label,  randomised  phase  3  trial.  Lancet  Oncol.  2018  May;19(5):603-615.  doi: 
 10.1016/S1470-2045(18)30142-6. Epub 2018 Mar 21 
 8. 
 BRAF/MEK  Combo  Approved  for  Melanoma.  Cancer  discovery  September  2018  Volume  8, 
 Issue 9 ( http://cancerdiscovery.aacrjournals.org/content/8/9/OF5 
 9. 
 Hauschild  A,  Grob  JJ,  et  al.  Dabrafenib  in  BRAF-mutated  metastatic  melanoma:  a 
 multicentre, 
 open-label, 
 phase 
 3 
 randomised 
 controlled 
 trial. 
 Lancet. 
 2012  Jul 
 28;380(9839):358-65. doi: 10.1016/S0140-6736(12)60868-X. Epub 2012 Jun 25. 
 10.  Kim  G,  McKee  AE,  et  al.  FDA  approval  summary:  vemurafenib  for  treatment  of  unresectable 
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 1;20(19):4994-5000. doi: 10.1158/1078-0432.CCR-14-0776. Epub 2014 Aug 5 
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 recombinant  interleukin  2  therapy  for  patients  with  metastatic  melanoma:  analysis  of  270 
 patients treated between 1985 and 1993. J Clin Oncol. 1999 Jul. 17(7):2105-16. [Medline]. 
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 Anexo 1: 
 EORTC QLQ-C30  (versión 3) 
 Estamos  interesados  en  conocer  algunas  cosas  sobre  usted  y  su  salud.  Por  favor,  responda  a  todas  las 
 preguntas  personalmente,  rodeando  con  un  círculo  el  número  que  mejor  se  aplique  a  su  caso.  No  hay 
 contestaciones  "acertadas"  o  "desacertadas".  La  información  que  nos  proporcione  será  estrictamente 
 confidencial. 
 Por favor ponga sus iniciales: 
 _________________ 
 Su fecha de nacimiento (día, mes, año): 
 _________________ 
 Fecha de hoy (día, mes, año): 
 31 
 _________________ 
 En 
 absoluto 
 Un 
 poco 
 Bastante 
 Mucho 
 1.  ¿Tiene  alguna  dificultad  para  hacer  actividades  que 
 requierea  un  esfuerzo  importante,  como  llevar  una  bolsa 
 de compra pesada o una maleta? 
 1 
 2 
 3 
 4 
 2.  ¿Tiene alguna dificultad para dar un paseo  largo ? 
 1 
 2 
 3 
 4 
 3.  ¿Tiene  alguna  dificultad  para  dar  un  paseo  corto 
 fuera de casa? 
 1 
 2 
 3 
 4 
 4.  ¿Tiene  que  permanecer  en  la  cama  o  sentado/a  en 
 una silla durante el día? 
 1 
 2 
 3 
 4 
 5.  ¿Necesita  ayuda  para  comer,  vestirse,  asearse  o  ir  al 
 servicio? 
 1 
 2 
 3 
 4 
 Durante la semana pasada: 
 En 
 absolu 
 to 
 Un 
 poco 
 Bastante 
 Mucho 
 6.  ¿Ha  tenido  algún  impedimento  para  hacer  su 
 trabajo u otras actividades cotidianas? 
 1 
 2 
 3 
 4 
 7.  ¿Ha  tenido  algún  impedimento  para  realizar  sus 
 aficiones u otras actividades de ocio? 
 1 
 2 
 3 
 4 
 GEM 1802 - Protocol version 5.0, 4. JUL. 2022 
 Page  88  of  94 


 8.  ¿Tuvo  sensación  de  "falta  de  aire"  o  dificultad  para 
 respirar? 
 1 
 2 
 3 
 4 
 9.  ¿Ha tenido dolor? 
 1 
 2 
 3 
 4 
 10. ¿Necesitó parar para descansar? 
 1 
 2 
 3 
 4 
 11. ¿Ha tenido dificultades para dormir? 
 1 
 2 
 3 
 4 
 12. ¿Se ha sentido débil? 
 1 
 2 
 3 
 4 
 13. ¿Le ha faltado el apetito? 
 1 
 2 
 3 
 4 
 14. ¿Ha tenido náuseas? 
 1 
 2 
 3 
 4 
 15. ¿Ha vomitado? 
 1 
 2 
 3 
 4 
 16. ¿Ha estado estreñido/a? 
 1 
 2 
 3 
 4 
 Por favor, continúe en la página siguiente 
 GEM 1802 - Protocol version 5.0, 4. JUL. 2022 
 Page  89  of  94 


 Durante la semana pasada: 
 En 
 absoluto 
 Un 
 poco 
 Bastante 
 Mucho 
 17. ¿Ha tenido diarrea? 
 1 
 2 
 3 
 4 
 18. ¿Estuvo cansado/a? 
 1 
 2 
 3 
 4 
 19.  ¿Interfirió  algún  dolor  en  sus  actividades 
 diarias? 
 1 
 2 
 3 
 4 
 20.  ¿Ha  tenido  dificultad  en  concentrarse  en  cosas 
 como leer el periódico o ver la televisión? 
 1 
 2 
 3 
 4 
 21. ¿Se sintió nervioso/a? 
 1 
 2 
 3 
 4 
 22. ¿Se sintió preocupado/a? 
 1 
 2 
 3 
 4 
 23. ¿Se sintió irritable? 
 1 
 2 
 3 
 4 
 24. ¿Se sintió deprimido/a? 
 1 
 2 
 3 
 4 
 25. ¿Ha tenido dificultades para recordar cosas? 
 1 
 2 
 3 
 4 
 26.  ¿Ha  interferido  su  estado  físico  o  el 
 tratamiento médico en su vida familiar? 
 1 
 2 
 3 
 4 
 27.  ¿Ha  interferido  su  estado  físico  o  el 
 tratamiento médico en sus actividades sociales? 
 1 
 2 
 3 
 4 
 28.  ¿Le  han  causado  problemas  económicos  su 
 estado físico o el tratamiento médico? 
 1 
 2 
 3 
 4 
 GEM 1802 - Protocol version 5.0, 4. JUL. 2022 
 Page  90  of  94 


 Por  favor  en  las  siguientes  preguntas,  ponga  un  círculo  en  el  número  del  1  al  7 
 que mejor se aplique a usted 
 29.  ¿Cómo valoraría su  salud  general durante la semana pasada? 
 1 
 2               3 
 4 
 5 
 6 
 7 
 Pésima 
 Excelente 
 30.  ¿Cómo valoraría su  calidad de vida  en general  durante la semana pasada? 
 1 
 2               3 
 4 
 5 
 6 
 7 
 Pésima 
 Excelente 
 © QLQ-C30 Copyright 1995 EORTC Quality of Life Group. Reservados todos los derechos. Versión 3.0 
 GEM 1802 - Protocol version 5.0, 4. JUL. 2022 
 Page  91  of  94 


 Appendix 2: 
 Í  NDICE  DE  B  ARTHEL  MODIFICADO  DE  ACTIVIDADES  BÁSICAS  DE  LA  VIDA  DIARIA 
 Instrucciones:  Seleccione  la  puntuación  para  cada  afirmación  que  más  se  ajuste  al  nivel  de  capacidad 
 actual  del  paciente  para  cada  uno  de  los  10  ítems  siguientes.  Registre  la  actividad  actual,  no  la  potencial.  La 
 información  puede  obtenerse  a  través  del  propio  paciente,  de  una  persona  que  esté  familiarizada  con  las 
 capacidades  del  paciente  (como  un  familiar),  o  de  la  observación.  Véase  el  apartado  de  directrices  de  la 
 página siguiente para más información sobre la puntuación e interpretación. 
 Control de heces 
 0  =  incontinente  (o  necesita  que  le  administren 
 enemas) 
 1 = accidente excepcional (uno/semana) 
 2 = continente 
 Puntuación del paciente: 
 Control de orina 
 0  =  incontinente,  o  sondado  e  incapaz  de  cambiarse 
 la bolsa. 
 1 = accidente excepcional (máximo uno/24 horas). 
 2 = continente (durante al menos 7 días) 
 Puntuación del paciente: 
 Aseo personal 
 0 = necesita ayuda con el aseo personal 
 1  =  independiente  para  lavarse  la  cara,  las  manos 
 y  los  dientes,  y  afeitarse  (proporcionados  los 
 instrumentos) 
 Puntuación del paciente: 
 Uso del retrete 
 0 = dependiente 
 1  =  necesita  alguna  ayuda,  pero  puede  hacer  algo 
 solo 
 2  =  independiente  (entrar  y  salir,  limpiarse  y 
 vestirse) 
 Puntuación del paciente: 
 Comer 
 0 = incapaz 
 1 
 = 
 necesita 
 ayuda 
 para 
 cortar, 
 extender 
 mantequilla, etc. 
 2  =  independiente  (la  comida  está  al  alcance  de  la 
 mano) 
 Puntuación del paciente: 
 Trasladarse entre la silla y la cama 
 0 = incapaz, no se mantiene sentado 
 1  =  necesita  ayuda  importante  (una  persona  o  dos 
 personas, física), puede estar sentado 
 2 = necesita algo de ayuda (física o verbal) 
 3 = independiente 
 Puntuación del paciente: 
 Desplazarse 
 0 = inmóvil 
 1  =  independiente  en  silla  de  ruedas,  incluidas  las 
 esquinas, etc. 
 2  =  anda  con  pequeña  ayuda  de  una  persona  (física 
 o verbal) 
 3  =  independiente  (pero  puede  usar  cualquier  tipo 
 de ayuda, p. ej., bastón) 
 Puntuación del paciente: 
 Vestirse y desvestirse 
 0 = dependiente 
 1 = necesita ayuda, pero puede hacerlo a medias 
 2  =  independiente  (incluidos  botones,  cremalleras, 
 cordones, etc.) 
 Puntuación del paciente: 
 Subir y bajar escaleras 
 0 = incapaz 
 1  =  necesita  ayuda  (física  o  verbal,  puede  llevar 
 cualquier tipo de muleta) 
 2 = independiente para subir y bajar 
 Puntuación del paciente: 
 Bañarse/Ducharse 
 0 = dependiente 
 1 = independiente 
 Puntuación del paciente: 
 Puntuación total: 
 -------------- 
 GEM 1802 - Protocol version 5.0, 4. JUL. 2022 
 Page  92  of  94 


 Puntuación: 
 Sume  las  puntuaciones  del  paciente  en  cada  ítem.  Las 
 puntuaciones totales posibles oscilan entre 0 y 
 20,  y  las  puntuaciones  más  bajas  indican  un 
 incremento  de  la  incapacidad.  Si  se  utiliza  para  medir 
 la  mejoría  después  de  rehabilitación,  los  cambios  en 
 más  de  dos  puntos  en  la  puntuación  total  reflejan 
 posible  cambios  reales,  y  también  es  probable  un 
 cambio  en  un  ítem  de  completamente  dependiente  a 
 independiente. 
 Directrices para el Índice de Barthel 
 de actividades básicas de la vida diaria 
 Aspectos generales 
 •  El  índice  de  Barthel  se  debe  utilizar  como  registro  de 
 lo que un paciente hace, NO como registro de lo 
 que el paciente podría hacer. 
 •  El  objetivo  principal  es  establecer  el  grado  de 
 independencia del paciente de cualquier tipo de 
 ayuda,  física  o  verbal,  por  mínima  que  sea  y  por 
 cualquier razón. 
 •  La  necesidad  de  supervisión  hace  al  paciente  no 
 independiente. 
 •  La  funcionalidad  del  paciente  se  debe  establecer 
 usando la mejor evidencia disponible. 
 Preguntar  al  paciente,  amigos/familiares  y  cuidadores 
 será la fuente habitual, pero la 
 observación  directa  y  el  sentido  común  también  son 
 importantes.  No  obstante,  no  será  necesaria  una 
 prueba directa. 
 •  Por  lo  general,  la  funcionalidad  del  paciente  durante 
 las  24  -  48  horas  anteriores  es  importante,  pero 
 ocasionalmente  serán  pertinentes  periodos  más  largos 
 de tiempo. 
 •  A  los  pacientes  con  pérdida  de  conciencia  se  les 
 puntuará con "0" en todos los ítems, aunque aún no 
 presenten incontinencia. 
 •  Las  categoría  intermedias  implican  que  el  paciente 
 realiza más del 50 % del esfuerzo. 
 •  Está  permitido  el  uso  de  ayudas  para  ser 
 independiente. 
 Control de heces (semana anterior) 
 •  Si  fue  necesario  que  el  cuidador  aplicará  un  enema, 
 se considera "incontinente". 
 • «Ocasional» = una vez a la semana. 
 Control de orina (semana anterior) 
 • «Ocasional» = menos de una vez al día. 
 •  Un  paciente  con  sonda  que  pueda  manejar 
 completamente  la  sonda  por  sí  solo  se  registrará  como 
 "continente". 
 Aseo personal (24 - 48 horas anteriores) 
 •  Se  refiere  a  la  higiene  personal:  lavarse  los  dientes, 
 colocarse la dentadura postiza, peinarse, 
 afeitarse,  lavarse  la  cara.  Los  instrumentos  los  puede 
 proporcionar el cuidador. 
 Uso del retrete 
 •  Si  es  capaz  de  alcanzar  el  retrete/tapa  del  retrete, 
 desvestirse de forma suficiente, limpiarse por sí 
 mismo, vestirse y salir. 
 •  "Con  ayuda"  =  puede  limpiarse  por  sí  solo  y  hacer 
 algunas de las tareas indicadas anteriormente 
 Comer 
 •  Capaz  de  ingerir  alimentos  normales  (no  solo 
 alimentos  blandos).  Alimentos  cocinados  y  servidos 
 un tercero, pero sin cortar. 
 •  «Ayuda»  =  cortándole  la  comida,  el  paciente  se 
 alimenta por sí solo. 
 Trasladarse entre la silla y la cama 
 • De la cama a la silla y al revés. 
 •  «Dependiente»  =  NO  se  mantiene  sentado  (incapaz 
 de sentarse); se necesitan dos personas para 
 levantarlo. 
 •  "Ayuda  importante"  =  una  persona  fuerte/entrenada 
 o dos personas normales. Puede sentarse. 
 •  "Ayuda  menor"  =  una  persona  fácilmente,  O  necesita 
 supervisión por motivos de seguridad. 
 Desplazarse 
 •  Hace  referencia  a  la  movilidad  en  la  casa  o  sala,  en 
 el interior. Puede usar ayuda. Si está en silla 
 de ruedas, puede pasar las esquinas/puertas sin ayuda. 
 •  «Ayuda»  =  por  una  persona  no  entrenada,  incluida  la 
 supervisión y el apoyo moral. 
 Vestirse y desvestirse 
 •  Si  es  capaz  de  seleccionar  y  ponerse  la  ropa,  que 
 puede estar adaptada. 
 •  «A  medias»  =  ayuda  con  los  botones,  cremalleras, 
 etc. (¡comprobar!), pero puede ponerse alguna 
 prendas por sí solo. 
 Subir y bajar escaleras 
 •  Puede  utilizar  cualquier  tipo  de  ayuda  para  andar 
 para considerarse independiente. 
 Bañarse/Ducharse 
 • Por lo general, la actividad más difícil. 
 •  Debe  entrar  y  salir  sin  supervisión  y  lavarse  por  sí 
 solo. 
 •  Independiente  en  la  ducha  =  "independiente"  si  no 
 necesita supervisión/ayuda. 
 GEM 1802 - Protocol version 5.0, 4. JUL. 2022 
 Page  93  of  94 


 Referencias: 
 •  Collin  C,  Wade  DT,  Davies  S,  Horne  V.  The  Barthel 
 ADL Index: a reliability study. Int Disabil Stud. 
 1988;10(2):61-63. 
 •  Mahoney  FI,  Barthel  DW.  Functional  evaluation:  the 
 Barthel Index. Md State Med J. 1965;14:61-65 
 •  Wade  DT,  Collin  C.  The  Barthel  ADL  Index:  a 
 standard  measure  of  physical  disability?  Int  Disabil 
 Stud. 
 1988;10(2):64-67. 
 GEM 1802 - Protocol version 5.0, 4. JUL. 2022 
 Page  94  of  94 


‭EBRAIN-MEL GEM1802 STUDY -‬
‭STATISTICAL REPORT (ANALYSIS)‬
‭JAN 2023‬


‭1.‬ ‭T‬‭ABLE‬‭OF‬‭C‬‭ONTENTS‬
‭2.‬‭PATIENT POPULATIONS‬
‭ITT Population‬‭:‬
‭The‬ ‭ITT‬ ‭population‬ ‭will‬ ‭include‬ ‭all‬‭patients‬‭who‬‭were‬‭included‬‭in‬‭the‬‭study,‬‭only‬
‭screening failures are excluded.‬
‭PP Population‬‭:‬
‭The‬‭PP‬‭population‬‭will‬‭include‬‭all‬‭patients‬‭who‬‭fulfilled‬‭the‬‭inclusion‬‭and‬‭exclusion‬
‭criteria and had at least 2 valid tumor evaluations (baseline + 1st assessment).‬
‭Safety Population‬‭:‬
‭The‬‭PP‬‭population‬‭will‬‭include‬‭all‬‭patients‬‭who‬‭received‬‭at‬‭least‬‭one‬‭dose‬‭of‬‭the‬
‭treatment.‬
‭Table 1: ITT population‬
‭Intention to treat population‬
‭   No‬
‭   Yes‬
‭Table 2: ITT Population: Patients excluded‬
‭Patient number‬
‭Cohort‬
‭ITT‬
‭Exclusion reason‬
‭Table 3: PP population‬
‭PP‬
‭   No‬
‭   Yes‬
‭Table 4: PP Population: Patients excluded‬


‭Patient number‬
‭Cohort‬
‭PP‬
‭PP: exclusion reason‬
‭Table 5: Safety population‬
‭Safety‬
‭   No‬
‭   Yes‬
‭Table 6: Safety Populattion: Patients excluded‬
‭Patient number‬
‭Cohort‬
‭Safety‬
‭Safety: exclusion reason‬
‭Table 7: Analysis populations, all patients‬
‭Patient‬
‭Number‬
‭Cohort‬
‭Intention to treat‬
‭population‬
‭PP‬
‭ITT/PP Exclusion reason‬
‭Safety‬
‭Safety: exclusion‬
‭reason‬
‭3.‬‭RESULTS‬
‭3.1.‬ ‭RECRUITED PATIENTS‬
‭All‬‭baseline‬‭characteristics‬‭will‬‭be‬‭performed‬‭using‬‭the‬‭ITT‬‭and‬‭PP‬‭population.‬‭In‬
‭order‬‭to‬‭report‬‭the‬‭main‬‭efficacy‬‭analysis,‬‭also‬‭both‬‭the‬‭ITT‬‭and‬‭PP‬‭population‬‭will‬
‭be‬‭used,‬‭meanwhile‬‭the‬‭secondary‬‭efficacy‬‭endpoints‬‭will‬‭be‬‭analyzed‬‭using‬‭the‬
‭PP population. Finally the safety population will be used to report the safety results.‬
‭Table 8: Patients recruited by Hospital‬
‭Hospital‬
‭   HOSPITAL GENERAL UNIVERSITARIO‬
‭GREGORIO MARAÑÓN‬
‭   HOSPITAL RAMÓN Y CAJAL‬
‭   HOSPITAL REINA SOFÍA‬
‭   HOSPITAL VIRGEN MACARENA‬
‭   HOSPITAL CLINIC I PROVINCIAL DE‬
‭BARCELONA‬


‭   HOSPITAL UNIVERSITARIO MARQUÉS DE‬
‭VALDECILLA‬
‭   HOSPITAL DEL MAR‬
‭   COMPLEJO HOSPITALARIO REGIONAL DE‬
‭MÁLAGA‬
‭   HOSPITAL CLÍNICO SAN CARLOS‬
‭   HOSPITAL UNIVERSITARI I POLITÈCNIC LA FE‬
‭   USP INSTITUT UNIVERSITARI DEXEUS‬
‭   HOSPITAL UNIVERSITARIO MIGUEL SERVET‬
‭   HOSPITAL UNIVERSITARI SON ESPASES‬
‭   HOSPITAL CLÍNICO UNIVERSITARIO VIRGEN‬
‭DE LA ARRIXACA‬
‭   INSTITUT CATALÀ D’‘ONCOLOGIA‬
‭L’’HOSPITALET (ICO)‬
‭3.2.‬ ‭BASELINE CHARACTERISTICS‬
‭BASELINE - DEMOGRAPHIC DATA‬
‭Table 9: Baseline - Socio demographic data ITT‬
‭Age (years)‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭Sex‬
‭   Female‬
‭   Male‬
‭Race‬
‭   Caucasian‬
‭   Latin‬
‭Table 10: Baseline - Socio demographic data PP‬
‭Age (years)‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭Sex‬
‭   Female‬
‭   Male‬
‭Race‬


‭Table 11: Baseline - Physical characteristics ITT‬
‭Phototype (n(%))‬
‭   Type I‬
‭   Type II‬
‭   Type III‬
‭   Type IV‬
‭   UK‬
‭Weight (kg)‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭Height (cm)‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭Systolic Blood Pressure (mmHg)‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭Diastolic Blood Pressure (mmHg)‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭Temperature (ºC)‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭Respiratory rate (BPM)‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭Pulse Rate (BPM)‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬


‭ECOG (n(%))‬
‭   0‬
‭   1‬
‭   2‬
‭Barthel index (categorical), (n(%)),‬
‭previous to November 2020‬
‭Barthel index (Arbitrary units, scale 0-100)‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭Barthel index modified, from November‬
‭2020‬
‭Barthel index modified (Arbitrary units,‬
‭scale 0-20), from November 2020‬
‭   N‬
‭   Mean (SD)‬
‭   Median‬
‭   Range‬
‭Barthel index final (all values transformed‬
‭to scale 0-20) (categorical) (n(%))‬
‭   ‬
‭Barthel index final (all values transformed‬
‭to scale 0-20)‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭Physical exam‬
‭   Normal‬
‭   Abnormal‬
‭Neurological exam‬
‭   Normal‬
‭   Abnormal‬
‭Ophthalmologic exam‬
‭   Normal‬
‭   Abnormal‬
‭Autoimmune concomitant diseases‬
‭   Yes‬
‭   No‬
‭   UK‬
‭Table 12: Baseline - Physical characteristics PP‬
‭Phototype (n(%))‬


‭   Type I‬
‭   Type II‬
‭   Type III‬
‭   Type IV‬
‭   UK‬
‭Weight (kg)‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭Height (cm)‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭Systolic Blood Pressure (mmHg)‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭Diastolic Blood Pressure (mmHg)‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭Temperature (ºC)‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭Respiratory rate (BPM)‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭PulseRate (BPM)‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭ECOG (n(%))‬
‭   0‬
‭   1‬
‭   2‬


‭Barthel index (categorical), (n(%)),‬
‭previous to November 2020‬
‭Barthel index (Arbitrary units, scale 0-100)‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭Barthel index modified, from November‬
‭2020‬
‭ ‬
‭Barthel index modified (Arbitrary units,‬
‭scale 0-20), from November 2020‬
‭   N‬
‭   Mean (SD)‬
‭   Median‬
‭   Range‬
‭Barthel index final (all values transformed‬
‭to scale 0-20) (categorical) (n(%))‬
‭Barthel index final (all values transformed‬
‭to scale 0-20)‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭Physical exam‬
‭   Normal‬
‭   Abnormal‬
‭Neurological exam‬
‭   Normal‬
‭   Abnormal‬
‭Ophthalmologic exam‬
‭   Normal‬
‭   Abnormal‬
‭Autoimmune concomitant diseases‬
‭   Yes‬
‭   No‬
‭   UK‬
‭3.3.‬ ‭PREVIOUS MELANOMA HISTORY‬
‭Table 13: Previous Melanoma History ITT‬
‭Time since First diagnose date until‬
‭treatment started (months)‬
‭   N‬
‭   Mean (95%CI)‬


‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭Histological Subtype‬
‭   NA/UK‬
‭   Superficial spreading‬
‭   Nodular‬
‭   Lentigo maligna‬
‭   Others‬
‭Histological Subtype Others‬
‭   ‬
‭Primary Melanoma Location‬
‭   NA/UK‬
‭   Face‬
‭   Scalp‬
‭   Back‬
‭   Upper extremities‬
‭   Feet palms‬
‭   Chest‬
‭   Abdomen‬
‭   Others‬
‭Primary Melanoma Location Others‬
‭Previous Multiple Nevus‬
‭   Yes‬
‭   No‬
‭   NA/UK‬
‭Primary Melanoma Stage‬
‭In transit metastases‬
‭   Yes‬
‭   No‬
‭   UK‬
‭Sentinel lymph node‬
‭   Yes‬
‭   No‬
‭   UK‬
‭Lymphadenectomy‬
‭   Yes‬
‭   No‬
‭   UK‬
‭Table 14: Previous Melanoma History PP‬
‭Time since First diagnose date until‬
‭treatment started (months)‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬


‭   Median (95%CI)‬
‭   Range‬
‭Histological Subtype‬
‭   NA/UK‬
‭   Superficial spreading‬
‭   Nodular‬
‭   Lentigo maligna‬
‭   Others‬
‭Histological Subtype Others‬
‭Primary Melanoma Location‬
‭   NA/UK‬
‭   Face‬
‭   Scalp‬
‭   Back‬
‭   Upper extremities‬
‭   Feet palms‬
‭   Chest‬
‭   Abdomen‬
‭   Others‬
‭Primary Melanoma Location Others‬
‭Previous Multiple Nevus‬
‭   Yes‬
‭   No‬
‭   NA/UK‬
‭Primary Melanoma Stage‬
‭  ‬
‭In transit metastases‬
‭   Yes‬
‭   No‬
‭   UK‬
‭Sentinel lymph node‬
‭   Yes‬
‭   No‬
‭   UK‬
‭Lymphadenectomy‬
‭   Yes‬
‭   No‬
‭   UK‬


‭Figure 1: Heatmap BRAF ITT‬
‭Table 15: BRAF ITT‬
‭V600E‬
‭   Missing data‬
‭   Mutated‬
‭   Not mutated‬
‭V600K‬
‭   Mutated‬
‭   Not mutated‬
‭   NA/UK‬
‭V600E/K‬
‭   Mutated‬
‭   Not mutated‬
‭   NA/UK‬
‭V600R‬
‭   Mutated‬
‭   Not mutated‬
‭   NA/UK‬
‭V600 other‬
‭   Mutated‬
‭   Not mutated‬
‭   NA/UK‬
‭V600 (NE)‬
‭   Mutated‬
‭   Not mutated‬
‭   NA/UK‬
‭Table 16: BRAF PP‬
‭V600E‬
‭   Missing data‬
‭   Mutated‬
‭   Not mutated‬
‭V600K‬
‭   Mutated‬
‭   Not mutated‬
‭   NA/UK‬
‭V600E/K‬
‭   Mutated‬
‭   Not mutated‬
‭   NA/UK‬
‭V600R‬
‭   Mutated‬
‭   Not mutated‬
‭   NA/UK‬


‭V600 other‬
‭   Mutated‬
‭   Not mutated‬
‭   NA/UK‬
‭V600 non specified‬
‭   Mutated‬
‭   Not mutated‬
‭   NA/UK‬
‭Figure 2: Heatmap BRAF PP‬
‭Table 17: Other mutations ITT‬
‭RAS‬
‭   Mutated‬
‭   Not mutated‬
‭   NA/UK‬
‭CKIT‬
‭   Mutated‬
‭   Not mutated‬
‭   UK‬
‭GNAQ‬
‭   Mutated‬
‭   Not mutated‬
‭   UK‬
‭Figure 3: Heatmap Other mutations ITT‬
‭Table 18: Other mutations PP‬
‭RAS‬
‭   Mutated‬
‭   Not mutated‬
‭   NA/UK‬
‭CKIT‬
‭   Mutated‬
‭   Not mutated‬
‭   UK‬
‭GNAQ‬
‭   Mutated‬
‭   Not mutated‬
‭   UK‬


‭Figure 4: Heatmap Other mutations PP‬
‭Table 19: Adjuvant therapy ITT‬
‭Adjuvant therapy‬
‭   Yes‬
‭   No‬
‭   UK‬
‭Previous adjuvant tx: Immunotherapy‬
‭   No‬
‭   Yes‬
‭   NA/UK‬
‭Type of previous Immunotherapy‬
‭   Anti-PD1 + anti-CTLA4‬
‭   Anti-PD1 monotherapy‬
‭   Anti-PD1 monotherapy / Anti-PD1‬
‭monotherapy‬
‭   NA/UK‬
‭Previous adjuvant tx: Interferon‬
‭   No‬
‭   Yes‬
‭   NA/UK‬
‭Previous adjuvant tx: Radiotherapy‬
‭   No‬
‭   Yes‬
‭   NA/UK‬
‭Table 20: Adjuvant therapy PP‬
‭Adjuvant therapy‬
‭   Yes‬
‭   No‬
‭   UK‬
‭Previous adjuvant tx: Immunotherapy‬
‭   No‬
‭   Yes‬
‭   NA/UK‬
‭Type of previous Immunotherapy‬
‭   Anti-PD1 + anti-CTLA4‬
‭   Anti-PD1 monotherapy‬
‭   Anti-PD1 monotherapy / Anti-PD1‬
‭monotherapy‬
‭   NA/UK‬
‭Previous adjuvant tx: Interferon‬
‭   No‬
‭   Yes‬
‭   NA/UK‬


‭Previous adjuvant tx: Radiotherapy‬
‭   No‬
‭   Yes‬
‭   NA/UK‬
‭Table 21: Therapy for unresectable locally advanced or metastatic melanoma ITT‬
‭Therapy for unresectable locally advanced or‬
‭metastatic melanoma‬
‭   Yes‬
‭   No‬
‭Therapy for unresectable locally advanced or‬
‭metastatic melanoma: Mts Surgery‬
‭   No‬
‭   Yes‬
‭   NA/UK‬
‭Therapy for unresectable locally advanced or‬
‭metastatic melanoma: Immunotherapy‬
‭   No‬
‭   Yes‬
‭   NA/UK‬
‭Therapy for unresectable locally advanced or‬
‭metastatic melanoma: Type of Immunotherapy‬
‭   Nivolumab‬
‭   Nivolumab+ipilimumab‬
‭   Pembrolizumab‬
‭   NA/UK‬
‭Therapy for unresectable locally advanced or‬
‭metastatic melanoma: Radiotherapy‬
‭   No‬
‭   Yes‬
‭   NA/UK‬
‭Therapy for unresectable locally advanced or‬
‭metastatic melanoma: Segmentectomy‬
‭   No‬
‭   Yes‬
‭   NA/UK‬
‭Therapy for unresectable locally advanced or‬
‭metastatic melanoma: Radiosurgery‬
‭   No‬
‭   Yes‬
‭   NA/UK‬
‭Table 22: Therapy for unresectable locally advanced or metastatic melanoma PP‬
‭Therapy for unresectable locally advanced or‬
‭metastatic melanoma‬


‭   Yes‬
‭   No‬
‭Therapy for unresectable locally advanced or‬
‭metastatic melanoma: Mts Surgery‬
‭   No‬
‭   Yes‬
‭   NA/UK‬
‭Therapy for unresectable locally advanced or‬
‭metastatic melanoma: Immunotherapy‬
‭   No‬
‭   Yes‬
‭   NA/UK‬
‭Therapy for unresectable locally advanced or‬
‭metastatic melanoma: Type of Immunotherapy‬
‭   Nivolumab‬
‭   Nivolumab+ipilimumab‬
‭   Pembrolizumab‬
‭   NA/UK‬
‭Therapy for unresectable locally advanced or‬
‭metastatic melanoma: Radiotherapy‬
‭   No‬
‭   Yes‬
‭   NA/UK‬
‭Therapy for unresectable locally advanced or‬
‭metastatic melanoma: Segmentectomy‬
‭   No‬
‭   Yes‬
‭   NA/UK‬
‭Therapy for unresectable locally advanced or‬
‭metastatic melanoma: Radiosurgery‬
‭   No‬
‭   Yes‬
‭   NA/UK‬
‭3.4.‬ ‭BASELINE CURRENT MELANOMA‬
‭Table 23: Baseline Current Melanoma ITT‬
‭Time since diagnosis of current melanoma until‬
‭treatment started (months)‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭Current Melanoma Histological Subtype‬
‭   Superficial spreading‬
‭   Nodular‬
‭   Lentigo maligna‬
‭   UK‬


‭   Others‬
‭Histological subtype specify‬
‭Current Melanoma Stage‬
‭   IV‬
‭Table 24: Baseline Current Melanoma PP‬
‭Time since diagnosis of current melanoma until‬
‭treatment started (months)‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭Current Melanoma Histological Subtype‬
‭   Superficial spreading‬
‭   Nodular‬
‭   Lentigo maligna‬
‭   UK‬
‭   Others‬
‭Histological subtype specify‬
‭Current Melanoma Stage‬
‭   IV‬
‭Table 25: TNM Current Melanoma ITT‬
‭Initial T Stage‬
‭   T0‬
‭   T1a‬
‭   T1b‬
‭   T2a‬
‭   T2b‬
‭   T3a‬
‭   T3b‬
‭   T4a‬
‭   T4b‬
‭   Tx‬
‭Initial N Stage‬
‭   N0‬
‭   N1a‬
‭   N1b‬
‭   N1c‬
‭   N2a‬
‭   N2b‬


‭   N2c‬
‭   N3b‬
‭   N3c‬
‭   Nx‬
‭Initial M Stage‬
‭   M1d(0)‬
‭   M1d(1)‬
‭Breslow (mm)‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Range‬
‭Mitotic Rate (mm^2)‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Range‬
‭Ulceration‬
‭   Yes‬
‭   No‬
‭   UK‬
‭Table 26: TNM Current Melanoma PP‬
‭Initial T Stage‬
‭   T0‬
‭   T1a‬
‭   T1b‬
‭   T2a‬
‭   T2b‬
‭   T3a‬
‭   T3b‬
‭   T4a‬
‭   T4b‬
‭   Tx‬
‭Initial N Stage‬
‭   N0‬
‭   N1a‬
‭   N1b‬
‭   N1c‬
‭   N2a‬
‭   N2b‬
‭   N2c‬
‭   N3b‬
‭   N3c‬
‭   Nx‬
‭Initial M Stage‬
‭   M1d(0)‬
‭   M1d(1)‬


‭Breslow (mm)‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Range‬
‭Mitotic Rate (mm^2)‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Range‬
‭Ulceration‬
‭   Yes‬
‭   No‬
‭   UK‬
‭Table 27: Metastases ITT‬
‭Brain Metastases‬
‭   Unique‬
‭   Multiple‬
‭Target Brain Metastases‬
‭   1‬
‭   2‬
‭   3‬
‭   4‬
‭   5‬
‭   UK‬
‭Extracranial Metastases‬
‭   Yes‬
‭   No‬
‭Lung Metastases‬
‭   Yes‬
‭   No‬
‭   UK‬
‭Lung Metastases Number‬
‭   1‬
‭   2‬
‭   3‬
‭   4‬
‭   >5‬
‭   NA/UK‬
‭Liver Metastases‬
‭   Yes‬
‭   No‬
‭   UK‬
‭Liver Metastases Number‬
‭   1‬
‭   2‬
‭   3‬


‭   >5‬
‭   NA/UK‬
‭Skin Metastases‬
‭   Yes‬
‭   No‬
‭   UK‬
‭Skin Metastases Number‬
‭   1‬
‭   2‬
‭   3‬
‭   >5‬
‭   UK‬
‭Bone Metastases‬
‭   Yes‬
‭   No‬
‭   UK‬
‭Bone Metastases Number‬
‭   1‬
‭   2‬
‭   NA/UK‬
‭Pleura Metastases‬
‭   Yes‬
‭   No‬
‭   UK‬
‭Pleural Effusion Volume‬
‭   0‬
‭   NA/UK‬
‭Soft Tissue Metastases‬
‭   Yes‬
‭   No‬
‭   UK‬
‭Soft Tissue Metastases Number‬
‭   1‬
‭   5‬
‭   NA/UK‬
‭Lymph Nodes Metastases‬
‭   Yes‬
‭   No‬
‭   UK‬
‭Lymph Nodes Metastases Number‬
‭   1‬
‭   2‬
‭   3‬
‭   >5‬
‭   UK‬
‭   NA/UK‬
‭Peritoneum Metastases‬
‭   Yes‬
‭   No‬
‭   UK‬
‭Peritoneum Metastases Number‬


‭   1‬
‭   NA/UK‬
‭Other Metastases‬
‭   Yes‬
‭   No‬
‭   UK‬
‭Other Metastases Number‬
‭   1‬
‭   2‬
‭   >5‬
‭   UK‬
‭Other Metastases Specify‬
‭Table 28: Metastases PP‬
‭Brain Metastases‬
‭   Unique‬
‭   Multiple‬
‭Target Brain Metastases‬
‭   1‬
‭   2‬
‭   3‬
‭   4‬
‭   5‬
‭   UK‬
‭Extracranial Metastases‬
‭   Yes‬
‭   No‬
‭Lung Metastases‬
‭   Yes‬
‭   No‬
‭   UK‬
‭Lung Metastases Number‬
‭   1‬
‭   2‬
‭   3‬
‭   4‬
‭   >5‬
‭   NA/UK‬
‭Liver Metastases‬
‭   Yes‬
‭   No‬
‭   UK‬
‭Liver Metastases Number‬
‭   1‬
‭   2‬
‭   3‬
‭   >5‬
‭   NA/UK‬
‭Skin Metastases‬


‭   Yes‬
‭   No‬
‭   UK‬
‭Skin Metastases Number‬
‭   1‬
‭   2‬
‭   3‬
‭   >5‬
‭   UK‬
‭Bone Metastases‬
‭   Yes‬
‭   No‬
‭   UK‬
‭Bone Metastases Number‬
‭   1‬
‭   2‬
‭   NA/UK‬
‭Pleura Metastases‬
‭   Yes‬
‭   No‬
‭   UK‬
‭Pleural Effusion Volume‬
‭   0‬
‭   NA/UK‬
‭Soft Tissue Metastases‬
‭   Yes‬
‭   No‬
‭   UK‬
‭Soft Tissue Metastases Number‬
‭   1‬
‭   5‬
‭   NA/UK‬
‭Lymph Nodes Metastases‬
‭   Yes‬
‭   No‬
‭   UK‬
‭Lymph Nodes Metastases Number‬
‭   1‬
‭   2‬
‭   3‬
‭   >5‬
‭   NA/UK‬
‭Peritoneum Metastases‬
‭   Yes‬
‭   No‬
‭   UK‬
‭Peritoneum Metastases Number‬
‭   1‬
‭   NA/UK‬
‭Other Metastases‬
‭   Yes‬


‭   No‬
‭   UK‬
‭Other Metastases Number‬
‭   1‬
‭   2‬
‭   >5‬
‭   UK‬
‭Other Metastases Specify‬
‭Table 29: LDH concentration and corticosteriods ITT‬
‭LDH Concentration‬
‭   Normal (≤ULN)‬
‭   Elevated (>ULN)‬
‭   UK‬
‭Corticosteroids Treatment‬
‭   Yes‬
‭   No‬
‭Corticosteroids Treatment Type‬
‭   Missing data‬
‭   Dexamethasone‬
‭   Metilprednisolona‬
‭   Prednisone‬
‭   UK‬
‭Administration‬
‭   Stable‬
‭   Decreasing‬
‭   NA‬
‭Table 30: LDH concentration and corticosteriods PP‬
‭LDH Concentration‬
‭   Normal (≤ULN)‬
‭   Elevated (>ULN)‬
‭   UK‬
‭Corticosteroids Treatment‬
‭   Yes‬
‭   No‬
‭Corticosteroids Treatment Type‬
‭   Missing data‬
‭   Dexamethasone‬
‭   Metilprednisolona‬
‭   Prednisone‬
‭   UK‬
‭Administration‬
‭   Stable‬


‭   Decreasing‬
‭   NA‬
‭3.4.1.‬‭BASELINE TUMOR BURDEN‬
‭Table 31: Brain Tumor burden (mm) ITT‬
‭Brain Tumor burden (mm) intracranial‬
‭Target lessions‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭Table 32: Brain Tumor burden (mm) PP‬
‭Brain Tumor burden (mm) intracranial‬
‭Target lessions‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭3.5.‬ ‭TREATMENT COMPLIANCE‬
‭Upon database closure, there are 4 patients still undergoing treatment.‬
‭3.5.1.‬‭B‬‭INIMETINIB‬‭C‬‭OMPLIANCE‬
‭Table 33: Incidence reason for Binimetinib‬
‭Incidence‬
‭N‬
‭No‬
‭Yes‬
‭Delay‬
‭Not available‬
‭N‬
‭No‬
‭Yes‬
‭Reduction‬


‭Not available‬
‭N‬
‭No‬
‭Yes‬
‭End of treatment‬‭1‬
‭Not available‬
‭N‬
‭No‬
‭Yes‬
‭Interruption due to local treatment‬
‭Not available‬
‭N‬
‭No‬
‭Yes‬
‭Interruption due to surgery‬
‭Not available‬
‭N‬
‭No‬
‭Yes‬
‭(1)‬ ‭The‬ ‭End‬ ‭of‬ ‭Treatment‬ ‭variable‬ ‭only‬ ‭reports‬ ‭'Yes'‬
‭incidents that were caused by 'End of Treatment'‬
‭Table 34: Reasons for incidence (free field to review)‬
‭PatientNumb‬
‭er.Inc‬
‭IncidenceSta‬
‭rtDate‬
‭IncidenceEn‬
‭dDate‬
‭Incidence‬
‭Reason‬
‭End of treatment‬
‭reason compiled‬
‭Table 35: Binimetinib Treatment duration (months)‬
‭Binimetinib gross duration time (months)‬
‭Missing‬
‭N‬
‭Mean (95%CI)‬
‭SD‬
‭Median (95%CI)‬
‭Range‬
‭Binimetinib net duration time (months)‬
‭Missing‬
‭N‬
‭Mean (95%CI)‬


‭SD‬
‭Median (95%CI)‬
‭Range‬
‭3.5.2.‬‭E‬‭NCORAFENIB‬‭C‬‭OMPLIANCE‬
‭Table 36: Incidence reason for Encorafenib‬
‭Incidence‬
‭N‬
‭No‬
‭Yes‬
‭Delay‬
‭Not available‬
‭N‬
‭No‬
‭Yes‬
‭Reduction‬
‭Not available‬
‭N‬
‭No‬
‭Yes‬
‭End of treatment‬‭1‬
‭Not available‬
‭N‬
‭No‬
‭Yes‬
‭Interruption due to local treatment‬
‭Not available‬
‭N‬
‭No‬
‭Yes‬
‭Interruption due to surgery‬
‭Not available‬
‭N‬
‭No‬
‭Yes‬
‭(1)‬ ‭The‬ ‭End‬ ‭of‬ ‭Treatment‬ ‭variable‬ ‭only‬ ‭reports‬ ‭'Yes'‬
‭incidents that were caused by 'End of Treatment'‬
‭Table 37: Encorafenib Treatment duration (months)‬


‭Encorafenib gross duration time (months)‬
‭Missing‬
‭N‬
‭Mean (95%CI)‬
‭SD‬
‭Median (95%CI)‬
‭Range‬
‭Encorafenib net duration time (months)‬
‭Missing‬
‭N‬
‭Mean (95%CI)‬
‭SD‬
‭Median (95%CI)‬
‭Range‬
‭Table 38: Reasons for incidence (free field to review)‬
‭PatientNumb‬
‭er.Inc‬
‭IncidenceSta‬
‭rtDate‬
‭IncidenceEn‬
‭dDate‬
‭Incidence‬
‭Reason‬
‭End of treatment‬
‭reason compiled‬
‭4.‬‭PRIMARY EFFICACY OBJECTIVE‬
‭4.1.‬ ‭ITT PRIMARY EFFICACY OBJECTIVE: RESPONSE‬
‭AT 56 DAYS‬
‭Table 39: Primary Efficacy Objective. Day 56 Evaluation. ITT‬
‭intracranial Evaluation at 56 days‬
‭   CR‬
‭   PR‬
‭   SD‬
‭PD‬
‭   NE‬
‭Table 40: ITT: intracranial Objective Response Rate at 56 days‬
‭All patients: ORR intracranial response‬
‭CR or PR‬


‭All patients: ORR intracranial response‬
‭SD or PD‬
‭NE‬
‭Total‬
‭Cohort 1: ORR intracranial response‬
‭CR or PR‬
‭SD or PD‬
‭NE‬
‭Total‬
‭Cohort 2: ORR intracranial response‬
‭CR or PR‬
‭SD or PD‬
‭Total‬
‭4.2.‬ ‭PP PRIMARY EFFICACY OBJECTIVE: RESPONSE‬
‭AT 56 DAYS‬
‭Table 41: Primary Efficacy Objective. Day 56 Evaluation. PP‬
‭intracranial Evaluation at 56 days‬
‭   CR‬
‭   PR‬
‭   SD‬
‭PD‬
‭NE‬
‭Table 42: PP: intracranial Objective Response Rate at 56 days‬
‭All patients: ORR intracranial response‬
‭CR or PR‬
‭SD or PD‬


‭All patients: ORR intracranial response‬
‭NE‬
‭Total‬
‭Cohort 1: ORR intracranial response‬
‭CR or PR‬
‭SD or PD‬
‭NE‬
‭Total‬
‭Cohort 2: ORR intracranial response‬
‭CR or PR‬
‭SD or PD‬
‭NE‬
‭Total‬


‭4.2.1.‬‭INTRACRANIAL RESPONSE DURATION‬
‭Table 43: Intracranial Response Duration (months) ITT‬
‭Duration of response (months)‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭Table 44: Intracranial Response Duration (months) PP‬
‭Duration of response (months)‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭4.3.‬ ‭RADIOTHERAPY TREATMENT‬
‭ITT: RADIOTHERAPY TREATMENT‬
‭Table 45: Radiotherapy treatment. ITT‬
‭Radiotherapy treatment (Local and/or Whole‬
‭Brain)‬
‭N‬
‭Yes‬
‭Yes (CR)‬‭1‬
‭No‬
‭No (CR)‬
‭LocaL Radiation treatment‬
‭N‬
‭Yes‬
‭Yes (CR)‬
‭No‬
‭No (CR)‬
‭Local Radiation Treatment type‬
‭N‬
‭No‬
‭Radiosurgery (RS)‬


‭Stereotactic radiosurgery (SRS)‬
‭Device Used‬
‭Missing‬
‭N‬
‭Gamma Knife‬
‭Accelerator Linac-Based Systems (IMRT, Rapid Arc,‬
‭VMAT)‬
‭Cyberknife‬
‭Whole Brain Radiotherapy‬
‭N‬
‭Yes‬
‭No‬
‭No (CR)‬
‭PP: RADIOTHERAPY TREATMENT‬
‭Table 46: Radiotherapy treatment. PP‬
‭Radiotherapy treatment (Local and/or Whole‬
‭Brain)‬
‭N‬
‭Yes‬
‭Yes (CR)‬‭1‬
‭No‬
‭No (CR)‬
‭Local Radiation treatment‬
‭N‬
‭Yes‬
‭Yes (CR)‬
‭No‬
‭No (CR)‬
‭Local Radiation Treatment type‬
‭N‬
‭No‬
‭Radiosurgery (RS)‬
‭Stereotactic radiosurgery (SRS)‬
‭Device Used‬
‭Missing‬
‭N‬
‭Gamma Knife‬
‭Accelerator Linac-Based Systems (IMRT, Rapid Arc,‬
‭VMAT)‬


‭Cyberknife‬
‭Whole Brain Radiotherapy‬
‭N‬
‭Yes‬
‭No‬
‭No (CR)‬
‭4.3.1.‬‭ALL PATIENTS: DETAILS OF LOCAL RADIATION‬
‭TREATMENT‬
‭Table 47: Details of local radiation treatment‬
‭Patient‬
‭Number‬
‭Coho‬
‭rt‬
‭Intention to‬
‭treat‬
‭population‬
‭PP‬
‭LocaL‬
‭Radiation‬
‭treatment‬
‭Local‬
‭Radiation‬
‭Treatment‬
‭type‬
‭Device Used‬
‭Whole Brain‬
‭Radiotherap‬
‭y‬
‭Radiotherapy‬
‭treatment (Local‬
‭and/or Whole Brain)‬
‭4.4.‬ ‭LAST STATUS‬
‭Table 48: Arithmetic median for all patients‬
‭Overall‬
‭Overall follow-up since cancer diagnosis: all patients (months)‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭Table 49: Arithmetic median for alive patients‬
‭Overall‬
‭Global follow-up since cancer diagnosis: patients alive (moths)‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭Table 50: Follow-up since cancer diagnosis based on reverse censoring (months)‬
‭Median‬
‭95%CI‬
‭Reverse censoring‬


‭ITT: LAST STATUS, PD AND DEATHS‬
‭Table 51: Progression, Death. ITT‬
‭Cohort‬
‭Progression type‬
‭   Only IntraPD‬
‭   No PD‬
‭   Both‬
‭   Only ExtraPD‬
‭Death‬
‭   No‬
‭   Yes‬
‭PP: LAST STATUS, PD AND DEATHS‬
‭Table 52: Progression, Death. PP‬
‭Cohort‬
‭Progression type‬
‭   Only IntraPD‬
‭   No PD‬
‭   Both‬
‭   Only ExtraPD‬
‭Death‬
‭   No‬
‭   Yes‬
‭Table 53: Last available status‬
‭Patient‬
‭Number‬ ‭Cohort‬ ‭Intention to treat‬
‭population‬
‭PP‬
‭Last‬
‭available‬
‭status‬
‭Last‬
‭available‬
‭date‬
‭End‬
‭Treatment‬
‭Date‬
‭Date of‬
‭last FU‬
‭Intracraneal‬
‭Progression‬
‭disease‬
‭Date‬
‭of PD‬
‭Date of‬
‭death‬
‭End‬
‭Trial‬
‭Date‬
‭4.5.‬ ‭I‬‭NTRACRANIAL‬‭O‬‭VERALL‬‭SURVIVAL‬‭(‬‭I‬‭OS).‬
‭4.5.1.‬‭ITT A‬‭LL‬‭PATIENTS‬‭:‬‭INTRACRANIAL‬‭O‬‭VERALL‬‭SURVIVAL‬‭(‬‭I‬‭OS).‬
‭Table 54: Events type OS‬
‭OS‬
‭N‬
‭%‬
‭95%CI‬
‭Alive‬
‭Death‬
‭Total‬
‭Table 55: Median/mean OS (estimated by Kaplan-Meier)‬


‭Median (months)‬
‭CI 95%‬
‭Mean‬
‭CI 95%‬
‭Overall survival‬
‭Table 56: OS estimated survival ratio‬
‭OS‬
‭Events (%, total‬
‭N)‬
‭Patients at‬
‭risk‬
‭% estimated cumulative survival‬
‭ratio‬
‭CI 95%‬
‭At 6 months‬
‭At 12‬
‭months‬
‭At 18‬
‭months‬
‭At 24‬
‭months‬
‭Figure 5: Overall survival‬
‭4.5.2.‬‭ITT - C‬‭OHORT‬‭1:‬‭INTRACRANIAL‬‭O‬‭VERALL‬‭SURVIVAL‬‭(‬‭I‬‭OS).‬
‭Table 57: Events type OS‬
‭OS‬
‭N‬
‭%‬
‭95%CI‬
‭Alive‬
‭Death‬
‭Total‬
‭Table 58: Median/mean OS (estimated by Kaplan-Meier)‬
‭Median (months)‬
‭CI 95%‬
‭Mean‬
‭CI 95%‬
‭Overall survival‬
‭Table 59: OS estimated survival ratio‬
‭OS‬
‭Events (%, total‬
‭N)‬
‭Patients at‬
‭risk‬
‭% estimated cumulative survival‬
‭ratio‬
‭CI 95%‬
‭At 6 months‬
‭At 12‬
‭months‬
‭At 18‬
‭months‬
‭At 24‬
‭months‬


‭Figure 6: Overall survival‬
‭4.5.3.‬‭ITT - C‬‭OHORT‬‭2:‬‭INTRACRANIAL‬‭O‬‭VERALL‬‭SURVIVAL‬‭(‬‭I‬‭OS).‬
‭Table 60: Events type OS‬
‭OS‬
‭N‬
‭%‬
‭95%CI‬
‭Alive‬
‭Death‬
‭Total‬
‭Table 61: Median/mean OS (estimated by Kaplan-Meier)‬
‭Median (months)‬
‭CI 95%‬
‭Mean‬
‭CI 95%‬
‭Overall survival‬
‭Table 62: OS estimated survival ratio‬
‭OS‬
‭Events (%, total‬
‭N)‬
‭Patients at‬
‭risk‬
‭% estimated cumulative survival‬
‭ratio‬
‭CI 95%‬
‭At 6 months‬
‭At 12‬
‭months‬
‭At 18‬
‭months‬
‭At 24‬
‭months‬
‭Figure 7: Overall survival‬
‭4.5.4.‬‭PP A‬‭LL‬‭PATIENTS‬‭:‬‭INTRACRANIAL‬‭O‬‭VERALL‬‭SURVIVAL‬‭(‬‭I‬‭OS).‬
‭Table 63: Events type OS‬
‭OS‬
‭N‬
‭%‬
‭95%CI‬
‭Alive‬
‭Death‬
‭Total‬
‭Table 64: Median/mean OS (estimated by Kaplan-Meier)‬


‭Median (months)‬
‭CI 95%‬
‭Mean‬
‭CI 95%‬
‭Overall survival‬
‭Table 65: OS estimated survival ratio‬
‭OS‬
‭Events (%, total‬
‭N)‬
‭Patients at‬
‭risk‬
‭% estimated cumulative survival‬
‭ratio‬
‭CI 95%‬
‭At 6 months‬
‭At 12‬
‭months‬
‭At 18‬
‭months‬
‭At 24‬
‭months‬
‭Figure 8: Overall survival‬
‭4.5.5.‬‭PP - C‬‭OHORT‬‭1:‬‭INTRACRANIAL‬‭O‬‭VERALL‬‭SURVIVAL‬‭(‬‭I‬‭OS).‬
‭Table 66: Events type OS‬
‭OS‬
‭N‬
‭%‬
‭95%CI‬
‭Alive‬
‭Death‬
‭Total‬
‭Table 67: Median/mean OS (estimated by Kaplan-Meier)‬
‭Median (months)‬
‭CI 95%‬
‭Mean‬
‭CI 95%‬
‭Overall survival‬
‭Table 68: OS estimated survival ratio‬
‭OS‬
‭Events (%, total‬
‭N)‬
‭Patients at‬
‭risk‬
‭% estimated cumulative survival‬
‭ratio‬
‭CI 95%‬
‭At 6 months‬
‭At 12‬
‭months‬
‭At 18‬
‭months‬
‭At 24‬
‭months‬


‭Figure 9: Overall survival‬
‭4.5.6.‬‭PP - C‬‭OHORT‬‭2:‬‭INTRACRANIAL‬‭O‬‭VERALL‬‭SURVIVAL‬‭(‬‭I‬‭OS).‬
‭Table 69: Events type OS‬
‭OS‬
‭N‬
‭%‬
‭95%CI‬
‭Alive‬
‭Death‬
‭Total‬
‭Table 70: Median/mean OS (estimated by Kaplan-Meier)‬
‭Median (months)‬
‭CI 95%‬
‭Mean‬
‭CI 95%‬
‭Overall survival‬
‭Table 71: OS estimated survival ratio‬
‭OS‬
‭Events (%, total‬
‭N)‬
‭Patients at‬
‭risk‬
‭% estimated cumulative survival‬
‭ratio‬
‭CI 95%‬
‭At 6 months‬
‭At 12‬
‭months‬
‭At 18‬
‭months‬
‭At 24‬
‭months‬
‭Figure 10: Overall survival‬
‭4.6.‬ ‭I‬‭NTRACRANIAL‬‭P‬‭ROGRESSION‬‭-‬‭FREE‬‭SURVIVAL‬‭(‬‭I‬‭PFS).‬
‭Intracranial‬ ‭Progression-free‬ ‭survival‬ ‭(PFS),‬ ‭defined‬ ‭as‬ ‭the‬ ‭time‬ ‭from‬
‭inclusion‬ ‭(first‬ ‭dose‬ ‭of‬ ‭treatment)‬ ‭until‬ ‭intracranial‬ ‭tumour‬ ‭progression‬
‭(RECIST‬ ‭1.1)‬ ‭or‬ ‭death.‬ ‭Patients‬ ‭without‬ ‭any‬ ‭of‬ ‭the‬ ‭previous‬ ‭events‬ ‭are‬
‭censored at the date of the last available tumor assessment.‬
‭4.6.1.‬‭ITT A‬‭LL‬‭PATIENTS‬‭:‬‭INTRACRANIAL‬‭P‬‭ROGRESSION‬‭-‬‭FREE‬‭SURVIVAL‬
‭(‬‭I‬‭PFS).‬
‭0 patient has been censored at time 0 due to lack of tumor assessments.‬


‭Table 72: iPFS (event). ITT All patients‬
‭PFS (event)‬
‭N‬
‭%‬
‭95%CI‬
‭Censored‬
‭Event (PD/death)‬
‭Total‬
‭Table 73: Median iPFS. ITT All patients‬
‭Median‬
‭95%CI‬
‭PFS‬
‭iPFS estimated at 3, 6 and 12 months (Kaplan-Meier)‬
‭Table 74: iPFS at 3, 6 and 12 months. ITT All patients‬
‭iPFS‬
‭Events (%, total N)‬
‭Patients at risk‬
‭% estimated cumulative survival ratio‬
‭95% IC‬
‭At 3 months‬
‭At 6 months‬
‭At 12 months‬
‭1‬‭Estimated using Kaplan-Meier product-limit method‬
‭Figure: intracranial Progression Free Survival (ITT: All patients)‬
‭4.6.2.‬‭ITT - C‬‭OHORT‬‭1:‬‭INTRACRANIAL‬‭P‬‭ROGRESSION‬‭-‬‭FREE‬‭SURVIVAL‬
‭(‬‭I‬‭PFS).‬
‭Table 75: iPFS (event). ITT Cohort 1‬
‭PFS (event)‬
‭N‬
‭%‬
‭95%CI‬
‭Censored‬
‭Event (PD/death)‬


‭PFS (event)‬
‭N‬
‭%‬
‭95%CI‬
‭Total‬
‭Table 76: Median iPFS. ITT Cohort 1‬
‭Median‬
‭95%CI‬
‭PFS‬
‭iPFS estimated at 3, 6 and 12 months (Kaplan-Meier)‬
‭Table 77: iPFS at 3, 6 and 12 months. ITT Cohort 1‬
‭iPFS‬
‭Events (%, total N)‬
‭Patients at risk‬
‭% estimated cumulative survival ratio‬
‭95% IC‬
‭At 3 months‬
‭At 6 months‬
‭At 12 months‬
‭1‬‭Estimated using Kaplan-Meier product-limit method‬
‭Figure: intracranial Progression Free Survival (ITT Cohort 1)‬
‭4.6.3.‬‭ITT - C‬‭OHORT‬‭2:‬‭INTRACRANIAL‬‭P‬‭ROGRESSION‬‭-‬‭FREE‬‭SURVIVAL‬
‭(‬‭I‬‭PFS).‬
‭Table 78: iPFS (event). ITT Cohort 2‬
‭PFS (event)‬
‭N‬
‭%‬
‭95%CI‬
‭Censored‬
‭Event (PD/death)‬
‭Total‬
‭Table 79: Median iPFS. ITT Cohort 2‬


‭Median‬
‭95%CI‬
‭PFS‬
‭iPFS estimated at 3, 6 and 12 months (Kaplan-Meier)‬
‭Table 80: iPFS at 3, 6 and 12 months. ITT Cohort 2‬
‭iPFS‬
‭Events (%, total N)‬
‭Patients at risk‬
‭% estimated cumulative survival ratio‬
‭95% IC‬
‭At 3 months‬
‭At 6 months‬
‭At 12 months‬
‭1‬‭Estimated using Kaplan-Meier product-limit method‬
‭Figure: intracranial Progression Free Survival (ITT Cohort 2)‬
‭4.6.4.‬‭PP A‬‭LL‬‭PATIENTS‬‭:‬‭INTRACRANIAL‬‭P‬‭ROGRESSION‬‭-‬‭FREE‬‭SURVIVAL‬
‭(‬‭I‬‭PFS).‬
‭Table 81: iPFS (event). PP All patients‬
‭PFS (event)‬
‭N‬
‭%‬
‭95%CI‬
‭Censored‬
‭Event (PD/death)‬
‭Total‬
‭Table 82: Median iPFS. PP All patients‬
‭Median‬
‭95%CI‬
‭PFS‬
‭iPFS estimated at 3, 6 and 12 months (Kaplan-Meier)‬


‭Table 83: iPFS at 3, 6 and 12 months. PP All patients‬
‭iPFS‬
‭Events (%, total N)‬
‭Patients at risk‬
‭% estimated cumulative survival ratio‬
‭95% IC‬
‭At 3 months‬
‭At 6 months‬
‭At 12 months‬
‭1‬‭Estimated using Kaplan-Meier product-limit method‬
‭Figure: intracranial Progression Free Survival (PP: All patients)‬
‭4.6.5.‬‭PP - C‬‭OHORT‬‭1:‬‭INTRACRANIAL‬‭P‬‭ROGRESSION‬‭-‬‭FREE‬‭SURVIVAL‬
‭(‬‭I‬‭PFS).‬
‭Table 84: iPFS (event). PP Cohort 1‬
‭PFS (event)‬
‭N‬
‭%‬
‭95%CI‬
‭Censored‬
‭Event (PD/death)‬
‭Total‬
‭Table 85: Median iPFS. PP Cohort 1‬
‭Median‬
‭95%CI‬
‭PFS‬
‭iPFS estimated at 3, 6 and 12 months (Kaplan-Meier)‬
‭Table 86: iPFS at 3, 6 and 12 months. PP Cohort 1‬
‭iPFS‬
‭Events (%, total N)‬
‭Patients at risk‬
‭% estimated cumulative survival ratio‬
‭95% IC‬
‭At 3 months‬
‭At 6 months‬


‭iPFS‬
‭Events (%, total N)‬
‭Patients at risk‬
‭% estimated cumulative survival ratio‬
‭95% IC‬
‭At 12 months‬
‭1‬‭Estimated using Kaplan-Meier product-limit method‬
‭Figure: intracranial Progression Free Survival (PP Cohort 1)‬
‭4.6.6.‬‭PP - C‬‭OHORT‬‭2:‬‭INTRACRANIAL‬‭P‬‭ROGRESSION‬‭-‬‭FREE‬‭SURVIVAL‬
‭(‬‭I‬‭PFS).‬
‭Table 87: iPFS (event). PP Cohort 2‬
‭PFS (event)‬
‭N‬
‭%‬
‭95%CI‬
‭Censored‬
‭Event (PD/death)‬
‭Total‬
‭Table 88: Median iPFS. PP Cohort 2‬
‭Median‬
‭95%CI‬
‭PFS‬
‭iPFS estimated at 3, 6 and 12 months (Kaplan-Meier)‬
‭Table 89: iPFS at 3, 6 and 12 months. PP Cohort 2‬
‭iPFS‬
‭Events (%, total N)‬
‭Patients at risk‬
‭% estimated cumulative survival ratio‬
‭95% IC‬
‭At 3 months‬
‭At 6 months‬
‭At 12 months‬
‭1‬‭Estimated using Kaplan-Meier product-limit method‬


‭Figure: intracranial Progression Free Survival (PP Cohort 2)‬
‭4.7.‬ ‭E‬‭XTRACRANIAL‬‭P‬‭ROGRESSION‬‭-‬‭FREE‬‭SURVIVAL‬‭(‬‭E‬‭PFS).‬
‭Extracranial‬ ‭Progression-free‬ ‭survival‬ ‭(PFS),‬ ‭defined‬ ‭as‬ ‭the‬ ‭time‬ ‭from‬
‭inclusion‬ ‭(first‬ ‭dose‬ ‭of‬ ‭treatment)‬ ‭until‬ ‭extracranial‬ ‭tumour‬ ‭progression‬
‭(RECIST‬ ‭1.1)‬ ‭or‬ ‭death.‬ ‭Patients‬ ‭without‬ ‭any‬ ‭of‬ ‭the‬ ‭previous‬ ‭events‬ ‭are‬
‭censored at the date of the last available tumor assessment.‬
‭4.7.1.‬‭ITT A‬‭LL‬‭PATIENTS‬‭:‬‭EXTRACRANIAL‬‭P‬‭ROGRESSION‬‭-‬‭FREE‬‭SURVIVAL‬
‭(‬‭E‬‭PFS).‬
‭Table 90: Events type PFS‬
‭PFS (event)‬
‭N‬
‭%‬
‭95%CI‬
‭Censored‬
‭Event (PD/death)‬
‭Total‬
‭Table 91: Median/mean PFS (estimated by Kaplan-Meier)‬
‭Median (months)‬
‭CI 95%‬
‭Mean‬
‭CI 95%‬
‭Progression free survival‬
‭Table 92: PFS estimated survival ratio‬
‭PFS‬
‭Events (%, total‬
‭N)‬
‭Patients at‬
‭risk‬
‭% estimated cumulative survival‬
‭ratio‬
‭CI 95%‬
‭At 6 months‬
‭At 12‬
‭months‬
‭At 18‬
‭months‬
‭At 24‬
‭months‬
‭Figure 11: Progression free survival‬
‭4.7.2.‬‭ITT - C‬‭OHORT‬‭1:‬‭EXTRACRANIAL‬‭P‬‭ROGRESSION‬‭-‬‭FREE‬‭SURVIVAL‬
‭(‬‭E‬‭PFS).‬
‭Table 93: Events type PFS‬


‭PFS (event)‬
‭N‬
‭%‬
‭95%CI‬
‭Censored‬
‭Event (PD/death)‬
‭Total‬
‭Table 94: Median/mean PFS (estimated by Kaplan-Meier)‬
‭Median (months)‬
‭CI 95%‬
‭Mean‬
‭CI 95%‬
‭Progression free survival‬
‭Table 95: PFS estimated survival ratio‬
‭PFS‬
‭Events (%, total‬
‭N)‬
‭Patients at‬
‭risk‬
‭% estimated cumulative survival‬
‭ratio‬
‭CI 95%‬
‭At 6 months‬
‭At 12‬
‭months‬
‭At 18‬
‭months‬
‭At 24‬
‭months‬
‭Figure 12: Progression free survival‬
‭4.7.3.‬‭ITT - C‬‭OHORT‬‭2:‬‭EXTRACRANIAL‬‭P‬‭ROGRESSION‬‭-‬‭FREE‬‭SURVIVAL‬
‭(‬‭E‬‭PFS).‬
‭Table 96: Events type PFS‬
‭PFS (event)‬
‭N‬
‭%‬
‭95%CI‬
‭Censored‬
‭Event (PD/death)‬
‭Total‬
‭Table 97: Median/mean PFS (estimated by Kaplan-Meier)‬
‭Median (months)‬
‭CI 95%‬
‭Mean‬
‭CI 95%‬
‭Progression free survival‬
‭Table 98: PFS estimated survival ratio‬


‭PFS‬
‭Events (%, total‬
‭N)‬
‭Patients at‬
‭risk‬
‭% estimated cumulative survival‬
‭ratio‬
‭CI 95%‬
‭At 3 months‬
‭At 6 months‬
‭At 9 months‬
‭At 12‬
‭months‬
‭At 15‬
‭months‬
‭Figure 13: Progression free survival‬
‭4.7.4.‬‭PP A‬‭LL‬‭PATIENTS‬‭:‬‭EXTRACRANIAL‬‭P‬‭ROGRESSION‬‭-‬‭FREE‬‭SURVIVAL‬
‭(‬‭E‬‭PFS).‬
‭Table 99: Events type PFS‬
‭PFS (event)‬
‭N‬
‭%‬
‭95%CI‬
‭Censored‬
‭Event (PD/death)‬
‭Total‬
‭Table 100: Median/mean PFS (estimated by Kaplan-Meier)‬
‭Median (months)‬
‭CI 95%‬
‭Mean‬
‭CI 95%‬
‭Progression free survival‬
‭Table 101: PFS estimated survival ratio‬
‭PFS‬
‭Events (%, total‬
‭N)‬
‭Patients at‬
‭risk‬
‭% estimated cumulative survival‬
‭ratio‬
‭CI 95%‬
‭At 6 months‬
‭At 12‬
‭months‬
‭At 18‬
‭months‬
‭At 24‬
‭months‬
‭Figure 14: Progression free survival‬


‭4.7.5.‬‭PP - C‬‭OHORT‬‭1:‬‭EXTRACRANIAL‬‭P‬‭ROGRESSION‬‭-‬‭FREE‬‭SURVIVAL‬
‭(‬‭E‬‭PFS).‬
‭Table 102: Events type PFS‬
‭PFS (event)‬
‭N‬
‭%‬
‭95%CI‬
‭Censored‬
‭Event (PD/death)‬
‭Total‬
‭Table 103: Median/mean PFS (estimated by Kaplan-Meier)‬
‭Median (months)‬
‭CI 95%‬
‭Mean‬
‭CI 95%‬
‭Progression free survival‬
‭Table 104: PFS estimated survival ratio‬
‭PFS‬
‭Events (%, total‬
‭N)‬
‭Patients at‬
‭risk‬
‭% estimated cumulative survival‬
‭ratio‬
‭CI 95%‬
‭At 6 months‬
‭At 12‬
‭months‬
‭At 18‬
‭months‬
‭At 24‬
‭months‬
‭Figure 15: Progression free survival‬
‭4.7.6.‬‭PP - C‬‭OHORT‬‭2:‬‭EXTRACRANIAL‬‭P‬‭ROGRESSION‬‭-‬‭FREE‬‭SURVIVAL‬
‭(‬‭E‬‭PFS).‬
‭Table 105: Events type PFS‬
‭PFS (event)‬
‭N‬
‭%‬
‭95%CI‬
‭Censored‬
‭Event (PD/death)‬
‭Total‬
‭Table 106: Median/mean PFS (estimated by Kaplan-Meier)‬
‭Median (months)‬
‭CI 95%‬
‭Mean‬
‭CI 95%‬
‭Progression free survival‬


‭Table 107: PFS estimated survival ratio‬
‭PFS‬
‭Events (%, total‬
‭N)‬
‭Patients at‬
‭risk‬
‭% estimated cumulative survival‬
‭ratio‬
‭CI 95%‬
‭At 3 months‬
‭At 6 months‬
‭At 9 months‬
‭At 12‬
‭months‬
‭At 15‬
‭months‬
‭Figure 16: Progression free survival‬
‭4.8.‬ ‭QUALITY OF LIFE QUESTIONARY: EORTC QLQ‬
‭C-30. COHORT 2‬
‭All‬‭scores‬‭are‬‭scaled‬‭to‬‭range‬‭from‬‭0-100,‬‭even‬‭scores‬‭based‬‭on‬‭single‬‭items.‬‭Be‬
‭aware‬‭that‬‭these‬‭single-item‬‭scales‬‭still‬‭have‬‭only‬‭4‬‭possible‬‭values,‬‭even‬‭though‬
‭they‬‭are‬‭transformed‬‭to‬‭range‬‭from‬‭0-100.‬‭The‬‭scale‬‭name‬‭and‬‭number‬‭of‬‭items‬
‭are listed below.‬
‭•‬
‭Global health status/QoL‬
‭QL - Global health status/QoL (revised) (from 2 items)‬
‭•‬
‭Functional Scales (higher is better functioning)‬
‭PF - Physical functioning (from 5 items)‬
‭RF - Role functioning (from 2 items)‬
‭EF - Emotional functioning (from 4 items)‬
‭CF - Cognitive functioning (from 2 items)‬
‭SF - Social functioning (from 2 items)‬
‭•‬
‭Symptom Scales (higher is more symptoms, worse functioning)‬
‭FA - Fatigue (from 3 items)‬
‭NV - Nausea and Vomiting (from 2 items)‬
‭PA - Pain (from 2 items)‬
‭•‬
‭Single-Item Symptom Scores (higher is more symptoms, worse‬
‭functioning)‬
‭DY - Dyspnoea‬
‭SL - Insomnia‬
‭AP - Appetite Loss‬
‭CO - Constipation‬


‭DI - Diarrhoea‬
‭FI - Financial Difficulties‬
‭•‬
‭QLQ-C30 Summary Score‬‭(higher is better functioning,‬‭fewer symptoms)‬
‭C30SUMMARY - QLQ-C30 Summary Score, composed by taking mean of‬
‭all scores except for QL (Global health status/QoL) and FI (Financial‬
‭Difficulties).‬
‭Reference:‬
‭https://rdrr.io/cran/PROscorer/man/qlq_c30.html‬
‭Aaronson‬‭NK,‬‭Ahmedzai‬‭S,‬‭Bergman‬‭B,‬‭Bullinger‬‭M,‬‭Cull‬‭A,‬‭Duez‬‭NJ,‬‭Filiberti‬‭A,‬
‭Flechtner‬‭H,‬‭Fleishman‬‭SB,‬‭Haes‬‭JCJM‬‭de,‬‭Kaasa‬‭S,‬‭Klee‬‭M,‬‭Osoba‬‭D,‬‭Razavi‬‭D,‬
‭Rofe‬ ‭PB,‬ ‭Schraub‬ ‭S,‬ ‭Sneeuw‬ ‭K,‬ ‭Sullivan‬ ‭M,‬ ‭Takeda‬ ‭F‬ ‭(1993).‬ ‭The‬ ‭European‬
‭Organization‬ ‭for‬ ‭Research‬ ‭and‬ ‭Treatment‬ ‭of‬ ‭Cancer‬‭QLQ-C30:‬‭A‬‭Quality-of-Life‬
‭Instrument‬‭for‬‭Use‬‭in‬‭International‬‭Clinical‬‭Trials‬‭in‬‭Oncology.‬‭JNCI‬‭J‬‭Natl‬‭Cancer‬
‭Inst 85:365-376.‬
‭Fayers‬ ‭PM,‬ ‭Aaronson‬ ‭NK,‬ ‭Bjordal‬ ‭K,‬ ‭Groenvold‬ ‭M,‬ ‭Curran‬ ‭D,‬ ‭Bottomley‬ ‭A,‬ ‭on‬
‭behalf‬‭of‬‭the‬‭EORTC‬‭Quality‬‭of‬‭Life‬‭Group.‬‭The‬‭EORTC‬‭QLQ-C30‬‭Scoring‬‭Manual‬
‭(3rd‬‭Edition).‬‭Published‬‭by:‬‭European‬‭Organisation‬‭for‬‭Research‬‭and‬‭Treatment‬‭of‬
‭Cancer, Brussels 2001.‬
‭Giesinger‬ ‭JM,‬ ‭Kieffer‬ ‭JM,‬ ‭Fayers‬ ‭PM,‬ ‭Groenvold‬ ‭M,‬ ‭Petersen‬ ‭MA,‬ ‭Scott‬ ‭NW,‬
‭Sprangers‬ ‭MAG,‬ ‭Velikova‬ ‭G,‬ ‭Aaronson‬ ‭NK‬‭(2016).‬‭Replication‬‭and‬‭validation‬‭of‬
‭higher‬‭order‬‭models‬‭demonstrated‬‭that‬‭a‬‭summary‬‭score‬‭for‬‭the‬‭EORTC‬‭QLQ-C30‬
‭is robust. Journal of Clinical Epidemiology 69:79-88.‬
‭4.8.1.‬‭G‬‭LOBAL‬‭HEALTH‬‭STATUS‬‭/Q‬‭O‬‭L‬
‭4.8.1.1.‬
‭QL - G‬‭LOBAL‬‭HEALTH‬‭STATUS‬‭/Q‬‭O‬‭L (‬‭REVISED‬‭) (‬‭FROM‬‭2‬‭ITEMS‬‭)‬
‭Table 108: Global health status/QoL‬
‭Global health status/QoL‬
‭N‬
‭Mean(SD)‬
‭Median(Min-Max)‬
‭p-value (wilcoxon test)‬
‭compared with baseline‬
‭Baseline‬
‭w8‬
‭w16‬


‭4.8.2.‬‭F‬‭UNCTIONAL‬‭S‬‭CALES‬‭(‬‭HIGHER‬‭IS‬‭BETTER‬‭FUNCTIONING‬‭)‬
‭4.8.2.1.‬
‭PF - P‬‭HYSICAL‬‭FUNCTIONING‬‭(‬‭FROM‬‭5‬‭ITEMS‬‭)‬
‭Table 109: Physical functioning/QoL‬
‭Physical functioning/QoL‬
‭N‬
‭Mean(SD)‬
‭Median(Min-Max)‬
‭p-value (wilcoxon test)‬
‭compared with baseline‬
‭Baseline‬
‭w8‬
‭w16‬
‭4.8.2.2.‬
‭RF - R‬‭OLE‬‭FUNCTIONING‬‭(‬‭FROM‬‭2‬‭ITEMS‬‭)‬
‭Table 110: Role functioning/QoL‬
‭Role functioning/QoL‬
‭N‬
‭Mean(SD)‬
‭Median(Min-Max)‬
‭p-value (wilcoxon test)‬
‭compared with baseline‬
‭Baseline‬
‭w8‬
‭w16‬
‭4.8.2.3.‬
‭EF - E‬‭MOTIONAL‬‭FUNCTIONING‬‭(‬‭FROM‬‭4‬‭ITEMS‬‭)‬
‭Table 111: Emotional functioning/QoL‬
‭Emotional functioning/QoL‬
‭N‬
‭Mean(SD)‬
‭Median(Min-Max)‬
‭p-value (wilcoxon test)‬
‭compared with baseline‬
‭Baseline‬
‭w8‬
‭w16‬


‭4.8.2.4.‬
‭CF - C‬‭OGNITIVE‬‭FUNCTIONING‬‭(‬‭FROM‬‭2‬‭ITEMS‬‭)‬
‭Table 112: Cognitive functioning/QoL‬
‭Cognitive functioning/QoL‬
‭N‬
‭Mean(SD)‬
‭Median(Min-Max)‬
‭p-value (wilcoxon test)‬
‭compared with baseline‬
‭Baseline‬
‭w8‬
‭w16‬
‭4.8.2.5.‬
‭SF - S‬‭OCIAL‬‭FUNCTIONING‬‭(‬‭FROM‬‭2‬‭ITEMS‬‭)‬
‭Table 113: Social functioning/QoL‬
‭Social functioning/QoL‬
‭N‬
‭Mean(SD)‬
‭Median(Min-Max)‬
‭p-value (wilcoxon test)‬
‭compared with baseline‬
‭Baseline‬
‭w8‬
‭w16‬
‭4.8.3.‬‭S‬‭YMPTOM‬‭S‬‭CALES‬‭(‬‭HIGHER‬‭IS‬‭MORE‬‭SYMPTOMS‬‭,‬‭WORSE‬
‭FUNCTIONING‬‭)‬
‭4.8.3.1.‬
‭FA - F‬‭ATIGUE‬‭(‬‭FROM‬‭3‬‭ITEMS‬‭)‬
‭Table 114: Fatigue/QoL‬
‭Fatigue/QoL‬
‭N‬
‭Mean(SD)‬
‭Median(Min-Max)‬
‭p-value (wilcoxon test)‬
‭compared with baseline‬
‭Baseline‬
‭w8‬
‭w16‬


‭4.8.3.2.‬
‭NV - N‬‭AUSEA‬‭AND‬‭V‬‭OMITING‬‭(‬‭FROM‬‭2‬‭ITEMS‬‭)‬
‭Table 115: Nausea and Vomiting/QoL‬
‭Nausea and Vomiting/QoL‬
‭N‬
‭Mean(SD)‬
‭Median(Min-Max)‬
‭p-value (wilcoxon test)‬
‭compared with baseline‬
‭Baseline‬
‭w8‬
‭w16‬
‭4.8.3.3.‬
‭PA - P‬‭AIN‬‭(‬‭FROM‬‭2‬‭ITEMS‬‭)‬
‭Table 116: Pain/QoL‬
‭Pain/QoL‬
‭N‬
‭Mean(SD)‬
‭Median(Min-Max)‬
‭p-value (wilcoxon test)‬
‭compared with baseline‬
‭Baseline‬
‭w8‬
‭w16‬
‭4.8.4.‬‭S‬‭INGLE‬‭-I‬‭TEM‬‭S‬‭YMPTOM‬‭S‬‭CORES‬‭(‬‭HIGHER‬‭IS‬‭MORE‬‭SYMPTOMS‬‭,‬
‭WORSE‬‭FUNCTIONING‬‭)‬
‭4.8.4.1.‬
‭DY - D‬‭YSPNOEA‬‭(‬‭FROM‬‭1‬‭ITEM‬‭)‬
‭Table 117: Dyspnoea/QoL‬
‭Dyspnoea/QoL‬
‭N‬
‭Mean(SD)‬
‭Median(Min-Max)‬
‭p-value (wilcoxon test)‬
‭compared with baseline‬
‭Baseline‬
‭w8‬
‭w16‬


‭4.8.4.2.‬
‭SL - I‬‭NSOMNIA‬‭(‬‭FROM‬‭1‬‭ITEM‬‭)‬
‭Table 118: Insomnia/QoL‬
‭Insomnia/QoL‬
‭N‬
‭Mean(SD)‬
‭Median(Min-Max)‬
‭p-value (wilcoxon test)‬
‭compared with baseline‬
‭Baseline‬
‭w8‬
‭w16‬
‭4.8.4.3.‬
‭AP - A‬‭PPETITE‬‭L‬‭OSS‬‭(‬‭FROM‬‭1‬‭ITEM‬‭)‬
‭Table 119: Appetite Loss/QoL‬
‭Appetite Loss/QoL‬
‭N‬
‭Mean(SD)‬
‭Median(Min-Max)‬
‭p-value (wilcoxon test)‬
‭compared with baseline‬
‭Baseline‬
‭w8‬
‭w16‬
‭4.8.4.4.‬
‭CO - C‬‭ONSTIPATION‬‭(‬‭FROM‬‭1‬‭ITEM‬‭)‬
‭Table 120: Constipation/QoL‬
‭Constipation/QoL‬
‭N‬
‭Mean(SD)‬
‭Median(Min-Max)‬
‭p-value (wilcoxon test)‬
‭compared with baseline‬
‭Baseline‬
‭w8‬
‭w16‬


‭4.8.4.5.‬
‭DI - D‬‭IARRHOEA‬‭(‬‭FROM‬‭1‬‭ITEM‬‭)‬
‭Table 121: Diarrhoea/QoL‬
‭Diarrhoea/QoL‬
‭N‬
‭Mean(SD)‬
‭Median(Min-Max)‬
‭p-value (wilcoxon test)‬
‭compared with baseline‬
‭Baseline‬
‭w8‬
‭w16‬
‭4.8.4.6.‬
‭FI - F‬‭INANCIAL‬‭D‬‭IFFICULTIES‬‭(‬‭FROM‬‭1‬‭ITEM‬‭)‬
‭Table 122: Financial Difficulties/QoL‬
‭Financial Difficulties/QoL‬
‭N‬
‭Mean(SD)‬
‭Median(Min-Max)‬
‭p-value (wilcoxon test)‬
‭compared with baseline‬
‭Baseline‬
‭w8‬
‭w16‬
‭4.9.‬ ‭QLQ-C30 S‬‭UMMARY‬‭S‬‭CORE‬‭(‬‭HIGHER‬‭IS‬‭BETTER‬‭FUNCTIONING‬‭,‬
‭FEWER‬‭SYMPTOMS‬‭)‬
‭4.9.1.‬‭C30SUMMARY - QLQ-C30 S‬‭UMMARY‬‭S‬‭CORE‬‭,‬‭COMPOSED‬‭BY‬
‭TAKING‬‭MEAN‬‭OF‬‭ALL‬‭SCORES‬‭EXCEPT‬‭FOR‬‭QL (G‬‭LOBAL‬‭HEALTH‬
‭STATUS‬‭/Q‬‭O‬‭L)‬‭AND‬‭FI (F‬‭INANCIAL‬‭D‬‭IFFICULTIES‬‭)‬
‭Table 123: QLQ-C30 Summary Score/QoL‬


‭QLQ-C30 Summary Score/QoL‬
‭N‬
‭Mean(SD)‬
‭Median(Min-Max)‬
‭p-value (wilcoxon test)‬
‭compared with baseline‬
‭Baseline‬
‭w8‬
‭w16‬
‭5.‬‭SAFETY ANALYSIS‬
‭In safety population.‬
‭Table 124: Overall safety‬
‭Cohort‬
‭Adverse Events‬
‭   No‬
‭   Yes‬
‭AE Grade >=3‬
‭   No‬
‭   Yes‬
‭Toxicity: AE related to Binimetinib‬
‭   No‬
‭   Yes‬
‭Toxicity: AE related to Encorafenib‬
‭   No‬
‭   Yes‬
‭Toxicity: AE related to any treatment‬
‭   No‬
‭   Yes‬
‭Toxicity: AE related to all treatments‬
‭   No‬
‭   Yes‬
‭Toxicity grade >=3‬
‭   No‬
‭   Yes‬
‭Toxicity related to Binimetinib grade >=3‬
‭   No‬
‭   Yes‬
‭Toxicity related to Encorafenib grade >=3‬
‭   No‬
‭   Yes‬
‭Toxicity related to all treatments grade‬
‭>=3‬
‭   No‬
‭   Yes‬
‭SAE‬
‭   No‬


‭Cohort‬
‭   Yes‬
‭Table 125: Most frequent Toxicity with 5% threshold‬
‭Toxicity‬
‭Frequency‬
‭Percentage (%)‬
‭Table 126: Grade of most frequent toxicities with 5% threshold overall‬
‭Toxicity‬
‭No‬
‭G-UK‬
‭G-1‬
‭G-2‬
‭G-3‬
‭G-4‬
‭G-5‬
‭Table 127: List of toxicities grade >=3 in all patients‬
‭Patient Number‬
‭Cohort‬
‭AE CTCAE‬
‭AE Grade‬
‭AE Related to‬
‭Table 128: Most frequent AEs with 5% threshold‬
‭AE‬
‭Frequency‬
‭Percentage (%)‬
‭Table 129: Grade of most frequent AEs with 5% threshold overall‬
‭AE‬
‭No‬
‭G-UK‬
‭G-1‬
‭G-2‬
‭G-3‬
‭G-4‬
‭G-5‬
‭Table 130: List of all SAEs‬
‭Patient‬
‭Number‬ ‭Cohort‬
‭AE CTCAE‬
‭AE CTCAE Other‬
‭AE‬
‭Grad‬
‭e‬
‭AE‬
‭Start‬
‭Date‬
‭AE‬
‭Stop‬
‭Date‬
‭AE‬
‭Relat‬
‭ed‬
‭AE‬
‭SAE‬ ‭AE Intensity‬
‭AE‬
‭Related‬
‭to‬
‭6.‬‭O‬‭THER‬‭ANALYSIS‬
‭6.1.‬ ‭D‬‭OSE‬‭ANALYSIS‬
‭In‬ ‭this‬ ‭section,‬ ‭we‬ ‭analyzed‬ ‭the‬ ‭pattern‬ ‭of‬ ‭Corticosteroids‬ ‭dosage‬ ‭between‬
‭Assessment‬ ‭1‬ ‭and‬ ‭2‬ ‭with‬ ‭the‬ ‭aim‬ ‭of‬ ‭observing‬ ‭any‬ ‭changes‬ ‭in‬ ‭Corticosteroids‬
‭usage‬ ‭during‬‭the‬‭second‬‭tumor‬‭assessment.‬‭To‬‭achieve‬‭this,‬‭we‬‭focused‬‭on‬‭the‬
‭active‬ ‭Corticosteroids‬ ‭treatments‬ ‭administered‬ ‭during‬ ‭the‬ ‭initial‬ ‭and‬ ‭follow-up‬
‭tumor‬‭assessments.‬‭Therefore,‬‭we‬‭included‬‭only‬‭those‬‭patients‬‭who‬‭had‬‭at‬‭least‬


‭one‬ ‭active‬ ‭Corticosteroids‬ ‭treatment‬ ‭during‬ ‭either‬ ‭the‬ ‭first‬ ‭or‬ ‭second‬ ‭tumor‬
‭assessment.‬
‭Table‬ ‭132:‬ ‭Frequency‬ ‭of‬ ‭Dose‬ ‭in‬ ‭Patients‬ ‭with‬ ‭Corticosteroid‬ ‭Treatment‬ ‭by‬
‭Assessment‬
‭case‬
‭CortiDose‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭Table‬ ‭133:‬ ‭Frequencies‬ ‭of‬‭Corticosteroid‬‭Dose‬‭Changes‬‭between‬‭Assessment‬‭1‬
‭and 2‬
‭Overall‬
‭Dose comparison between Assessment 1 and 2 for each patient‬
‭   Decreased Dose‬
‭   Increased Dose‬
‭   Maintained Dose‬
‭Table 134: Dose distribution according Assessment‬
‭Dose‬
‭   Mean (SD)‬
‭   Range‬
‭1.‬
‭Paired samples t-test‬
‭Table 135: Mean Difference in Change between Assessment 1 and Assessment 2‬
‭Overall‬
‭Dose difference between Assessment 1 and‬
‭2‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭Figure 17: Trends in Assessment Differences‬
‭*The‬‭dose‬‭scale‬‭(mg)‬‭on‬‭the‬‭vertical‬‭axis‬‭has‬‭been‬‭plotted‬‭on‬‭a‬‭logarithmic‬‭scale‬‭to‬‭show‬
‭trends more clearly.‬
‭Table‬ ‭136:‬ ‭List‬ ‭of‬ ‭all‬ ‭analyzed‬ ‭patients‬ ‭with‬ ‭their‬ ‭respective‬ ‭tumor‬ ‭assessment‬
‭information‬‭and‬‭ongoing‬‭corticosteroid‬‭treatment.‬‭This‬‭includes‬‭both‬‭treatment‬‭and‬
‭specific tumor assessment information‬


‭Patient‬
‭Number‬
‭CortiMedication‬
‭Name‬
‭Corti‬
‭Dose‬
‭Cort‬
‭iUni‬
‭ts‬
‭CortiStar‬
‭tDate‬
‭Corti‬
‭Stop‬
‭Date‬
‭Corti‬
‭Ong‬
‭oing‬
‭TumA‬
‭ssmT‬
‭argSu‬
‭m‬
‭TumAs‬
‭smNon‬
‭TargLe‬
‭sNA‬
‭TumAs‬
‭smNon‬
‭TargSu‬
‭m‬
‭TumA‬
‭ssmT‬
‭argRe‬
‭sp‬
‭TumAs‬
‭smNon‬
‭TargRe‬
‭sp‬
‭TumA‬
‭ssmN‬
‭ewLe‬
‭s‬
‭EvlInt‬
‭rCran‬
‭Resp‬
‭Asses‬
‭sment‬
‭1 date‬
‭Assessm‬
‭ent 2‬
‭date‬
‭6.2.‬ ‭N‬‭EUROLOGICAL‬‭S‬‭YMPTOMS‬
‭Next,‬‭we‬‭present‬‭the‬‭frequency‬‭distributions‬‭of‬‭neurological‬‭symptoms‬‭for‬‭Cohort‬‭2‬
‭according‬ ‭to‬ ‭the‬ ‭three‬ ‭temporal‬ ‭moments:‬ ‭baseline,‬ ‭assessment‬ ‭1,‬ ‭and‬
‭assessment 2.‬
‭6.2.1.‬‭O‬‭VERALL‬‭N‬‭EUROLOGICAL‬‭S‬‭YMPTOMS‬‭: C‬‭OMPARISON‬‭BETWEEN‬
‭B‬‭ASELINE‬‭AND‬‭F‬‭IRST‬‭T‬‭WO‬‭A‬‭SSESSMENTS‬
‭Table 146: Comparison of Neurological Symptoms‬
‭Headache‬
‭   No‬
‭   Yes‬
‭Epilepsy‬
‭   No‬
‭   Yes‬
‭Motor deficit‬
‭   No‬
‭   Yes‬
‭Sensory deficit‬
‭   No‬
‭   Yes‬
‭Speech deficit‬
‭   No‬
‭   Yes‬
‭Others‬
‭   No‬
‭   Yes‬
‭Presence of at least‬
‭one symptom‬
‭   No‬
‭   Yes‬
‭Number of‬
‭neurological‬
‭symptoms‬
‭   1‬
‭   2‬
‭   3‬
‭   4‬
‭   0‬
‭1.‬
‭We‬ ‭report‬ ‭four‬ ‭p-values‬ ‭for‬ ‭each‬ ‭variable,‬ ‭separated‬ ‭by‬ ‭semicolons.‬ ‭The‬ ‭first‬ ‭p-value‬
‭represents‬‭the‬‭comparison‬‭of‬‭the‬‭differences‬‭between‬‭the‬‭three‬‭assessments.‬‭Subsequent‬
‭p-values‬ ‭correspond‬ ‭to‬ ‭pairwise‬ ‭comparisons:‬ ‭Baseline‬ ‭vs. Assessment‬ ‭1,‬ ‭Baseline‬
‭vs. Assessment‬ ‭3,‬ ‭and‬ ‭Assessment‬ ‭2‬ ‭vs. Assessment‬ ‭3.‬ ‭For‬ ‭dichotomous‬ ‭variables,‬


‭Cochran’s‬ ‭Q‬ ‭test‬ ‭and‬ ‭McNeiman’s‬ ‭test‬ ‭were‬ ‭used.‬ ‭The‬ ‭discrete‬ ‭variable‬ ‭‘number‬ ‭of‬
‭symptoms’ was analyzed with the Friedman and Wilcoxon tests, respectively.‬
‭7.‬‭OTHER ANALYSES REQUIRED BY THE‬
‭COORDINATOR‬
‭Group A: Symptomatic patients (Those belonging tp symptomatic cohort 2).‬
‭Group‬ ‭B:‬ ‭Asymptomatic‬ ‭patients,‬ ‭both‬ ‭those‬ ‭who‬ ‭were‬ ‭not‬ ‭treated‬ ‭with‬
‭corticosteroids‬‭or‬‭anticonvulsants‬‭and‬‭those‬‭who‬‭were‬‭treated‬‭without‬‭association‬
‭with brain metastases.‬
‭Group‬‭C:‬‭Patients‬‭who‬‭were‬‭asymptomatic‬‭at‬‭the‬‭time‬‭of‬‭study‬‭treatment‬‭but‬‭had‬
‭been‬ ‭treated‬ ‭with‬ ‭corticosteroids‬ ‭in‬ ‭the‬ ‭days‬ ‭before‬ ‭due‬ ‭to‬ ‭a‬ ‭symptom‬ ‭of‬ ‭the‬
‭disease.‬
‭7.1.‬ ‭I‬‭NTRACRANIAL‬‭O‬‭VERALL‬‭SURVIVAL‬‭(‬‭I‬‭OS).‬
‭7.1.1.‬‭S‬‭YMPTOMATIC‬‭PATIENTS‬‭A+C:‬‭INTRACRANIAL‬‭O‬‭VERALL‬‭SURVIVAL‬
‭(‬‭I‬‭OS).‬
‭Table 147: Events type OS‬
‭OS‬
‭Alive‬
‭Death‬
‭Total‬
‭Table 148: Median/mean OS (estimated by Kaplan-Meier)‬
‭Median (months)‬
‭CI 95%‬
‭Mean‬
‭CI 95%‬
‭Overall survival‬
‭Table 149: OS estimated survival ratio‬
‭OS‬
‭Events (%, total‬
‭N)‬
‭Patients at‬
‭risk‬
‭% estimated cumulative survival‬
‭ratio‬
‭CI 95%‬
‭At 6 months‬
‭At 12‬
‭months‬
‭At 18‬
‭months‬
‭At 24‬
‭months‬


‭Figure 18: Overall survival‬
‭7.1.2.‬‭A‬‭SYMPTOMATIC‬‭PATIENTS‬‭B:‬‭INTRACRANIAL‬‭O‬‭VERALL‬‭SURVIVAL‬
‭(‬‭I‬‭OS).‬
‭Table 150: Events type OS‬
‭OS‬
‭N‬
‭%‬
‭95%CI‬
‭Alive‬
‭Death‬
‭Total‬
‭Table 151: Median/mean OS (estimated by Kaplan-Meier)‬
‭Median (months)‬
‭CI 95%‬
‭Mean‬
‭CI 95%‬
‭Overall survival‬
‭Table 152: OS estimated survival ratio‬
‭OS‬
‭Events (%, total‬
‭N)‬
‭Patients at‬
‭risk‬
‭% estimated cumulative survival‬
‭ratio‬
‭CI 95%‬
‭At 6 months‬
‭At 12‬
‭months‬
‭At 18‬
‭months‬
‭At 24‬
‭months‬
‭Figure 19: Overall survival‬
‭7.1.3.‬‭INTRACRANIAL‬‭O‬‭VERALL‬‭SURVIVAL‬‭(‬‭I‬‭OS)‬‭VS‬‭S‬‭YMPTOMATIC‬‭.‬
‭Table 153: Events type OS‬
‭Symptomatic group‬
‭ ‬
‭   Death‬
‭   Alive‬
‭1.‬
‭Pearson’s Chi-squared test‬
‭Table 154: Median/mean OS (estimated by Kaplan-Meier)‬


‭Median (months)‬
‭CI 95%‬
‭Mean‬
‭CI 95%‬
‭No‬
‭Yes‬
‭Table 155: OS estimated survival ratio‬
‭OS‬
‭Events (%, total‬
‭N)‬
‭Patients at‬
‭risk‬
‭% estimated cumulative survival‬
‭ratio‬
‭CI 95%‬
‭No‬
‭At 6 months‬
‭At 12‬
‭months‬
‭At 18‬
‭months‬
‭At 24‬
‭months‬
‭Yes‬
‭At 6 months‬
‭At 12‬
‭months‬
‭At 18‬
‭months‬
‭At 24‬
‭months‬
‭Figure 20: Overall survival vs Symptomatic group‬
‭7.2.‬ ‭I‬‭NTRACRANIAL‬‭P‬‭ROGRESSION‬‭-‬‭FREE‬‭SURVIVAL‬‭(‬‭I‬‭PFS).‬
‭7.2.1.‬‭S‬‭YMPTOMATIC‬‭PATIENTS‬‭A+C:‬‭INTRACRANIAL‬‭P‬‭ROGRESSION‬‭-‬‭FREE‬
‭SURVIVAL‬‭(‬‭I‬‭PFS).‬
‭Table 156: Events type PFS‬
‭PFS‬
‭N‬
‭%‬
‭95%CI‬
‭Censored‬
‭Event (PD/death)‬
‭Total‬
‭Table 157: Median/mean PFS (estimated by Kaplan-Meier)‬
‭Median (months)‬
‭CI 95%‬
‭Mean‬
‭CI 95%‬
‭Progression-free survival‬


‭Table 158: PFS estimated survival ratio‬
‭PFS‬
‭Events (%, total‬
‭N)‬
‭Patients at‬
‭risk‬
‭% estimated cumulative survival‬
‭ratio‬
‭CI 95%‬
‭At 3 months‬
‭At 6 months‬
‭At 9 months‬
‭At 12‬
‭months‬
‭At 15‬
‭months‬
‭At 18‬
‭months‬
‭At 21‬
‭months‬
‭Figure 21: Progression-free survival‬
‭7.2.2.‬‭A‬‭SYMPTOMATIC‬‭PATIENTS‬‭B:‬‭INTRACRANIAL‬‭P‬‭ROGRESSION‬‭-‬‭FREE‬
‭SURVIVAL‬‭(‬‭I‬‭PFS).‬
‭Table 159: Events type PFS‬
‭PFS‬
‭N‬
‭%‬
‭95%CI‬
‭Censored‬
‭Event (PD/death)‬
‭Total‬
‭Table 160: Median/mean PFS (estimated by Kaplan-Meier)‬
‭Median (months)‬
‭CI 95%‬
‭Mean‬
‭CI 95%‬
‭Progression-free survival‬
‭Table 161: PFS estimated survival ratio‬
‭PFS‬
‭Events (%, total‬
‭N)‬
‭Patients at‬
‭risk‬
‭% estimated cumulative survival‬
‭ratio‬
‭CI 95%‬
‭At 6 months‬
‭At 12‬
‭months‬
‭At 18‬
‭months‬
‭At 24‬
‭months‬


‭Figure 22: Progression-free survival‬
‭7.2.3.‬‭INTRACRANIAL‬‭P‬‭ROGRESSION‬‭-‬‭FREE‬‭SURVIVAL‬‭(‬‭I‬‭PFS)‬‭VS‬
‭S‬‭YMPTOMATIC‬‭.‬
‭Table 162: Events type PFS‬
‭Symptomatic group‬
‭ ‬
‭   Event (PD/death)‬
‭   Censored‬
‭1.‬
‭Pearson’s Chi-squared test‬
‭Table 163: Median/mean PFS (estimated by Kaplan-Meier)‬
‭Median (months)‬
‭CI 95%‬
‭Mean‬
‭CI 95%‬
‭No‬
‭Yes‬
‭Table 164: PFS estimated survival ratio‬
‭PFS‬
‭Events (%, total‬
‭N)‬
‭Patients at‬
‭risk‬
‭% estimated cumulative survival‬
‭ratio‬
‭CI 95%‬
‭No‬
‭At 6 months‬
‭At 12‬
‭months‬
‭At 18‬
‭months‬
‭At 24‬
‭months‬
‭Yes‬
‭At 6 months‬
‭At 12‬
‭months‬
‭At 18‬
‭months‬
‭At 24‬
‭months‬
‭Figure 23: Progression-free survival vs Symptomatic group‬


‭7.3.‬ ‭PRIMARY EFFICACY OBJECTIVE: RESPONSE AT‬
‭56 DAYS‬
‭Table‬‭165:‬‭Symptomatic‬‭group‬‭(A+C):‬‭intracranial‬‭Objective‬‭Response‬‭Rate‬‭at‬‭56‬
‭days‬
‭ORR: Intracraneal Evaluation at 56 days‬
‭N‬
‭%‬
‭95%CI‬
‭CR or PR‬
‭SD‬
‭NE‬
‭Total‬
‭Table‬ ‭166:‬ ‭Asymptomatic‬ ‭group‬ ‭(B):‬ ‭intracranial‬ ‭Objective‬‭Response‬‭Rate‬‭at‬‭56‬
‭days‬
‭ORR: Intracraneal Evaluation at 56 days‬
‭N‬
‭%‬
‭95%CI‬
‭CR or PR‬
‭SD‬
‭Total‬
‭7.3.1.‬‭INTRACRANIAL RESPONSE DURATION‬
‭Table 167: Intracranial Response Duration (months)‬
‭Duration of response‬
‭(months)‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭8.‬‭A‬‭NNEX‬‭1‬
‭Table 168: List of all toxicities‬
‭Patient Number‬ ‭Cohort‬
‭AE CTCAE‬
‭AE CTCAE Other‬
‭AE‬
‭Grade‬
‭AE Start‬
‭Date‬
‭AE Stop‬
‭Date‬
‭AE‬
‭Relat‬
‭ed‬
‭AE‬
‭SAE‬
‭AE‬
‭Intensi‬
‭ty‬
‭AE Related‬
‭to‬


‭EBRAIN-MEL GEM1802 STUDY -‬
‭STATISTICAL REPORT (APPENDIX‬
‭ANALYSIS)‬
‭JAN 2023‬


‭T‬‭ABLE‬‭OF‬‭C‬‭ONTENTS‬
‭1.‬‭BASELINE CHARACTERISTICS‬
‭BASELINE - DEMOGRAPHIC DATA‬
‭Table 1: Baseline - Socio demographic data ITT‬
‭Symptomatic (A+C)‬
‭Asymptomatic (B)‬
‭Total‬
‭Age (years)‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median‬
‭(95%CI)‬
‭   Range‬
‭Sex‬
‭   Female‬
‭   Male‬
‭Race‬
‭   Caucasian‬
‭   Latin‬
‭Table 2: Baseline - Physical characteristics ITT‬
‭Symptomatic‬
‭(A+C)‬
‭Asymptomatic (B)‬
‭Total‬
‭Phototype (n(%))‬
‭   Type I‬
‭   Type II‬
‭   Type III‬
‭   Type IV‬
‭   UK‬
‭Weight (kg)‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭Height (cm)‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬


‭Symptomatic‬
‭(A+C)‬
‭Asymptomatic (B)‬
‭Total‬
‭Systolic Blood Pressure (mmHg)‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭Diastolic Blood Pressure (mmHg)‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭Temperature (ºC)‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭Respiratory rate (BPM)‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭Pulse Rate (BPM)‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭ECOG (n(%))‬
‭   0‬
‭   1‬
‭   2‬
‭Barthel index (categorical), (n(%)),‬
‭previous to November 2020‬
‭   ‬
‭Barthel index (Arbitrary units, scale‬
‭0-100)‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭Barthel index modified, from‬
‭November 2020‬
‭   ‬
‭Barthel index modified (Arbitrary‬
‭units, scale 0-20), from November‬
‭2020‬
‭   N‬


‭Symptomatic‬
‭(A+C)‬
‭Asymptomatic (B)‬
‭Total‬
‭   Mean (SD)‬
‭   Median‬
‭   Range‬
‭Barthel index final (all values‬
‭transformed to scale 0-20)‬
‭(categorical) (n(%))‬
‭   ‬
‭Barthel index final (all values‬
‭transformed to scale 0-20)‬
‭   N‬
‭   Mean (95%CI)‬
‭   SD‬
‭   Median (95%CI)‬
‭   Range‬
‭Physical exam‬
‭   Normal‬
‭   Abnormal‬
‭Neurological exam‬
‭   Normal‬
‭   Abnormal‬
‭Ophthalmologic exam‬
‭   Normal‬
‭   Abnormal‬
‭Autoimmune concomitant diseases‬
‭   Yes‬
‭   No‬
‭   UK‬
‭1.1.‬ ‭B‬‭ASELINE‬‭CURRENT‬‭MELANOMA‬
‭Table 3: Metastases ITT‬
‭Symptomatic (A+C)‬
‭Asymptomatic (B)‬
‭Total‬
‭Brain Metastases‬
‭   Unique‬
‭   Multiple‬
‭Target Brain Metastases‬
‭   1‬
‭   2‬
‭   3‬
‭   4‬
‭   5‬
‭   UK‬
‭Extracranial Metastases‬
‭   Yes‬
‭   No‬
‭Lung Metastases‬
‭   Yes‬
‭   No‬
‭   UK‬
‭Lung Metastases Number‬


‭Symptomatic (A+C)‬
‭Asymptomatic (B)‬
‭Total‬
‭   1‬
‭   2‬
‭   3‬
‭   4‬
‭   >5‬
‭   NA/UK‬
‭Liver Metastases‬
‭   Yes‬
‭   No‬
‭   UK‬
‭Liver Metastases Number‬
‭   1‬
‭   2‬
‭   3‬
‭   >5‬
‭   NA/UK‬
‭Skin Metastases‬
‭   Yes‬
‭   No‬
‭   UK‬
‭Skin Metastases Number‬
‭   1‬
‭   2‬
‭   3‬
‭   >5‬
‭   UK‬
‭Bone Metastases‬
‭   Yes‬
‭   No‬
‭   UK‬
‭Bone Metastases Number‬
‭   1‬
‭   2‬
‭   NA/UK‬
‭Pleura Metastases‬
‭   Yes‬
‭   No‬
‭   UK‬
‭Pleural Effusion Volume‬
‭   0‬
‭   NA/UK‬
‭Soft Tissue Metastases‬
‭   Yes‬
‭   No‬
‭   UK‬
‭Soft Tissue Metastases‬
‭Number‬
‭   1‬
‭   5‬
‭   NA/UK‬
‭Lymph Nodes Metastases‬


‭Symptomatic (A+C)‬
‭Asymptomatic (B)‬
‭Total‬
‭   Yes‬
‭   No‬
‭   UK‬
‭Lymph Nodes Metastases‬
‭Number‬
‭   1‬
‭   2‬
‭   3‬
‭   >5‬
‭   UK‬
‭   NA/UK‬
‭Peritoneum Metastases‬
‭   Yes‬
‭   No‬
‭   UK‬
‭Peritoneum Metastases‬
‭Number‬
‭   1‬
‭   NA/UK‬
‭Other Metastases‬
‭   Yes‬
‭   No‬
‭   UK‬
‭Other Metastases Number‬
‭   1‬
‭   2‬
‭   >5‬
‭   UK‬
‭Other Metastases Specify‬
‭Table 4: BRAF ITT‬
‭Symptomatic (A+C)‬
‭Asymptomatic (B)‬
‭Total‬
‭V600E‬
‭   Missing data‬
‭   Mutated‬
‭   Not mutated‬
‭V600K‬
‭   Mutated‬
‭   Not mutated‬
‭   NA/UK‬
‭V600E/K‬
‭   Mutated‬
‭   Not mutated‬
‭   NA/UK‬
‭V600R‬
‭   Mutated‬
‭   Not mutated‬
‭   NA/UK‬
‭V600 other‬
‭   Mutated‬


‭Symptomatic (A+C)‬
‭Asymptomatic (B)‬
‭Total‬
‭   Not mutated‬
‭   NA/UK‬
‭V600 (NE)‬
‭   Mutated‬
‭   Not mutated‬
‭   NA/UK‬
‭2.‬‭PRIMARY EFFICACY OBJECTIVE‬
‭2.1.‬ ‭R‬‭ADIOTHERAPY‬‭TREATMENT‬
‭Table 5: Radiotherapy treatment. ITT‬
‭Symptomatic‬
‭(A+C)‬
‭Asymptomatic (B)‬
‭Total‬
‭Radiotherapy treatment (Local and/or‬
‭Whole Brain)‬
‭N‬
‭Yes‬
‭Yes (CR)‬
‭No‬
‭No (CR)‬
‭LocaL Radiation treatment‬
‭N‬
‭Yes‬
‭Yes (CR)‬
‭No‬
‭No (CR)‬
‭Local Radiation Treatment type‬
‭N‬
‭No‬
‭Radiosurgery (RS)‬
‭Stereotactic radiosurgery (SRS)‬
‭Device Used‬
‭Missing‬
‭N‬
‭Gamma Knife‬
‭Accelerator Linac-Based Systems (IMRT,‬
‭Rapid Arc, VMAT)‬
‭Cyberknife‬
‭Whole Brain Radiotherapy‬
‭N‬
‭Yes‬
‭No‬
‭No (CR)‬


‭2.2.‬ ‭OS‬‭ON‬‭ITT‬‭ACCORDING‬‭TO‬‭R‬‭ADIOTHERAPY‬
‭Table 6: Events type OS‬
‭Radiotherapy‬
‭ ‬
‭   Death‬
‭   Alive‬
‭1.‬
‭Pearson’s Chi-squared test‬
‭Table 7: Median/mean OS (estimated by Kaplan-Meier)‬
‭Median (months)‬
‭CI 95%‬
‭Mean‬
‭CI 95%‬
‭No‬
‭Yes‬
‭Table 8: OS estimated survival ratio‬
‭OS‬
‭Events (%, total‬
‭N)‬
‭Patients at‬
‭risk‬
‭% estimated cumulative survival‬
‭ratio‬
‭CI 95%‬
‭No‬
‭At 6 months‬
‭At 12‬
‭months‬
‭At 18‬
‭months‬
‭At 24‬
‭months‬
‭Yes‬
‭At 6 months‬
‭At 12‬
‭months‬
‭At 18‬
‭months‬
‭At 24‬
‭months‬
‭Figure 25: Overall survival vs Radiotherapy‬
‭2.3.‬ ‭I‬‭PFS‬‭ON‬‭ITT‬‭ACCORDING‬‭TO‬‭R‬‭ADIOTHERAPY‬
‭Table 9: Events type PFS‬
‭Radiotherapy‬
‭PFS Event‬
‭   PD‬
‭   Censored‬
‭   Death (without previous PD)‬
‭1.‬
‭Pearson’s Chi-squared test‬


‭Table 10: Median/mean PFS (estimated by Kaplan-Meier)‬
‭Median (months)‬
‭CI 95%‬
‭Mean‬
‭CI 95%‬
‭No‬
‭Yes‬
‭Table 11: PFS estimated survival ratio‬
‭PFS‬
‭Events (%, total‬
‭N)‬
‭Patients at‬
‭risk‬
‭% estimated cumulative survival‬
‭ratio‬
‭CI 95%‬
‭No‬
‭At 6 months‬
‭At 12‬
‭months‬
‭At 18‬
‭months‬
‭At 24‬
‭months‬
‭Yes‬
‭At 6 months‬
‭At 12‬
‭months‬
‭At 18‬
‭months‬
‭At 24‬
‭months‬
‭Figure 26: Progression free survival vs Radiotherapy‬
‭2.4.‬ ‭E‬‭PFS‬‭ACCORDING‬‭TO‬‭S‬‭YMPTOMATIC‬‭GROUP‬
‭Table 12: Events type PFS‬
‭Symptomatic‬
‭group‬
‭Symptomatic (A+C)‬
‭Asymptomatic (B)‬
‭Total‬
‭p‬
‭value‬
‭PFS (event)‬
‭   Event‬
‭(PD/death)‬
‭   Censored‬
‭1.‬
‭Pearson’s Chi-squared test‬
‭Table 13: Median/mean PFS (estimated by Kaplan-Meier)‬
‭Median (months)‬
‭CI 95%‬
‭Mean‬
‭CI 95%‬
‭Symptomatic (A+C)‬
‭Asymptomatic (B)‬
‭Table 14: PFS estimated survival ratio‬


‭PFS‬
‭Events (%, total‬
‭N)‬
‭Patients at‬
‭risk‬
‭% estimated cumulative survival‬
‭ratio‬
‭CI 95%‬
‭Symptomatic‬
‭(A+C)‬
‭At 6 months‬
‭At 12 months‬
‭At 18 months‬
‭At 24 months‬
‭Asymptomatic (B)‬
‭At 6 months‬
‭At 12 months‬
‭At 18 months‬
‭At 24 months‬
‭Figure 27: Progression free survival vs Symptomatic group‬


‭EBRAIN-MEL GEM1802 STUDY -‬
‭STATISTICAL REPORT (2‬‭nd‬‭APPENDIX‬
‭ANALYSIS: QUALITY OF LIFE‬
‭QUESTIONARY)‬
‭JAN2023‬


‭1.‬ ‭T‬‭ABLE‬‭OF‬‭C‬‭ONTENTS‬
‭The database containing the results for the following report was locked on‬
‭2.‬‭ALL COHORTS‬
‭2.1.‬ ‭QUALITY OF LIFE QUESTIONARY: EORTC QLQ‬
‭C-30‬
‭All‬‭scores‬‭are‬‭scaled‬‭to‬‭range‬‭from‬‭0-100,‬‭even‬‭scores‬‭based‬‭on‬‭single‬‭items.‬‭Be‬
‭aware‬‭that‬‭these‬‭single-item‬‭scales‬‭still‬‭have‬‭only‬‭4‬‭possible‬‭values,‬‭even‬‭though‬
‭they‬‭are‬‭transformed‬‭to‬‭range‬‭from‬‭0-100.‬‭The‬‭scale‬‭name‬‭and‬‭number‬‭of‬‭items‬
‭are listed below.‬
‭•‬
‭Global health status/QoL‬
‭QL - Global health status/QoL (revised) (from 2 items)‬
‭•‬
‭Functional Scales (higher is better functioning)‬
‭PF - Physical functioning (from 5 items)‬
‭RF - Role functioning (from 2 items)‬
‭EF - Emotional functioning (from 4 items)‬
‭CF - Cognitive functioning (from 2 items)‬
‭SF - Social functioning (from 2 items)‬
‭•‬
‭Symptom Scales (higher is more symptoms, worse functioning)‬
‭FA - Fatigue (from 3 items)‬
‭NV - Nausea and Vomiting (from 2 items)‬
‭PA - Pain (from 2 items)‬
‭•‬
‭Single-Item Symptom Scores (higher is more symptoms, worse‬
‭functioning)‬
‭DY - Dyspnoea‬
‭SL - Insomnia‬
‭AP - Appetite Loss‬
‭CO - Constipation‬
‭DI - Diarrhoea‬
‭FI - Financial Difficulties‬
‭•‬
‭QLQ-C30 Summary Score‬‭(higher is better functioning,‬‭fewer symptoms)‬
‭C30SUMMARY - QLQ-C30 Summary Score, composed by taking mean of‬
‭all scores except for QL (Global health status/QoL) and FI (Financial‬
‭Difficulties).‬


‭Reference:‬
‭https://rdrr.io/cran/PROscorer/man/qlq_c30.html‬
‭Aaronson‬‭NK,‬‭Ahmedzai‬‭S,‬‭Bergman‬‭B,‬‭Bullinger‬‭M,‬‭Cull‬‭A,‬‭Duez‬‭NJ,‬‭Filiberti‬‭A,‬
‭Flechtner‬‭H,‬‭Fleishman‬‭SB,‬‭Haes‬‭JCJM‬‭de,‬‭Kaasa‬‭S,‬‭Klee‬‭M,‬‭Osoba‬‭D,‬‭Razavi‬‭D,‬
‭Rofe‬ ‭PB,‬ ‭Schraub‬ ‭S,‬ ‭Sneeuw‬ ‭K,‬ ‭Sullivan‬ ‭M,‬ ‭Takeda‬ ‭F‬ ‭(1993).‬ ‭The‬ ‭European‬
‭Organization‬ ‭for‬ ‭Research‬ ‭and‬ ‭Treatment‬ ‭of‬ ‭Cancer‬‭QLQ-C30:‬‭A‬‭Quality-of-Life‬
‭Instrument‬‭for‬‭Use‬‭in‬‭International‬‭Clinical‬‭Trials‬‭in‬‭Oncology.‬‭JNCI‬‭J‬‭Natl‬‭Cancer‬
‭Inst 85:365-376.‬
‭Fayers‬ ‭PM,‬ ‭Aaronson‬ ‭NK,‬ ‭Bjordal‬ ‭K,‬ ‭Groenvold‬ ‭M,‬ ‭Curran‬ ‭D,‬ ‭Bottomley‬ ‭A,‬ ‭on‬
‭behalf‬‭of‬‭the‬‭EORTC‬‭Quality‬‭of‬‭Life‬‭Group.‬‭The‬‭EORTC‬‭QLQ-C30‬‭Scoring‬‭Manual‬
‭(3rd‬‭Edition).‬‭Published‬‭by:‬‭European‬‭Organisation‬‭for‬‭Research‬‭and‬‭Treatment‬‭of‬
‭Cancer, Brussels 2001.‬
‭Giesinger‬ ‭JM,‬ ‭Kieffer‬ ‭JM,‬ ‭Fayers‬ ‭PM,‬ ‭Groenvold‬ ‭M,‬ ‭Petersen‬ ‭MA,‬ ‭Scott‬ ‭NW,‬
‭Sprangers‬ ‭MAG,‬ ‭Velikova‬ ‭G,‬ ‭Aaronson‬ ‭NK‬‭(2016).‬‭Replication‬‭and‬‭validation‬‭of‬
‭higher‬‭order‬‭models‬‭demonstrated‬‭that‬‭a‬‭summary‬‭score‬‭for‬‭the‬‭EORTC‬‭QLQ-C30‬
‭is robust. Journal of Clinical Epidemiology 69:79-88.‬
‭2.1.1.‬‭G‬‭LOBAL‬‭HEALTH‬‭STATUS‬‭/Q‬‭O‬‭L‬
‭2.1.1.1.‬
‭QL - G‬‭LOBAL‬‭HEALTH‬‭STATUS‬‭/Q‬‭O‬‭L (‬‭REVISED‬‭) (‬‭FROM‬‭2‬‭ITEMS‬‭)‬
‭Table 1: Global health status/QoL‬
‭Global health status/QoL‬
‭N‬
‭Mean(SD)‬
‭Median(Min-Max)‬
‭p-value (wilcoxon test)‬
‭compared with baseline‬
‭Baseline‬
‭w8‬
‭w16‬
‭2.1.2.‬‭F‬‭UNCTIONAL‬‭S‬‭CALES‬‭(‬‭HIGHER‬‭IS‬‭BETTER‬‭FUNCTIONING‬‭)‬
‭2.1.2.1.‬
‭PF - P‬‭HYSICAL‬‭FUNCTIONING‬‭(‬‭FROM‬‭5‬‭ITEMS‬‭)‬
‭Table 2: Physical functioning/QoL‬
‭Physical functioning/QoL‬
‭N‬
‭Mean(SD)‬
‭Median(Min-Max)‬
‭p-value (wilcoxon test)‬
‭compared with baseline‬
‭Baseline‬
‭w8‬


‭Physical functioning/QoL‬
‭N‬
‭Mean(SD)‬
‭Median(Min-Max)‬
‭p-value (wilcoxon test)‬
‭compared with baseline‬
‭w16‬
‭2.1.2.2.‬
‭RF - R‬‭OLE‬‭FUNCTIONING‬‭(‬‭FROM‬‭2‬‭ITEMS‬‭)‬
‭Table 3: Role functioning/QoL‬
‭Role functioning/QoL‬
‭N‬
‭Mean(SD)‬
‭Median(Min-Max)‬
‭p-value (wilcoxon test)‬
‭compared with baseline‬
‭Baseline‬
‭w8‬
‭w16‬
‭2.1.2.3.‬
‭EF - E‬‭MOTIONAL‬‭FUNCTIONING‬‭(‬‭FROM‬‭4‬‭ITEMS‬‭)‬
‭Table 4: Emotional functioning/QoL‬
‭Emotional functioning/QoL‬
‭N‬
‭Mean(SD)‬
‭Median(Min-Max)‬
‭p-value (wilcoxon test)‬
‭compared with baseline‬
‭Baseline‬
‭w8‬
‭w16‬
‭2.1.2.4.‬
‭CF - C‬‭OGNITIVE‬‭FUNCTIONING‬‭(‬‭FROM‬‭2‬‭ITEMS‬‭)‬
‭Table 5: Cognitive functioning/QoL‬
‭Cognitive functioning/QoL‬
‭N‬
‭Mean(SD)‬
‭Median(Min-Max)‬
‭p-value (wilcoxon test)‬
‭compared with baseline‬
‭Baseline‬


‭Cognitive functioning/QoL‬
‭N‬
‭Mean(SD)‬
‭Median(Min-Max)‬
‭p-value (wilcoxon test)‬
‭compared with baseline‬
‭w8‬
‭w16‬
‭2.1.2.5.‬
‭SF - S‬‭OCIAL‬‭FUNCTIONING‬‭(‬‭FROM‬‭2‬‭ITEMS‬‭)‬
‭Table 6: Social functioning/QoL‬
‭Social functioning/QoL‬
‭N‬
‭Mean(SD)‬
‭Median(Min-Max)‬
‭p-value (wilcoxon test)‬
‭compared with baseline‬
‭Baseline‬
‭w8‬
‭w16‬
‭2.1.3.‬‭S‬‭YMPTOM‬‭S‬‭CALES‬‭(‬‭HIGHER‬‭IS‬‭MORE‬‭SYMPTOMS‬‭,‬‭WORSE‬
‭FUNCTIONING‬‭)‬
‭2.1.3.1.‬
‭FA - F‬‭ATIGUE‬‭(‬‭FROM‬‭3‬‭ITEMS‬‭)‬
‭Table 7: Fatigue/QoL‬
‭Fatigue/QoL‬
‭N‬
‭Mean(SD)‬
‭Median(Min-Max)‬
‭p-value (wilcoxon test)‬
‭compared with baseline‬
‭Baseline‬
‭w8‬
‭w16‬
‭2.1.3.2.‬
‭NV - N‬‭AUSEA‬‭AND‬‭V‬‭OMITING‬‭(‬‭FROM‬‭2‬‭ITEMS‬‭)‬
‭Table 8: Nausea and Vomiting/QoL‬


‭Nausea and Vomiting/QoL‬
‭N‬
‭Mean(SD)‬
‭Median(Min-Max)‬
‭p-value (wilcoxon test)‬
‭compared with baseline‬
‭Baseline‬
‭w8‬
‭w16‬
‭2.1.3.3.‬
‭PA - P‬‭AIN‬‭(‬‭FROM‬‭2‬‭ITEMS‬‭)‬
‭Table 9: Pain/QoL‬
‭Pain/QoL‬
‭N‬
‭Mean(SD)‬
‭Median(Min-Max)‬
‭p-value (wilcoxon test)‬
‭compared with baseline‬
‭Baseline‬
‭w8‬
‭w16‬
‭2.1.4.‬‭S‬‭INGLE‬‭-I‬‭TEM‬‭S‬‭YMPTOM‬‭S‬‭CORES‬‭(‬‭HIGHER‬‭IS‬‭MORE‬‭SYMPTOMS‬‭,‬
‭WORSE‬‭FUNCTIONING‬‭)‬
‭2.1.4.1.‬
‭DY - D‬‭YSPNOEA‬‭(‬‭FROM‬‭1‬‭ITEM‬‭)‬
‭Table 10: Dyspnoea/QoL‬
‭Dyspnoea/QoL‬
‭N‬
‭Mean(SD)‬
‭Median(Min-Max)‬
‭p-value (wilcoxon test)‬
‭compared with baseline‬
‭Baseline‬
‭w8‬
‭w16‬


‭2.1.4.2.‬
‭SL - I‬‭NSOMNIA‬‭(‬‭FROM‬‭1‬‭ITEM‬‭)‬
‭Table 11: Insomnia/QoL‬
‭Insomnia/QoL‬
‭N‬
‭Mean(SD)‬
‭Median(Min-Max)‬
‭p-value (wilcoxon test)‬
‭compared with baseline‬
‭Baseline‬
‭w8‬
‭w16‬
‭2.1.4.3.‬
‭AP - A‬‭PPETITE‬‭L‬‭OSS‬‭(‬‭FROM‬‭1‬‭ITEM‬‭)‬
‭Table 12: Appetite Loss/QoL‬
‭Appetite Loss/QoL‬
‭N‬
‭Mean(SD)‬
‭Median(Min-Max)‬
‭p-value (wilcoxon test)‬
‭compared with baseline‬
‭Baseline‬
‭w8‬
‭w16‬
‭2.1.4.4.‬
‭CO - C‬‭ONSTIPATION‬‭(‬‭FROM‬‭1‬‭ITEM‬‭)‬
‭Table 13: Constipation/QoL‬
‭Constipation/QoL‬
‭N‬
‭Mean(SD)‬
‭Median(Min-Max)‬
‭p-value (wilcoxon test)‬
‭compared with baseline‬
‭Baseline‬
‭w8‬
‭w16‬


‭2.1.4.5.‬
‭DI - D‬‭IARRHOEA‬‭(‬‭FROM‬‭1‬‭ITEM‬‭)‬
‭Table 14: Diarrhoea/QoL‬
‭Diarrhoea/QoL‬
‭N‬
‭Mean(SD)‬
‭Median(Min-Max)‬
‭p-value (wilcoxon test)‬
‭compared with baseline‬
‭Baseline‬
‭w8‬
‭w16‬
‭2.1.4.6.‬
‭FI - F‬‭INANCIAL‬‭D‬‭IFFICULTIES‬‭(‬‭FROM‬‭1‬‭ITEM‬‭)‬
‭Table 15: Financial Difficulties/QoL‬
‭Financial Difficulties/QoL‬
‭N‬
‭Mean(SD)‬
‭Median(Min-Max)‬
‭p-value (wilcoxon test)‬
‭compared with baseline‬
‭Baseline‬
‭w8‬
‭w16‬
‭2.2.‬ ‭QLQ-C30 S‬‭UMMARY‬‭S‬‭CORE‬‭(‬‭HIGHER‬‭IS‬‭BETTER‬‭FUNCTIONING‬‭,‬
‭FEWER‬‭SYMPTOMS‬‭)‬
‭2.2.1.‬‭C30SUMMARY - QLQ-C30 S‬‭UMMARY‬‭S‬‭CORE‬‭,‬‭COMPOSED‬‭BY‬
‭TAKING‬‭MEAN‬‭OF‬‭ALL‬‭SCORES‬‭EXCEPT‬‭FOR‬‭QL (G‬‭LOBAL‬‭HEALTH‬
‭STATUS‬‭/Q‬‭O‬‭L)‬‭AND‬‭FI (F‬‭INANCIAL‬‭D‬‭IFFICULTIES‬‭)‬
‭Table 16: QLQ-C30 Summary Score/QoL‬
‭QLQ-C30 Summary Score/QoL‬
‭N‬
‭Mean(SD)‬
‭Median(Min-Max)‬
‭p-value (wilcoxon test)‬
‭compared with baseline‬
‭Baseline‬
‭w8‬
‭w16‬


‭3.‬‭COHORTS A-C (S‬‭YMPTOMATIC‬‭PATIENTS‬‭)‬
‭Analyses‬ ‭were‬ ‭conducted‬ ‭exclusively‬ ‭on‬ ‭significant‬ ‭variables‬ ‭across‬ ‭the‬ ‭entire‬
‭sample.‬
‭3.1.1.‬‭G‬‭LOBAL‬‭HEALTH‬‭STATUS‬‭/Q‬‭O‬‭L‬
‭3.1.1.1.‬
‭QL - G‬‭LOBAL‬‭HEALTH‬‭STATUS‬‭/Q‬‭O‬‭L (‬‭REVISED‬‭) (‬‭FROM‬‭2‬‭ITEMS‬‭)‬
‭Table 17: Global health status/QoL‬
‭Global health status/QoL‬
‭N‬
‭Mean(SD)‬
‭Median(Min-Max)‬
‭p-value (wilcoxon test)‬
‭compared with baseline‬
‭Baseline‬
‭w8‬
‭w16‬
‭3.1.2.‬‭F‬‭UNCTIONAL‬‭S‬‭CALES‬‭(‬‭HIGHER‬‭IS‬‭BETTER‬‭FUNCTIONING‬‭)‬
‭3.1.2.1.‬
‭EF - E‬‭MOTIONAL‬‭FUNCTIONING‬‭(‬‭FROM‬‭4‬‭ITEMS‬‭)‬
‭Table 18: Emotional functioning/QoL‬
‭Emotional functioning/QoL‬
‭N‬
‭Mean(SD)‬
‭Median(Min-Max)‬
‭p-value (wilcoxon test)‬
‭compared with baseline‬
‭Baseline‬
‭w8‬
‭w16‬
‭3.1.3.‬‭S‬‭INGLE‬‭-I‬‭TEM‬‭S‬‭YMPTOM‬‭S‬‭CORES‬‭(‬‭HIGHER‬‭IS‬‭MORE‬‭SYMPTOMS‬‭,‬
‭WORSE‬‭FUNCTIONING‬‭)‬
‭3.1.3.1.‬
‭SL - I‬‭NSOMNIA‬‭(‬‭FROM‬‭1‬‭ITEM‬‭)‬
‭Table 19: Insomnia/QoL‬


‭Insomnia/QoL‬
‭N‬
‭Mean(SD)‬
‭Median(Min-Max)‬
‭p-value (wilcoxon test)‬
‭compared with baseline‬
‭Baseline‬
‭w8‬
‭w16‬
‭3.2.‬ ‭QLQ-C30 S‬‭UMMARY‬‭S‬‭CORE‬‭(‬‭HIGHER‬‭IS‬‭BETTER‬‭FUNCTIONING‬‭,‬
‭FEWER‬‭SYMPTOMS‬‭)‬
‭3.2.1.‬‭C30SUMMARY - QLQ-C30 S‬‭UMMARY‬‭S‬‭CORE‬‭,‬‭COMPOSED‬‭BY‬
‭TAKING‬‭MEAN‬‭OF‬‭ALL‬‭SCORES‬‭EXCEPT‬‭FOR‬‭QL (G‬‭LOBAL‬‭HEALTH‬
‭STATUS‬‭/Q‬‭O‬‭L)‬‭AND‬‭FI (F‬‭INANCIAL‬‭D‬‭IFFICULTIES‬‭)‬
‭Table 20: QLQ-C30 Summary Score/QoL‬
‭QLQ-C30 Summary Score/QoL‬
‭N‬
‭Mean(SD)‬
‭Median(Min-Max)‬
‭p-value (wilcoxon test)‬
‭compared with baseline‬
‭Baseline‬
‭w8‬
‭w16‬
‭4.‬‭COHORT B (A‬‭SYMPTOMATIC‬‭PATIENTS‬‭)‬
‭Analyses‬ ‭were‬ ‭conducted‬ ‭exclusively‬ ‭on‬ ‭significant‬ ‭variables‬ ‭across‬ ‭the‬ ‭entire‬
‭sample.‬
‭4.1.1.‬‭G‬‭LOBAL‬‭HEALTH‬‭STATUS‬‭/Q‬‭O‬‭L‬
‭4.1.1.1.‬
‭QL - G‬‭LOBAL‬‭HEALTH‬‭STATUS‬‭/Q‬‭O‬‭L (‬‭REVISED‬‭) (‬‭FROM‬‭2‬‭ITEMS‬‭)‬
‭Table 21: Global health status/QoL‬
‭Global health status/QoL‬
‭N‬
‭Mean(SD)‬
‭Median(Min-Max)‬
‭p-value (wilcoxon test)‬
‭compared with baseline‬
‭Baseline‬
‭w8‬
‭w16‬


‭4.1.2.‬‭F‬‭UNCTIONAL‬‭S‬‭CALES‬‭(‬‭HIGHER‬‭IS‬‭BETTER‬‭FUNCTIONING‬‭)‬
‭4.1.2.1.‬
‭EF - E‬‭MOTIONAL‬‭FUNCTIONING‬‭(‬‭FROM‬‭4‬‭ITEMS‬‭)‬
‭Table 22: Emotional functioning/QoL‬
‭Emotional functioning/QoL‬
‭N‬
‭Mean(SD)‬
‭Median(Min-Max)‬
‭p-value (wilcoxon test)‬
‭compared with baseline‬
‭Baseline‬
‭w8‬
‭w16‬
‭4.1.3.‬‭S‬‭INGLE‬‭-I‬‭TEM‬‭S‬‭YMPTOM‬‭S‬‭CORES‬‭(‬‭HIGHER‬‭IS‬‭MORE‬‭SYMPTOMS‬‭,‬
‭WORSE‬‭FUNCTIONING‬‭)‬
‭4.1.3.1.‬
‭SL - I‬‭NSOMNIA‬‭(‬‭FROM‬‭1‬‭ITEM‬‭)‬
‭Table 23: Insomnia/QoL‬
‭Insomnia/QoL‬
‭N‬
‭Mean(SD)‬
‭Median(Min-Max)‬
‭p-value (wilcoxon test)‬
‭compared with baseline‬
‭Baseline‬
‭w8‬
‭w16‬
‭4.2.‬ ‭QLQ-C30 S‬‭UMMARY‬‭S‬‭CORE‬‭(‬‭HIGHER‬‭IS‬‭BETTER‬‭FUNCTIONING‬‭,‬
‭FEWER‬‭SYMPTOMS‬‭)‬
‭4.2.1.‬‭C30SUMMARY - QLQ-C30 S‬‭UMMARY‬‭S‬‭CORE‬‭,‬‭COMPOSED‬‭BY‬
‭TAKING‬‭MEAN‬‭OF‬‭ALL‬‭SCORES‬‭EXCEPT‬‭FOR‬‭QL (G‬‭LOBAL‬‭HEALTH‬
‭STATUS‬‭/Q‬‭O‬‭L)‬‭AND‬‭FI (F‬‭INANCIAL‬‭D‬‭IFFICULTIES‬‭)‬
‭Table 24: QLQ-C30 Summary Score/QoL‬


‭QLQ-C30 Summary Score/QoL‬
‭N‬
‭Mean(SD)‬
‭Median(Min-Max)‬
‭p-value (wilcoxon test)‬
‭compared with baseline‬
‭Baseline‬
‭w8‬
‭w16‬