Clinical trial NCT04310397
Conditions: Pathologic Stage IIIB Cutaneous Melanoma AJCC v8 Pathologic Stage IIIC Cutaneous Melanoma AJCC v8 Pathologic Stage IIID Cutaneous Melanoma AJCC v8
Keywords: Melanoma Neoadjuvant Pathological Response Targeted Therapy Immunotherapy
Sponsor: M.D. Anderson Cancer Center
Start date: 2020-01-29; Completion date: 2023-10-09
Enrollment: 4 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This phase II trial studies how well dabrafenib, trametinib, and spartalizumab works in treating patients with BRAF V600E or V600K mutation positive stage IIIB/C/D melanoma, who do not achieve a pathologic complete response after 8 weeks of dabrafenib and trametinib treatment. Patients who achieve a pathologic complete response after 8 weeks of neoadjuvant dabrafenib and trametinib will receive adjuvant dabrafenib and trametinib. Dabrafenib and trametinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as spartalizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving dabrafenib, trametinib, and spartalizumab may help to control melanoma.

Detailed description:
PRIMARY OBJECTIVE:

I. To determine the 12-month relapse free survival (RFS) rate in stage IIIB/C/D melanoma patients who, after 8 weeks of neoadjuvant dabrafenib and trametinib, do not achieve a pathologic complete response (pCR) and receive adjuvant dabrafenib, trametinib and spartalizumab.

SECONDARY OBJECTIVES:

I. To evaluate the safety of neoadjuvant dabrafenib and trametinib and adjuvant dabrafenib, trametinib and spartalizumab.

II. To determine the 12-month relapse free survival (RFS) rate in stage IIIB/C/D.

III. Melanoma patients who, after 8 weeks of neoadjuvant dabrafenib and trametinib, achieve a pCR and receive adjuvant dabrafenib and trametinib.

IV. To assess the recurrence patterns, distant metastasis-free survival (DMFS), and overall survival (OS) in all patients treated on protocol.

EXPLORATORY OBJECTIVES:

I. To assess immunological and molecular features of treatment response and resistance.

II. To assess circulating markers and correlate them with treatment response and relapse and toxicity III. To assess the impact of neoadjuvant therapy on surgical resectability.

OUTLINE:

NEOADJUVANT TREATMENT: Patients receive dabrafenib orally (PO) twice daily (BID) and trametinib PO once daily (QD) on days 1-28. Treatment repeats every 28 days for 2 cycles in the absence of disease progression or unacceptable toxicity.

SURGERY: Patients undergo surgical resection of melanoma.

ADJUVANT TREATMENT OF pCR PATIENTS: Patients receive dabrafenib PO BID and trametinib PO QD on days 1-28. Cycles repeats every 28 days for 44 weeks in the absence of disease progression or unacceptable toxicity.

ADJUVANT TREATMENT OF NON pCR PATIENTS: Patients receive spartalizumab intravenously (IV) over 30 minutes on day 1, dabrafenib PO BID and trametinib PO QD on days 1-28. Cycles repeats every 28 days for 44 weeks in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3-4 months for 2 years.

Arms: arm 1: NEOADJUVANT TREATMENT: Patients receive dabrafenib PO BID and trametinib PO QD on days 1-28. Treatment repeats every 28 days for 2 cycles in the absence of disease progression or unacceptable toxicity.

SURGERY: Patients undergo surgical resection of melanoma.

ADJUVANT TREATMENT OF pCR PATIENTS: Patients receive dabrafenib PO BID and trametinib PO QD on days 1-28. Cycles repeats every 28 days for 44 weeks in the absence of disease progression or unacceptable toxicity.

ADJUVANT TREATMENT OF NON pCR PATIENTS: Patients receive spartalizumab IV over 30 minutes on day 1, dabrafenib PO BID and trametinib PO QD on days 1-28. Cycles repeats every 28 days for 44 weeks in the absence of disease progression or unacceptable toxicity.
Interventions: intervention 1: Dabrafenib intervention 2: Spartalizumab intervention 3: Therapeutic Conventional Surgery intervention 4: Trametinib
Intervention descriptions: intervention 1: Given PO intervention 2: Given IV intervention 3: Undergo surgery intervention 4: Given PO

Protocol documents:
Prot_SAP_000.pdf: 
Page 1 
     Version 01 – 2019-0906 
MD Anderson IND Sponsor Cover Sheet 
Protocol ID 
2019-0906 
Protocol Title 
Altering Adjuvant Therapy based on Pathologic Response 
to Neoadjuvant Dabrafenib and Trametinib (ALTER-PATH 
NeoDT) 
Protocol 
Version 
01 
Version Date 
December 19, 2019 
Protocol PI 
Rodabe Amaria, MD 
Department 
Melanoma Medical Oncology 
IND Sponsor 
MD Anderson Cancer Center 
IND # 
146797 
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   Table of Contents 
1.0 BACKGROUND & RATIONALE....................................................................................................................................... 4 
1.1 BACKGROUND ................................................................................................................................................................ 4 
1.2  MODERN NEOADJUVANT TRIALS ............................................................................................................................. 5 
1.3 RATIONALE ...................................................................................................................................................................... 8 
2.0 OBJECTIVES ........................................................................................................................................................................ 9 
2.1 PRIMARY OBJECTIVE ................................................................................................................................................... 9 
2.2 SECONDARY OBJECTIVES ........................................................................................................................................... 9 
2.3 EXPLORATORY OBJECTIVES .................................................................................................................................... 10 
3.0 STUDY DESIGN ................................................................................................................................................................. 10 
Figure 1: Study Overview ....................................................................................................................................................... 11 
3.1 Inclusion Criteria ................................................................................................................................................................. 12 
Table 1: Organ function criteria .............................................................................................................................................. 13 
3.2 Exclusion Criteria ................................................................................................................................................................ 14 
3.3 TRIAL TREATMENT – Study Drugs and Administration Details................................................................................ 15 
Table 3: Trial Treatments and Description .............................................................................................................................. 16 
3.3.1 
Dose Selection Rationale .......................................................................................................................................... 18 
3.3.2 
Dose Modification .................................................................................................................................................... 19 
3.3.3 
Dose Modification Guidelines – Adverse Events of Special Interest ....................................................................... 21 
3.3.4 
Visual changes .......................................................................................................................................................... 23 
3.3.5 
Cardiovascular Toxicity ............................................................................................................................................ 25 
3.3.6 
Decreased Left Ventricular Ejection Fraction (LVEF) ............................................................................................. 25 
3.3.7 
Hypertension ............................................................................................................................................................. 26 
3.3.8 
QTc Prolongation ...................................................................................................................................................... 26 
3.3.9 
CUTANEOUS SQUAMOUS CELL CARCINOMA (CUSCC) AND KERATOACANTHOMA (KA) ................. 26 
3.4 MONITORING, INTERRUPTION, AND STOPPING CRITERIA FOR HEPATOBILIARY EVENTS ................. 27 
3.5 SPARTALIZUMAB DOSE MODIFICATIONS .............................................................................................................. 27 
3.6 THERAPY ADMINISTRATION ...................................................................................................................................... 28 
3.6.1 
Dabrafenib and trametinib administration................................................................................................................. 28 
3.6.2 
Spartalizumab administration in adjuvant setting for non pCR patients ................................................................... 29 
3.7 MANAGEMENT OF IRAES ............................................................................................................................................. 29 
3.8 CONCOMITANT AND EXCLUDED THERAPIES ....................................................................................................... 29 
4.0 STUDY ASSESSMENTS .................................................................................................................................................... 30 
4.1 CRITICAL BASELINE ASSESSMENTS ....................................................................................................................... 31 
4.2 BASELINE CONFIRMATION OF BRAF MUTATION-POSITIVE MELANOMA ..................................................... 31 
4.3  SCHEDULE OF ASSESSMENTS .................................................................................................................................... 32 
4.4 SAFETY EVALUATIONS ................................................................................................................................................. 39 
4.4.1 
Physical exams/ECOG/Vital Signs ........................................................................................................................... 39 
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4.4.2 
ECG .......................................................................................................................................................................... 39 
4.4.3 
Echocardiogram ........................................................................................................................................................ 40 
4.4.4 
Ophthalmic ................................................................................................................................................................ 40 
4.5 LABORATORY ASSESSMENTS ..................................................................................................................................... 40 
4.6 BIOMARKER COLLECTIONS AND ANALYSES ........................................................................................................ 42 
4.7 BIOMARKER ANALYSES ............................................................................................................................................... 42 
4.8 IMAGING ASSESSMENTS ............................................................................................................................................... 43 
4.9 PATHOLOGIC ASSESSMENTS ...................................................................................................................................... 44 
4.9.1 
Surgical Ease Surveys ............................................................................................................................................... 44 
5.0 ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS .......................................................................................... 44 
5.1 DEFINITION OF AN AE ................................................................................................................................................... 45 
5.2 ADVERSE EVENT GRADING .......................................................................................................................................... 46 
5.3 SERIOUS ADVERSE EVENT REPORTING (SAE)....................................................................................................... 47 
6.0 DATA MANAGEMENT ..................................................................................................................................................... 50 
6.1 RECORDS RETENTION ................................................................................................................................................... 51 
7.0 DATA ANALYSIS AND STATISTICAL CONSIDERATIONS .................................................................................... 51 
8.0 INSTITUTIONAL REVIEW BOARD (IRB) APPROVAL ............................................................................................ 53 
9.0 COMPLIANCE WITH TRIAL REGISTRATION AND RESULTS ............................................................................. 53 
POSTING REQUIREMENTS ..................................................................................................................................................... 53 
10.0 ETHICAL CONSIDERATIONS ........................................................................................................................................ 53 
11.0 INFORMED CONSENT ..................................................................................................................................................... 54 
12.0 STUDY DOCUMENTATION, MONITORING, AND .................................................................................................... 54 
ADMINISTRATION.................................................................................................................................................................... 54 
13.0 REFERENCES .................................................................................................................................................................... 55 
APPENDICES .............................................................................................................................................................................. 57 
 
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1.0 
BACKGROUND & RATIONALE 
 
1.1 
BACKGROUND 
 
Clinical Stage III Melanoma 
Clinical stage III melanoma is defined as patients with clinically detected, palpable 
(macroscopic) lymph nodes with or without in-transit or satellite metastases and no 
evidence of distant metastases. This group of patients is staged as at least Stage 
IIB/IIIC (by AJCC version 7) or IIIB/IIIC/IIID (by AJCC version 8) and has 
heterogeneous outcomes when viewed as a whole with 5-year survival varying from 
32-83%1. 
In a recent analysis of 144 clinical Stage III melanoma patients with a BRAF 
mutation identified at MD Anderson, average time to disease relapse was less 
than 2 year, highlighting the high-risk nature of this disease stage (MD Anderson 
internal data). Traditionally, this group of patients have high-risk disease even 
with upfront surgery and newly available adjuvant therapy options including high 
dose ipilimumab2, nivolumab3, dabrafenib and trametinib4 and pembrolizumab5. 
 
Neoadjuvant Therapy 
Neoadjuvant (preoperative) therapy has a long history of use in a variety of solid 
tumors including breast cancer6-7, rectal cancer8, gastric cancer9, esophageal 
cancer10 and bladder cancer11. The use of neoadjuvant therapy in melanoma was 
previously limited in use due to limited number of drugs producing benefit and 
the most commonly used regimen was a multi-drug combination approach known 
as biochemotherapy. Although this regimen yielded response rates of 
approximately 40%, patients experienced extensive toxicity and required inpatient 
administration of this regimen12-13. However, as multiple new targeted and 
immunotherapy options have been FDA approved in melanoma since 2011 that 
have improved the survival of metastatic patients14-16, there is great interest in 
using these agents in earlier stage disease patients. 
 
Neoadjuvant therapy offers a number of potential advantages for patient care. 
Successful neoadjuvant therapy that results in tumor shrinkage can potentially 
render surgery less morbid17-18. Earlier administration of systemic therapy can 
potentially more expeditiously destroy micrometastses which may have the 
opportunity to grow during the relatively immunosuppressed period after surgery 
and subsequent recovery19. Response to neoadjuvant therapy can be helpful in 
determining patient prognosis as complete lack of viable tumor in the resected 
specimen (pathologic complete response or pCR) has been correlated with 
improved patient outcomes7-11. Additionally, neoadjuvant trials offer the 
opportunity for biomarker discovery as longitudinal blood and tumor samples can 
be obtained to facilitate study of mechanisms of treatment response or 
resistance20. Neoadjuvant therapy can be a robust platform for drug development 
and has been utilized as an avenue for new drug registration21. 
 
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Prior to 2014, neoadjuvant therapy in melanoma traditionally had been limited to 
a multidrug regimen called biochemotherapy. This 5-drug regimen consisted of 
infusional therapy requiring inpatient hospital stays and was associated with 
significant hematologic toxicity, cardiac and pulmonary toxicities. This regimen 
did produce 22% partial response by imaging and pathologic complete response 
rates of approximately 26%12. Due to the toxicity and need for inpatient 
admission, this regimen was not widely used across the melanoma community. 
Another neoadjuvant trial utilized ipilimumab 10mg/kg which was given 
intravenously every 3 weeks for 2 doses prior to surgery. In this trial, there were no 
pathologic complete responses and only a small number of patients achieving a 
minor pathologic response22. This regimen was thus not widely utilized in the 
neoadjuvant setting. 
 
1.2  
MODERN NEOADJUVANT TRIALS 
 
Dabrafenib plus trametinib 
 
There are two mature studies evaluating the combination of dabrafenib (150 mg 
twice daily) and trametinib (2 mg daily) in the neoadjuvant setting. 
 
In the Combi-Neo trial (MD Anderson Protocol 2014-0409; NCT02231775), 
patients with stage IIIB/C (AJCC 7th edition) or oligometastatic stage IV BRAF-
mutant melanoma were randomized to either surgery followed by standard of care 
adjuvant therapy (which could be observation alone, high dose interferon, 
pegylated IFN-α2b, high-dose ipilimumab, or biochemotherapy) or neoadjuvant 
combination dabrafenib and trametinib (8 weeks) followed by 44 weeks 
postoperatively. Interim analysis of the initial 21 patients enrolled demonstrated 
that neoadjuvant dabrafenib and trametinib was associated with a high imaging 
response rate (77%) and pCR rate of 58%. At a median follow-up of 18.6 months, 
neoadjuvant targeted therapy was associated with significantly better RFS than 
patients randomized to surgery followed by possible postoperative adjuvant 
therapy (HR 60.2, 95% CI 6.7-7965, p<0.0001). 
There was also improved distant metastasis-free survival (HR 0.024, p=0.001) 
and trend towards improved overall survival (HR 0.28, [=0.22) for the 
neoadjuvant dabrafenib and trametinib treated patients. Of note, pCR patients had 
a trend towards improved relapse free survival and overall survival compared to 
the upfront surgery patients and did have statistically significant improvement in 
distant metastasis-free survival over non-pCR patients; indicating that pathologic 
responses can influence patient survival outcomes23. 
 
This regimen also showed a manageable safety profile for dabrafenib and 
trametinib, similar to that observed in patients with metastatic melanoma, with 
pyrexia and chills as the most commonly reported adverse events (AEs), none of 
which interfered with the ability to carry out planned surgery. There were no 
progression events during the neoadjuvant treatment and all patients were able to 
proceed to surgical intervention23. 
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Due to the clear superiority in achieving the primary objective of improved 
progression free survival in the neoadjuvant dabrafenib and trametinib treated 
patients, the MD Anderson Data Safety Monitoring Board closed the randomized 
trial at only a quarter of the planned accrual23. Thus, our group re-designed the 
trial as a single-arm study of neoadjuvant dabrafenib and trametinib. This 
redesigned trial is now powered to determine patient survival outcomes based on 
the pathologic response at the time of surgery. 
 
As of September 2019, a total of 37 patients have been treated with neoadjuvant, 
dabrafenib and trametinib on this protocol at MD Anderson with an overall pCR 
rate of 40%in the 32 patients who have gone to surgery. As additional patients 
have been treated, we have been able to ascertain trends in survival and 
recurrence. Specifically, in the patients who did not achieve a pCR, we have noted 
11% of patients have experienced locoregional recurrence and 43% have 
developed CNS disease. In the patients who did achieve a pCR, locoregional 
relapse rate was 23% and CNS metastasis development was 8%. These data 
indicate clearly divergent outcomes in patients depending on pathologic response 
and demonstrate the need to improve outcomes in those not achieving a pCR 
(unpublished data). 17.6 months, 38% of patients developed distant extracranial 
relapse, 38% had loco-regional relapse and 23% intra-cranial relapse, including 
35% of pCR patients24. 
 
Both of these studies demonstrate that neoadjuvant, dabrafenib and trametinib can 
achieve high rates of pCR and that pCR patients tend to have superior clinical 
outcomes compared to the non pCR patients. However, relapses, with tendency 
for CNS-specific relapse in the non pCR cohort of patients is a concerning 
finding. 
 
Neoadjuvant immune checkpoint inhibitors 
 
Pembrolizumab 
NCT02434354 enrolled patients with clinical stage III or resectable stage IV 
melanoma. Patients received one dose of neoadjuvant pembrolizumab 3 weeks 
prior to surgery followed by a year of adjuvant pembrolizumab. Interestingly, 
8/27 treated patients had pCR or near pCR (<10% viable tumor) at time of 
surgery. Neoadjuvant pembrolizumab was well tolerated with no major AEs 
prohibiting on- time surgical procedure. All patients with pCR or near pCR 
remain free of disease with median follow up time of 25 months; again, 
highlighting the prognostic importance of pCR25. 
 
Ipilimumab plus nivolumab 
NCT02519322 is a phase 2 trial conducted at MD Anderson Cancer Center in 
which patients with clinically detected but resectable stage III and oligometastatic 
stage IV melanoma are randomized to receive either nivolumab alone (3 mg/kg 
every 2 weeks for up to 4 doses, Arm A) or in combination with ipilimumab 
(nivolumab 1 mg/kg with ipilimumab 3 mg/kg every 3 weeks for up to 3 doses, 
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Arm B) prior to surgery. Adjuvant nivolumab (3 mg/kg every 2 months) will be 
administered postoperatively to patients on both arms for 6 months. In this single-
institution trial run at MD Anderson Cancer Center, planned accrual was 40 
patients, however this trial was closed after 23 patients were enrolled (12  patients 
to Arm A, 11 to Arm B) due to concerns about poor efficacy in Arm A and 
toxicity in Arm B. Neoadjuvant nivolumab (Arm A) was associated with pCR in 
25% of patients and 25% radiographic response rate. However, 17% of patients 
receiving neoadjuvant nivolumab therapy were unable to proceed to surgery due 
to disease progression and development of distant metastases during neoadjuvant 
treatment. All patients who received neoadjuvant ipilimumab plus nivolumab 
(Arm B) underwent surgery, with 45% pCR and 73% radiographic response rate. 
However, patients who received neoadjuvant ipilimumab plus nivolumab also 
experienced significantly higher numbers of grade 3 treatment-related AEs (73% 
in Arm B versus 8% in Arm A), which at times led to surgical delays due to the 
need for high dose steroids to mitigate immune mediated toxicities26. 
 
 
The OpACIN trial randomized 20 patients with resectable, clinical nodal disease 
to adjuvant or neoadjuvant ipilimumab 3 mg/kg and nivolumab 1 mg/kg either as 
4 doses given postoperatively or split as 2 doses given preoperatively and 2 doses 
postoperatively. Although most patients (18 of 20) were unable to complete all 4 
planned doses due to grade 3 or 4 toxicities, neoadjuvant therapy produced 3 pCR 
and 3 near pCR of the 10 treated patients. Patients with pCR or near pCR had not 
developed any disease relapse with a median follow up of 25.6 months. In total, 4 
patients in the adjuvant arm relapsed while 2 patients in the neoadjuvant arm 
relapsed with median 32 month follow up27. 
 
The OpACIN-Neo study (NCT02977052) is an open-label, three-arm phase II 
trial in which 86 stage III melanoma patients were randomized 1:1:1 to receive 
either: (Arm A) 2 courses of ipilimumab 3 mg/kg + nivolumab 1 mg/kg every 3 
weeks; n=30; (Arm B) 2 courses of ipilimumab 1 mg/kg + nivolumab 3 mg/kg 
every 3 weeks, n=30; or (Arm C) 2 courses of ipilimumab 3 mg/kg, directly 
followed by 2 courses of nivolumab 3 mg/kg every 2 weeks, n=26, with the 
second dose of ipilimumab and the first dose of nivolumab given on the same day 
to keep the overall duration of therapy the same as the other two arms. Patients in 
all three treatment arms then undergo surgery at 6 weeks.  
 
In Arm A, 47% of patients had pCR and 23% had near pCR and this cohort 
experienced 40% grade 3-4 immune mediated toxicities. In Arm B, 57% of 
patients had a pCR, 7% near pCR and 20% experienced grade 3-4 toxicities. In 
Arm C, 23% of patients had pCR, 23% had near pCR and grade 3-4 toxicity rate 
was 50%. Thus, the authors concluded that the combination therapy groups were 
most effective in producing pCR/near pCR but that toxicity was less in the group 
using ipilimumab 1mg/kg with nivolumab 3mg/kg28. 
 
 
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Neoadjuvant checkpoint inhibitor therapy in combination with other therapies 
 
There are also ongoing phase I and II studies to investigate combining immune 
checkpoint blockade with targeted therapies for patients with BRAF mutated 
melanoma. 
The NeoTrio trial (NCT02858921) is a phase II study of patients with BRAF 
mutant resectable stage IIIB, IIIC and IV melanoma who are randomized to 
receive either dabrafenib plus trametinib for 2 weeks followed by pembrolizumab 
for 50 weeks (Arm A), concurrent dabrafenib plus trametinib and pembrolizumab 
for 52 weeks (Arm B), or pembrolizumab monotherapy for 52 weeks (Arm C). Of 
the 52 weeks of systemic therapy in each arm, 12 weeks are administered in the 
neoadjuvant setting and the remaining 40 weeks of therapy are administered in the 
adjuvant setting. The primary outcome is pathological response rate after 12 
weeks of treatment, assessed at the time of surgery. Secondary outcomes include 
objective response rate by RECIST criteria, RFS, OS, and safety29. 
The NeoACTIVATE trial (NCT03554083) is enrolling BRAF mutated patients 
with vemurafenib (BRAF inhibitor), cobimetinib (MEK inhibitor) with 
atezolizumab (anti PD-L1 antibody) with clinical stage III melanoma. 
Neoadjuvant therapy is being administered for three months prior to surgery and 
an adjuvant phase with triplet therapy is also offered. The primary objective is 
pCR rate29. 
 
1.3 RATIONALE 
 
Clinical Stage III melanoma patients with BRAF mutations represent a high-risk 
patient population with need for improved clinical outcomes from standard of 
care upfront surgery and adjuvant therapy. We have previously demonstrated that 
neoadjuvant dabrafenib and trametinib is safe, leads to pathologic complete 
response and improves EFS over standard of care surgery and adjuvant therapy23 
in MD Anderson protocol 2014-0409. At the time this protocol was starting 
enrollment, neoadjuvant therapy in melanoma was in its infancy and thus we 
proactively had engaged the melanoma research community to develop the 
International Neoadjuvant Melanoma Consortium which has worked to provide a 
frame- work for best practices for neoadjuvant trial design, patient enrolment, 
responses assessment and translational research. As part of these efforts, our 
group has been instrumental in defining the pathologic features of response to 
neoadjuvant therapy and have defined pCR as the absence of any residual 
invasive malignant cells on hematoxylin and eosin evaluation of the resected 
melanoma specimen. Near pCR is defined as less than 10% viable tumor. pPR is 
defined as less than 50% viable tumor cells or more than 50% fibrosis on 
pathological evaluation. pNR is defined as no viable tumor31. 
With additional patients enrolled and with the benefit of additional follow up time 
on protocol 2014- 0409, we have appreciated a trend towards development of 
CNS metastases in treated patients, specifically in patients not achieving a pCR to 
neoadjuvant therapy. Of 15 patients who have not achieved a pCR to neoadjuvant 
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dabrafenib/trametinib, 8 (53%) have experienced disease recurrence in the brain 
predominantly (unpublished data). Relapses have been seen shortly after 
completing the year duration of treatment (3 patients) or even while on 
dabrafenib/trametinib in the adjuvant setting (5 patients). Conversely, of those 
who have achieved a pCR, only 1/12 (8%) patients has relapsed with CNS 
disease. These data suggest that the patients who do not achieve a pCR are at high 
risk for recurrence and are in need of alternative adjuvant treatment options23. 
We have previously demonstrated that patients who do not achieve a pCR tend to 
have a more exhausted T cell phenotype in their baseline, on-treatment and 
surgical samples, characterized by higher amounts of PD-1 +, TIM-3+, LAG-3+ T 
cells compared to those who achieve a pCR23. We therefore hypothesize that 
addition of PD-1 blockade on the backbone of dabrafenib and trametinib in the 
adjuvant setting for patient who do not achieve a pCR will improve RFS 
outcomes compared to historical controls. There have been a number of prior 
trials utilizing BRAF/MEK inhibition with anti PD-1/PD-L1 in melanoma 
(NCT02910700, NCT02130466, NCT02027961) including the COMBI-I study 
which utilized dabrafenib, trametinib and spartalizumab in metastatic melanoma 
patients with BRAF V600 mutations. This study demonstrated the safety and 
efficacy of this approach (see section 3.2.1 for further details)30 and thus we 
believe these agents will be appropriate for use in the adjuvant setting for the non 
pCR patients. 
 
2.0 
OBJECTIVES 
 
2.1 
PRIMARY OBJECTIVE 
 
• To determine the 12-month relapse free survival (RFS) rate in  
stage IIIB/C/D melanoma patients who, after 8 weeks of 
neoadjuvant dabrafenib and trametinib, do not achieve a pCR 
and receive adjuvant dabrafenib, trametinib and spartalizumab 
 
2.2  SECONDARY OBJECTIVES 
 
• To evaluate the safety of neoadjuvant dabrafenib and trametinib and 
adjuvant dabrafenib, trametinib and spartalizumab 
• To determine the 12-month relapse free survival (RFS) rate in stage 
IIIB/C/D  
• Melanoma patients who, after 8 weeks of neoadjuvant dabrafenib and 
trametinib, achieve a pCR and receive adjuvant dabrafenib and 
trametinib. 
• To assess the recurrence patterns, distant metastasis-free survival 
(DMFS), and overall survival (OS) in all patients treated on protocol. 
 
 
 
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2.3  EXPLORATORY OBJECTIVES 
 
• 
To assess immunological and molecular features of treatment  
  
response and resistance 
• 
To assess circulating markers and correlate them with treatment  
response and relapse andtoxicity 
• 
To assess the impact of neoadjuvant therapy on surgical resectablity 
 
3.0 
STUDY DESIGN 
 
This is an open-label single arm Phase II study that aims to examine the strategy 
of altering adjuvant therapy depending on pathologic response to neoadjuvant 
dabrafenib and trametinib therapy. Clinical stage III B/C/D BRAF V600E/K 
mutation with resectable disease will be enrolled. Patients will undergo 8 weeks 
of neoadjuvant dabrafenib and trametinib, followed by restaging scans and then 
definitive surgery if disease remains resectable. Surgical pathology will be 
analyzed for pathologic complete response (pCR), which is defined as absence of 
any residual tumor by H&E assessment. 
Near pCR will be defined as less than 10% viable melanoma in the surgical 
specimen. Pathologic partial response (pPR) is defined as less than 50% viable 
tumor in the surgical specimen. No pathologic response (pNR) is defined as ≥50% 
viable tumor in the surgical specimen31. 
Patients who achieve a pCR will continue with adjuvant dabrafenib and 
trametinib for an additional 44 weeks in order to complete a total 1 year of 
therapy. Patients who do not achieve a pCR after 8 weeks  of neoadjuvant 
dabrafenib and trametinib will receive dabrafenib, trametinib and spartalizumab in 
the adjuvant setting for a total of 44 weeks.  Patients with no resectable disease 
after neoadjuvant therapy will be removed from the study and replaced. 
Longitudinal blood and tumor will be collected in accordance with the study 
schedule. 
 
 
 
 
 
 
 
 
 
 
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Figure 1: Study Overview 
 
Patients 
with 
resectable 
stage 
IIIB/IIIC/IIID 
melanoma 
with BRAF 
V600E/K 
mutation 
 
pCR 
 
 
 
 
 
 
 
 
 
No pCR 
 
 
*pCR: absence of any viable tumor by H&E evaluation 
Tetzlaff at et al. Ann Oncol 2018; 29: 1861-6831 
Clinical and 
radiographic 
follow up for 
2 years post 
surgery 
Adjuvant 
dabrafenib 
+ trametinib 
+ 
spartalizumab 
for 44 
Neoadjuvant 
dabrafenib 
150mg po 
bid + 
trametinib 
2mg po 
qday for 8 
weeks 
(n=45) 
Adjuvant 
dabrafenib + 
trametinib 
for 44 weeks 
CT scans 
for RECIST 
response 
Surgical 
resection 
for 
assessment 
of 
pathologic 
response 
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3.1 
Inclusion Criteria 
A subject will be eligible for inclusion in this study only if all of the following criteria apply: 
• Capable of giving written informed consent, which includes compliance with the 
requirements and restrictions listed in the consent form 
• Patients must have histologically or cytologically confirmed clinically detected, 
node involved Stage IIIB/C/D melanoma by AJCC version 81 and surgically 
resectable disease. The definition of resectability can be determined by the 
patient’s surgical oncologist and verified via discussion at Multidisciplinary 
Tumor Conference attended by melanoma medical and surgical oncology staff. 
Resectable tumors are defined as having no significant vascular, neural or bony 
involvement that would preclude complete resection or necessitate the use of 
adjuvant radiation. Only cases where a complete surgical resection with tumor- 
free margins can safely be achieved are defined as resectable. 
• BRAF mutation-positive melanoma (V600E or V600K) based on report from a 
CLIA certified laboratory.  
• Patients must have measurable disease, defined by RECIST 1.132 
• Patients who have been previously treated in the adjuvant setting with 
ipilimumab or interferon alpha or investigational vaccines for melanoma will be 
eligible for treatment after a 28 day wash-out period 
• Patients who have previously received anti PD-1 in the adjuvant setting will be 
allowed if it has been six months or longer since previous drug exposure 
• Age >=18 years 
• ECOG performance status 0-1 (See Appendix A) 
• Women of childbearing potential, defined as all women physiologically capable 
of becoming pregnant will be required to use highly effective methods of 
contraception during dosing and for 150-days after stopping treatment with 
spartalizumab. Highly effective contraception methods include:  
•  Highly effective contraception methods include: 
a. Total abstinence (when this is in line with the preferred and usual lifestyle of the subject). 
Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) 
and withdrawal are not acceptable methods of contraception. 
b. Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy), total hysterectomy, or tubal ligation at least six weeks before taking study 
treatment. In case of oophorectomy alone, only when the reproductive status of the woman 
has been confirmed by follow up hormone level assessment. 
c. Male sterilization (at least 6 months prior to screening). The vasectomized male 
partner should be the sole partner for that subject 
d. Placement of a non-hormonal intrauterine device (IUD) or intrauterine system (IUS) with 
a documented failure rate of less than 1% per year. 
Notes: 
• Double-barrier contraception: condom and occlusive cap (diaphragm or cervical/vault 
caps) with a vaginal spermicidal agent (foam/gel/cream/suppository) are not considered 
highly effective methods of contraception. 
• 
Hormonal-based methods (e.g., oral contraceptives) are not considered as 
highly effective methods of contraception due to potential drug-drug interactions 
with dabrafenib. 
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• 
Women are considered post-menopausal and not of child bearing potential if they 
have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical 
profile (i.e. age appropriate, history of vasomotor symptoms) or have had surgical bilateral 
oophorectomy (with or without hysterectomy), total hysterectomy, or tubal ligation at least 
six weeks ago. In the case of oophorectomy alone, only when the reproductive status of the 
woman has been confirmed by follow up hormone level assessment is she considered not of 
childbearing potential. 
• Sexually active males must use a condom during intercourse while on treatment and for 150 
days after stopping treatment with spartalizumab and should not father a child in this 
period. A condom is required to be used by vasectomized men as well during intercourse in 
order to prevent delivery of the drug via semen 
• Organ function as defined below in Table 1: 
 
Table 1: Organ function criteria 
Hematological 
Absolute neutrophil count (ANC) 
≥1500/µL 
Platelets 
≥100 000/µL 
Hemoglobin 
≥9.0 g/dL or ≥5.6 mmol/La 
Renal 
Creatinine OR 
Measured or calculated b creatinine clearance 
(GFR can also be used in place of creatinine 
or CrCl) 
≤1.5 × ULN OR 
≥30 mL/min for participant with 
creatinine levels >1.5 × institutional ULN 
Hepatic 
Total bilirubin 
≤1.5 ×ULN OR direct bilirubin ≤ULN for 
participants with total bilirubin levels 
>1.5 × ULN 
AST (SGOT) and ALT (SGPT) 
≤2.5 × ULN 
Coagulation 
International normalized ratio (INR) OR 
prothrombin time (PT) 
Activated partial thromboplastin time (aPTT) 
≤1.5 × ULN unless participant is 
receiving anticoagulant therapy as long 
as PT or aPTT is within therapeutic range 
of intended use of anticoagulants 
ALT (SGPT)=alanine aminotransferase (serum glutamic pyruvic transaminase); 
AST (SGOT)=aspartate aminotransferase (serum glutamic oxaloacetic transaminase); 
GFR=glomerular filtration rate; ULN=upper limit of normal. 
a Criteria must be met without erythropoietin dependency and without packed red blood 
cell (pRBC) transfusion within last 2 weeks. 
b Creatinine clearance (CrCl) should be calculated per institutional standard. 
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3.2 
Exclusion Criteria 
 
A subject will not be eligible for inclusion in this study if any of the following criteria 
apply: 
 
• 
Currently receiving cancer therapy (chemotherapy, radiation therapy, 
immunotherapy, or biologic therapy) or investigational anti-cancer drug 
within 28 days 
• 
Evidence of metastatic melanoma or patients with only in-transit metastases 
without involved nodes 
• 
Prior BRAF or MEK inhibitor use 
• 
Prior anti PD-1 or anti PD-L1 inhibitor use in last 6 months 
• 
Prior malignancy active within the previous 2 years except for patient’s prior 
diagnosis of melanoma and locally curable cancers that have been apparently 
cured, such as basal or squamous cell skin cancer, superficial bladder cancer, 
or carcinoma in situ of the prostate, cervix, or breast with local control 
measures (surgery, radiation). 
• 
Subjects with active, known or suspected autoimmune disease. Subjects with 
vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune 
condition only requiring hormone replacement, psoriasis not requiring 
systemic treatment, or conditions not expected to recur in the absence of an 
external trigger are permitted to enroll. 
• 
Subjects with a condition requiring systemic treatment with either 
corticosteroids (> 10 mg daily prednisone equivalents) or other 
immunosuppressive medications within 14 days of study drug administration. 
Inhaled or topical steroids and adrenal replacement doses  >  10  mg  daily  
prednisone  equivalents  are permitted in the absence of active autoimmune 
disease. 
• 
Any positive test result for hepatitis B or C and HIV virus indicating acute or 
chronic infection 
• 
Known history of testing positive for human immunodeficiency virus or 
known acquired immunodeficiency syndrome 
• 
History of severe hypersensitivity reaction to any monoclonal antibody 
• 
History of Central serous retinopathy (CSR) or retinal vein occlusion (RVO), 
or predisposing factors to RVO or CSR (e.g. uncontrolled glaucoma or ocular 
hypertension, uncontrolled systemic disease such as hypertension, diabetes 
mellitus, or history of hyperviscosity or hypercoagulability syndromes). 
Presence of active gastrointestinal disease or other condition that will interfere 
significantly with the absorption, distribution, metabolism, or excretion of 
drugs. QTc interval ≥ 480 msec (≥ 500 msec for subjects with Bundle Branch 
Block) Uncontrolled arrhythmias 
Class II, III, or IV heart failure as defined by the New York Heart 
Association (NYHA) functional classification system 
• Pregnant or lactating female 
• Unwillingness or inability to follow the procedures required in the protocol 
• Uncontrolled diabetes, hypertension or other medical conditions that 
may interfere with assessment of toxicity 
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Subjects with known glucose 6 phosphate dehydrogenase (G6PD) deficiency 
3.3 
TRIAL TREATMENT – Study Drugs and Administration Details 
 
Table 2a: Neoadjuvant Treatment 
 
Study Drug 
Dose 
Dabrafenib 
150mg by mouth twice daily 
Trametinib 
2mg by mouth daily 
 
Table 2b: Adjuvant Treatment of pCR patients 
 
Study Drug 
Dose 
Dabrafenib 
150mg by mouth twice daily 
Trametinib 
2mg by mouth daily 
 
Table 2c: Adjuvant Treatment of non pCR Patients 
 
Study Drug 
Dose 
Dabrafenib 
150mg by mouth twice daily 
Trametinib 
2mg by mouth daily 
Spartalizumab 
400mg IV every 28 days 
 
 
 
 
 
 
 
 
 
 
 
 
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Table 3: Trial Treatments and Description 
Table 3a: Neoadjuvant Treatment 
 
Product 
Dose 
Dose 
Frequency 
Route of 
Administratio 
n 
Appearanc 
e 
Storage 
Conditions 
(per label) 
Dabrafenib 
150 
mg 
BID 
By mouth 
Capsules 
for oral use 
Refer to 
study 
treatment 
label 
Trametinib 
2mg 
Daily 
By mouth 
Tablets for 
oral use 
Refer to 
Associated 
IB 
 
 
 
Table 3b: Adjuvant Treatment of pCR patients 
 
Product 
Dose 
Dose 
Frequency 
Route of 
Administratio 
n 
Appearanc 
e 
Storage 
Conditions 
(per label) 
Dabrafenib 
150 
mg 
BID 
By mouth 
Capsules 
for oral use 
Refer to 
Associated 
IB 
Trametinib 
2mg 
Daily 
By mouth 
Tablets for 
oral use 
Refer to 
Associated 
IB 
 
Table 3c: Adjuvant Treatment of non pCR Patients 
 
Product 
Dose 
Dose 
Frequency 
Route of 
Administratio 
n 
Appearanc 
e 
Storage 
Conditions 
(per label) 
Dabrafenib 
150 
mg 
BID 
By mouth 
Capsules 
for oral use 
Refer to 
Associated 
IB 
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Trametinib 
2mg 
Daily 
By mouth 
Tablets for 
oral use 
Refer to 
Associated 
IB 
Spartalizumab 
400mg Every 28 
days 
Intravenous 
Liquid in 
vial for 
infusion 
Refer to 
Associated 
IB 
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3.3.1 Dose Selection Rationale 
 
The dose of dabrafenib is 150mg BID which is the FDA approved dose for 
patients with unresectable or metastatic melanoma with BRAF V600E or V600K 
mutations. 
The dose of trametinib is 2mg daily, which is the FDA, approved dose for 
patients with unresectable or metastatic melanoma with BRAF V600E or 
V600K mutations. 
The dose of spartalizumab is 400mg every 28 days, administered as an intravenous 
infusion. In study [CPDR001X2101],PDR001 single-agent was administered as an 
intravenous infusion over 30 minutes at doses ranging from 1 to 10 mg/kg on an every 2 
weeks (Q2W) schedule or at 3 and 5 mg/kg every 4 weeks (Q4W) schedules. 
Approximately dose proportional increase in exposure (C1D1 AUC0- 336) was observed 
with doses from 1 to 10 mg/kg and no DLTs were observed. 
Accumulation of approximately 2.1-3.4-fold was observed with Q2W dosing and 1.6-2.2-
fold with Q4W dosing. Population PK analysis indicated that the changes in exposure due 
to patient weight differences are minimal across the anticipated weight range of 30 to 150 
kg for the patient population. Therefore, a flat dosing scheme was selected. Based on the 
safety profile observed in study [CPDR001X2101] and the expected Ctrough values, 400 
mg Q4W is expected to be a safe and efficacious dose. For further details on 
spartalizumab, please see the investigator’s brochure. 
 
Prior Experience with Investigational Agents 
 
The COMBI-I study is a multicenter trial exploring the safety and efficacy of dabrafenib, 
trametinib and spartalizumab in patients with BRAF V600 mutated unresectable or 
metastatic melanoma. In Part 1 of the trial (safety run-in cohort), standard dosing of 
dabrafenib (150mg orally twice daily), trametinib (2mg daily) and spartalizumab (400mg 
IV every 4 weeks) was utilized. A total of 9 patients were enrolled and there was no 
excessive toxicity seen and this dosing was utilized in Part 2 which was designed to be a 
biomarker exploration cohort. An additional 27 patients were treated on Part 2 for a total 
of 36 evaluable patients for safety and efficacy. At the time of data analysis, the median 
follow up time was 19.9 months (16.5-25.1 months range) and treatment was ongoing for 
13 patients. All patients had some form of adverse event, with 78% having experienced a 
grade 3 toxicity. The most common grade 3 toxicities were pyrexia (17%) and pruritus 
(11%). Grade 3 laboratory evaluations were noted including elevated creatinine 
phosphokinase (8%), amylase (8%) and gamma-glutamyltransferase (8%) levels, in 
keeping with prior studies. All patients required dose adjustment/interruption to mitigate 
toxicities and 17% of patients had toxicities leading to cessation of the triplet therapy. In 
terms of efficacy, the overall response rate was 78% with 42% achieving confirmed 
complete response, which included 20% with elevated LDH at baseline and 40% with 
stage IV M1c disease. The median PFS was 23.7 months, including 10.7 months for 
higher risk patients with elevated LDH values at time of enrollment. The median duration 
of response was 20.7 months with 29% of responders experiencing subsequent 
progression. The median overall survival was not reached in this cohort. Part 3 of this 
trial which is a global, placebo-controlled randomized trial of dabrafenib, trametinib and 
placebo vs. dabrafenib, trametinib and spartalizumab is currently in enrollment30. 
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3.3.2 Dose Modification 
 
 
Dose Modification of Dabrafenib and Trametinib and Spartalizumab for General 
Toxicities Related to Study Drug(s) 
In the event of a clinically significant grade 3 or 4 hematologic or non-hematologic AE, 
treatment may be withheld and supportive therapy administered as clinically indicated. 
If the toxicity or event resolves to baseline or Grade 1 in less than or equal to 21 days of 
stopping therapy, treatment may be restarted. Dose reduction should be considered as 
clinically indicated at the discretion of the treating oncologist. Any dose adjustment or 
interruption will be recorded. 
If the toxicity does not resolve to at least Grade 1 in less than or equal to 21 days, 
withdrawal from the trial is recommended. However, if the investigator agrees that 
further treatment will benefit the subject, treatment can continue with a reduction of 
one or both study drugs. 
Suggested dose reduction of each drug is as follows in Table 4. These dose reductions 
of dabrafenib and trametinib do not need to be made concurrently and will be up to the 
discretion of the treating investigator.  
Table 4 
Dose Levels 
 
Drug 
Starting Dose 
Dose level -1 
Dose level -2 
Dose level -3 
Dabrafenib 
150mg BID 
100mg BID 
75mg BID 
50mg BID 
Trametinib 
2mg daily 
1.5mg daily 
1.0 mg daily 
------------------ 
---- 
Spartalizumab 400mg IV 
every 28 days 
------------------ 
---- 
------------------ 
---- 
------------------ 
---- 
 
If treatment related toxicities occur that are specific to combination treatment of 
dabrafenib and trametinib, then both treatments should be simultaneously dose 
reduced, interrupted or discontinued with the exceptions shown below: 
Exception where dose modification is necessary for only dabrafenib: 
• Uveitis 
Exception where dose modifications are necessary for only trametinib: 
• Retinal vein occlusions (RVO) and retinal pigment epithelial detachment (RPED) 
• Left ventricular ejection fraction (LVEF) reduction 
If a subject’s dose of dabrafenib and trametinib has been reduced per the dose 
modification instructions, re-escalation of the subject’s dose is recommended 
provided the following criteria are met: 
• a period of 4 weeks of treatment has passed since restarting dosing at the lower 
dose level and there is no recurrence of the AE 
• the subject is deriving clinical benefit 
 
 
 
 
 
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General dose modification guidelines are provided in Table 5 
 
Table 5 Dose Modification Guidelines – General 
 
CTCAE Grade 
Action and Dose Modification 
Grade 1 or 
Grade 2 
(tolerable) 
Continue study treatments at same dose level (no dose modification) 
Grade 2 (Intolerable) 
1st or 2nd 
occurrence 
Interrupt study treatments until toxicity resolves to ≤ grade 1 then restart 
at same dose level 
3rd or occurrence 
Interrupt study treatments until toxicity resolves to ≤ grade 1 then restart 
at next lower dose level 
4th or greater 
occurrence 
Interrupt study treatments until toxicity resolves to ≤ grade 1 then restart at 
two dose levels lower than the starting dose or discontinue treatments per 
investigator discretion 
Grade 3 
1st occurrence 
Interrupt study treatments until toxicity resolves to ≤ grade 1 or 
baseline then restart at next lower dose level 
2nd occurrence 
Interrupt study treatments until toxicity resolves to ≤ grade 1 or baseline 
then restart at two dose levels lower than the starting dose 
3rd occurrence 
Discontinue treatments. 
Grade 4 
1st occurrence 
Discontinue treatments 
 
For dabrafenib and/or trametinib related adverse events: if following an 
interruption of dabrafenib and trametinib, an AE doesn’t recover to ≤ Grade 1 or 
baseline within 4 weeks, dabrafenib and trametinib must be discontinued. 
No dose reductions are allowed for spartalizumab. Dose interruption for spartalizumab 
includes delaying or withholding the treatment for any reason as well as an interruption 
of treatment during an infusion. All dose interruptions and the reason for the dose 
interruption must be recorded. Dose interruption for spartalizumab includes delaying or 
withholding the treatment for any reason as well as an interruption of treatment during an 
infusion. Subjects with adverse events suspected to be related to spartalizumab including 
those of potential immune-mediated etiology (irAE) must be permanently discontinued 
from spartalizumab if (1) the AE doesn’t recover to ≤ Grade 1 or baseline within 12 
weeks and/or (2) the dose of steroids (for the management of irAE) remains > 10 mg/day 
prednisone or equivalent for >12 weeks. The 12 week timeframe will begin from the time 
the irAE reaches a grade that leads to spartalizumab interruption. 
 
 
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3.3.3 Dose Modification Guidelines – Adverse Events of Special Interest 
 
Pyrexia 
Mandatory dose modification and recommended clinical management for pyrexia 
syndrome suspected to be related to dabrafenib and/or trametinib treatment 
Episodes of pyrexia syndrome have been observed in subjects receiving dabrafenib 
monotherapy or in combination with trametinib. The pyrexia syndrome is defined as 
treatment-related fever (≥ 38°C) or chills/rigors/night sweats or flu-like symptoms. In a 
minority of cases the pyrexia was accompanied by symptoms such as severe rigors/chills, 
dehydration, hypotension, dizziness or weakness and required hospitalization. The 
incidence and severity of pyrexia syndrome are increased when dabrafenib is used in 
combination with trametinib compared to dabrafenib monotherapy. 
Dabrafenib and trametinib must be interrupted promptly at the very first symptom of 
pyrexia or its associated prodrome (chills or rigors or night sweats or flu-like symptoms) 
and should be restarted upon improvement of symptoms at the same dose if symptom free 
at least 24 hours. 
Subjects should be instructed on the importance of immediately reporting febrile 
episodes. In the event of a fever, the subject should be instructed to take non-steroidal 
anti-pyretics as appropriate to control fever. The use of oral corticosteroids should be 
considered in those instances in which anti-pyretics are insufficient. In subjects 
experiencing pyrexia associated with rigors, severe chills, dehydration or hypotension, 
serum creatinine and other evidence of renal function should be monitored carefully 
during and following severe events of pyrexia. 
Pyrexia accompanied by hypotension, dehydration requiring intravenous fluids, renal 
insufficiency and/or severe rigors, (dehydration requiring intravenous fluids, documented 
infectious cause should be reported as a SAE. 
Guidelines for dose modification and management for pyrexia syndrome considered to be 
related to dabrafenib are provided in Table 6. 
 
 
 
Table 6: Pyrexia Management Guidelines 
 
 
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3.3.4 
Visual changes 
 
 
Episodes of visual changes have been observed in subjects receiving 
trametinib. The causal relationship between a change in vision and the 
study treatment should be carefully explored and an ophthalmologist 
should be consulted. Special attention should be given to retinal (e.g., 
CSR) or retinal vein abnormalities (e.g., RVO). 
 
 
 
 
 
 
 
 
 
 
 
 
 
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TABLE 7 
MANAGEMENT AND DOSE MODIFICATION GUIDELINES FOR VISUAL CHANGES 
 
CTCAE 
Gradea 
Adverse Event Management 
Action and Dose Modification 
Grade 1 
• Consult ophthalmologist within 
7 days of onset 
• 
Exclude CSR or RVO 
• Consult retinal specialist if 
available in case of CSR or RVO 
• Continue follow up 
examination(s) (by retinal 
specialist if available) for CSR 
and RVO 
• Continue trametinib at the same dose 
level until ophthalmologic 
examination can be conductedb 
• If ophthalmologic examination cannot 
be performed within 7 days of onset, 
interrupt trametinib until CSR and 
RVO can be excluded and symptoms 
resolve 
• If CSR and RVO excluded 
restart trametinib at same 
dose level 
• CSR: Interrupt trametinib until 
symptoms resolve and exam (by retinal 
specialist if available) shows resolution; 
report as SAE 
• If CSR resolves restart with 
trametinib reduced by one dose 
level 
• RVO: Permanently 
discontinue trametinib and 
report as SAE 
Grade 2 and 
Grade 3 
• Consult ophthalmologist 
immediately 
• 
Exclude CSR and RVO 
• Consult retinal specialist if 
available in case of RVO or CSR 
for follow-up exam 
• Continue follow up 
examination(s) (by retinal 
specialist if available) for CSR 
and RVO 
• Interrupt trametinib until signs 
and symptoms have resolved to 
baseline 
• If CSR and RVO excluded and 
symptoms resolved to baseline restart 
trametinib reduced by one dose level 
• CSR: Interrupt trametinib until 
symptoms resolve and exam (by retinal 
specialist if available) shows resolution; 
report as SAE 
• 
If CSR resolves restart trametinib 
reduced by one dose level 
RVO: Permanently discontinue 
study treatments and report as 
SAE 
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Grade 4 
• Consult ophthalmologist 
immediately 
• 
Exclude CSR and RVO 
• Continue follow up 
examination(s) (by retinal 
specialist if available) for CSR 
and RVO 
• Permanently 
discontinue 
trametinib 
• If CSR or RVO then report as SAE 
Abbreviations: CSR = central serous retinopathy; CTCAE = Common Terminology Criteria for Adverse 
Events; RVO = retinal vein occlusion; SAE = serious adverse event 
CTCAE 
Gradea 
Adverse Event Management 
Action and Dose Modification 
a. Refers to CTCAE Version 5.0 ‘Eye disorders – Other, specify 
b. If visual changes are clearly unrelated to study treatment (e.g., allergic conjunctivitis), monitor 
closely but ophthalmic examination is not required. 
 
3.3.5 Cardiovascular Toxicity 
 
Cardiovascular adverse events have been seen in subjects receiving trametinib 
and dabrafenib, either as monotherapy or in combination. Dose modification of 
either agent may be required for decreased LVEF, hypertension or QTc 
prolongation. 
 
3.3.6 Decreased Left Ventricular Ejection Fraction (LVEF) 
Decreases of the left-ventricular-ejection-fraction (LVEF) have been observed 
in subjects receiving trametinib monotherapy and with trametinib in 
combination with dabrafenib. 
Therefore, a baseline echocardiogram will be performed to assess for 
adequate LVEF function. Repeat echocardiograms will be performed every 
3 months during the duration of dabrafenib and trametinib therapy or at any 
point if patients develop heart failure symptoms. Management will be per 
the guidelines in Table 8. 
 
TABLE 8 
DOSE MODIFICATION GUIDELINES AND STOPPING CRITERIA FOR LVEF 
DECREASE 
 
Clinic 
LVEF-drop (%) or 
CTCAE grade 
Action and Dose Modification 
Symptomatica Grade 3: resting LVEF 39- 
20% or >20% absolute 
reduction from baseline 
• Permanently discontinue 
trametinib. 
• Consult with cardiologist 
• Repeat ECHO after 2, 4, 8, 12, and 
16 weeks or until resolution 
Grade 4: resting LVEF 
<20% 
Abbreviations: CTCAE = Common Terminology Criteria for Adverse 
Events; ECHO = echocardiogram; LLN = lower limit of normal; LVEF 
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= left ventricular ejection fraction; 
a. Symptoms may include: dyspnea, orthopnea, and other 
signs and symptoms ofpulmonary congestion and edema. 
 
 
3.3.7 Hypertension 
Any level of hypertension should be actively managed. Trametinib does not 
need to be interrupted while mild hypertension is brought under control; 
however, treatment interruption and dose-reduction are recommended for 
more severe or symptomatic hypertension (e.g. persistent systolic blood 
pressure (SBP) ≥160 mmHg or diastolic blood pressure (DBP) ≥100 mmHg 
despite antihypertensive treatment). 
 
3.3.8 QTc Prolongation 
 
 
Guidelines for dose modification and stopping criteria due to 
QTc-prolongation are provided in Table 9 below: 
 
TABLE 9 
WITHHOLDING AND STOPPING CRITERIA FOR QTC-PROLONGATION 
 
QTc-Prolongationa 
Action and Dose Modification 
• 
QTcB ≥501 msec 
• 
Interrupt all study treatments until QTcB 
prolongation resolves to grade 1 or baseline 
• 
Recommend Testing serum potassium, calcium, 
phosphorus and magnesium. If abnormal, correct per 
routine clinical practice to within normal limits. 
• 
Review concomitant medication usage for a 
prolonged QTc. 
• 
Restart at current dose level 
• 
If event recurs, permanently discontinue study 
treatments 
 
Abbreviations: msec = milliseconds; QTcB = QT interval on electrocardiogram 
corrected using the Bazett’s formula a: Based on average QTc value of triplicate 
ECGs. For example, if an ECG demonstrates a prolonged QT interval, obtain 
two or more ECGs over a brief period, and then use the averaged QTc values of 
the three ECGs to determine if study treatments should be interrupted or 
discontinued.If the QTc prolongation resolves to grade 1 or baseline, the subject 
may resume study treatment if the investigator agrees. 
 
3.3.9 CUTANEOUS SQUAMOUS CELL CARCINOMA (CUSCC) AND KERATOACANTHOMA (KA) 
 
Both cuSCC and KA have been observed in subjects treated with dabrafenib and the 
combination of dabrafenib and trametinib [GlaxoSmithKline Document Number 
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2011N126811_00, GlaxoSmithKline Document Number 2012N136095_00, and 
GlaxoSmithKline Document Number HM2009/00151/02]. These should be surgically 
removed according to institutional practices. Dose modification or interruption of study 
treatment is not required for cuSCC or KA, however they should be reported as an SAE 
(refer to Section 7.7). 
 
 
3.4 
MONITORING, INTERRUPTION, AND STOPPING CRITERIA FOR 
HEPATOBILIARY EVENTS 
 
These liver chemistry stopping and follow up criteria have been designed to assure 
subject safety and evaluate liver event etiology in alignment with the FDA Guidance for 
Industry – Drug-Induced Liver Injury: Premarketing Clinical Evaluation (July 2009, 
www.fda.gov). 
Liver chemistry stopping criteria 1-5 are defined as follows: 
ALT ≥  3 x ULN and bilirubin ≥ 2 x ULN (>35% direct bilirubin) (or ALT ≥  3 x ULN 
and INR>1.5, if INR measured) 
 
NOTE: If serum bilirubin fractionation is not immediately available and if ALT ≥  3 x ULN 
and bilirubin ≥  2 x ULN, subject should be discontinued from study treatments. Serum 
bilirubin fractionation should be performed if testing is available. 
ALT ≥ 8 x ULN;ALT ≥ 5 x ULN but < 8 x ULN persists for ≥ 2 weeks; ALT ≥ 3 x ULN 
if associated with symptoms (new or worsening) believed to be related to hepatitis (such as 
fatigue, nausea, vomiting, right upper quadrant pain or tenderness, or jaundice) or 
hypersensitivity (such as fever, rash or eosinophilia). 
 
3.5 
Adverse events of special interest (AESI) 
 
Adverse events of special interest include AEs of a potential irAE that are associated with 
spartalizumab treatment. An irAE may be experienced by subjects treated with 
spartalizumab due to its mechanism of action and predicted based on the reported 
experience with other immunotherapies that have a similar mechanism of action. 
Investigators must be vigilant and carefully identify AEs that may be suggestive of 
potential irAEs as their appearance may be sub- clinical and early diagnosis is critical for 
its adequate management and resolution. 
An irAE is typically low grade and self-limited, often occurring after multiple doses, and 
most frequently involving the GI tract (diarrhea/colitis), skin (rashes), liver (hepatitis), 
lung (pneumonitis), kidneys (nephritis) and endocrine systems (a variety of 
endocrinopathies) and rarely CNS (encephalitis). Serological, immunological and 
histological assessments should be performed as deemed appropriate by the investigator, 
to verify the potential immune-related nature of the AE, and exclude a neoplastic, 
infectious or metabolic origin of the AE. 
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Severe grade or persistent lower grade irAEs typically require interrupting or 
permanently discontinuing treatment and administration of systemic steroids or other 
non-corticosteroid immunosuppressive medication when systemic steroids are not 
effective. Early recognition of irAEs and initiation of treatment are critical to reduce the 
risk of complications, since the majority of irAEs are reversible with the use of steroids 
and other immune suppressants. 
In some cases, it may be unclear to determine if an adverse event is immune related or not, 
thus the following dose reduction guidelines should be followed. 
 
The following sections address the specific instructions for mandatory dose modifications 
and recommended management for AEs considered suspected to be related to study 
treatment. For subjects who do not tolerate the protocol-specified dosing schedule, dose 
interruptions or modifications are mandated in order to allow subjects to continue study 
treatment. 
 
3.6 
THERAPY ADMINISTRATION 
 
3.6.1 Dabrafenib and trametinib administration 
 
• Dabrafenib and trametinib will be provided by the Supporting 
Company, Novartis free of charge and will be disposed of per 
Institutional Guidelines 
• Dabrafenib and trametinib should be taken as follows: 
Dabrafenib will be administered orally twice daily (BID) for Days 
1-28 of a 28-day cycle. 
• Trametinib will be administered orally once daily (QD) for Days 1-
28 of a 28-day cycle. 
• Subjects should be instructed to take the dabrafenib and trametinib 
concurrently in the morning, at approximately the same time every 
day. The second (evening) dose of dabrafenib (150 mg) should be 
administered approximately 12 (± 4) hours apart from the first dose 
(morning) of dabrafenib. 
• Subjects should be instructed to swallow whole capsules of 
dabrafenib and not chew or open them. 
• If a subject vomits after taking study drug, the subject should be 
instructed not to retake the dose and wait for the next scheduled 
dose. The occurrence and frequency of any vomiting during a 
treatment cycle must be noted 
• If a subject misses a dose, he/she should be instructed not to 
double the next regularly scheduled dose. However, subject may 
take the missed dose immediately if the next scheduled dose is at 
least 6 hours later for dabrafenib and 12 hours later for trametinib. 
Subject may then take the next dose at the scheduled time. 
• Subjects must avoid consumption of grapefruit, grapefruit hybrids, 
pomelos, star-fruit, Seville oranges or products containing the juice 
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of each 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. 
• No herbal or dietary supplements are permitted. 
• Multivitamins are permitted. 
 
3.6.2 Spartalizumab administration in adjuvant setting for non pCR patients 
Spartalizumab (100mg liquid in vial for infusion solution) will be administered as 
a flat dose of 400mg intravenously over at least 30 minutes every 28 days in the 
adjuvant setting along with dabrafenib and trametinib in patients who have not 
achieved a pCR. Infusion can be up to 2 hours if clinically indicated. Subjects 
should not receive pre-medication to prevent infusion reaction before the first 
infusion of study treatment. If a subject experiences an infusion reaction, he/she 
may receive pre- medication on subsequent dosing days. The pre-medication 
should be chosen per institutional standard of care, at the discretion of the 
investigator.    Spartalizumab will be provided by Novartis free of charge and will 
be disposed of per Institutional Guidelines. 
Acute allergic reactions should be treated as needed per institutional standard of 
care. In the event of anaphylactic/anaphylactoid reactions, this includes any 
therapy necessary to restore normal cardiopulmonary status. If a subject 
experiences a Grade 3 anaphylactic/anaphylactoid reaction, the subject will be 
discontinued from the study. 
 
3.7 
MANAGEMENT OF IRAES 
 
Management of spartalizumab induced immune mediated adverse events should be as per 
the guidance documents in Appendix B. 
If a patient does experience an irAE and prednisone is administered, reduce prednisone 
dose by 2.5 to 10.0 mg decrements every 3–7 days until physiologic dose (5 to 7.5 mg of 
prednisone per day) is reached. Consider to complete tapering over a period of at least 4 
weeks. Slower tapering of corticosteroids therapy may be recommended if the adverse 
event is not showing improvement. 
Once corticosteroid tapering is achieved at a level of 10 mg of prednisone/day (or 
equivalent) spartalizumab can be restarted. 
 
3.8 
CONCOMITANT AND EXCLUDED THERAPIES 
 
The following medications or non-drug therapies are prohibited while on treatment in this 
study: 
 
• Other anti-cancer therapies 
 
3.8.1 Other investigational drugs 
 
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The investigator must be informed as soon as possible about any medication taken 
from the time of screening until 30 days after the last dose of study treatment. 
Any concomitant medication(s), including dietary supplements, taken during the 
study will be recorded. The minimum requirement is that drug name, dose, and 
the dates of administration are to be recorded.  ConMeds will be recorded in both 
EMR and CRF. 
 
Subjects should receive full supportive care during the study, including 
transfusions of blood and blood products, and treatment with antibiotics, anti-
emetics, anti-diarrheals, and analgesics, and other care as deemed appropriate, and 
in accordance with their institutional guidelines. 
 
 
 
3.8.2 Prohibited Concomitant Medications 
The use of systemic steroid therapy and other immunosuppressive drugs is not 
allowed except for the treatment of infusion reaction, irAEs, and for prophylaxis 
against imaging contrast dye allergy or replacement-dose steroids in the setting of 
adrenal insufficiency (providing this is <10 mg/day prednisone or equivalent), or 
transient exacerbations of other underlying diseases such as COPD requiring 
treatment for ≤ 3 weeks. If systemic corticosteroids are required for the control of 
infusion reactions, pyrexia or irAEs, it must be tapered and be at non-
immunosuppressive doses (< 10 mg/day of prednisone or equivalent) before the 
next administration of study treatment. 
If the dose of prednisone or equivalent cannot be reduced to less than 10 mg/day 
before the administration of next dose of study treatment then spartalizumab must 
be discontinued. 
The use of live vaccines is not allowed through the whole duration of the study. 
Inactivated vaccines are allowed. 
Dabrafenib induces CYP3A4- and CYP2C9- mediated metabolism and may 
induce other enzymes including CYP2B6, CYP2C8, CYP2C19 and UDP 
glucuronosyltransferases (UGT). Dabrafenib may also induce transporters (e.g., 
P-glycoprotein (P-gp)). Co-administration of dabrafenib and medicinal products 
which are affected by the induction of CYP3A4 or CYP2C9 such as hormonal 
contraceptives, warfarin or dexamethasone may result in decreased concentrations 
and loss of efficacy. If co- administration of these medications is necessary, 
monitor subjects for loss of efficacy or consider substitutions of these medicinal 
products. Use caution if co-administration of CYP2C or CYP3A4  substrates with 
narrow therapeutic index is required. Refer to the dabrafenib label for further 
information. 
Based on in vitro and in vivo data, trametinib is unlikely to significantly affect the 
pharmacokinetics of other medicinal products via interactions with CYP enzymes 
or transporters. 
 
4.0 
STUDY ASSESSMENTS 
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4.1 
CRITICAL BASELINE ASSESSMENTS 
 
Baseline (Screening) assessments obtained will include: 
• Documentation of relevant medical history Complete physical 
examination, including weight and single height measurement 
• Review of concomitant medications and documentation baseline 
toxicity information 
• Verification of BRAF mutation at V600 position by a CLIA 
certified assay.  Presence of BRAF by IHC is acceptable to begin 
screening evaluations. 
• Documentation of surgical resectability from multi-disciplinary 
tumor conference 
• Vital signs: blood pressure, temperature, respiratory rate, pulse rate 
• Eastern Cooperative Oncology Group (ECOG) performance status 
• Clinical laboratory tests: hematology, thyroid (TSH and fT4) and 
clinical chemistry 
• Coagulation Panel (PT/PTT) 
• Serum or urine beta-human chorionic gonadotropin (β-HCG) 
pregnancy test for female subjects of childbearing potential only 
• 12-lead electrocardiogram (ECG) 
• 2D complete echocardiogram for assessment of ejection fraction 
• Ophthalmic exam by ophthalmologist to include indirect 
fundoscopic examination, visual acuity, visual field examination, 
tonometry, and direct fundoscopy, with special attention to retinal 
abnormalities that are predisposing factors for RVO or CSR 
• Brain magnetic resonance imaging (MRI) with contrast or a 
computed tomography (CT) scan (with/without contrast) if MRI is 
contraindicated 
• CT of the chest, abdomen and pelvis with contrast or PET/CT, 
imaging of body site of interest (neck, extremity) if indicated 
• Research blood collection 
• Research microbiome collection 
• Research tumor biopsy 
 
4.2 
BASELINE CONFIRMATION OF BRAF MUTATION-POSITIVE MELANOMA 
 
Patients may be enrolled and started on study if they have local molecular testing that is 
positive for BRAF mutation in the V600 position by a CLIA certified assay. Only 
patients with V600E or V600K mutations are eligible for enrollment. Presence of BRAF 
by IHC is acceptable to begin screening evaluations. 
 
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4.3  
SCHEDULE OF ASSESSMENTS 
 
Table 10 Time and Event Table—Neoadjuvant Phase 
 
Screeningj 
Cycle 1 
Cycle 1 
Cycle 2 
Cycle 2 
Day 1 
Day 
15k 
Day 1k 
Day 28k 
Informed consent 
X 
 
 
 
 
Demographics 
X 
 
 
 
 
Medical history 
X 
 
 
 
 
Concurrent 
medications 
X 
X 
X 
X 
X 
AEs 
a 
X 
X 
X 
X 
X 
PE/Vitals/ECOG 
X 
X 
X 
X 
X 
Pregnancy testb 
X 
 
 
 
 
CBC with diff 
c 
X 
X 
X 
X 
X 
Serum chemistry 
X 
X 
X 
X 
X 
Thyroid TSH, fT4 
X 
 
 
 
X 
Coagulation 
X 
 
 
 
X 
Echocardiogram 
X 
 
 
 
 
12-lead EKG 
X 
 
X 
 
X 
Ophthalmic exam 
X 
 
 
 
 
Research Tissued 
X 
 
 
 
X (surgery) 
Research Bloode 
X 
 
X 
X 
X 


 
 
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                            Version 01 – 2019-0906 
 
 
Research microbiome 
Collectionf 
X 
 
 
 
X 
Disease 
Assessmentg 
X 
 
 
 
X 
Surgical resectionh 
 
 
 
 
X 
Dabrafenib and 
trametinibi 
 
Continuous Daily Dosing 
a. Systolic and diastolic blood pressure, pulse rate, temperature, including weight and single height measurement. 
b. Serum or urine β-hCG - For women of childbearing potential only within 7 days of start of study drugs. 
c. Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, LDH, magnesium, 
phosphorus, potassium, total protein, AST, ALT, sodium 
d. Mandatory biopsy at baseline and collection of residual tumor at surgery. 
e. 50ml of blood will be obtained at each time point for correlative correlates 
f. 
OMNIgene gut kits, or equivalent, will be provided for stool collection at screening and Cycle 2 
g. PET/CT or CT of the chest, abdomen, pelvis (neck if clinically indicated) and brain MRI (or CT of the head with contrast if 
MRI is contraindicated). 
h. Surgical resection of residual tumor if restaging scans show disease stability or response. If disease progression is 
confirmed, surgery may still occur if disease is still deemed resectable 
i. 
Dabrafenib and trametinib will be held starting the day prior to planned surgical intervention. 
j. 
Screening is defined as within 35 days prior to treatment initiation. 
k.    +/- 7 days


 
 
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Table 11 Adjuvant Time and Event Table for Pathologic Complete Responders 
(dabrafenib and trametinib only) 
 
Post- 
operative 
We 
ek 
12i 
Week 
16i 
Week 
20i 
Week 
24i 
Week 
28i 
Week 
32i 
Week 
36i 
Week 
40i 
Week 
44i 
Week 
48i 
Week 
52i 
EOTj 
Concurrent 
medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AEs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PE/Vitals/ECO 
Ga 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CBC with diff 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum 
chemistryb 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
TSH, 
fT4 
 
 
 
X 
 
 
X 
 
 
X 
 
 
 
Echocardiogra 
mc 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
12-lead EKG 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
X 
Research 
Biopsyd 
 
 
If evidence of disease recurrence or metastasis 


 
 
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Research 
Bloode 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
X 
Research 
microbi ome 
collectio nf 
 
X 
 
 
 
 
 
X 
 
 
 
 
X 
Disease 
Assessmentg 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
Dabrafenib and 
trametinib 
dosing 
X 
Continuous Daily Dosing 
 
a. Includes systolic and diastolic blood pressure, pulse rate, temperature and weight. 
b. Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, LDH, magnesium, 
phosphorus, potassium, total protein, AST, ALT, sodium. 
c. Repeat echocardiogram will be performed at month 3 and 6 and at the discretion of the investigator if there are symptoms 
concerning for heart failure. 
d. Should a biopsy be performed as part of standard practice, this study may request up to 4 additional cores for correlative 
studies. 
e. 50ml of blood will be obtained at each time point for correlative correlates. 
f. 
Micobiome will be collected at week 12, 36 and at recurrence. OMNIgene kits, or equivalent, will be provided 
g. PET/CT or CT of the chest, abdomen, pelvis (neck if clinically indicated) and brain MRI (or CT of the head with contrast if 
MRI is contraindicated). 
h. Dabrafenib and trametinib combination therapy will resume approximately two days after the patients is able to resume 
normal oral intake and ideally should be within 2 weeks of date of surgery. This visit could be a telephone assessment by 
research nurse 
i. 
These time points are +/- 7 days. 
j. 
End of treatment is defined as completion of 44 weeks of adjuvant dabrafenib/trametinib, experiencing SAE or intolerable 


 
 
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AE mandating discontinuation of treatment or the development of progressive disease. 


 
 
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Table 12 Adjuvant Time and Event Table for Pathologic Non-Responders (spartalizumab, dabrafenib and trametinib) 
 
Post 
Operat 
iv eh 
Week 
12i 
Week 
16i 
Week 
20i 
Week 
24i 
Week 
28i 
Week 
32i 
Week 
36i 
Week 
40i 
Week 
44i 
Week 
48i 
Wee 
k 52i 
EOTj 
Concurrent 
medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AEs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PE/Vitals/ECO Ga 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CBC with diff 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum 
chemistryb 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
TSH, fT4 
 
 
 
X 
 
 
X 
 
 
X 
 
 
 
Echocardiogram c 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
12-lead EKG 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
X 
Research 
Biopsyd 
 
 
If evidence of disease recurrence or metastasis 
Research 
Bloode 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
X 
Research 
microbiome 
collectionf 
 
X 
 
 
 
 
 
X 
 
 
 
 
X 


 
 
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Disease 
Assessmentg 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
Spartalizumab 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Dabrafenib and 
trametinib dosing 
X 
Continuous Daily Dosing 
 
a. Includes systolic and diastolic blood pressure, pulse rate, temperature and weight. 
b. Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, LDH, magnesium, 
phosphorus, potassium, total protein, AST, ALT, sodium. 
c. Repeat echocardiogram will be performed at month 3 and 6 and at the discretion of the investigator if there are symptoms 
concerning for heart failure. 
d. Should a biopsy be performed as part of standard practice, this study may request up to 4 additional cores for correlative 
studies. 
e. 50ml of blood will be obtained at each time point for correlative correlates. 
f. 
Micobiome will be collected at week 12, 36 and at recurrence. OMNIgene kits, or equivalent, will be provided 
g. PET/CT or CT of the chest, abdomen, pelvis (neck if clinically indicated) and brain MRI (or CT of the head with contrast if 
MRI is contraindicated). 
h. Dabrafenib and trametinib combination therapy will resume approximately two days after the patients is able to resume 
normal oral intake and ideally should be within 2 weeks of date of surgery. This visit could be a telephone assessment by 
research nurse 
i. 
These time points are +/- 7 days. 
j. 
End of treatment is defined as completion of 44 weeks of adjuvant dabrafenib/trametinib, experiencing SAE or intolerable 
AE mandating discontinuation of treatment or the development of progressive disease 


 
 
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4.4 
SAFETY EVALUATIONS 
 
4.4.1 Physical exams/ECOG/Vital Signs 
A complete physical examination will be performed by a qualified 
physician or a midlevel provider (physician’s assistant, nurse 
practitioner). Documentation of Eastern Cooperative Oncology Group 
status is required. 
Baseline skin exam must be performed. Skin photography of new skin 
lesions or lesions that change during therapy recommended at each 
reassessment while the subject is on therapy. 
Vital sign measurements will include systolic and diastolic blood pressure, 
pulse rate, and temperature. On days where vital signs are measured multiple 
times, temperature does not need to be repeated. 
The performance status assessment is based on the ECOG scale: 
 
0 
Fully active, able to carry on all pre-disease performance without  
restriction. 
 
 
1 
Restricted in physically strenuous activity but ambulatory and able  
to carry out work of a light or sedentary nature (e.g., light house work 
or office work). 
2 
Ambulatory and capable of all self-care but unable to carry out any 
work activities. Up and about more than 50% of waking hours. 
3 
Capable of only limited self-care, confined to bed or chair more than 50% 
of waking hours. 4– Completely disabled. Cannot carry on any self-care. 
Totally confined to bed or chair. 
4.4.2 ECG 
12-lead ECG will be obtained as indicated in the Times and Events 
Tables in Section 7.2. Each 12-lead ECG will be performed after the 
subject has rested at least five minutes in a semi- recumbent or supine 
position. 
Those QTc values greater than 480msec as calculated by the machine 
must be confirmed manually using Bazett’s formula given below: 
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If there are any clinically significant abnormalities including but 
not limited to a QTcB > 500msec, confirm with two additional 
ECGs taken at least 5 minutes apart. 
 
4.4.3 
Echocardiogram 
 
An echocardiogram will be performed to assess cardiac ejection fraction and 
cardiac valve abnormalities as indicated in the Times and Events Tables in 
Section 7.2. 
Echocardiography should include an evaluation for left ventricular ejection 
fraction and both right- and left sided valvular lesions. For each subject, the 
same procedure should be performed at the screening and as clinically 
warranted during the course of the study. 
 
4.4.4 
Ophthalmic 
 
Patients will have a standard ophthalmic exam performed by an ophthalmologist 
at screening. The exam will include indirect fundoscopic examination, visual 
acuity, visual field examination, tonometry, and direct fundoscopy, with special 
attention to retinal abnormalities that are predisposing factors for RVO or CSR. 
 
4.5 
LABORATORY ASSESSMENTS 
 
Hematology, clinical chemistry, and additional parameters to be tested are 
listed below: 
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Hematology 
 
Platelet Count 
RBC Indices: 
Automated WBC Differential: 
WBC Count (absolute) 
MCV 
Neutrophils 
Hemoglobin 
Lymphocytes 
Hematocrit 
Monocytes 
Eosinophils 
Basophils 
 
Clinical Chemistry 
 
BUN 
Potassium 
AST (SGOT) 
Total and direct bilirubin 
Creatinine 
Chloride 
ALT (SGPT) 
Total protein 
Glucose 
Total CO2 
Lactate dehydrogenase (LDH) Albumin 
Sodium 
Calcium 
Alkaline phosphatase 
Phosphorus 
Magnesium 
TSH 
Free T4 
 


 
 
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4.6 
BIOMARKER COLLECTIONS AND ANALYSES 
 
Biospecimen Collection 
For blood and tissue correlative studies, specimens will be collected as part of the 
protocol study assessments and stored for later analysis. Missed tissue or blood 
collections, will not be classed as a deviation. Below are proposed analysis for tissue 
and blood as availability and quality of each permits. The priority of analysis will be 
determined by investigators. 
In the neoadjuvant setting, patients will have mandatory baseline biopsy as well as 
research collection of part of the surgical sample. On the occasion where available 
tissue or blood is limited and we did not receive enough for analysis or where the 
tissue or blood collection was missed, specimens collected from MD Anderson 
patients at the same time points as part of protocol 2012- 0846 and/or LAB00-063 
may be requested for use as long as the patient has a valid informed consent. 
Available paraffin embedded tumor tissue from prior biopsies or excisions may also 
be collected as pre-treatment comparator samples, so long as the patient provides 
consent for use in this study. 
 
Tissue will be collected as per the Institute guidelines and standard operating 
procedures. All samples will be processed, labeled, and stored in accordance with 
NCI best practices for biospecimens. General details regarding tissue procurement are 
indicated below: 
Tumor Tissue: Each set of core biopsies or surgical specimen may be divided in up to 
4 portions and processed as below for later analysis: 
(1) 
FFPE for histology and IHC (25% of the specimen, or 1 core biopsy) 
(2) 
Snap frozen tumor in a cryovial (75% of the specimen or 3 core biopsies) 
Blood processing and storage for circulating correlative analysis: 
Two 10 ml tubes of blood will be collected for PBMC isolation and 
cryopreserved, for subsequent evaluation. Plasma will be collected 
and stored at -80°C. One 10ml serum will be collected and stored at 
-80°C. Two 10ml tubes of blood will be collected for cfDNA and 
genomic DNA, for analysis of circulating tumor markers and 
genomic analysis. 
Stool samples for microbiome analysis: OMNIgene Gut Kits, or 
equivalent, will be provided for stool sampling for microbiome 
analysis. The kits come with full instructions on use (Appendix C). 
 
4.7 
BIOMARKER ANALYSES 
Tumor samples may be assessed for expression of immune or melanoma related 
genes, RNAs, and/or proteins to identify molecular or immune features of response 
and resistance. Methodologies may include, tissue availability permitting, single stain 
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immunohistochemistry (IHC) or multiplex IHC, DNA profiling (WES or targeted 
panel, TCR sequencing), expression profiling (RNAseq or panel-based such as 
Nanostring). 
Analyses on blood may include flow cytometry, ctDNA, CTC, proteomics, cytokine, 
and exosomal studies. Additional immune and molecular analyses may be conducted 
per the discretion of the study team. 
In addition to immune studies, we may assess circulating tumor cells (CTC) and 
circulating free DNA (cfDNA) in these patients during the course of therapy. Our 
hypothesis is that the levels of CTC and cfDNA will correlate with disease burden, 
and will decrease during therapy and will rise at time of relapse. We will use a 
microfluidics system to isolate and enrich CTC from peripheral blood at baseline, at 
week 3 on neoadjuvant therapy, at Week 8 (surgery), and at Weeks 12, 24 and 36 post 
surgery). Blood will also be drawn at relapse (when applicable) and these assays will 
be performed. We will use cfDNA plasma to perform ddPCR to determine CNV for 
two mutations (V600K and V600E). 
There is a growing appreciation of the influence of host factors on treatment to therapy 
in patients with cancer, such as microbiome. Microbiome samples collected from these 
patients will provide insight into this patient population, previously unstudied. 
Analyses of the gut microbiome samples may include 16s or metagenome sequencing. 
 
4.8 
IMAGING ASSESSMENTS 
 
Disease assessment will include imaging (computed tomography, magnetic resonance 
imaging) and physical examination (as indicated for palpable/superficial lesions). At 
screening, an MRI or CT of the head is required. At minimum, CT of the chest, 
abdomen and pelvis are required but additional imaging of affected areas (neck or 
extremities) may be required for documentation of target lesions. 
 
Disease assessment will be completed within 35 days prior to the first dose of study 
drug, then as indicated in the Time and Events Tables Section 4.3. It is not necessary 
to repeat radiologic assessments at the final study visit if the subject was withdrawn 
due to disease progression. More frequent disease assessments may be performed at 
the discretion of the investigator. To ensure comparability between baseline and 
subsequent assessments, the same method of assessment and the same technique will 
be used when assessing response. 
 
Disease response will be recorded as complete response (CR), partial response (PR), 
stable disease (SD), or progressive disease (PD) according to RECIST 1.1 criteria 31. 
 
 
 
 
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4.9 PATHOLOGIC ASSESSMENTS 
 
All patients will be evaluated after 8 weeks of induction dabrafenib and trametinib 
therapy immediately prior to the planned surgical resection. All patients who 
experience a PR or SD will be eligible for surgical resection. Those patients who 
develop PD will be allowed to continue on to surgery as long as disease is still deemed 
resectable. Patients who initially had lymph node involvement but appear to have 
achieved a CR on imaging after the 8 week induction period will proceed on to 
completion lymph node dissection. 
Tumor specimens of patients undergoing treatment will undergo evaluation for 
pathologic complete response (pCR) and pathologic partial response (pPR). pCR is 
defined as the absence of any residual invasive malignant cells on hematoxylin and 
eosin evaluation of the resected melanoma specimen. Near pCR is defined as less than 
10% viable tumor. pPR is defined as less than 50% viable tumor cells or more than 
50% fibrosis on pathological evaluation. pNR is defined as no viable tumor31. 
After surgery, pathology will be reviewed by pathology collaborators and formal 
reporting on tumor viability, fibrosis and necrosis will be reported. This report should 
be issued within 2 weeks of surgery date to allow for assignment of adjuvant therapy. 
 
4.9.1 
Surgical Ease Surveys 
Assessment of surgical ease or difficulty after neoadjuvant therapy administration is 
not currently well understood. In order to obtain data on this important subject, we will 
be asking collaborating surgical oncologists to complete surveys on the subjective 
difficulty or ease of surgery compared to comparable surgery in patients who have not 
undergone neoadjuvant therapy. Surveys will be administered at time of patient trial 
enrollment, within 1 week of surgical resection and approximately 30 days after 
surgery is complete. These time-points are selected with the hope of obtaining initial 
thoughts on surgical difficulty and how this is altered by the neoadjuvant treatment. 
The 30-day post-operative survey is to capture complications, if any.  Sample surveys 
are located in Appendix D.  The surveys will be performed for the purpose of 
determining if neoadjuvant treatment influences the outcomes of surgery.  Data will be 
recorded utilizing the Prometheus database.   
 
5.0 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
 
An adverse event is the appearance or worsening of any undesirable sign, symptom, or 
medical condition occurring after the first protocol intervention, even if the event is not 
considered to be related to study treatment. Medical conditions/diseases present before 
starting study therapy are only considered adverse events if they worsen after starting 
study treatment. Abnormal laboratory values or test results constitute adverse events 
only if they induce clinical signs or symptoms, are considered clinically significant, or 
require therapy. 
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The investigator (or physician designee) isnresponsible for verifying and providing source 
documentation for all adverse events and assigning the attribution for all adverse events for 
subjects enrolled. 
 
 
 
Recommended Adverse Event Recording Guidelines 
 
Attribution 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Unrelated 
Phase I 
Phase I 
Phase I 
Phase II   
 
Phase I 
Phase II   
Phase III 
Phase I  
Phase II   
Phase III 
Unlikely 
Phase I 
Phase I 
Phase I  
Phase II   
Phase I 
Phase II   
Phase III 
Phase I 
Phase II   
Phase III 
Possible 
Phase I 
Phase II   
Phase I 
Phase II   
Phase III 
Phase I 
Phase II   
Phase III 
Phase I 
Phase II   
Phase III 
Phase I 
Phase II   
Phase III 
Probable 
Phase I 
Phase II  
 
Phase I 
Phase II   
Phase III 
Phase I 
Phase II   
Phase III 
Phase I 
Phase II   
Phase III 
Phase I 
Phase II   
Phase III 
Definitive 
Phase I 
Phase II  
  
Phase I 
Phase II   
Phase III 
Phase I 
Phase II   
Phase III 
Phase I 
Phase II  
Phase III  
Phase I 
Phase II   
Phase III 
 
 
 
The Adverse Event Recording period will be from the first protocol intervention to 150 days 
after the last dose of study drug. 
 
5.1 
DEFINITION OF AN AE 
 
Any untoward medical occurrence in a subject or clinical investigation subject, 
temporally associated with the use of a medicinal product, whether or not considered 
related to the medicinal product. 
Note: An adverse event (AE) can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease (new or 
exacerbated) temporally associated with the use of a medicinal product. For 
marketed medicinal products, this also includes failure to produce expected 
benefits, abuse, or misuse. Examples of events meeting the definition of an AE 
include: 
• 
Exacerbation of a chronic or intermittent pre-existing condition 
including either an increase in frequency and/or grade of the 
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condition 
• 
New conditions detected or diagnosed after study treatment 
administration even though it may have been present prior to the start of 
the study 
• 
Signs, symptoms, or the clinical sequelae of a suspected interaction 
• 
Signs, symptoms, or the clinical sequelae of a suspected overdose 
of either study treatment or a concomitant medication (overdose 
per se will not be reported as an AE/serious adverse event [SAE]). 
 
Events that do not meet the definition of an AE include: 
• 
Medical or surgical procedure (e.g., endoscopy, appendectomy); the 
condition that leads to the procedure is an AE 
• 
Situations where an untoward medical occurrence did not 
occur (social and/or convenience admission to a hospital). 
• 
Anticipated day-to-day fluctuations of pre-existing disease(s) or 
condition(s) present or detected at the start of the study that do not 
worsen. 
• 
The disease/disorder being studied or expected progression, signs, or 
symptoms of the disease/disorder being studied, unless more severe than 
expected for the subject’s condition. 
 
5.2 
ADVERSE EVENT GRADING 
 
Grading of AE’s will be per the National Cancer Institute Common Terminology 
Criteria for Adverse Events (CTCAE v.5.0). 
The following categories and definitions of causal relationship to study 
medication as determined by a physician should be used for adverse events: 
• 
Definitive: There is a reasonable causal relationship between the 
study medication product and the AE. The event responds to 
withdrawal of study medication (re-challenge), and recurs with re-
challenge when clinically feasible. 
• 
Probable: There is a reasonable causal relationship between the study 
medication and the AE. The event responds to re-challenge. Re-challenge is 
not required. 
• 
Possible: There is reasonable causal relationship between the study 
medication and the AE. Re-challenge information is lacking or unclear. 
• 
Unlikely: There is a temporal relationship to study medication administration, 
but 
there is not a reasonable causal relationship between the study medication and 
the AE. 
• 
Unrelated: There is not a temporal relationship to study medication  
administration (too early, or late, or study medication not taken), or there is a 
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reasonable causal relationship between non-study medication, concurrent 
disease, or circumstance and the AE. 
• 
The expression “reasonable causal relationship” is meant to convey in general that 
there are facts (eg, evidence such as de-challenge/re-challenge) or other arguments to 
suggest a positive causal relationship. 
 
5.3 
SERIOUS ADVERSE EVENT REPORTING (SAE) 
 
Serious adverse event (SAE) is defined as one of the following: 
• Is fatal or life-threatening 
• Results in persistent or significant disability/incapacity 
• Constitutes a congenital anomaly/birth defect 
• Is medically significant, i.e., defined as an event that jeopardizes the patient or 
may require medical or surgical intervention to prevent one of the outcomes 
listed above 
• Requires inpatient hospitalization or prolongation of existing hospitalization, 
• Note that hospitalizations for the following reasons should not be 
reported as serious adverse events: 
• Routine treatment or monitoring of the studied indication, not 
associated with any deterioration in condition 
• Elective or pre-planned treatment for a pre-existing condition that is 
unrelated to the indication under study and has not worsened since 
signing the informed consent 
• Social reasons and respite care in the absence of any deterioration in 
the patient’s general condition 
 
Note that treatment on an emergency outpatient basis that does not result in 
hospital admission and involves an event not fulfilling any of the definitions of 
a SAE given above is not a serious adverse event. 
 
 
SAE REPORTING 
 
The principal investigator has the obligation to report all serious adverse 
events to the FDA (if applicable), IRB, and Novartis Patient Safety 
Department (For patients taking Novartis drugs). 
All events reported to the FDA by the investigator are to be filed utilizing the 
Form FDA 3500A (MedWatch Form), if applicable. 
• To ensure patient safety, every SAE, regardless of suspected causality, occurring 
after the patient has provided informed consent and until at least 1 50 days after 
the patient has stopped study treatment or until the start of a new anti-neoplastic 
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medication if sooner than 150 days must be reported to Novartis within 24 hours of 
learning of its occurrence. If a subject starts a post-treatment antineoplastic 
therapy, then only adverse events suspected to be related to study treatment should 
be collected out to 150 days after discontinuation of PDR001. Reporting to 
Novartis should also occur within 30 days after the last dose of dabrafenib or 120 
days after the last dose of trametinib, if the subject continued the combination 
partner more than 150 days after the last dose of PDR001). Information about all 
SAEs is collected and recorded on a Serious Adverse Event Report Form. The 
investigator must assess and record the relationship of each SAE to each specific 
study treatment (if there is more than one study treatment), complete the SAE 
Report Form in English, and send the completed, signed form along with the 
Novartis provided cover sheet to the Novartis Patient Safety department by 
email (clinicalsafetyop.phuseh@novartis.com) within 24 hours. 
 
Any additional information for the SAE including complications, progression 
of the initial SAE, and recurrent episodes must be reported as follow-up to the 
original episode within 24 hours of the investigator receiving the follow-up 
information. An SAE occurring at a different time interval or otherwise 
considered completely unrelated to a previously reported one should be 
reported separately as a new event. 
Any SAEs experienced after the reporting period described above period should 
only be reported to Novartis if the investigator suspects a causal relationship to the 
study treatment. 
Follow-up information is submitted in the same way as the original SAE Report. 
Each re- occurrence, complication, or progression of the original event should be 
reported as a follow-up to that event regardless of when it occurs. The follow-up 
information should describe whether the event has resolved or continues, if and how 
it was treated, whether the blind was broken or not, and whether the patient 
continued or withdrew from study participation. 
If the SAE is not previously documented in the Investigator’s Brochure or 
Package Insert (new occurrence) and is thought to be related to the Novartis 
study treatment, an oncology Novartis Patient Safety department associate may 
urgently require further information from the investigator for Health Authority 
reporting. Novartis may need to issue an Investigator Notification (IN), to 
inform all investigators involved  in  any study with  the  same drug that this 
SAE has been reported. Suspected Unexpected Serious Adverse Reactions 
(SUSARs) will be collected and reported  to  the  competent  authorities  and  
relevant ethics committees in accordance with Directive 2001/20/EC or as per 
national regulatory requirements in participating countries. 
 
PREGNANCIES 
To ensure patient safety, each pregnancy occurring while the patient is on study 
treatment must be reported to Novartis within 24 hours  of  learning  of  its  
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occurrence.  The pregnancy should be followed up to determine outcome, 
including spontaneous or voluntary termination, details of the birth, and the 
presence or absence of any birth defects, congenital abnormalities, or maternal 
and/or newborn complications. 
Pregnancy should be reported by the investigator to the Novartis Patient Safety 
department by email (clinicalsafetyop.phuseh@novartis.com).). Pregnancy follow-
up should include an assessment of the possible relationship to the study 
treatment and any pregnancy outcome. Any SAE experienced during 
pregnancy must be reported on the SAE Report Form. 
Pregnancy outcomes must be collected for the female partners of any males 
who took  study treatment in this study. Consent to report information 
regarding these pregnancy outcomes should be obtained from the mother. 
 
Serious Adverse Event (SAE) Reporting 
 
An adverse event or suspected adverse reaction is considered “serious” if, in the view of either 
the investigator or the sponsor, it results in any of the following outcomes: 
 
• Death 
• A life-threatening adverse drug experience – any adverse experience that places the patient, in 
the view of the initial reporter, at immediate risk of death from the adverse experience as it 
occurred. It does not include an adverse experience that, had it occurred in a more severe form, 
might have caused death. 
• Inpatient hospitalization or prolongation of existing hospitalization 
• A persistent or significant incapacity or substantial disruption of the ability to conduct normal 
life functions. 
• A congenital anomaly/birth defect. 
 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based upon 
appropriate medical judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition. 
Examples of such medical events include allergic bronchospasm requiring intensive treatment 
in an emergency room or at home, blood dyscrasias or convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or drug abuse (21 CFR 312.32). 
 
• Important medical events as defined above, may also be considered serious adverse events. 
Any important medical event can and should be reported as an SAE if deemed appropriate by 
the Principal Investigator or the IND Sponsor, IND Office. 
• All events occurring during the conduct of a protocol and meeting the definition of a SAE must 
be reported to the IRB in accordance with the timeframes and procedures outlined in “The 
University of Texas M. D. Anderson Cancer Center Institutional Review Board Policy for 
Investigators on Reporting Serious Unanticipated Adverse Events for Drugs and Devices”.  
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Unless stated otherwise in the protocol, all SAEs, expected or unexpected, must be reported to 
the IND Office, regardless of attribution (within 5 working days of knowledge of the event). 
• All life-threatening or fatal events, that are unexpected, and related to the study drug, must 
have a written report submitted within 24 hours (next working day) of knowledge of the event 
to the Safety Project Manager in the IND Office.   
• Unless otherwise noted, the electronic SAE application (eSAE) will be utilized for safety 
reporting to the IND Office and MDACC IRB.  
• Serious adverse events will be captured from the time of the first protocol-specific intervention, 
until 150 days after the last dose of drug, unless the participant withdraws consent. Serious 
adverse events must be followed until clinical recovery is complete and laboratory tests have 
returned to baseline, progression of the event has stabilized, or there has been acceptable 
resolution of the event. 
• Additionally, any serious adverse events that occur after the 150 day time period that are 
related to the study treatment must be reported to the IND Office. This may include the 
development of a secondary malignancy. 
 
Reporting to FDA: 
• Serious adverse events will be forwarded to FDA by the IND Sponsor (Safety Project Manager 
IND Office) according to 21 CFR 312.32. 
 
It is the responsibility of the PI and the research team to ensure serious adverse events are 
reported according to the Code of Federal Regulations, Good Clinical Practices, the 
protocol guidelines, the sponsor’s guidelines, and Institutional Review Board policy. 
 
 
6.0 
DATA MANAGEMENT 
 
For the purposes of this study at data will be captured in a secure, password protected, 
encrypted and security compliant database (eg, CORe, Prometheus, MelCore). All patients 
will be registered in CORe before any study specific tests are performed. A brief 
explanation for required but missing data should be recorded as a comment. The 
investigator is required to retain, in a confidential manner, the data pertinent to the study 
for the duration of the study or the maximum period required by applicable regulations 
and guidelines or institutional procedures. If the investigator withdraws from the study 
(e.g., relocation, retirement), the records shall be transferred to a mutually agreed-upon 
designee (e.g., another investigator or IRB). Documentation of such transfer must be 
provided to the sponsor. 
CORe, Prometheus, and Melcore are databases internally accessible to MD Anderson. Patient 
registration from all participating sites will be made through the CORe database. The 
Prometheus database will be used for clinical data capture on research participants, data entry 
on internal (MDACC) research patients will be performed by the MDACC’s Department of 
Melanoma. 
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The study coordinator and investigators are responsible for ensuring that the eligibility 
checklist is completed in a legible and timely manner for every patient enrolled in the 
study, and that data are recorded on the appropriate forms and in a timely manner in the 
electronic case report forms (eCRFs) in the Prometheus database. All source documents 
will be available for inspection by the FDA and the MDACC IRB. 
 
6.1 
RECORDS RETENTION 
 
Following closure of the study, the investigator must maintain all site study records 
(except for those required by local regulations to be maintained elsewhere) in a safe 
and secure location. The records must be easily accessible when needed and must 
be available for review in conjunction with assessment of the facility, supporting 
systems, and relevant site staff. 
The investigator must retain investigational product disposition records, source 
documents, and case histories designed to record all observations and other data 
pertinent to the investigation (e.g. medical records) for two years. The records must 
be available for review in conjunction with assessment of the facility, supporting 
systems, and relevant staff. 
 
7.0 
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS 
 
Overview 
This will be a Phase II, open-label study of dabrafenib in patients with clinical Stage III 
melanoma who harbor a BRAF V600E or V600K mutation. In patients who achieve a pCR 
at the time of surgery, they will continue on dabrafenib and trametinib in the adjuvant 
setting. For those patients who do not achieve a pCR at the time of surgery, they will be 
treated with dabrafenib, trametinib and spartalizumab in the adjuvant setting. 
The primary objective is to independently determine the 12-month relapse-free survival 
(RFS) rate in stage IIIB/C/D melanoma patients who, after 8 weeks of neoadjuvant 
dabrafenib and trametinib, do not achieve a pCR and receive adjuvant dabrafenib, 
trametinib and spartalizumab. 
Secondary objectives include assessing safety in both the neoadjuvant and adjuvant 
settings. Recurrence patterns, including assessment of distant metastasis-free survival and 
overall survival separately by pathologic response status will also be addressed. The 12 
month RFS of patients who achieve a pCR after receiving neoadjuvant and adjuvant 
treatment with dabrafenib and trametinib will also be assessed. 
Exploratory objectives include assessing immune and molecular features of response and 
resistance, assessing the association between circulating blood markers and treatment 
response and relapse, and assessing surgical resectability. 
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A total of 45 patients will be initially treated with dabrafenib and trametinib for 8 weeks. 
Patients will be assessed for pCR as defined above based on the results of their surgical 
pathology. Patients who achieve a pCR will continue with the dabrafenib and trametinib 
combination for an additional 44 weeks. Patients who do not achieve a pCR will have 
spartalizumab added to dabrafenib and trametinib for an additional 44 weeks. 
Sample Size and Power 
A sample size argument will be based upon patients who do not have a pCR. We expect 
approximately 60% of enrolled patients to not achieve a pCR after 8 weeks on the 
dabrafenib/trametinib combination. Historically, these patients experience a 12-month 
relapse-free survival (RFS) rate of 50%, and we hope to increase this to 75%. Under the 
assumptions of 2 years for patient accrual and an additional 2 years of follow-up after 
accrual ends, exponentially- distributed RFS times, and a two-sided exponential maximum-
likelihood test with a 5% Type 1 error rate (alpha), a total of 24 non-pCR patients will 
provide 80% power to detect a minimum increase in RFS at 1 year to 75%. If 60% of 
patients do not have a pCR, we would need to enroll a total of 40 patients to have a total of 
24 non-pCR patients, but to account for a potentially higher pCR rate and patient dropout, 
we will accrue a total of 45 patients. 
Statistical Analyses 
For the primary objective, separately by group (patients who do/do not achieve a pCR at 8 
weeks), the 12-month RFS rate will be estimated with a 95% confidence interval by using 
the Kaplan-Meier method. RFS is defined from time of surgery to any recurrence event 
(local or distant disease development or death due to melanoma. In addition, in patients 
who do not achieve a pCR, the 12-month RFS rate will be compared with the historical 
rate of 50% by using a two-sided exponential MLE test. Cox proportional hazards 
regression models will be fit to assess the association between various clinical, 
demographic, and disease covariates and RFS separately by pathologic response group. 
For safety, the rate of grade 3+ adverse events will be tabulated and presented by group. 
For overall survival (OS) and distant metastasis-free survival (DMFS), 12-month rates will 
be reported with 95% confidence intervals, and Cox regression models will be used to 
assess the association between similar covariates as above and both OS and DMFS 
separately by group. OS is defined as time from treatment initiation to death. DMFS is 
defined as time from treatment initiation to development of documented distant metastatic 
disease outside the loco-regional site of the primary tumor or lymph node metastasis. 
For the exploratory objectives, immunological and molecular features will be assessed 
quantitatively at baseline and at surgical resection. Kruskal-Wallis tests will be used to 
compare these parameters at each time point between responders (pCR) and non-responders 
(no pCR). Changes in each parameter from baseline to surgery will also be compared 
between responders and non-responders. Circulating tumor markers will be assessed at 
baseline and several on-study time points. Markers and changes in markers over time will 
be compared between responders and non-responders by using Kruskal-Wallis tests.  In 
addition, generalized linear mixed models may be used to model these markers over time. 
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Finally, to assess the impact of neoadjuvant therapy on surgical resectability, a survey will 
be provided to surgeons regarding the difficulty of surgery (Appendix D). These data will 
be subjective and will be summarized graphically as numbers permit. 
 
The Investigator is responsible for completing an efficacy/safety summary report, and 
submitting it to the IND Office Medical Affairs and Safety Group, for review and approval. 
Please submit efficacy and toxicity summary for the first 5 patients after 8 weeks of 
treatment and every 5 patients thereafter.  Copy of the cohort summary should be placed in 
the Investigator’s Regulatory Binder under “sponsor correspondence”.  
 
 
8.0 
INSTITUTIONAL REVIEW BOARD (IRB) APPROVAL 
 
The investigator (i.e., the study site principal investigator) will obtain, from the MD 
Anderson Cancer Center Institutional Review Board (IRB), prospective approval of the 
clinical protocol and corresponding informed consent form(s); modifications to the clinical 
protocol and corresponding informed consent forms, and advertisements (i.e., directed at 
potential research subjects) for study recruitment, if applicable. 
The only circumstance in which a deviation from the current IRB-approved clinical 
protocol/consent form(s) may be initiated in the absence of prospective IRB 
approval is to eliminate an apparent immediate hazard to the research subject(s). In 
such circumstances, the investigator will promptly notify the MD Anderson Cancer 
Center IRB of the deviation. 
The MD Anderson Cancer Center IRB operates in compliance with FDA regulations at 21 
CFR Parts 50 and 21 CFR 56, and in conformance with applicable International 
Conference on Harmonization (ICH) Guidelines on Good Clinical Practice. 
 
9.0 
COMPLIANCE WITH TRIAL REGISTRATION AND RESULTS  
POSTING REQUIREMENTS 
 
Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and 
the Food and Drug Administration Amendments Act (FDAAA), the Sponsor of the trial is 
solely responsible for determining whether the trial and its results are subject to the 
requirements for submission to the Clinical Trials Data Bank, 
http://www.clinicaltrials.gov. Information posted will allow subjects to identify potentially 
appropriate trials for their disease conditions and pursue participation by calling a central 
contact number for further information on appropriate trial locations and trial site contact 
information. 
 
10.0 ETHICAL CONSIDERATIONS 
 
The clinical study will be conducted in accordance with the current IRB- approved 
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clinical protocol; ICH Guidelines on Guidelines on Good Clinical Practice; and relevant 
policies, requirements, and regulations of the University of Texas MD Anderson Cancer 
Center IRB, and applicable federal agencies. 
 
11.0 INFORMED CONSENT 
 
The investigator (i.e., the study site principal investigator) will make certain that an 
appropriate informed consent process is in place to ensure that potential research subjects, 
or their authorized representatives, are fully informed about the nature and objectives of 
the clinical study,  the potential risks and benefits of study participation, and their rights as 
research subjects. The investigator, or a sub-investigator(s) designated by the MD 
Anderson IND Office, will obtain the written, signed informed consent  of  each  subject,  
or  the  subject’s authorized representative, prior to performing any study-specific 
procedures on the subject. The date and time that the subject, or the subject’s authorized 
representative, signs the informed consent form and a narrative of the issues discussed 
during the informed consent process will be documented in the subject’s case history. The 
investigator or sub-investigator will retain the original copy of the signed informed consent 
form, and a copy will be provided to the subject, or to the subject’s authorized 
representative. 
 
12.0 STUDY DOCUMENTATION, MONITORING, AND  
ADMINISTRATION 
 
The investigator and the head of the medical institution (where applicable) agrees to allow 
the IND Office monitor direct access to all relevant documents and to allocate their time 
and the time to their staff to monitor to discuss findings and any issues. 
• Monitoring visits will be conducted in a manner to ensure that the: 
• Data are authentic, accurate, and complete. 
• Safety and rights of subjects are being protected. 
• Study is conducted in accordance with the currently approved protocol and any other 
study agreements, ICH GCP, and all applicable regulatory requirements. 
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13.0 REFERENCES 
1. 
Gershenwald JE, Scolyer RA, Hess KR, et al. Melanoma staging: Evidence-based changes 
in the American Joint Committee on Cancer eighth edition cancer staging manual. CA Cancer J Clin 
2017;67:472-92. 
2. 
Eggermont AM, Chiarion-Sileni V, Grob JJ, et al. Prolonged survival in stage III 
melanoma with ipilimumab adjuvant therapy. N Engl J Med 2016; 375: 1845-1855. 
3. 
Weber J, Mandala M, Del Vecchio M, et al. Adjuvant Nivolumab versus Ipilimumab 
in Resected Stage III or IV Melanoma. N Engl J Med 2017;377:1824-35. 
4. 
Long GV, Hauschild A, Santinami M, et al. Adjuvant Dabrafenib plus Trametinib in 
Stage III BRAF-Mutated Melanoma. The New England journal of medicine 2017;377:1813-23. 
5. 
Eggermont AMM, Blank CU, Mandala M, et al. Adjuvant Pembrolizumab versus Placebo 
in Resected Stage III Melanoma. The New England journal of medicine 2018;378:1789-801. 
6. 
Rastogi P, Anderson SJ, Bear HD, et al. Preoperative chemotherapy: updates of National 
Surgical Adjuvant Breast and Bowel Project Protocols B-18 and B-27. Journal of clinical 
oncology : official journal of the American Society of Clinical Oncology 2008;26:778-85. 
7. 
Cortazar P, Zhang L, Untch M, et al. Pathological complete response and long-term 
clinical benefit in breast cancer: the CTNeoBC pooled analysis. Lancet (London, England) 
2014;384:164 
8. 
Sauer R, Becker H, Hohenberger W, et al. Preoperative versus postoperative 
chemoradiotherapy for rectal cancer. The New England journal of medicine 2004;351:1731- 40. 
9. 
Ajani JA, Mansfield PF, Crane CH et al. J Clin Oncol 2005; 23: 1237-44. 
10. 
Sioquest KM, Burmeister BH, Smithers BM, et al. Survival after neoadjuvant 
chemotherapy or chemoradiotherapy for resectable oesophageal carcinoma: an updated meta-
analysis. Lancet Oncol 2011; 12: 681-92 
11. 
Grossman HB, Natale RB, Tangen CM, et al. Neoadjuvant chemotherapy plus 
cystectomy compared with cystectomy alone for locally advanced bladder cancer. N Engl J 
Med. 2003;349(9):859-866. 
12. 
Lewis KD, Robinson WA, McCarter M, et al. Phase II multicenter study of 
neoadjvuant biochemotherapy for patients with stage III malignant melnaoma. J Clin Oncol 
2006; 24: 3157-63. 
13. 
Buzaid AC, Colome M, Bedikian A, et al. Phase II study of neoadjuvant concurrent 
biochemotherapy in melanoma patients with local-regional metastases. Melanoma Res. 
1998;8(6):549-556. 
14. 
Hodi, F.S., et al., Improved survival with ipilimumab in patients with metastatic melanoma. 
N Engl J Med, 2010. 363. 
15. 
Wolchok, J.D., et al., Overall Survival with Combined Nivolumab and Ipilimumab 
in Advanced Melanoma. N Engl J Med, 2017. 377(14): p. 1345-1356. 
16. 
Long, G.V., et al., Dabrafenib and trametinib versus dabrafenib and placebo for Val600 
BRAF-mutant melanoma: a multicentre, double-blind, phase 3 randomised controlled trial. 
Lancet, 2015. 386(9992): p. 444-51. 
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17. 
Killelea BK, Yang VQ, Mougalian S, et al. Neoadjuvant chemotherapy for breast cancer 
increases the rate of breast conservation: results from the National Cancer Database. J Am Coll 
Surg. 2015;220(6):1063-1069. 
18. 
Fisher B, Brown A. Effect of preoperative chemotherapy on local-regional disease in 
women with operable breast cancer: findings from National Surgical Adjuvant Breast and Bowel. J 
Clin Oncol. 1997;15(7):2483-2493. 
19. 
Hogan B V, Peter MB, Shenoy HG, Horgan K, Hughes TA. Surgery 
induced immunosuppression. Surgeon. 2011;9(1):38-43. 
20. 
Bardia A and Baselga J. Neoadjuvant therapy as a platform for drug development 
and approval in breast cancer. Clin Cancer Res 2013; 19: 6360-70. 
21. 
Gianni L, Pienkowski T, Im Y-H, et al. Efficacy and safety of neoadjuvant pertuzumab 
and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast 
cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial. Lancet Oncol. 
2012;13(1):25-32. 
22. 
Tarhini AA, Edington H, Butterfield LH, et al. PLoS One 2014; 9: e87705. 
23. 
Amaria RN, Prieto PA, Tetzlaff MT, et al. Neoadjuvant plus adjuvant dabrafenib and 
trametinib versus standard of care in patients with high-risk, surgically resectable melanoma: a 
single-centre, open-label, randomised, phase 2 trial. Lancet Oncol 2018;19:181-93. 
24. 
Long GV, Saw RPM, Lo S, et al. Neoadjuvant dabrafenib and trametinib for resectable, 
stage IIIB-C BRAF V600 mutation-positive melanoma (NeoCombi): a single arm-open-label, 
single-centre, phase 2 trial. Lanct Oncol 2019; epub. 
25. 
Huang AC, Orlowski RJ, Xu X, et al. A single dose of neoadjuvant PD-1 blockade 
predicts clinical outcomes in resectable melanoma. Nat Med 2019; 25: 454-61. 
26. 
Amaria RN, Reddy SM, Tawbi HA, et al. Neoadjuvant immune checkpoint blockade in 
high- risk resectable melanoma. Nat Med 2018; 24: 1649-54. 
27. 
Blank CU, Rozeman EA, Fanchi LF, et al. Neoadjuvant versus adjuvant ipilimumab 
plus nivolumab in macroscopic stage III melanoma. Nat Med 2018; 24: 1655-61. 
28. 
Identification of the optimal combination dosing schedule of neoadjuvant ipilimumab 
plus nivolumab in macroscopic stage III melanoma (OpACIN-neo): a multicentre, phase 2, 
randomised, controlled trial. Lancel Oncol 2019; epub. 
29. 
www.clinicaltrials.gov 
30. 
Long GV, Lebbe C, Atkinson V, et al. The anti-PD-1 antibody spartalizumab in 
combination with dabrafenib and trametinib in previously untreated patients with advanced BRAF 
V600- mutant melanoma: updated efficacy and safety from parts 1 and 2 of COMBI-I. Presented at 
ASCO 2019, Chicago, IL, Abst 9531. 
31. 
Tetzlaff MT, Messina JL, Stein JE, et al. Pathological assessment of resection specimens 
after neoadjuvant therapy for metastatic melanoma. Annals of oncology : official journal of the 
European Society for Medical Oncology 2018;29:1861-8. 
32. 
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in 
solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009;45:228-47. 
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APPENDICES 
 
Appendix A: Eastern Cooperative Oncology Group (ECOG) 
Performance Status Scale 
 
 
 
Grade 
Description 
0 
Fully active, able to carry on all pre-disease performance without 
restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to 
carry out work of a light or sedentary nature, e.g., light housework or 
office work 
2 
Ambulatory and capable of all self-care but unable to carry out any 
work activities; up and about > 50% of waking hours 
3 
Capable of only limited self-care, confined to a bed or chair > 50% of 
waking hours 
4 
Completely disabled; cannot carry on any self-care; totally confined to 
bed or chair 
5 
Dead 
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Appendix B: Management of Spartalizumab-Induced Immune Mediated AEs 
Recommended clinical management for suspected immune-related diarrhea/colitis 
 
Diarrhea/colitis (NCI-CTCAE v5) 
Grade 
Recommended management 
Grade 1 (Increase of < 4 stools per 
day over baseline) mild increase in 
ostomy output compared to 
baseline. 
Grade 2 (Increase of 4 - 6 stools per 
day over baseline; moderate increase 
in ostomy output compared to 
baseline; limiting instrumental ADL) 
and/or abdominal pain/ mucus or 
blood in stool. 
• Diet & Hydration 
• Loperamide: initially 4 mg, followed by 2 mg every four hours or after 
every unformed stool; maximum 16 mg/d. Continue until free of 
diarrhea for 12h 
• Diarrhea > 24h: loperamide 2 mg every two hours; maximum 16 
mg/d. Consider adding oral antibiotics. 
• Diarrhea > 48h: loperamide 2 mg every two hours; maximum 16 
mg/d. Consider other second-line therapies for diarrhea (e.g. 
(octreotide, oral diphenoxylate) and oral antibiotics 
• If grade 2 and no improvement in 5 days: consider oral steroids 
• If grade 2 diarrhea persists > 1 week consider gastroenterologist 
consultation and endoscopy to evaluate for colitis 
• If grade 2 persists for 5 days and worsening of symptoms or diffuse 
ulcerations and bleeding seen on endoscopy, initiat steroids (0.5 - 1 
mg/kg/d of prednisone or equivalent) and continue until symptoms 
improve to grade 1. 
• If no improvement occurs, manage as per grade 3. Steroids 
should be tapered slowly  
• Sigmoidoscopy and biopsy can be considered and may assist in 
determining the duration of steroid taper based on the evidence of 
macroscopic and microscopic inflammation. 
Grade 3 diarrhea: Increase of ≥ 7 
stools per day over baseline; 
incontinence; hospitalization 
indicated; severe increase in ostomy 
output compared to baseline; limiting 
self-care ADL; 
Grade 3 colitis: Severe abdominal 
pain; change in bowel habits; medical 
intervention indicated; peritoneal 
signs 
• Clinical evaluation and hospitalization indicated; rule out bowel 
perforation and intravenous hydration. 
• Consider consultation with gastroenterologist and biopsy with 
endoscopy. 
• In addition to symptomatic treatment (diet, hydration, loperamide, 
antibiotics if indicated); initiate immediate treatment with intravenous 
steroids (methylprednisolone 125 mg) followed by high dose oral 
steroids (prednisone 1 to 2 mg/kg once per day or dexamethasone 4 mg 
every 4 hours) is recommended. 
• When symptoms improve to ≤ grade 1, taper steroids slowly (see Taper 
over 6 to 8 weeks in patients with diffuse and severe ulceration and/or 
bleeding. 
• If no improvement in 2-3 d: consider initiating infliximab 5 mg/kg 
and continue steroids. Note: infliximab is contraindicated in patients 
with sepsis or a perforation. Upon symptomatic relief initiate a 
prolonged steroid taper over 6 to 8 weeks. 
• If symptoms worsen during steroid reduction, initiate a re-tapering of 
steroids starting at a higher dose of 80 or 100 mg/d followed by a more 
prolonged taper and administer infliximab. 
• If symptoms persist despite the above treatment a surgical consult should 
be obtained. 
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Grade 4: Life-threatening 
consequences; urgent 
intervention indicated 
Same as grade 3 
 
Recommended clinical management for suspected immune-related liver laboratory  
alterations 
 
Abnormal liver tests (NCI-CTCAE v5) 
Grade 
Recommended management 
Grade 2: 
• Monitor hepatic laboratory tests more frequently (every 2-3 days) until 
returned to baseline values 
• 
Rule-out alternative causes (e.g. concomitant medications, 
infection, disease progression) 
• Consider prednisone (0.5-1 mg/kg/d) if liver tests worsen and/or 
significant symptoms 
AST or ALT > 3 × ULN to ≤ 
5.0x ULN;  or if baseline 
abnormal >3.0 
– 5.0 x baseline 
or bilirubin > 1.5 × ULN to ≤ 
3 × ULN ; or if baseline 
abnormal >1.5 – 3.0 x 
baseline 
(if patient meets criteria for 
Hy’s law refer to  
Grade 3 or 4: AST or ALT > 5.0 × 
ULN; or if baseline abnormal 
>5.0 x baseline. 
bilirubin > 3.0 × ULN; or if 
baseline abnormal >3.0 x baseline. 
• Monitor hepatic laboratory tests more frequently (every 2-3 days) until 
returned to baseline values. 
• Consider viral serology (i.e. hepatitis A/B/C, CMV, and rule out other 
potential cause of liver injury such as concomitant medications or 
alcohol), consultation with hepatologist and liver biopsy to establish 
etiology of hepatic injury 
• If after 2-3 days new liver assessment shows worsening of 
laboratory test consider to initiate treatment with steroids 
prednisone 1-2 mg/kg/day or i.v. equivalents. 
• Add prophylactic antibiotics for opportunistic infections as 
appropriate 
• When symptoms/liver tests improve to grade ≤ 1, taper steroids over 
at least 4 weeks. 
• If serum transaminase levels or bilirubin do not decrease 48-72 hours 
after initiation of systemic steroids, oral mycophenolate mofetil 500 
mg every 12 hours may be given as per institutional guidelines. 
• Infliximab is not recommended due to its potential for 
hepatotoxicity 
 
 
 
 
 
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Recommended clinical management for suspected immune-related rash and other skin 
events 
 
Rash and other skin Events (NCI-CTCAE v5) 
Grade 
Recommended management 
Grade 1: rash covering < 10% 
Body Surface Area (BSA) 
• Initiate prophylactic and symptomatic treatment measures. 
• Consider use of topical corticosteroids or urea containing creams in 
combination with oral antipruritics or moderate strength topical steroid 
(hydrocortisone 2.5% cream or fluticasone propionate 0.5% cream) 
• Reassess after 2 weeks. 
 
Rash and other skin Events (NCI-CTCAE v5) 
Grade 
Recommended management 
Grade 2: 10-30% of BSA 
• If tolerable, treat as per grade 1; 
• If intolerable, initiate systemic steroids (e.g. oral prednisolone 0.5- 1 
mg/kg/d) and consider dose interruption until tolerable or recovery to 
grade ≤ 1 or baseline 
• If symptoms persist or recur consider skin biopsy. 
Grade 3: More than 30% of BSA 
• Obtain a skin biopsy and dermatology consult. 
• Initiate systemic steroids with 1mg/kg/d of prednisone or 
equivalent. 
Grade 4: Life-threatening 
Same as grade 3; additional measures as per local institutional guidelines 
Other skin events 
Stevens-Johnson syndrome, 
toxic epidermal necrolysis 
• Hospitalization and urgent dermatology consultation 
• Institute supportive care immediately as per institutional guidelines 
 
Recommended clinical management for suspected immune-related nephritis 
 
Nephritis (NCI-CTCAE v5) 
Grade 
Recommended management 
Grade 1: Creatinine > ULN to ≤ 
1.5 × ULN); or if baseline 
abnormal >1 – 1.5 x baseline 
• Monitor creatinine weekly 
• If creatinine return to baseline resume routine creatinine 
monitoring per protocol 
• Promote hydration and cessation of nephrotoxic drugs 
Grade 2: Creatinine > 1.5 to ≤ 3 × 
ULN; or if baseline 
abnormal >1.5 – 3.0 x baseline 
• Monitor creatinine every 2 to 3 days 
• Initiate 0.5 to 1 mg/kg/d prednisone or equivalents 
• If worsening or no improvement: 1 to 2 mg/kg/day prednisone or 
equivalents 
• Promote hydration and cessation of nephrotoxic drugs 
• Consult with specialist and consider renal biopsy 
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Grade 3: Creatinine >3.0 to ≤ 6.0 
× ULN; or if baseline 
abnormal >3.0 – 6.0 x baseline 
• Monitor creatinine every 1 to 2 days 
• Start 1 to 2 mg/kg/day prednisone or equivalents 
• Consult with nephrologist and consider renal biopsy 
Grade 4: Creatinine > 6.0 × ULN 
• Monitor creatinine daily 
• Initiate steroids with 1 to 2 mg/kg/d prednisone or equivalent 
• Consult with nephrologist and consider renal biopsy 
Recommended clinical management for suspected immune-related pneumonitis 
 
Pneumonitis (NCI-CTCAE v5) 
Grade 
Recommended management 
Grade 1: Asymptomatic; clinical or 
diagnostic 
observations 
only; 
intervention not indicated 
• High-resolution CT with lung windows recommended, with serial 
imaging to monitor for resolution or progression. Repeat at least every 
3 weeks 
• Monitor for symptoms every 2-3 days - Clinical evaluation and 
laboratory work-up for infection 
• Monitoring of oxygenation via pulse oximetry recommended 
 
Pneumonitis (NCI-CTCAE v5) 
Grade 
Recommended management 
• Consultation of pulmonologist recommended 
Grade 2: Symptomatic-medical 
intervention indicated; limits 
instrumental ADLs 
• Perform high-resolution CT with lung windows 
• Monitor symptoms daily, consider hospitalization 
• Clinical evaluation and laboratory work up for infection 
• Consult pulmonologist 
• Pulmonary function tests - if normal at baseline, repeat every 8 
weeks 
• Bronchoscopy with biopsy and/or BAL recommended 
• Symptomatic therapy including corticosteroids if clinically indicated (1 
to 2 mg/kg/d prednisone or equivalent as clinically indicated). 
Grade 3: Severe symptoms; 
limits self-care ADLs; oxygen 
indicated 
Grade 4: Life- threatening 
respiratory compromise; urgent 
intervention required 
• Hospitalization and pulmonary and infectious disease consultation 
• Methylprednisolone (1-2 mg/kg/d or equivalent) until symptoms 
improve to Grade ≤1, then slow taper over ≥4-6 weeks 
• If no improvement within 48 hours, consider infliximab and/or other 
immune-suppressive therapy, or i.v. Ig as per local guidelines 
• Empiric antibiotics 
 
Recommended clinical management for suspected immune-related endocrinopathies 
 
Endocrine events (NCI-CTCAE v5) 
Grade 
Recommended management 
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Asymptomatic, intervention not 
indicated (e.g. hyperthyroidism or 
hypothyroidism) 
• If TSH < 0.5 × LLN, or TSH > 2 × ULN, or consistently out of range in 2 
subsequent measurements, include free T4 at subsequent cycles as 
clinically indicated 
• Consider endocrinologist consult 
• If hypophysitis is considered, pituitary gland imaging should be 
considered (MRIs with gadolinium and selective cuts of the pituitary 
can show enlargement or heterogeneity and confirm the diagnosis) 
• Repeat labs in 1 to 3 weeks/MRI in 1 month if laboratory 
abnormalities persist but normal lab/pituitary scan 
Symptomatic endocrinopathy 
(e.g., hypophysitis, adrenal 
insufficiency, hypothyroidism, 
hyperthyroidism) 
• Endocrinology consultation 
• Rule out infection/sepsis and other alternative causes with 
appropriate cultures and imaging 
• Evaluate hormone levels (e.g. ACTH, cortisol, FSH/LH, TSH, free T4, 
testosterone/estrogen), metabolic panel (e.g. Na, K, CO2, glucose), and 
imaging (e.g. brain MRI) as clinically indicated 
• Initiate hormone replacement therapy as appropriate 
• Consider steroids (methylprednisolone 1 to 2 mg/kg/d or 
equivalent) in case of sever hypophysitis or thyrotoxicosis 
• Replacement of appropriate hormones may be required as the steroid 
dose is tapered 
• Hypophysitis with clinically significant adrenal insufficiency and 
hypotension, dehydration, and electrolyte abnormalities (such as 
hyponatremia and hyperkalemia) constitutes adrenal crisis 
• Consider a beta-blocker in case of severe hyper-thyroidism. 
 
Endocrine events (NCI-CTCAE v5) 
Grade 
Recommended management 
• Consider hospitalization (e.g. in case of severe adrenal 
insufficiency/crisis), fluid replacement, and other supportive 
measures as clinically be initiate 
Autoimmune diabetes 
(Grade 3 or symptomatic 
hyperglycemia) 
• Initiate anti-glycemic therapy (i.e. insulin) as medically indicated and 
monitor glucose levels regularly until metabolic control is achieved 
• Evaluate for ketoacidosis as medically indicated 
• Consultation with endocrinologist 
• 
Consider hospitalization (e.g. in case of ketoacidosis) 
Autoimmune diabetes 
(Grade 4 hyperglycemia or life- 
threatening complications) 
Same as grade 3 
 
 
 
 
 
 
 
 
 
 
 
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Recommended clinical management for suspected infusion reaction or cytokine 
release syndrome 
 
Infusion reaction (NCI-CTCAE v5) 
Grade 
Recommended management 
Grade 1 
Mild reaction; infusion 
interruption not indicated; 
intervention not indicated 
• Increase monitoring of vital signs as medically indicated until the 
patient is deemed medically stable in the opinion of the investigator. 
• 
Consider slowing infusion rate until recovery of symptoms 
• 
May continue spartalizumab 
Grade 2 
Requires infusion interruption but 
responds promptly to symptomatic 
treatment (e.g., antihistamines, 
NSAIDS, narcotics, IV fluids); 
prophylactic medications indicated 
for < =24 hrs 
• Stop infusion 
• Additional medical therapy as per local institutional guidelines that may 
include: 
• 
i.v. fluids 
• 
Antihistamines 
• 
NSAIDS 
• 
Acetaminophen 
• 
Narcotics 
• 
Oxygen and corticosteroids as indicated 
• Increase monitoring of vital signs as medically indicated until the 
patient is deemed medically stable in the opinion of the investigator. 
• If symptoms resolve within one hour of stopping drug infusion, the 
infusion may be restarted at 50% of the original infusion rate (e.g. from 
100 mL/hr to 50 mL/hr). Otherwise dosing will be held until symptoms 
resolve and the patient should be re-premedicated for the next scheduled 
dose. 
• Patient may be premedicated 1.5h (± 30 minutes) prior to infusion with 
diphenhydramine 50 mg p.o. (or equivalent dose of antihistamine) and 
acetaminophen 500-1000 mg p.o. (or equivalent dose of analgesic). 
• Consider permanent discontinuation of study treatment in case of 
recurring infusion reaction despite premedication and prolonged 
infusion 
Grade 3: 
• Stop infusion 
Infusion reaction (NCI-CTCAE v5) 
Grade 
Recommended management 
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Prolonged (i.e., not rapidly responsive 
to symptomatic medication and/or 
brief interruption of infusion); 
recurrence of symptoms following 
initial improvement; hospitalization 
indicated for other clinical sequelae 
(e.g., renal impairment, pulmonary 
infiltrates) 
Grade 4: 
Life-threatening; pressor or 
ventilatory support indicated 
• 
Additional medical therapy as per local institutional guidelines that 
may include: 
• 
i.v. fluids 
• 
Antihistamines 
• 
NSAIDS 
• 
Acetaminophen 
• 
Narcotics 
• 
Oxygen 
• 
Corticosteroids 
• 
Epinephrine 
• 
Close monitoring of vital signs, pulse oximetry and ECG as medically 
indicated until the subject is deemed medically stable. 
• Hospitalization as indicated 
 
Recommended clinical management guidelines for suspected other potential immune-
related events 
 
Other (i.e. Autoimmune neuropathy, Demyelinating polyneuropathy, Guillain Barre, Myasthenia Gravis-
like syndrome, non-infectious myocarditis, pericarditis, pancreatitis, encephalitis, and Grade 3 Fatigue 
with rapid onset in absence of disease progression) (NCI-CTCAE v5) 
Grade 
Recommended management 
Mild (Grade 1) 
Provide symptomatic treatment 
Moderate (Grade 2) 
• Consider treatment interruption until recovery to ≤ grade 1 or baseline. 
• Ensure adequate evaluation to confirm etiology or exclude other causes 
• Provide symptomatic treatment 
• Systemic corticosteroids may be indicated 
• Consider biopsy for confirmation of diagnosis 
• A specialist should be consulted 
Severe (Grade 3) 
• Initiate systemic corticosteroids (prednisone or equivalent) at a dose of 1-2 
mg/kg/d and other therapies as appropriate 
• Monitor closely and consult with a specialist 
Grade 4 
• 
Hospitalization and consult with specialist 
• 
Initiate systemic corticosteroids (prednisone a dose of 1-2 mg/kg/d or 
equivalent) and other therapies as appropriate 
Encephalitis 
(any 
grade) or aseptic 
meningitis 
• Rule out infectious or other causes of moderate to severe neurologic 
deterioration, and consult with specialist. 
• If other etiologies are ruled out, administer corticosteroids at a dose of 1 to 2 
mg/kg/d prednisone equivalents. 
Guillain-Barre Severe 
peripheral or 
autonomic neuropathy, 
or transverse myelitis 
• Hospitalization and consult with specialist 
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Myasthenia gravis 
• Consult with specialist 
• Consider pyridostigmine and systemic corticosteroids (prednisone or 
equivalent) at a dose of 1-2 mg/kg/d; other therapies as appropriate (e.g. IVIG) 
• Hospitalization in case of severe cases 
Other (i.e. Autoimmune neuropathy, Demyelinating polyneuropathy, Guillain Barre, Myasthenia Gravis-
like syndrome, non-infectious myocarditis, pericarditis, pancreatitis, encephalitis, and Grade 3 Fatigue 
with rapid onset in absence of disease progression) (NCI-CTCAE v5) 
Grade 
Recommended management 
Myocarditis (any grade) or 
cardiac event grade 
≥ 3 
Urgent cardiology consult is essential to initiate high dose systemic corticosteroids 
(prednisone or equivalent). Hospitalization as indicated 
Pancreatitis 
Amylase/lipase 
elevation 
• Evaluate for pancreatitis (clinical assessment, abdominal imaging and/or 
magnetic resonance cholangiopancreatography as appropriate) 
• Treatment may be continued in case of asymptomatic, isolated enzyme 
elevations without evidence for pancreatitis 
• Initiate steroids in case of ≥ grade 2 acute pancreatitis 
Autoimmune hemolytic 
anemia, hemolytic uremic 
syndrome, or acquired 
hemophilia grade ≥3 
• Consult with specialist 
• Consider systemic corticosteroids and other therapies as appropriate (e.g. 
transfusion) per local institutional guidelines 
 
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Appendix C
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Appendix D: Neoadjuvant Therapy Surgical Resectability, Ease and Complications Questionnaire 
 
Questionnaire 1 (Baseline/at time of trial enrollment) 
 
- 
Surgeon name 
- 
Patient idenitification 
- 
Date of questionnaire 
- 
Which lymph node basin(s) is involved? (can be more than one) 
o Femoral/Inguinal 
o Iliac/obturator 
o Axilla 
o Cervical 
 
Level 1 
 
Level 2 
 
Level 3 
 
Level 4 
 
Level 5 
o Popliteal 
o Epitrochlear 
o Other, specify 
- 
Number of involved lymph nodes? 
- 
Largest dimension of largest lymph node? 
- 
Suspected fixation or narrow margin to adjacent anatomic structure? (can be more than one) 
o Skin 
o Muscle/fascia 
o Artery 
o Vein 
o Nerve 
- 
On a scale of 1-10 (1 = most easy, 10 = most difficult) how difficult do you anticipate the surgery 
will be if done now? 
- 
Any remarks? 
- 
 
Questionnaire 2 (To be completed at pre-op visit after completion of neoadjuvant 
therapy) 
 
- 
Surgeon name 
- 
Patient identificaiton 
- 
Date of questionnaire 
- 
Which lymph node basin(s) is involved? (can be more than one) 
o Femoral/Inguinal 
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o Iliac/obturator 
o Axilla 
o Cervical 
 
Level 1 
 
Level 2 
 
Level 3 
 
Level 4 
 
Level 5 
o Popliteal 
o Epitrochlear 
o Other, specify 
- 
Number of involved lymph nodes? 
- 
Largest dimension of largest lymph node? 
- 
Suspected fixation or narrow margin to adjacent anatomic structure? (can be more than one) 
o Skin 
o Muscle/fascia 
o Artery 
o Vein 
o Nerve 
- 
On a scale of 1-10 (1 = most easy, 10 = most difficult) how difficult do you anticipate the surgery 
will be if done now? 
- 
Do you think the resection is easier or more difficult compared to baseline? 
o No 
o Yes, specify 
- 
Any remarks? 
Questionnaire 3 (≤ 30 Days of surgery) 
 
- 
Surgeon name 
- 
Patient identification 
- 
Date of questionnaire 
- 
Date of surgery 
- 
Which basin(s) did you resect? (can be more than 1) 
o Femoral/Inguinal 
o Iliac/obturator 
o Axilla 
o Cervical 
 
Level 1 
 
Level 2 
 
Level 3 
 
Level 4 
 
Level 5 
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o Popliteal 
o Epitrochlear 
o Other, specify 
- 
Date of drain removal 
- 
Did the patient have any complications ≤ 30 days postoperatively? 
o No 
o Yes, seroma/lymphocele 
 
Please enter Clavien-Dindo Grade ……… 
o Yes, surgical site infection 
 
Please enter Clavien-Dindo Grade ……… 
- 
Was the patient re-operated? 
o No 
o Yes 
- 
Was the patient re-admitted? 
o No 
o Yes 
- 
Did the patient undergo any other interventions? 
o Drain replacement 
o Seroma/lymphocele aspiration 
o Oral or IV antibiotics 
o Opening of wound 
o Other, specify 
- 
Any other complications (i.e. pneumonia, urinary tract infection, thrombosis, etc.)? 
o No 
o Yes, specify 
 
Please enter Clavien-Dindo Grade ……… 
- 
Any remarks? 
 
Clavien et al. Ann Surg 2009 
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