Conditions: Non Small Cell Lung Cancer KRAS Gene Mutation
Keywords: trametinib Ponatinib KRAS Mutant Advanced Non-Small Cell Lung Cancer 17-297 Memorial Sloan Kettering Cancer Center
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 12
Healthy volunteers: no

Brief summary:
The purpose of this study is to evaluate the safety of the combination of ponatinib and trametinib as well as the most appropriate dosages of the combination.

Detailed description:

Arms:
arm 1: Trametinib 0.5mg PO q daily Ponatinib 15mg PO q daily arm 2: Trametinib 1.0 mg PO q daily Ponatinib 15mg PO q daily arm 3: Trametinib 1.5 mg PO q daily 15mg PO q daily arm 4: Trametinib 2 mg PO q daily Ponatinib 15mg PO q daily arm 5: Trametinib 2 mg PO q daily Ponatinib 30mg PO q daily arm 6: Maximum tolerated dose as established in Phase I portion

Interventions: intervention 1: Trametinib 0.5 mg intervention 2: Trametinib 1 MG intervention 3: Trametinib 1.5 MG intervention 4: Trametinib 2 mg intervention 5: Ponatinib 15 MG intervention 6: Ponatinib 30 MG
Intervention descriptions: intervention 1: 0.5mg PO q daily intervention 2: 1.0 mg PO q daily intervention 3: 1.5mg PO q daily intervention 4: 2 mg PO q daily intervention 5: 15mg PO q daily intervention 6: 30mg PO q daily

Protocol document:
Prot_SAP_000.pdf: 
Memorial Sloan Kettering Cancer Center 
IRB Number: 17-297 A(7) 
Approval date: 08-Oct-2019 
Administrative Update 1 : 10-Mar-2020 
Page 1 of 54 
 
 
 
 
 
 
A Phase 1/2 Trial of Trametinib and Ponatinib in Patients with KRAS Mutant Advanced Non- 
Small Cell Lung Cancer 
 
PROTOCOL FACE PAGE FOR 
MSK THERAPEUTIC/DIAGNOSTIC  PROTOCOL 
 
Principal Investigator/Department: 
Kathryn Arbour, MD 
Medicine 
Co-Principal 
Investigator(s)/Department: 
Gregory Riely, MD, PhD 
Medicine 
Investigator(s)/Department: 
Charles Rudin, MD, PhD 
Jamie Chaft, MD 
Alexander Drilon, MD 
Robert Daly, MD, MBA 
Matthew Hellmann, MD 
Mark G. Kris, MD 
Bob T. Li, MD 
Piro Lito, MD, PhD 
Paul K. Paik, MD 
Marjorie G. Zauderer, MD 
Stephen Veach, MD 
Helena Yu, MD 
Victoria Lai, MD 
Michael Offin, MD 
Elizabeth Panora, NP 
Linda Ahn, NP 
Christina Larsen, NP 
Leslie Tyson, NP, MSN 
Erica Stumpf, NP 
Diana Velez, NP 
Medicine 
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Page 2 of 54 
 
 
 
Memorial Sloan Kettering Cancer Center 
IRB Number: 17-297 A(7) 
Approval date: 08-Oct-2019 
Administrative Update 1 : 10-Mar-2020 
Radiology 
Radiology 
Radiology 
Radiology 
Medicine 
Pathology 
Ophthalmology 
Ophthalmology 
Nursing 
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Nursing 
Consenting  Professional(s)/Department: 
Kathryn Arbour, MD 
Jamie Chaft, MD 
Robert Daly, MD, MBA 
Alexander Drilon, MD 
Matthew Hellmann, MD 
Mark G. Kris, MD 
Bob T. Li, MD 
Piro Lito, MD, PhD 
Paul K. Paik, MD 
Gregory J. Riely, MD, PhD 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
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Page 3 of 54 
Memorial Sloan Kettering Cancer Center 
IRB Number: 17-297 A(7) 
Approval date: 08-Oct-2019 
Administrative Update 1 : 10-Mar-2020 
 
 
 
 
Charles Rudin, MD, PhD 
Medicine 
Marjorie G. Zauderer, MD 
Medicine 
Stephen Veach, MD 
Medicine 
Helena Yu, MD 
Medicine 
Victoria Lai, MD 
Medicine 
Michael Offin, MD 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
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Medicine 
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Medicine 
Medicine 
 
 
 
 
 
 
Please Note: A Consenting Professional must have completed the mandatory Human Subjects 
Education and Certification Program. 
 
 
 
One MSK Sites 
Manhattan 
All Protocol Activities 
Commack 
Limited Protocol Activities 
Basking Ridge 
Limited Protocol Activities 
Westchester 
Limited Protocol Activities 


Page 4 of 54 
Memorial Sloan Kettering Cancer Center 
IRB Number: 17-297 A(7) 
Approval date: 08-Oct-2019 
Administrative Update 1 : 10-Mar-2020 
 
 
 
 
Nassau 
Limited Protocol Activities 
Monmouth 
Limited Protocol Activities 
Bergen 
Limited Protocol Activities 
 
 
 
 
Memorial Sloan Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 


Memorial Sloan Kettering Cancer Center 
IRB Number: 17-297 A(7) 
Approval date: 08-Oct-2019 
Administrative Update 1 : 10-Mar-2020 
Page 5 of 54 
 
 
 
Table of Contents 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA ....................................................................... 6 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS ................................................................................ 9 
3.0 
BACKGROUND AND RATIONALE ................................................................................... 10 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION ................................................................. 15 
4.1 
Design................................................................................................................................. 15 
4.2 
Intervention .............................................................................................................................. 15 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS ........................................................................... 16 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY ............................................................................... 17 
6.1 
Subject Inclusion Criteria ..................................................................................................... 17 
6.2 
Subject Exclusion Criteria ................................................................................................... 18 
7.0 
RECRUITMENT PLAN .................................................................................................................... 19 
8.0 
PRETREATMENT EVALUATION ...................................................................................... 20 
9.0 
TREATMENT/INTERVENTION PLAN ................................................................................ 20 
10.0 
EVALUATION DURING TREATMENT/INTERVENTION .................................................... 23 
11.0 
TOXICITIES/SIDE EFFECTS .................................................................................................... 24 
12.0 
CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT ......................... 40 
13.0 
CRITERIA FOR REMOVAL FROM STUDY ....................................................................... 41 
14.0 
BIOSTATISTICS ............................................................................................................... 42 
15.0 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES 44 
15.1  Research Participant Registration ....................................................................................... 44 
15.2 
Randomization .................................................................................................................... 44 
16.0 
DAT A M ANAGEMENT ISSUES ........................................................................................ 44 
16.1 
Quality Assurance............................................................................................................... 45 
16.2 
Data and Safety Monitoring .................................................................................................... 45 
17.0 
PROTECTION OF HUMAN SUBJECTS ............................................................................ 46 
17.1 
Privacy ................................................................................................................................ 47 
17.2 
Serious Adverse Event (SAE) Reporting ................................................................................ 47 
17.2.1 Novartis Reporting ............................................................................................................... 46 
18.0 
INFORMED CONSENT PROCEDURES................................................................................... 52 
19.0 
REFERENCES ....................................................................................................................... 53 
20.0 
APPENDICES ................................................................................................................... 54 


Memorial Sloan Kettering Cancer Center 
IRB Number: 17-297 A(7) 
Approval date: 08-Oct-2019 
Administrative Update 1 : 10-Mar-2020 
Page 6 of 54 
 
 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA 
 
Study Title: 
A Phase 1/2 Trial of Trametinib and Ponatinib in Patients with 
KRAS-Mutant  Lung Adenocarcinomas 
Study Objectives: 
Phase 1: Dose escalation 
Primary Objective: Determine the maximum tolerated dose of 
Trametinib and Ponatinib in patients with KRAS mutant NSCLC 
Phase 2: 
Primary Objective: Assess overall response rate (CR+PR) of 
Trametinib and Ponatinib for patients with KRAS-mutant 
NSCLC. 
Secondary Objectives: 1) Measure progression-free survival and 
overall survival among patients treated with Trametinib and 
Ponatinib 2) describe the toxicity profile of the combination 
Correlative Objectives (to be performed in Phase 2 portion): 
1) Assess for sustained MAPK inhibition by assessment of 
pERK on pre-treatment and on treatment biopsies 
2) Assess for sustained PI3K inhibition by assessment of 
pAKT on pre-treatment and on treatment biopsies 
3) Assess for sustained FGFR by assessment of pFRS2 on 
pre-treatment and on treatment biopsies 
4) Explore role of concurrent genetic alterations identified 
on routine molecular profiling 
5) Evaluate for changes in circulating tumor DNA (ctDNA) 
during treatment 
Patient 
Population 
Patients with locally advanced or metastatic lung 
adenocarcinomas with a confirmed KRAS mutation who have 
developed progressive disease during or following treatment 
with at least one prior line of platinum containing chemotherapy 
and at least one prior line of PD-1/L1 inhibitor. 
Number of 
Patients 
Phase 1: up to 12 patients if only dose levels 1-3 are used 
Phase 2: a maximum of 25 patients (including 6 patients from 
Phase I) 
Inclusion Criteria 
All patients must have: 
• 
Histologically or cytologically proven of advanced lung 
adenocarcinoma 
• 
KRAS mutation 
• 
Radiographic progression following prior treatment with 
platinum doublet chemotherapy and prior treatment with 
a PD-1/L1 inhibitor. Patients who are deemed not eligible 
for therapy with a PD-1/L1 inhibitor will also be eligible. 
• 
Able to take oral medications 
• 
Measurable disease as per RECIST 1.1. Previously 
irradiated sites of tumor may be considered measurable 
if there is radiographic progression at the site 
subsequent to the time of completing radiation. 
• 
Karnofsky performance status (KPS) ≥ 70% 
• 
Age >18 years old 


Memorial Sloan Kettering Cancer Center 
IRB Number: 17-297 A(7) 
Approval date: 08-Oct-2019 
Administrative Update 1 : 10-Mar-2020 
Page 7 of 54 
 
 
 
 
• 
Adequate organ function: 
- 
AST, ALT ≤ 2.5 x ULN - Total bilirubin ≤ 
1.5 x ULN -Albumin≥2.5g/dL 
- 
Creatinine < 1.5 x ULN OR calculated 
creatinine clearance ≥50mL/min 
- 
Absolute neutrophil count (ANC) ≥ 1,200 
cells/mm3 
- 
Hemoglobin≥9.0  g/dL 
- 
Platelets ≥100,000/mm3. 
• 
A negative serum pregnancy test obtained within two 
weeks prior to the administration of the experimental 
agents in all women of child bearing potential 
Exclusion Criteria 
Patients are to be excluded from the study if they meet any of 
the following criteria: 
• Patients with symptomatic brain metastasis requiring 
escalating doses of steroids 
• Patients with grade 2 or greater diarrhea prior to study 
initiation despite maximal medical management 
• History of acute pancreatitis within 1 year of study entry or 
history of chronic pancreatitis. 
• History of or ongoing alcohol abuse that, in the opinion of 
the Investigator, would compromise compliance or impart 
excess risks associated with study participation. 
• Pregnant or lactating women 
• Any type of systemic therapy (chemotherapy or 
experimental drugs) within 2 weeks of starting treatment 
on protocol 
• Patients who have received prior treatment with MEK 
inhibitor 
• A history of clinically significant interstitial lung disease or 
pneumonitis 
• Significant uncontrolled or active cardiovascular disease, 
specifically including, but not restricted to: History of 
clinically significant (as determined by the treating 
physician) atrial arrhythmia; or any ventricular 
arrhythmia, History of congenital long QT syndrome., 
Abnormal QTc (≥ 450 msec in males and ≥ 470 msec in 
females), Ejection fraction ≤ 50% as assessed by 
echocardiogram. 
• History of arterial thrombotic disease, specifically 
including, but not restricted to: Myocardial infarction or 
unstable angina, cerebrovascular event (CVA) or 
transient ischemic attack (TIA), Peripheral vascular 
disease or claudication. 
• 
Uncontrolled hypertension (Diastolic blood pressure > 100 
mmHg; Systolic blood pressure > 150 mmHg). 
• 
History of venous thromboembolism (e.g. deep venous 
thrombosis or pulmonary embolism) within 6 months of 
study entry. Note: Participants enrolled after this window 
must be on appropriate therapeutic anticoagulation. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 17-297 A(7) 
Approval date: 08-Oct-2019 
Administrative Update 1 : 10-Mar-2020 
Page 8 of 54 
 
 
 
 
• History of central serous retinopathy or retinal vein 
occlusion 
• Patients with baseline risk factors for central serous 
retinopathy or retinal vein occlusion such as evidence of 
new optic disc cupping, evidence of new visual field 
defects, and intraocular pressure >21 mmHg are 
excluded from the trial 
• History of prior malignancy within 2 years that requires 
treatment. Patients who are considered NED from a 
malignancy may be considered on a case by case basis. 
• Any other condition that, in the opinion of the investigator, 
may compromise the safety, compliance of the patient, 
or would preclude the patient from successful completion 
of the study 
Study Drug 
Trametinib and Ponatinib 


Memorial Sloan Kettering Cancer Center 
IRB Number: 17-297 A(7) 
Approval date: 08-Oct-2019 
Administrative Update 1 : 10-Mar-2020 
Page 9 of 54 
 
 
 
Study Design 
Phase 1: Dose Escalation 
This study will determine the maximum tolerated dose of 
Trametinib and Ponatinib. 
 
Dose levels 
Trametinib Dose 
Ponatinib Dose 
Dose level -3 
0.5mg PO q daily 
15mg PO q daily 
Dose Level -2 
1.0 mg PO q daily 
15mg PO q daily 
Dose Level -1 
1.5mg PO q daily 
15mg PO q daily 
Dose Level 1 
2 mg PO q daily 
15mg PO q daily 
Dose Level 2 
2 mg PO q daily 
30mg PO q daily 
 
Phase 2: 
Once the phase 1 portion of the study has been completed, 
patients will be enrolled in the phase 2 portion of the single-arm, 
two-stage, open-label study of Trametinib and Ponatinib in the 
treatment of patients with KRAS-mutant lung cancers.  After 
screening and registration, patients will be treated with the 
combination of Trametinib and Ponatinib. Response to therapy 
will be assessed by interval imaging every 8 weeks (every 2 
cycles) with CT scan of the chest and imaging of any other 
target lesion with response evaluated by RECIST 1.1.  Patients 
with known brain metastases at the time of screening will also 
undergo CT/MRI Brain every 8 weeks. A maximum of 25 
patients will be enrolled during this portion of the study. 
 
Correlative studies: 
Biopsies will be required before beginning treatment, 28 +/- 7 
days after initiation of study drug and at the time of progression 
in patients enrolled in the phase 2 portion. At prespecified time 
points, patients will have image-guided core needle biopsies 
with 3-4 cores obtained. At least 2 cores will be immediately 
frozen in liquid nitrogen with the remaining cores fixed in 
formalin. IHC will be performed to evaluate expression of 
specific proteins of interest including: pERK, pFRS2, pAKT. 
IMPACT,  our next-generation sequencing based mutation 
platform that assesses for genetic alterations in 410 cancer- 
related genes, will be used for molecular analysis. 
 
 
 
2.1 
OBJECTIVES AND SCIENTIFIC AIMS 
 
 
Phase 1 Trial: 
 
A. Primary Objective: Determine the maximum tolerated dose of the combination of 
Trametinib and Ponatinib 
Phase 2 Trial: 


Memorial Sloan Kettering Cancer Center 
IRB Number: 17-297 A(7) 
Approval date: 08-Oct-2019 
Administrative Update 1 : 10-Mar-2020 
Page 10 of 54 
 
 
 
A. Primary Objectives: Assess overall response rate (CR+PR) of Trametinib and Ponatinib 
patients with KRAS mutant NSCLC. 
B. Secondary Objectives: Measure progression free survival and overall survival among 
patients treated with Trametinib and Ponatinib and define the safety and tolerability of the 
combination. 
 
Correlative Studies: Only Phase II patients will be included in correlative analysis 
 
1) Assess for sustained MAPK inhibition by assessment of pERK on pre-treatment and on 
treatment biopsies 
2) Assess for sustained PI3K inhibition by assessment of pAKT on pre-treatment and on 
treatment biopsies 
3) Assess for sustained FGFR by assessment of pFRS2 on pre-treatment and on 
treatment biopsies 
4) Explore role of concurrent genetic alterations identified on routine molecular profiling 
5) Evaluate for changes in circulating tumor DNA (ctDNA) during treatment 
 
3.0 
BACKGROUND AND RATIONALE 
 
Background: 
 
3.1 Oncogene identification in NSCLC 
 
NSCLC is the leading cause of cancer death, causing an estimated 158,000 deaths in the US1. 
Recent major advances include the development of PD-1 checkpoint inhibitors (Nivolumab2, 
Pembrolizumab3, and Atezolizumab4) has demonstrated benefit in this patient population, 
however response rates remain low and despite these advances, median survival for metastatic 
lung cancer measured in recent trials is only 12 months. 
In the past decade, there has been a shift from classifying lung cancer by histology to molecular 
classification based on presence or absence of oncogenic mutations5. The efforts to molecularly 
classify lung cancer began with the discovery of EGFR (epidermal growth factor receptor) 
mutations and its therapeutic implications. EGFR tyrosine kinase inhibitors (TKIs) were developed 
and studied extensively in clinical trials and in EGFR mutant NSCLC induce disease responses 
superior to cytotoxic chemotherapy. Similarly, other oncogenic drivers have been identified (ALK, 
ROS1) in small subsets of patients and treatment with targeted therapy has been successful. 
 
 
3.2 KRAS mutation in NSCLC 
 
Somatic KRAS mutations occur in 20% of patients with metastatic lung adenocarcinomas, the  
vast majority of mutations occurring at codon 12 or 13. While numerous different point mutations 
have been described, among individuals with KRAS mutant metastatic lung cancers treated, there 
are no apparent differences in outcome based on KRAS mutation subtype. Identification of 
effective therapies for these patients has been elusive.  Direct RAS inhibitors are in development, 
but thus far have limited selectivity for individual genotypes and have not yet entered clinical 
trials.6 KRAS encodes a GTPase that couples growth factor signaling to the MAPK cascade. 
Oncogenic KRAS mutations compromise its GTPase activity, leading to accumulation of KRAS in 


Memorial Sloan Kettering Cancer Center 
IRB Number: 17-297 A(7) 
Approval date: 08-Oct-2019 
Administrative Update 1 : 10-Mar-2020 
Page 11 of 54 
 
 
 
the active GTP-bound state and thereby to hyperactive signaling that initiates and maintains 
cancer growth. The MAPK pathway converges at the MEK1/MEK kinases, for which the only 
known substrates are the ERK1/ERK2 kinases. 
3.3 Trametinib 
 
3.3.1 Trametinib in Pre-clinical studies 
 
Trametinib is a reversible, highly selective allosteric inhibitor of MEK1/MEK2 activation and kinase 
activity, with a half-maximum inhibitory concentration (IC50) of 0·7–0·9 nmol/L. It is currently FDA 
approved as both a single agent and in combination with dabrafenib for the treatment of BRAF 
mutant melanoma. In enzymatic and cellular studies, Trametinib inhibited kinase activity of MEK1 
and MEK2, prevented RAF-dependent MEK phosphorylation, and prolonged inhibition of 
phosphorylated ERK (a substrate of MEK). Cell lines and mouse xenograft models with activating 
mutations in RAS were also sensitive to Trametinib7.   Pharmacokinetic profiling in mice indicated 
a mean effective half-life (t1/2) of 33 h, with a low peak: trough ratio (around 1·6–2·8) after single  
or repeat dosing of Trametinib.8 
 
3.3.2 Clinically described adverse events with Trametinib 
 
Data reported from the initial phase I9  and phase II10   studies of Trametinib indicate skin toxicity 
was the most common treatment-related adverse event observed 11% had grade 3 events. 
Diarrhea, the next most common non-hematological adverse event, was predominantly grade 1 
(all doses combined and 2 mg a day) and was manageable with standard treatments. Peripheral 
edema was reported in one third of all patients, with no occurrences higher than grade 2. 
Treatment-related ocular toxic effects were recorded in 31 (15%) patients, including three events 
of central serous retinopathy and one of retinal vein occlusion.  Cardiovascular toxicity has been 
reported, most commonly in the form of hypertension (including 8% of patients with grade 3 
hypertension), as well as decrease in left-ventricular ejection fraction and left-ventricular 
dysfunction. Further details regarding clinically described adverse events can be found in the 
Trametinib package insert11. 
 
 
3.3.3 Trametinib in Phase 1 and Phase II trials in NSCLC 
 
A multicenter phase I study conducted in patients with advanced solid tumor malignancies, 
including lung cancer, explored multiple dosing strategies. Pharm acokinetic data showed that 
steady state could be achieved without loading doses. The dose of 2mg once daily was chosen 
as the recommended phase 2 dose based on combined safety, pharmacokinetic, 
pharmacodynamics, and efficacy data.  The objective response rate in an unselected NSCLC 
patient population in this study was 7%, both in patients with and without KRAS mutations.9 
In a subsequent randomized open label phase II study, Trametinib was compared to docetaxel as 
second-line treatment in patients with advanced or metastatic NSCLC harboring a KRAS mutation 
who failed one prior platinum-containing chemotherapy regimen. 129 patients were randomized in 
the 2:1 fashion. Median PFS was 12 weeks in the Trametinib arm and 11 weeks in the docetaxel 
arm (hazard ratio [HR] 1.14; 95% CI 0.75–1.75;P = 0.5197). There were 10 (12%) partial 
responses (PRs) in the Trametinib arm and 5 (12%) PRs in the docetaxel arm (P = 1.0000).10 
 
 
3.4.1 Ponatinib 


Memorial Sloan Kettering Cancer Center 
IRB Number: 17-297 A(7) 
Approval date: 08-Oct-2019 
Administrative Update 1 : 10-Mar-2020 
Page 12 of 54 
 
 
 
Ponatinib (AP24534) is a tyrosine kinase inhibitor recently approved by the FDA for the treatment 
of chronic myeloid leukemia (CML) and Philadelphia chromosome positive acute lymphoblastic 
leukemia (ALL). Ponatinib was initially developed as an inhibitor of the BCR-ABL fusion protein, 
which is formed by a reciprocal translocation involving chromosomes 9 and 22 in hematopoietic 
stem cells and characterizes approximately 95% of cases of chronic myeloid leukemia. In addition 
to its inhibitory activity against the BCR-ABL fusion oncoprotein, Ponatinib is a potent inhibitor of a 
number of tyrosine kinases relevant to the treatment of human malignancies, including FLT3, KIT, 
VEGFR2, FGFR1, PDGFR and RET (Table 3.4.1). Ponatinib’s activity as an FGFR inhibitor has 
also been validated in multiple FGFR amplified and mutated cancer cell models (endometrial, 
bladder, gastric, breast, lung and colon).12 
Table 3.4.1 
Ponatinib Kinase Screening Data 
 
Kinase 
IC50 (nM) 
ABL 
0.37 
ABLT315I 
2.00 
FLT3 
12.6 
KIT 
12.5 
RET 
0.16 
SRC 
5.4 
VEGFR2 
1.5 
FGFR1 
2.2 
PDGRFα 
1.1 
 
 
3.4.2 Ponatinib in clinical trials 
 
AP24534-07-101 was a phase 1 dose escalation trial to determine the safety, tolerability and 
maximum tolerated dose (MTD) of Ponatinib in patients with refractory chronic myeloid leukemia 
(CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). Enrollment 
in the United States was completed at 81 patients as of October 2010. The primary objective of 
the trial was to determine the MTD of daily oral Ponatinib. Following oral administration, maximum 
plasma levels of Ponatinib occurred between 4 and 6 hours after dosing. The steady-state 
terminal elimination half-life (t1/2) was 20-28 hours for doses exceeding 15mg. Initial Ponatinib 
dosing was 2 mg orally once daily, escalating up to 60 mg once daily. At the 45 mg dose level, 1 
dose limiting toxicity (DLT) of grade 3 rash was observed. At the 60 mg dose level, 4 patients 
experienced DLTs of clinical pancreatitis or elevation of pancreatic enzymes. At this dose level, 1 
patient also experienced grade 3 fatigue and an additional patient experienced grade 3 elevated 
AST and ALT. Based upon these findings, the recommended Ponatinib dose for future phase 2 
clinical trials was 45 mg once daily.13 


Memorial Sloan Kettering Cancer Center 
IRB Number: 17-297 A(7) 
Approval date: 08-Oct-2019 
Administrative Update 1 : 10-Mar-2020 
Page 13 of 54 
 
 
 
AP24534-10-201 was conducted as a phase 2 registration trial of Ponatinib in patients with 
refractory CML and Philadelphia chromosome-positive ALL. 449 heavily pretreated patients who 
had CML or Ph-positive ALL were enrolled. Ponatinib was administered at an initial dose of 45 mg 
once daily. The median follow-up was 15 months. Among 267 patients with chronic-phase CML, 
56% had a major cytogenetic response, 46% had a complete cytogenetic response, and 34% had 
a major molecular response.14 
 
3.4.3 Clinically described adverse events with Ponatinib 
 
The adverse reactions described in this section were identified in AP24534-10-20, a phase 2 
registration trial of Ponatinib with CML or Ph+ ALL whose disease was considered to be resistant 
or intolerant to prior tyrosine kinase inhibitor (TKI) therapy including those with the BCR-ABL 
T315I mutation. All patients received a starting dose of 45 mg Ponatinib once daily. Overall, the 
most common non-hematologic adverse reactions (≥ 20%) were hypertension, rash, abdominal 
pain, fatigue, headache, dry skin, constipation, arthralgia, nausea, and pyrexia.   The rates of 
treatment-emergent adverse events resulting in discontinuation were 13% in CP-CML, 11% in 
AP-CML, 15% in BP-CML, and 9% in Ph+ ALL. The most common adverse events that led to 
treatment discontinuation were thrombocytopenia (4%) and infections (1%).   Dose modifications 
(dose delays or dose reductions) due to adverse reactions occurred in 74% of the patients. The 
most common adverse reactions (≥5%) that led to dose modifications include thrombocytopenia 
(30%), neutropenia (13%), lipase increased (12%), rash (11%), abdominal pain (11%), 
pancreatitis (6%), and ALT, AST, or GGT increased (6%). Complete description of toxicity 
information can be found in the must updated version of Ponatinib package insert.15 
Adverse Events of Special Concern 
 
Vascular Occlusion 
 
Arterial and venous thrombosis and occlusions, including fatal myocardial infarction, stroke, 
stenosis of large arterial vessels of the brain, severe peripheral vascular disease, and the need  
for urgent revascularization procedures have occurred in at least 27% of Ponatinib-treated 
patients from the phase 1 and phase 2 trials. Ponatinib can cause fatal and life-threatening 
vascular occlusion within 2 weeks of starting treatment. Ponatinib can also cause recurrent or 
multi-site vascular occlusion.  In the dose-escalation (phase 1) clinical trial, 49% (32/65) of 
patients with CML or Ph+ ALL developed vascular occlusive events. The median time to onset of 
the first vascular occlusion event was 5 months. Ponatinib can cause fatal and life-threatening 
vascular occlusion in patients treated at dose levels as low as 15 mg per day.  Patients with and 
without cardiovascular risk factors, including patients age 50 years or younger, experienced these 
events. Vascular occlusion adverse events were more frequent with increasing age and in 
patients with prior history of ischemia, hypertension, diabetes, or hyperlipidemia. 
 
Arterial Occlusion and Thrombosis 
 
Arterial occlusion and thrombosis occurred in at least 20% (92/449) of Ponatinib-treated patients 
with some patients experiencing events of more than one type. Patients have required 
revascularization procedures (cerebrovascular, coronary, and peripheral arterial) due to vascular 
occlusion from Ponatinib. 
 
Cardiac vascular occlusion, including fatal and life-threatening myocardial infarction and coronary 
artery occlusion has occurred in 12% (55/449) of Ponatinib-treated patients. Patients have 
developed heart failure concurrent or subsequent to the myocardial ischemic event. 
Cerebrovascular occlusion, including fatal stroke, has occurred in 6% (27/449) of Ponatinib- 


Memorial Sloan Kettering Cancer Center 
IRB Number: 17-297 A(7) 
Approval date: 08-Oct-2019 
Administrative Update 1 : 10-Mar-2020 
Page 14 of 54 
 
 
 
treated patients. Ponatinib can cause stenosis over multiple segments in major arterial vessels 
that supply the brain (e.g., carotid, vertebral, middle cerebral artery). 
 
Peripheral arterial occlusive events, including fatal mesenteric artery occlusion and life- 
threatening peripheral arterial disease, have occurred in 8% (38/449) of Ponatinib-treated 
patients. Patients have developed digital or distal extremity necrosis and have required 
amputations. Renal artery stenosis, associated with worsening, labile or treatment-resistant 
hypertension, has occurred in some Ponatinib-treated patients. 
 
Venous  Thromboembolism 
 
Venous thromboembolic events occurred in 5% (23/449) of Ponatinib-treated patients, including 
deep venous thrombosis (8 patients), pulmonary embolism (6 patients), superficial 
thrombophlebitis (3 patients), and retinal vein thrombosis (2 patients). 
3.6 Rationale for combination of Trametinib and Ponatinib: MEK and FGFR1 inhibition 
 
Recent efforts in the laboratories of Dr. Scott Lowe and Dr. Neal Rosen explored potential 
resistance mechanisms to MEK inhibition.16 In KRAS mutant lung cancer cell lines, while Trametinib 
stably inhibited ERK signaling initially, prolonged exposure resulted in increased ERK signaling, as 
measured by pERK, suggesting pathway reactivation occurs after prolonged drug exposure. 
Prolonged exposure to Trametinib also resulted in compensatory activation of the PI3K pathway 
(assessed by AKT phosphorylation). After demonstrating MEK inhibition alone was not sufficient 
for sustained MAPK inhibition, a pool-based shRNA screen was performed to identify genes whose 
inhibition 
sensitizes 
KRAS-mutant 
lung 
cancer cells to Trametinib. FGFR1 was 
identified as a top candidate and subsequent 
work 
demonstrated 
that 
exposure 
to 
Trametinib resulted in significant upregulation 
of FGFR1 expression and 
increase in 
phosphorylation of the FGFR adaptor protein 
FRS2. 
These 
findings 
were 
confirmed 
clinically as paired tumor biopsies of 2 
patients undergoing treatment with single 
agent Trametinib demonstrated increase in 
pFRS2 compared to pre-treatment biopsy. 
 
Knockdown of FGFR1 via shRNAs alone did 
not 
impact cell 
proliferation; synergistic 
effects were seen when combined with 
Trametinib. 
These 
findings led to 
the 
hypothesis that the combination of MEK and 
FGFR1 inhibition could enhance the activity of MEK inhibitors providing an effective therapeutic 
strategy for KRAS mutant lung cancers. Suppression of FGFR1 synergized with Trametinib to 
promote tumor cell death in vitro and in vivo. 
While this effect what seen with multiple FGFR inhibitors, the greatest synergy was observed with 
Ponatinib,  an  FDA-approved  multi-targeted  tyrosine kinase  inhibitor  that  blocks  signaling from 
Figure 1: In vivo effects of MEK/FGFR1 inhibition11 
Waterfall plot depicting tumor growth in genetically 
engineered mouse model of KrasG12D-induced lung 
adenocarcinoma treated with Trametinib and Ponatinib 
(as single agents and in combination). 


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FGFR as well as ABL.17  The combination of Trametinib and Ponatinib blocked the rebound in 
MAPK and PI3K signaling following Trametinib treatment, as measured by pERK and pAKT 
respectively. Combination therapy resulted in marked tumor regression in multiple in vivo models 
including KRAS-mutant patient derived xenografts and a genetically engineered mouse model of 
KRAS-mutant lung cancer (Figure 1).16 Sensitivity to the combination was precisely predicted by 
FRS2 phosphorylation, confirming its status as a measurable marker of FGFR activation. 
 
3.7 Benefit and Desired Outcome: 
 
While great strides have been made in identifying molecular drivers of NSCLC leading to the 
development of targeted therapies (EGFR, ROS1, ALK), strategies to combat KRAS driven 
tumors have been largely ineffective. Overcoming resistance to MEK inhibition with Trametinib 
through the addition of the FGFR inhibitor Ponatinib is an innovative approach to achieve 
sustained MAPK pathway inhibition. Tolerability and preliminary evidence of efficacy in this phase 
1/2 study would justify further evaluation of the combination, potentially changing our fundamental 
approach towards treating KRAS mutant NSCLC 
4.1 
OVERVIEW OF STUDY DESIGN/INTERVENTION 
 
4.2 
Design 
 
This phase 1/2 study is a single arm, open label, single institution study of Trametinib and 
Ponatinib in patients with KRAS mutant NSCLC 
Planned accrual: 
Phase 1: up to 12 patients (if only dose level 1-2 are used) 
 
Phase 2: up to 25 patients (including up 6 patients from Phase 1 portion) 
4.3 
Intervention 
 
Phase 1 
 
The phase 1 portion will be open to patients with KRAS mutant advanced stage NSCLC who have 
progressed following treatment with at least one line of platinum-doublet chemotherapy and at 
least one line of immunotherapy (PD-1 inhibitor). The study will follow a standard 3+3 dose 
escalation. All patients within a cohort will be observed for toxicity for 4 weeks, prior to enrollment 
at the next dose level. We predict three dose levels (33% and 67%of the MTD) of Ponatinib will  
be required. Given concerns of vascular events with escalating doses of Ponatinib, the MTD of 
Ponatinib (45mg) will not be explored. 
The FDA approved dose of Trametinib that has been evaluated in patients with NSCLC is 2mg 
daily and will be used in a continuous fashion. The FDA approved dose of Ponatinib is 45mg  
daily, and the dose will be 15mg or 30mg, depending on the dose level. If dose de-escalation is 
needed, the dose of Ponatinib will remain at 15mg daily and the dose of Trametinib will be 
decreased to 1.5mg, 1.0mg, and 0.5mg daily according to the dose level. By trial design, a 
maximum of 18 patients will be required to complete the phase I portion if only dose levels 1-3 are 
used. Patients who discontinue treatment before completing 21 of 28 days of therapy for reasons 
other than development of a DLT (progression of disease or withdrawal of consent) will be 


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replaced. Toxicity will be graded according to the National Cancer Institute Common Terminology 
Criteria for Adverse Events (NCI CTCAE) version 4.0. At the end of the phase 1 portion, a total of 
6 patients will have been treated at the MTD and will be counted towards accrual to the phase 2 
portion. Patients will continue to receive treatment until intolerable toxicity or progression of 
disease. All patients who receive at least one dose of treatment with Trametinib and Ponatinib will 
be evaluable for toxicity. Patients must receive at least 21 days of therapy to be considered 
evaluable for response. 
Phase 2 
 
Once the phase 1 portion of the study has been completed, patients will be enrolled in the phase 2 
portion of the single-arm, two-stage, open-label study of Trametinib and Ponatinib in the  
treatment of patients with KRAS-mutant lung cancers.  After screening and registration, patients 
will be treated with the combination of Trametinib and Ponatinib. Response to therapy will be 
assessed by interval imaging every 8 weeks (every 2 cycles) with CT scan of the chest and 
imaging of any other target lesion with response evaluated by RECIST 1.1.  Best overall response 
rate is the primary endpoint of the study. Patients remaining on trial will be followed for 6 months 
to determine best overall response rate and patients must receive at least 21 days of therapy to  
be considered evaluable for response. Following completion of the first stage, investigators will 
halt accrual until the first stage decision rule has been determined. A maximum of 25 patients will 
be enrolled in the phase 2 study. Dosing for the phase 2 portion of the study will depend on the 
results from MTD established in the Phase I portion of the study.  Patients will continue to receive 
treatment until intolerable toxicity or progression of disease. 
 
 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS 
 
5.1 Trametinib 
 
Drug: Trametinib (GSK 1120212) 
 
Classification: MEK inhibitor 
 
Chemical Name:  Acetamide, N-(3-{3-Cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]-6,8-dimethyl- 
2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl}phenyl)-dimethylsulfoxide 
Description: Trametinib dimethyl sulfoxide is a white to almost white powder 
 
Trametinib Tablets: Trametinib will be supplied at 0.5 mg and 1mg (as free base) tablets. 0.5mg 
tablets are white or yellow, modified oval, biconvex and film-coated. 
Schedule, route of administration, and dosing: Subjects will receive Trametinib at the prescribed 
dose by mouth once daily. In all subjects dose reductions and delays to manage toxicity are 
allowed under the guidelines in Section 11. Take by mouth on an empty stomach, either one hour 
before or two hours after a meal. 
Compliance: Drug accountability and subject compliance will be assessed with drug dispensing 
and return records 


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Study Drug Accountability: The investigator will maintain accurate records of receipt of all 
Trametinib, including dates of receipt. In addition, accurate records will be kept regarding when 
and how much study treatment is dispensed and used by each subject in the study. Reasons for 
deviation from the expected dispensing regimen will be recorded. At completion of the study, all 
unused Trametinib will be reconciled and destroyed in accordance with applicable state and 
federal regulations. 
 
Additional  information regarding Trametinib can be found in the Trametinib® Package Insert. 
5.2 Ponatinib 
 
Drug: Ponatinib 
 
Classification: kinase inhibitor 
 
Chemical Name:  3-(imidazo[1,2-b]pyridazin-3- ylethynyl)-4-methyl-N-{4-[(4-methylpiperazin-1- 
yl)methyl]-3-(trifluoromethyl)phenyl}benzamide   hydrochloride 
Description: Ponatinib hydrochloride off-white to yellow powder 
 
Ponatinib Tablets: Ponatinib will be supplied at 15 mg (as free base) tablets. 
 
Schedule, route of administration, and dosing: Subjects will receive dose of Ponatinib according  
to dose level as outlined section 4.2. In all subjects dose reductions and delays to manage toxicity 
are allowed under the guidelines in Section 11. Take by mouth on an empty stomach, either one 
hour before or two hours after a meal. 
Compliance: Drug accountability and subject compliance will be assessed with drug dispensing 
and return records 
Study Drug Accountability: The investigator will maintain accurate records of receipt of all 
Trametinib, including dates of receipt. In addition, accurate records will be kept regarding when 
and how much study treatment is dispensed and used by each subject in the study. Reasons for 
deviation from the expected dispensing regimen will be recorded. At completion of the study, all 
unused Ponatinib will be reconciled and destroyed in accordance with applicable state and federal 
regulations. 
Additional information regarding Ponatinib can be found in the Ponatinib® Package Insert. 
 
 
6.1 
CRITERIA FOR SUBJECT ELIGIBILITY. 
 
6.2 
Subject Inclusion Criteria 
 
• 
Histologically or cytologically proven diagnosis of advanced lung adenocarcinoma 
• 
KRAS mutation 
• 
Radiographic progression following prior treatment with platinum doublet chemotherapy 
and prior treatment with a PD-1 inhibitor. Patients who are deemed not eligible for therapy 
with a PD-1 inhibitor by their treating physician will also be eligible. 
• 
Able to take oral medications 


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• 
Measurable disease as per RECIST 1.1. Previously irradiated sites of tumor may be 
considered measurable if there is radiographic progression at the site subsequent to the 
time of completing radiation. 
• 
Karnofsky performance status (KPS) ≥ 70% 
• 
Age >18 years old 
• 
Adequate organ function: 
- 
AST, ALT ≤ 2.5 x ULN - Total bilirubin ≤ 1.5 x ULN -Albumin≥2.5g/dL 
- 
Creatinine < 1.5 x ULN OR calculated creatinine clearance ≥50mL/min 
- 
Absolute neutrophil count (ANC) ≥ 1,200 cells/mm3 
- 
Hemoglobin≥9.0  g/dL 
- 
Platelets ≥100,000/mm3. 
- 
Amylase and lipase within normal limits (amylase ≤100, lipase ≤78) 
 
• 
Female patients who: 
− 
Are postmenopausal for at least 1 year before the screening visit, OR 
− 
Are surgically sterile, OR 
− 
If they are of childbearing potential, agree to practice 2 effective methods of 
contraception, at the same time, from the time of signing the informed consent 
through 30 days after the last dose of study drug, or agree to completely abstain 
from heterosexual intercourse 
• 
Male patients, even if surgically sterilized (i.e., status post-vasectomy), who: 
− 
Agree to practice effective barrier contraception during the entire study treatment 
period and through 30 days after the last dose of study drug, or 
− 
Agree to completely abstain from heterosexual intercourse 
6.3 
Subject Exclusion Criteria 
 
Patients are to be excluded from the study if they meet any of the following c riteria: 
 
• Patients with symptomatic brain metastasis requiring escalating doses of steroids 
• Patients with grade 2 or greater diarrhea prior to study initiation despite maximal medical 
management 
• History of acute pancreatitis within 1 year of study entry or history of chronic pancreatitis. 
• History of or ongoing alcohol abuse that, in the opinion of the Investigator, would 
compromise compliance or impart excess risks associated with study participation. 
• Pregnant or lactating women 
• Any type of systemic therapy (chemotherapy or experimental drugs) within 2 weeks of 
starting treatment on protocol 
• Patients who have received prior treatment with MEK inhibitor 
• A history of clinically significant interstitial lung disease or pneumonitis 
• Significant uncontrolled or active cardiovascular disease, specifically including, but not 
restricted to: History of clinically significant (as determined by the treating physician) atrial 
arrhythmia; or any ventricular arrhythmia, History of congenital long QT syndrome., 
Abnormal QTc (≥ 450 msec in males and ≥ 470 msec in females), Ejection fraction ≤ 50% 
as assessed by echocardiogram. 


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• History of arterial thrombotic disease, specifically including, but not restricted to: Myocardial 
infarction or unstable angina, cerebrovascular event (CVA) or transient ischemic attack 
(TIA), Peripheral vascular disease or claudication. 
• Uncontrolled hypertension (Diastolic blood pressure > 100 mmHg; Systolic blood pressure 
> 150 mmHg). 
• History of venous thromboembolism (e.g. deep venous thrombosis or pulmonary embolism) 
within 6 months of study entry. Note: Participants enrolled after this window must be on 
appropriate therapeutic anticoagulation. 
• History of central serous retinopathy or retinal vein occlusion 
• Patients with baseline risk factors for central serous retinopathy or retinal vein occlusion 
such as evidence of new optic disc cupping, evidence of new visual field defects, and 
intraocular pressure >21 mmHg are excluded from the trial 
• History of prior malignancy within 2 years that requires treatment. Patients who are 
considered NED from a malignancy may be considered on a case by case basis. 
• Any other condition that, in the opinion of the investigator, may compromise the safety, 
compliance of the patient, or would preclude the patient from successful completion of the 
study 
 
7.0 
RECRUITMENT PLAN 
 
A member of the patient's treatment team, the protocol investigator, or research team at the 
Memorial Sloan Kettering Cancer Center will identify poential research participants. If the 
investigator is part of the treatment team s/he will screen the patient as to eligibility and will 
discuss the study and possibility of enrollment in the research study with the patient. The 
preliminary screen of eligibility will be confirmation of the diagnosis of NSCLC, ascertaining the 
exact stage of the disease and confirmation of the presence of a KRAS mutation. Potential 
subjects that meet these basic criteria will be referred by their treating physician to the 
investigator/research staff of the study. 
Minorities and women are well represented in the thoracic oncology clinics and we expect that 
they will be well represented in the trial accrual. The principal investigator, Kathryn Arbour, will be 
available to all patients for further questions and information through a contact number which will 
be provided on the consent form itself. 
Additional participants may be identified by several institutional databases. The IMPACT  project 
tests all consented patients for mutations in 410 genes including the KRAS mutation. The protocol 
is in place to identify all patients with a targetable mutation and to guide them to appropriate 
clinical trials. Patient identified in this manner will be approached about possible participation in 
this clinical trial. 
During the initial conversation between the investigator/research staff and the patients, the patient 
may be asked to provide certain health information that is necessary to the recruitment and 
enrollment process. The investigator/research staff may also review portions of their medical 
records at MSKCC in order to assess eligibility. They will use the information provided by the 
patient and/or medical records to confirm that the patient is eligible and to contact the patient 
regarding study enrollment. If the patient turns out to be ineligible for the research study, the 
research staff will destroy all information collected on the patients during the initial conversation 


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and medical records review, except for any information that must be maintained for screening log 
purposes. 
8.1 
PRETREATMENT EVALUATION 
 
Study eligibility is based on meeting all of the study inclusion criteria and none of the exclusion 
criteria at screening. The following assessments will be conducted prior to subjects receiving their 
first dose of Trametinib and Ponatinib on this protocol. All aspects of the screening evaluation 
(with the exception of radiologic tumor assessments) should be completed within 2 weeks of 
starting treatment: 
• 
Documented presence of a KRAS mutation 
• 
Full medical history and physical examination 
• 
Baseline tumor assessment: of the CT scan of the chest (and other additional studies 
based on the patient’s known sites of disease). 
• 
Complete vital signs (pulse, blood pressure, temperature, respiratory rate) as well as 
weight 
• 
12 lead electrocardiogram (ECG) and echocardiogram within 1 month of study initiation 
• 
Serum pregnancy test for women of child bearing potential 
• 
Complete blood count with differential 
• 
Comprehensive metabolic panel (glucose, blood urea nitrogen, creatinine, sodium, 
potassium, chloride, bicarbonate, calcium, total protein, albumin, serum bilirubin, alkaline 
phosphatase, ALT, AST) 
• 
Pancreatic enzymes (amylase, lipase) 
• 
Ophthalmology Exam (See Section 10 for more details) 
• 
Biopsy for baseline tumor tissue (required only for patients in the Phase II portion of the 
study) 
9.0 
TREATMENT/INTERVENTION PLAN 
9.1.1 Therapeutic Agent-Trametinib 
Trametinib is given once daily and should be taken by mouth on an empty stomach, either one 
hour before or two hours after a meal, at approximately the same time of the day each day 
 
A pill diary will be used to record adherence. 
 
9.1.2 Therapeutic Agent-Ponatinib 
 
Ponatinib is given once daily and should be taken by mouth on an empty stomach, either one 
hour before or two hours after a meal at approximately the same time of the day each day. A pill 
diary will be used to record adherence. 
9.2 Treatment Arms 
 
All patients will receive Trametinib and Ponatinib in this single-arm study. 
 
9.3 Study design 
 
Table 9.3.1: Cohort dose levels for Trametinib and Ponatinib 
 
Dose levels 
Trametinib Dose 
Ponatinib Dose 


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Dose level -3 
0.5mg PO q daily 
15mg PO q daily 
Dose Level -2 
1.0 mg PO q daily 
15mg PO q daily 
Dose Level -1 
1.5mg PO q daily 
15mg PO q daily 
Dose Level 1 
2 mg PO q daily 
15mg PO q daily 
Dose Level 2 
2 mg PO q daily 
30mg PO q daily 
 
 
Phase 1: The phase I portion will accrue cohorts of 3-6 patients (maximum enrollment: 18  
patients if no de-escalation). Patients will receive Trametinib once daily and Ponatinib once daily 
as defined by dose level outline in table 9.3.1. Three patients will be enrolled per dose level. Each 
group of patients enrolled at the same dose level comprises a cohort. Patients in each cohort 
must complete at 4 weeks of study therapy (28 days) prior to enrollment of the next cohort. 
Patients will be monitored for toxicity weekly for the first cycle (4 weeks per cycle) and on week 1 
of each cycle thereafter. Dose-limited toxicities are described in section 9.4 below. Patients will be 
monitored for response by CT every 2 cycles (8 weeks). The schedule of evaluations and 
interventions is described in section 10.0.  Patients who do not complete at least 21 out of 28  
days of treatment for reasons other than developing a DLT (e.g. withdrawal of consent or 
progression of disease), will be replaced. Patients will continue to receive treatment until 
intolerable toxicity or progression of disease. 
Phase 2: All patients will receive Trametinib and Ponatinib at the MTD defined during the phase 1 
portion of the study. Patients will be monitored for response by CT every 2 cycles (8 weeks). The 
schedule of evaluations and interventions is described in Section 10.0. Patients will continue to 
receive treatment until intolerable toxicity or progression of disease. 
 
 
9.4 Dose Limiting Toxicities: 
 
The NCI Common Terminology Criteria for Adverse Events Version 4.0 (NCI CTCAE) will be used 
to grade toxicities during the trial. Dose limiting toxicities (DLTs) are defined as any of the  
following events occurring during the first cycle of treatment (i.e. 4 weeks) that are, in the opinion 
of the treatment physician, possibly, probably, or definitely related to the investigational regimen: 
• 
Death related to the investigational regimen 
• 
Any toxicities for which the dose modification tables (in section 11) recommends 
discontinuation or dose reduction of Trametinib or Ponatinib 
• 
Hematologic toxicities including: 
o Grade=4 neutropenia lasting >5 days 
o Grade=4 thrombocytopenia (<25,000/mm3) 
o Grade= 3 thrombocytopenia with evidence of clinically significant bleeding 
o Grade=4 anemia 
• 
Non-hematologic toxicities include: 
o Grade ≥ 3 AST, ALT, alkaline phosphatase, total bilirubin, amylase, or lipase 
o Grade  3 diarrhea, nausea, vomiting that lasts >72 hours despite optimal maximum 
supportive care 
o Grade 4 diarrhea, nausea, vomiting 


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o Any other non-hematologic grade  ≥3  major organ toxicity not described in section 
11, specifically renal toxicity 
o Central serous retinopathy or retinal vein occlusion 
o Arterial or venous thrombotic event 
Patients in each cohort must complete the first four weeks of study therapy prior to enrollment of 
subsequent cohorts as outlined in Table 9.4.1.The MTD will be defined at the highest dose where 
not more than 1 of the 6 patients develops a DLT. Dose levels are outlined in Table 9.3.1 above 
Table 9.4.1: Dose Escalation Schema 
 
# of patients with DLT at a given dose level 
Escalation decision rule 
0 of 3 
Enter the next cohort (3 patients) at the next 
dose level 
1 of 3 
Enter next cohort (3 patients) at the same 
dose level 
• 
If 0 of 3 experience DLT, proceed to 
the next dose level 
• 
If 1 or more experience DLT, dose 
escalation stopped. 3 additional 
patients will be entered at the next 
lowest dose level is only 3 patients 
were treated previously at that dose 
level 
> 2 of 3 
Dose escalation stopped. 3 additional patients 
will be entered at the next lowest dose level if 
only 3 patients were treated previously at that 
dose level 
< 1 of 6 at the highest dose level 
Recommended phase II dose. 6 patients must 
be entered at the recommended phase II dose 
prior to proceeding to the phase II study 
 
 
9.5 Supportive Care 
 
Palliative and supportive care for disease related symptoms may be administered at the 
investigator's discretion and according to available American Society of Clinical Oncology (ASCO) 
guidelines. All concomitant medications and blood products, as well as interventions 
(thoracentesis, paracentesis, etc) will be recorded in the patient's medical records. 
9.6 Correlative Studies: Biopsies will be required prior to start of study treatment, 28 +/- 7 days 
after initiation of study drug and at the time of progression for patients participating in the Phase II 
portion of the trial. This biopsy is mandatory unless there is a safety reason not to perform. For 
example, if due to the location of the tumor, the biopsy is high risk as decided by treating 
physician. At prespecified time points, patients will have image-guided core needle biopsies with 
3-4 cores obtained. Blood will also be used to obtain germline DNA for next-generation 
sequencing based testing if not obtained previously. One fixed core will be used for 
immunohistochemistry to determine protein expression for transcripts of interest, including:  
pERK, pFRS2 and pAKT. 


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Plasma will be collected during pretreatment evaluation and at the time of each radiographic 
assessment for ctDNA analysis (for Phase I and Phase II patients). 
1) Samples should be sent same day, ambient with overnight delivery via FedEx to: 
a. Translational Research Laboratory 
Dana-Farber Cancer Institute 
Attn. Bryan Ulrich (e-mail: Bryan_Ulrich@DFCI.HARVARD.EDU) 
360 Longwood Ave. / LC4202 
Boston, MA 02215 
 
2) Samples can be shipped Monday through Thursday, but not on Fridays, weekends and 
holidays.  Samples can be kept at room temperature, onsite, until Dana-Farber Cancer 
Institute can receive the samples for processing (i.e. Friday blood draws should be 
shipped Monday). 
 
 
Samples are to be de-identified, labeled without PHI identifiers, and shipped with requisition form, 
cooling gel packs in Styrofoam container and cardboard shipping box with appropriate absorbent 
materials and dangerous goods warning label. 
 
 
10.1 EVALUATION DURING TREATMENT/INTERVENTION 
 
Table 10.1 outlines the schedule of assessments. If the subject is unable to have a study 
assessment taken within the defined time window due to an event outside of his or her control 
(e.g. clinic closure, personal emergency, inclement weather, vacation) the assessment should be 
performed as close as possible to the required schedule. Subjects will return to the study site 
within 30 days after their last dose of Trametinib and Ponatinib to complete end of study 
assessments outlined below. Additional follow up will occur for subjects with AEs related to study 
treatment that are ongoing at the time of this visit and for subjects with SAEs related to study 
treatment that occur after the time of this visit. 
 
 
Table 10.1 Study Calendar 
 
1 cycle=28 days 
Screening 
Cycle 1 
Cycle 2 
Cycle 3+ 
At 
progression/ 
Off Study 
Within 2 
weeks 
unless 
otherwise 
noted 
C1D1 
C1D8 
C1D15 
C2D1 
Day 1 
Informed 
Consent11 
X 
Medical History 
X 
X 
X 
X 
X 
X 
X 
Concurrent 
Medication 
Reconciliation 
X 
X 
X 
X 
X 
X 
X 
Physical Exam 1 
X 
X 
X 
X 
X 
X 
X 


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Ophthalmology 
Exam 2 
X 
X 
Complete Blood 
Count w/ 
differential1 
X 
X 
X 
X 
X 
X 
Serum Chemistries 
1,3 
X 
X 
X 
X 
X 
X 
Pancreatic 
Enzymes 4 
X 
X 
X 
X 
X 
X 
12 lead EKG5 
X 
X 
X 
Echocardiogram6 
X 
X6 
Adverse Events 
Evaluation1 
X 
X 
X 
X 
X 
X 
X 
Radiologic Tumor 
Assessments7 
X 
X 
X 
B-HCG8 
X 
Tumor Tissue9 
X 
X 
X 
Research blood for 
10
X 
X 
X 
 
1. Study Assessments (physical exams, vitals, weight, CBC, CMP, adverse events evaluation) will be repeated 
C1D1, C1D15 (first cycle), then monthly subsequently. C1 assessments have a window of +/- 3 days; C2 
onward assessments have a window of +/- 2 weeks. In addition, on C1D8, patients will have study 
assessments including physical exam, adverse event evaluation. 
2. Baseline Opthalmic exam will include visual acuity, visual field examination, tonometry, slit lamp 
biomicroscopyof the anterior segment (with special attention to inflammation) and the posterior segment, and 
indirect funduscopic examination with special attention to possible retinal abnormalities. Exams are required at 
screening, cycle 2 day 1 +/- 2 week, and cycle 6 day 1 +/- 4 weeks. Additional ophthalmic exams will be 
performed if symptomaticallywarranted. 
3. Serum chemistries includes glucose, blood urea nitrogen, creatinine, sodium, potassium, chloride, 
bicarbonate, calcium, phosphorus, total protein, albumin, serum bilirubin, alkaline phosphatase, ALT, AST4. 
Pancreatic enzyme analysis includes amylase and lipase 
5. A single 12 lead ECG should be performed at screening and day 1 of every cycle +/- 2 weeks. 
6. Echocardiogram should be performed at screening, after 4 weeks, and every 12 weeks thereafter (+/- 2 
weeks) 
7. Response to therapywill be assessed byinterval imaging studies every 2 cycles (8 weeks) +/- 2 weeks with 
response evaluated using RECIST version 1.1. Radiologic imaging will include a CT chest +/- abdomen/pelvis 
depending on sites of disease with or without contrast and CT/MRI brain (if screening CT/MRI brain identified 
brain metastases). Screening radiologic tumor assessments are required within 4 weeks of start of treatment. 
If an appropriate imaging studyis performed earlyfor any reason (i.e. hospitalization), it can be used for 
disease assessment. CT scans should be completed if the patient comes off study for any reason other than 
progression. If a CT scan was completed within the last 8 weeks, it will not need to be repeated.8. B -HCG 
testing (serum or urine) should be performed onlyin women of child bearing potential. Follow up of elevated B- 
HCG will be determined in accordance to MSKCC policy. 
9. Tumor biopsywill be performed within 1 month of treatment initiation, at day 28+/-7 days after initiation of 
study drugs, and at time of progression +/- 4 weeks for patients in the Phase II portion of the study. 
10. Blood for plasma ctDNAtesting to be collected before treatment on Cycle 1 Day 1 and every 8 weeks 
thereafter. One 10mL Streck tube of blood will be drawn with each blood draw. 
11. Informed Consent can be obtained up to 28 days p rior to Screening. 
 
After completion of the study drug, the patients will be followed for overall survival data. This data 
will be obtained by review of the MSKCC electronic medical record. 
 
 
11.0 
TOXICITIES/SIDE EFFECTS 
 
Toxicity grading will be performed in accordance with NCI CTCAE version 4.0. If toxicities are 
encountered, dosing adjustments will be made based on the likely causative agent as outlined 
below. If toxicities continue despite dose reductions and it is clear by the nature of the side effect 


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which is the causative agent, the treating physician may choose to discontinue the causative 
agent and may continue the patient on the other drug as monotherapy. During cycle 1 of phase 1 
portion, doses of drugs will not be dose reduced unless a DLT has been declared. 
11.1 Management of Trametinib related toxicities: 
 
Toxicities with Trametinib that are likely (>20%) include: 
• 
Fatigue 
• 
Rash 
• 
Diarrhea 
• 
Nausea/Vomiting 
• 
Leg or arm swelling 
• 
Constipation 
• 
Decreased appetite 
• 
Decreased red block cell count leading to fatigue 
 
Toxicities with Trametinib that are less likely (<20%) include: 
• 
dehydration 
• 
Cough 
• 
Shortness of breath 
• 
Itching 
• 
Abdominal pain 
• 
Dry skin 
• 
Fever/chills 
• 
Dizziness 
• 
Pain in the bones 
• 
Difficulty sleeping 
• 
Dry mouth 
• 
Headache 
• 
Increases in blood pressure 
• 
Loss of hair 
• 
Headaches 
• 
Blurry vision 
• 
Changes or infection in fingernails 
 
Side effects of Trametinib that are rare, but serious include: 
• 
Changes in the eye that can cause blindness or serious vision problems 
(Chorioretinopathy or central serous retinopathy (CSR), retinal vein occlusion (RVO), 
Retinal Detachment) 
• 
Impaired heart function (decreased in cardiac ejection fraction) 
• 
Liver failure or abnormalities in the liver function blood tests 
• 
Pneumonitis 
• 
Infections in the lung or urinary tract 
Trametinib Dose Modifications 
The tables below outline the dose levels to be used for any necessary Trametinib dose 
modification: 
 
Dose Reduction Trametinib Dose/Schedule 
-1 
1.5mg QD 
-2 
1mg QD 


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A maximum of two Trametinib dose level reductions are allowed.  If a third dose level reduction is 
required, treatment will be permanently discontinued. If dose reduction beyond dose level -3 is 
required (0.5mg), treatment will be permanently discontinued. 
 
Trametinib Dose Modification for Toxicities Not Specified in Subsequent Sections 
 
Trametinib Treatment Modification for  Clinically Significant Toxicities Deemed Related to 
Trametinib 
(This section is not for specific AEs such as rash, pneumonitis, diarrhea,  liver chemistry, QTc 
prolongation,  or visual changes.   Refer to other sections for these specific AEs). 
CTCAE  v4 
Grade 
Dose  Modification 
Management Guideline 
Grade 1 
Continue Trametinib  at current dose level. 
Monitor as clinically indicated. 
Provide  supportive  care 
according  to institutional 
standards 
Grade 2 
• Consider interrupting  treatment until resolution to 
grade 1 or baseline. 
• Upon resolution, restart treatment at current dose 
level. 
Grade 3 
• Interrupt  Trametinib  if clinically indicated 
• When toxicity resolves to Grade 1 or baseline, restart 
Trametinib  reduced by one dose level. 
• If the Grade 3 toxicity recurs, interrupt  Trametinib; 
When toxicity resolves to grade ≤1, restart  Trametinib 
reduced by another dose  level 
Grade 4 
• 
Interrupt  treatment until resolution to grade ≤1 
Upon resolution to grade ≤1, restart with one 
level of dose reduction. 
• 
It toxicity does not resolve  to ≤1 or baseline, 
permanently  discontinue Trametinib. 
Trametinib  should be discontinued if treatment delay is >28 days due to toxicities.  If the investigator 
concludes that continued Trametinib  will benefit  a patient, the study PI may be consulted for the 
possibility of resuming  Trametinib,  provided  that toxicities have  resolved  to grade ≤1. 
 
 
11.2 Management of Ponatinib related toxicities: 
 
Toxicities with Ponatinib that are likely (>20%) include: 
• 
Low blood counts including white blood cells, red blood cells, and platelets 
• 
Increased serum lipase 
• 
Increase in liver enzymes (AST and/or ALT) 
• 
Abdominal pain 
• 
Nausea 
• 
Vomiting 
• 
Constipation 
• 
Diarrhea 
• 
Decreased appetite 
• 
Fever 
• 
Fatigue 
• 
Weakness 
• 
Pain 
-3 
0.5mg QD 


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IRB Number: 17-297 A(7) 
Approval date: 08-Oct-2019 
Administrative Update 1 : 10-Mar-2020 
Page 27 of 54 
 
 
 
• 
Headache 
• 
Dry skin 
• 
Skin rash 
• 
High blood pressure 
• 
Shortness of breath 
• 
Fluid retention 
• 
Pain that may occur in the joints, muscles, bone, back, or limbs 
Toxicities with Ponatinib that are less likely (<20%) include: 
• 
Pancreatitis 
• 
Stroke 
• 
Heart attack 
• 
Irregular heart rhythm including atrial fibrillation, supraventricular tachycardia, or 
bradycardia 
• 
Impaired heart function (decreased in cardiac ejection fraction) 
• 
Increase in bilirubin 
• 
Hyperglycemia 
• 
Hyperuricemia 
• 
Electrolyte disturbances including hyponatremia, hypokalemia, hypophosphatemia, 
hypocalcemia and/or hypophosphatemia 
• 
Heartburn, indigestion, or upset stomach 
• 
Mucositis 
• 
Bloating 
• 
Weight loss 
• 
Muscle cramps and pain 
• 
Dizziness 
• 
Cough 
• 
Upper respiratory infection 
• 
Pneumonia 
• 
Sepsis 
• 
Febrile neutropenia 
• 
Cranial or peripheral neuropathy 
• 
Peripheral vascular disease 
• 
Insomnia 
• 
Voice impairment such as hoarseness 
 
Side effects of Ponatinib that are rare, but serious include: 
• 
Venous thromboembolic events (DVT, PE) 
• 
Liver failure or abnormalities in the liver function blood tests 
• 
Changes in the eye that can cause blindness or serious vision problems (including 
macular edema, retinal vein occlusion, and retinal hemorrhage) 
• 
Bleeding events 
• 
Pleural effusion 
• 
Pericardial effusion 
 
Ponatinib Dose Modifications 
The tables below outlines the dose levels to be used for any necessary Ponatinib dose 
modification: 
 
 
Dose 
Reduction 
Trametinib Dose/Schedule 


Memorial Sloan Kettering Cancer Center 
IRB Number: 17-297 A(7) 
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Administrative Update 1 : 10-Mar-2020 
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A maximum of one Ponatinib dose level reductions are allowed.  If a third dose level reduction is 
required, treatment will be permanently discontinued. If dose reduction beyond dose level -1 is 
required (15mg), treatment will be permanently discontinued. 
 
 
Ponatinib Dose Modification for Toxicities Not Specified in Subsequent Sections 
 
Ponatinib Treatment Modification for Clinically Significant Toxicities Deemed Related to 
Ponatinib 
(This section is not for specific AEs such as liver chemistry, pancreatitis,  and hematologic  toxicity.  Refer 
to other sections for these specific AEs). 
CTCAE  v4 
Grade 
Dose  Modification 
Management Guideline 
Grade 1 
Continue Ponatinib at current dose level. 
Monitor as clinically indicated. 
Provide  supportive  care 
according  to institutional 
standards 
Grade 2 
• Consider interrupting  treatment until resolution to 
grade 1 or baseline. 
• Upon resolution, restart treatment at current dose 
level. 
Grade 3 
• Interrupt  Ponatinib  if clinically indicated 
• When toxicity resolves to Grade 1 or baseline, restart 
Ponatinib reduced by one dose level (15mg) 
• If the Grade 3 toxicity recurs, interrupt  Ponatinib; 
When toxicity resolves to grade ≤1, restart  Trametinib 
reduced by another dose  level 
Grade 4 
• 
Interrupt  treatment until resolution to grade ≤1 
Upon resolution to grade ≤1, restart with one 
level of dose reduction. 
• 
It toxicity does not resolve  to ≤1 or baseline, 
permanently  discontinue Ponatinib 
Ponatinib should be discontinued if treatment delay is >28 days due to toxicities.  If the investigator 
concludes that continued Ponatinib will benefit  a patient, the study PI may be consulted for the 
possibility of resuming  Ponatinib, provided  that toxicities have  resolved  to grade ≤1. 
 
 
11.3 Specific Dose Modifications: 
 
11.3.1 Rash 
 
Rash is a frequent AE observed in patients receiving Trametinib (package insert). 
Recommendations for supportive care and guidelines for dose modifications for rash are based  
on experience with other MEK inhibitors18,19. Patients should be informed that skin toxicity is likely 
during treatment with Trametinib. Skin toxicity can take the form of dry skin, rash, acneiform 
eruption, and hair/nail changes. Prophylactic treatment of the skin for Phase I participants with the 
recommendations below may prevent or reduce skin toxicity. Participants enrolled into the Phase 
II portion of the study will be required to follow the guidelines below for supportive care of rash. 
 
Patients with significant skin toxicity will be referred to dermatology for management. Any 
treatment provided must be documented in the participants medical record. For more severe 
cases, oral corticosteroids may be administered. Patients who fail to respond to these measures 
may have Trametinib interrupted, dose reduced, or discontinued. 
-1 
15mg QD 


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IRB Number: 17-297 A(7) 
Approval date: 08-Oct-2019 
Administrative Update 1 : 10-Mar-2020 
Page 29 of 54 
 
 
 
 
 
 
Guidelines for Supportive  Care of Rash 
Type of Care 
Recommendations 
Prevention/Prophylaxisa 
• Avoid unnecessary exposure to sunlight. 
• Apply broad-spectrum sunscreen (containing titanium dioxide or 
zinc oxide) with a skin protection factor (SPF) ≥15 at least twice 
daily. 
• Use thick, alcohol-free  emollient cream (e.g., glycerine and 
cetomacrogol cream) on dry areas of the body at least twice daily. 
• Topical steroids and antibiotics should be applied at least twice 
daily, starting on Day 1 of study treatment, to affected  body areas 
such as face, chest, and upper back. 
Symptomatic  Careb 
• Pruritic lesions:  Cool compresses and oral antihistamine therapies. 
• Fissuring lesions:  Monsel’s solution, silver nitrate, or zinc oxide 
cream. 
• Desquamation:   Thick emollients and mild soap. 
• Paronychia:   Antiseptic bath, local potent corticosteroids in addition 
to antibiotics; if no improvement,  consult dermatologist  or surgeon. 
• Infected lesions:  Appropriate  bacterial/fungal  culture-driven 
systemic or topical antibiotics. 
a Rash prophylaxis  is recommended  for the first 6 weeks of study treatment. 
b Patients who develop  rash/skin toxicities should be seen by a qualified  dermatologist and should 
receive  evaluation  for  symptomatic/supportive  care management. 
 
 
 
Trametinib Dose  Modification Guidelines and Management for Rash 
Rash  Severity 
Management Guideline 
Dose  Modification 
Grade 1 
• Initiate prophylactic and 
symptomatic  treatment 
measures.1 
Continue Trametinib  at same dose level. 
Grade 2 
Initiate prophylactic and 
symptomatic  treatment 
measures.1 
Continue at same dose level.  If rash persists or 
worsens over  14 days consider dose reduction of 
Trametinib  by one dose level at discretion of 
investigator. 
Grade 3 
Suggest withholding  Trametinib  until toxicity is 
grade ≤2. If rash persists or worsens over  14 
days, consider dose reduction at discretion of 
investigator.2 
Grade 4 
Withhold Trametinib until toxicity is grade ≤2. 
Restart with Trametinib  reduced by one dose 
level.2  If No recovery  to ≤ grade 2 within 4 weeks, 
permanently  discontinue Trametinib 
1. Rash prophylaxis  is recommended  for the first 6 weeks of study treatment. See above  table. 
2. Trametinib may be escalated to previous  dose level if no rash is evident  4 weeks after restarting 
study treatment. 
 
11.3.2 Diarrhea 


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IRB Number: 17-297 A(7) 
Approval date: 08-Oct-2019 
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Episodes of diarrhea have occurred in patients receiving Trametinib and Ponatinib, though less 
commonly (package insert).  Other frequent causes of diarrhea may include concomitant 
medications (e.g., stool softeners, laxatives, antacids, etc.), infections by C. difficile or other 
pathogens, or partial bowel obstruction.  Those conditions should be excluded, as clinically 
indicated. 
 
Guidelines regarding management and dose modification for diarrhea considered related to 
Trametinib and/or Ponatinib are provided in the table below. 
 
Management and Trametinib Dose  Modification Guidelines for  Diarrhea 
CTCAE  Grade 
Adverse  Event Management 
Action and Dose  Modification 
Grade 1 or 2 
• Diet:  Stop all lactose containing 
products; eat small meals, 
BRAT-diet  (bananas,  rice, 
apples,  toast) recommended. 
• Hydration:   8-10 large glasses 
of clear liquids per day (e.g., 
Gatorade or broth). 
• Loperamide1:   Initially 4 mg, 
followed  by 2 mg every  4 hours 
or after every  unformed  stool; 
maximum 16 mg/day.  Continue 
until diarrhea-free  for 12 hours. 
• Lomotil1: 2.5-5mg of 
diphenoxylate up to 4x a day; 
maximum 20mg/daily. Continue 
until diarrhea-free  for 12 hours. 
• Diarrhea  >24 hours: 
Loperamide  2 mg every  2 
hours; maximum 16 mg/day. 
Consider adding oral antibiotics. 
• Continue  Trametinib  and/or 
Ponatinib at same dose. Initiate 
adverse  event  management 


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IRB Number: 17-297 A(7) 
Approval date: 08-Oct-2019 
Administrative Update 1 : 10-Mar-2020 
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Management and Trametinib Dose  Modification Guidelines for  Diarrhea 
CTCAE  Grade 
Adverse  Event Management 
Action and Dose  Modification 
Grade 3 diarrhea 
• Clinical evaluation  mandatory. 
• Loperamide1:   Initially 4 mg, 
followed  by 2 mg every  4 hours 
or after every  unformed  stool; 
maximum 16 mg/day.  Continue 
until diarrhea-free  for 12 hours. 
• Lomotil1: 2.5-5mg of 
diphenoxylate up to 4x a day; 
maximum 20mg/daily. Continue 
until diarrhea-free  for 12 hours. 
• Oral antibiotics and second-line 
therapies  if clinically indicated 
• Hydration:   Intravenous   fluids if 
clinically indicated. 
• Antibiotics (oral or intravenous) 
if clinically indicated. 
• Intervention  should be 
continued until the subject is 
diarrhea-free  for ≥24 hours. 
• Intervention  may require 
hospitalization for  subjects at 
risk of life-threatening 
complications. 
• Interrupt  Trametinib  and/or 
Ponatinib until diarrhea resolves 
to ≤ grade 2. 
• Restart treatment at same dose 
or with a dose reduction at 
discretion of investigator.2 
Grade 4 
• Withhold Trametinib  and/or 
Ponatinib until toxicity is grade 
<=2. Initiate adverse  event 
management.  Discontinue 
permanently  or restart with a 
dose reduction at the discretion 
of the investigator.2 
1. Loperamide  and Lomotil should be made available  prior to start of study treatment so loperamide 
administration can begin at the first signs of diarrhea. 
2. Escalation of Trametinib and/or Ponatinib to previous dose level is allowed after consultation with the 
medical monitor and in the absence of another episode of complicated or severe diarrhea in the 4 weeks 
subsequent  to dose reduction. 
 
 
11.3.3 Pancreatitis and elevation of Lipase: 
 
 
Pancreatitis (symptomatic abdominal pain associated with pancreatic enzyme elevation)  and/or 
elevations in lipase and amylase are known AEs associated with Ponatinib. Pancreatitis was 
reported in 7% of patients in the phase 2 study of Ponatinib and 12% in the phase 1 dose- 
escalation study. Most cases of pancreatitis or elevated pancreatic enzymes occur within the first 
month of treatment with Ponatinib. The events are generally uncomplicated and reversible and 
can be managed with a brief interruption of treatment and standard medical therapies. Almost all 
patients are able to continue on with Ponatinib treatment at the same or a reduced dose once the 
event has improved to grade 1 or resolved.  Patients with low-grade (1 or 2) elevation in amylase 
can be continued without dose reduction but should be monitored closely with serial enzyme level 
determination. 


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IRB Number: 17-297 A(7) 
Approval date: 08-Oct-2019 
Administrative Update 1 : 10-Mar-2020 
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Table 11.3.3 Dose modification for Pancreatitis 
 
CTCAE Grade 
Action and Dose Modification 
Asymptomatic Grade 1 or 
Grade 2 elevation or 
serum lipase 
• Consider interruption or dose reduction of Ponatinib 
Asymptomatic Grade 3 or 
Grade 4 elevation or 
serum lipase (>2 x ULN) 
or asymptomatic 
radiologic  pancreatitis 
(grade 2 pancreatitis) 
• Occurrence at 30mg: hold until event is < grade 1, or has 
returned to baseline. Resume at 15mg 
• Occurrence at 15mg: discontinue study drug 
Any Recurrence at any dose level, discontinue Ponatinib 
Symptomatic grade 3 
pancreatitis (severe pain, 
vomiting, medical 
intervention indicated [eg 
analgesia, nutritional 
support]) 
• Occurrence at 30mg: hold until complete resolution of 
symptoms and after recovery of lipase elevation to < grade 1 
(<1.5X ULN), or has returned to baseline. Resume at 15mg 
• Occurrence at 15mg: discontinue study drug 
Grade 4 pancreatitis 
Permanently discontinue Ponatinib 
 
 
11.3.4 Hepatotoxicity 
Hepatotoxicity, most commonly manifested by reversible transaminase and alkaline phosphatase 
elevation and hyperbilirubinemia,  has been observed with Ponatinib. Monitoring of hepatic 
function is recommended and management of laboratory abnormalities should be managed with 
dose interruption and/or dose reduction according to grade of toxicity. 
 
 
CTCAE Grade 
Action and Dose Modification 
Elevation of liver 
transaminase >3 x ULND 
(grade 2 or higher) 
• Occurrence at 30mg: hold until event is < grade 1, or has 
returned to baseline. Resume at 15mg 
• Occurrence at 15mg: discontinue study drug 
Elevation of AST or ALT 
>3 x ULN concurrent with 
an elevation of bilirubin 
>2 x ULN and alkaline 
phosphatase <2 x ULN 
Permanently discontinue Ponatinib 
 
 
11.3.5 Pneumonitis 
 
Pneumonitis has been observed in patients receiving Trametinib.  To reduce the risk of 
pneumonitis, patients will be monitored closely for symptoms and evaluated with imaging.  Dose 
modification and supportive care guidelines for pneumonitis are described in the tables below. 
 
 
CTCAE 
Grade 
Adverse Event 
Management 
Action and  Trametinib Dose 
Modification 


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Grade 1 
• CT scan (high- 
resolution with lung 
windows) 
recommended 
• Clinical evaluation and 
laboratory work-up for 
infection 
• Monitoring  of 
oxygenation via pulse- 
oximetry recommended 
• Consultation of 
pulmonologist 
recommended 
• Continue Trametinib at current dose if 
clinically indicated. 
Grade 2 
• CT scan (high- 
resolution with lung 
windows) 
• Clinical evaluation and 
laboratory work-up for 
infection 
• Consult pulmonologist 
• Pulmonary function 
tests –if < normal, 
repeat every 8 weeks 
until ≥ normal 
• Bronchoscopy with 
biopsy and/or BAL 
recommended 
• Symptomatic therapy 
including corticosteroids 
if clinically indicated 
• Interrupt Trametinib until recovery to 
grade ≤1 
• Consider restarting with  Trametinib 
reduced by one dose level 
• Escalation to previous dose level after 
4 weeks and consultation with medical 
monitor possible 
• If no recovery to grade ≤1 within 4 
weeks, permanently discontinue study 
treatment 
Grade 3 
• CT scan (high- 
resolution with lung 
windows) 
• Clinical evaluation and 
laboratory work-up for 
infection 
• Consult pulmonologist 
• Pulmonary function 
tests-if < normal, repeat 
every 8 weeks until ≥ 
normal 
• Bronchoscopy with 
biopsy and/or BAL if 
possible 
• Symptomatic therapy 
including corticosteroids 
as clinically indicated 
• Interrupt Trametinib until recovery to 
grade ≤1 
• After consultation with PI, study 
treatment may be restarted reduced by 
one dose level 
• If no recovery to grade ≤1 within 4 
weeks, permanently discontinue study 
treatment 
Grade 4 
• Same as grade 3 
• Permanently discontinue Trametinib 


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Approval date: 08-Oct-2019 
Administrative Update 1 : 10-Mar-2020 
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11.3.6 Reduced Left Ventricular Ejection Fraction 
Decreases of the left ventricular ejection fraction (LVEF) have been observed in patients receiving 
Trametinib and Ponatinib.  Therefore, echocardiograms must be performed in regular intervals 
outlined in the Study Calendar.  The same procedure (either ECHO or MUGA, although ECHO is 
preferred) should be performed at baseline and at follow-up visits 
 
Trametinib and Ponatinib Dose  Modification Guidelines and Stopping Criteria for LVEF Decrease 
Clinic 
LVEF-drop (%) or 
CTCAE  grade 
Action and Dose 
Modification 
Asymptomatic 
Absolute decrease of >10% in 
LVEF compared to baseline and 
ejection fraction below the 
institution’s LLN. 
• Interrupt  Trametinib  and 
Ponatinib and repeat  ECHO 
within 2 weeks.a 
• If the LVEF recovers within 4 
weeks (defined as LVEF ≥LLN 
and absolute decrease ≤10% 
compared  to baseline): 
− Consult with the Trametinib 
medical monitor, Ponatinib 
medial monitor, and PI and 
request approval  for restart. 
− Restart treatment with 
Trametinib  at reduced dose 
by one dose level  and 
Ponatinib reduced by one 
dose levelb 
− Repeat ECHO 2, 4, and 12 
weeks after re-start; continue 
in intervals  of 12 weeks 
thereafter. 
• If LVEF does not recover  within 
4 weeks: 
− Consult with cardiologist. 
− Permanently  discontinue 
Trametinib  and Ponatinib. 
− Report  as SAE 
− Repeat ECHO after 2, 4, 8, 
12, and 16 weeks or until 
resolution. 
Symptomaticb 
• Grade 3:  resting LVEF 39-20% 
or >20% absolute reduction 
from baseline 
• Grade 4:  Resting LVEF ≤20%. 
• Permanently discontinue 
Trametinib and Ponatinib 
• Report as SAE. 
• Consult  with cardiologist. 
• Repeat ECHO after 2, 4, 8, 12, 
and 16 weeks or until resolution. 
a If ECHO does not show LVEF recovery  after 2 weeks, repeat  ECHO 2 weeks later. 
b Escalation of Trametinib and Ponatinib to previous  dose level can be considered if LVEF remains 
stable for 4 weeks after restarting both agents.  Approval  from  PI is required. 
CSymptoms may include:  dyspnea, orthopnea,  and other signs and symptoms of pulmonary  congestion 
and edema. 


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Approval date: 08-Oct-2019 
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11.3.5 QTc Prolongation 
 
QTc prolongation has been observed in patients receiving Trametinib.  Therefore, 12 lead EKGs 
must be performed in regular intervals outlined in the Study Calendar. 
 
Trametinib Withholding and Stopping Criteria for QTc Prolongation 
Prolongation* 
Action and Dose  Modification 
• QTcB ≥501 msec, or 
• Uncorrected QT >600 msec, or 
• QTcB >530 msec for subjects 
with bundle branch block 
• Interrupt  study treatment until QTcB prolongation  resolves  to grade 
1 or baseline. 
• Test electrolytes (K, Ca, Phos, and Mg). If abnormal,  replete to 
normal limits. 
• Review  concomitant medication usage for a prolonged  QTc 
• If the QTc prolongation  resolves  to grade 1 or baseline, Trametinib 
may be resumed at current dose level 
• If the event does not resolve, permanently discontinue  study 
treatment. 
• If the event recurs, permanently discontinue  study  treatment. 
Abbreviations:   msec = milliseconds; QTcB = QT interval  on electrocardiogram  corrected using the 
Bazett’s formula 
* 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. 
 
 
11.3.6  Arterial Thrombotic and Occlusive Events 
In patients suspected of developing any arterial thrombotic occlusive event, Ponatinib should be 
immediately interrupted. Patients should be discontinued form Ponatinib in the event of MI, 
unstable angina, cerebrovascular accident, or TIA, or revascularization procedures. For all other 
arterial thrombotic occlusive events, dose modification guidelines are outlined in table below. 
 
CTCAE  Grade 
Action and Ponatinib Dose  Modification 
Vascular Occlusion:  other cardiovascular and cerebrovascular events 
Grade 1 
• Consider interruption  or dose reduction of Ponatinib until the event  resolves 
Grade 2 
First occurrence at any dose level: 
• Hold until event  is < grade 1 or has returned  to baseline.  Resume at current dose 
level 
Recurrence  at 30mg: discontinue study drug 
Recurrence  at 15mg: discontinue study drug 
Grade 3 or 4 
• Permanently  discontinue Ponatinib 
Other vascular occlusions  including peripheral vascular events 
Grade 1 
• Consider interruption  or dose reduction of Ponatinib until the event  resolves 


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Grade 2 
First occurrence at any dose level: 
• Hold until event  is < grade 1 or has returned  to baseline.  Resume at current dose 
level 
• Resume at 30mg 
• Recurrence  at 30mg: hold until event  is < grade 1, or has returned to baseline. 
Resume at 15mg 
• Recurrence  at 15mg: discontinue study drug 
Grade 3 
• Occurrence at 30mg: hold until event  is < grade 1, or has returned to baseline. 
Resume at 15mg 
• Occurrence  at 15mg: discontinue study drug 
• Any Recurrence at any dose level,  discontinue Ponatinib 
Grade 4 
• Permanently  discontinue Ponatinib 
 
a"Recurrence" means the second vascular occlusive event (VOE), not necessarily recurrence of 
the same VOE, is encountered by a patient at any dose level. 
b"Occurrence" means the first time an AE is encountered by a patient at a given dose level  
Note: patients should be discontinued from Ponatinib in the even of a myocardial infarction (MI), 
unstable angina, cerebrovascular accident or transient ischemic attack (TIA) or revascularization 
procedures. 
 
11.3.7 Venous Thromboembolic Events 
Venous thromboembolic events have been observed in patients receiving Ponatinib Patients 
should be discontinued from Ponatinib in the event of life-threatening pulmonary embolism or 
retinal vein thrombosis 
 
 
CTCAE  Grade 
Action and Ponatinib Dose  Modification 
Venous Thromboembolic  Events 
Grade 1 
• Consider interruption  or dose reduction of Ponatinib until the event  resolves 
Grade 2 
First occurrence at any dose level: 
• Hold until event  is < grade 1 or has returned  to baseline.  Resume at current dose 
level 
• Recurrence  at 30mg: hold until event  is < grade 1, or has returned to baseline. 
Resume at 15mg 
Recurrence  at 15mg: discontinue study drug 
Grade 3 
• Occurrence at 30mg: hold until event  is < grade 1, or has returned to baseline. 
Resume at 15mg 
• Occurrence  at 15mg: discontinue study drug 
• Any Recurrence at any dose level,  discontinue Ponatinib 
Grade 4 
Permanently  discontinue Ponatinib 
11.3.8 Visual Changes 
 
Episodes of visual changes have been observed in patients receiving Trametinib.  The causal 
relationship between a change in vision and the study treatment should be carefully explored and 
an ophthalmologist should be consulted.  Patients are required to have a standard ophthalmic 
exam performed by an ophthalmologist at baseline and follow up exams as outlined in study 
calendar.  The exam will include indirect funduscopic examination, visual acuity (corrected), visual 
field examination, tonometry, and direct funduscopy.  Special attention should be given to retinal 
(e.g., CSR) or retinal vein abnormalities (e.g., RVO). 


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Guidelines regarding event management and dose reduction for visual changes considered to be 
related to study treatment are provided in the table below 
 
 
Management and Trametinib Dose  Modification for Visual Changes 
Event 
CTCAE  Grade 
Management Guideline 
Dose  Modification 
Grade 1 
Asymptomatic or symptomatic but 
not limiting ADL; intervention  not 
indicated. 
• 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 conducted.* 
• 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. 
• If CSR:  Interrupt  Trametinib 
until symptoms resolve  and 
exam (by retinal specialist if 
available)  shows resolution. 
May restart Trametinib  with one 
dose level  reduction. 
• If RVO:  Permanently 
discontinue  Trametinib. 
Grade 2 and 3 
Grade 2 defined as: 
Symptomatic with moderate 
decrease in visual acuity (20/40 
or better; limiting instrumental 
ADL; local or non-invasi ve 
intervention  indicated.) 
Grade 3 defined as:  
Symptomatic with marked 
decrease in visual acuity or 
marked visual  field defect (worse 
than 20/40 but better than 
20/200);  severe pain or medically 
significant; operative  intervention 
indicated. 
• Consult  ophthalmologist 
immediately. 
• Exclude CSR and RVO. 
• Consult retinal specialist 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. 
• If CSR:  Interrupt  Trametinib 
until symptoms resolve  and 
exam (by retinal specialist if 
available)  shows resolution.   If 
CSR resolves  restart Trametinib 
reduced by one dose level. 
• If RVO:  Permanently 
discontinue  study  treatment. 
Grade 4 
Sight-threatening  consequences; 
urgent  intervention  indicated; 
blindness (20/200 or worse). 
• Consult  ophthalmologist 
immediately. 
• Exclude CSR and RVO. 
• Continue follow up 
examination(s)  (by retinal 
specialist if available)  for CSR 
and RVO. 
Permanently discontinue 
Trametinib. 


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IRB Number: 17-297 A(7) 
Approval date: 08-Oct-2019 
Administrative Update 1 : 10-Mar-2020 
Page 38 of 54 
 
 
 
 
Management and Trametinib Dose  Modification for Visual Changes 
Event 
CTCAE  Grade 
Management Guideline 
Dose  Modification 
Abbreviations:   CSR = central serous retinopathy; RVO = retinal vein  occlusion; SAE = serious adverse 
event 
* If visual  changes are clearly unrelated  to study treatment (e.g., allergic conjunctivitis),  monitor closely 
but ophthalmic examination is not required. 
* If ocular toxicities do not resolve within 21 days, permanently  discontinue  Trametinib. 
 
 
11.3.9 Hypertension 
 
Hypertension has occurred in patients taking Trametinib and Ponatinib. Blood pressure should be 
monitored at each visit.  Hypertension (HTN) by at least two blood pressure measurements 
should be graded according to CTCAE version 4.0.  For participants who develop HTN or 
worsening HTN during study treatment, anti-hypertensive medication should be initiated or 
optimized to achieve target blood pressure before interruption or dose reduction of the study 
treatment at the discretion of the investigator.  If hypertension is persistent despite adequate anti- 
hypertensive therapy including titration of anti-hypertensive medication or introduction of 
additional anti-hypertensive medications, or if grade 4 HTN develops, dose interruption and 
reduction is recommended according to Dose Modification  Guidelines below. 


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Management and Dose Modification Guidelines for Hypertension 
 
Hypertension 
Action and Dose  Modification 
(Scenario  A) 
• 
Asymptomatic and persistenta  SBP of ≥140 and 
<160 mmHg, or DBP ≥90 and <100 mmHg, 
or 
• 
Clinically significant increase in DBP of 20 
mmHg (but DBP still <100 mmHg). 
• 
Continue Trametinib  and Ponatinib at the 
current dose 
• 
Adjust current or initiate new 
antihypertensive   medication 
• 
Titrate  antihypertensive  medication(s) 
during the next 2 weeks as indicated to 
achieve  well-controlledb   BP 
• 
If BP is not well controlled within 2 weeks, 
consider referral  to a specialist and go to 
scenario (B). 
(Scenario  B) 
• 
Asymptomatic SBP ≥160 mmHg, or DBP 
≥100 mmHg, 
or 
• 
Failure to achieve  well-controlled  BP within 2 
weeks in Scenario A 
• 
Interrupt  both Trametinib  and Ponatinib if 
clinically indicated 
• 
Adjust current or initiate new 
antihypertensive   medication(s) 
• 
Titrate  antihypertensive  medication(s) 
during the next 2 weeks to achieve  well- 
controlled  BP 
• 
Once BP is well controlledb, restart 
Trametinib  and Ponatinib, both reduced by 
one dose  levelc 
(Scenario  C) 
• 
Symptomaticd   hypertension 
or 
• 
Persistent SBP ≥160 mmHg, or DBP 
≥100 mmHg, despite antihypertensive 
medication and dose reduction of Trametinib 
• 
Interrupt  Trametinib  and Ponatinib 
• 
Adjust current or initiate new 
antihypertensive   medication(s) 
• 
Titrate  antihypertensive  medication  during 
the next 2 weeks to achieve well-controlled 
BP 
• 
Referral  to a specialist for further evaluation 
and follow-up  is recommended 
• 
Once BP is well controlled, restart 
Trametinib  and Ponatinib, both reduced by 
one dose  levelc 
(Scenario  D) 
• 
Refractory  hypertension unresponsive  to above 
interventions  or having  hypertensive  crisis. 
• 
Permanently discontinue  Trametinib and 
Ponatinib 
• 
Continue follow-up  per protocol. 
Abbreviations:   BP = blood pressure;  DBP = diastolic blood pressure;  mmHg = millimetres mercury; SBP 
= systolic blood pressure; 
a. 
Hypertension detected in two separate readings  during up to three consecutive visits 
b. 
Well-controlled blood pressure defined as SBP ≤140 mm Hg and DBP ≤90 mm Hg in two separate 
readings  during up to three consecutive visits. 
c. 
Escalation of Trametinib  and Ponatinib to previous  dose level can be considered if BPs remains well- 
controlled for 4 weeks after restarting of Trametinib  and Ponatinib.  Approval  from PI is required. 


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Administrative Update 1 : 10-Mar-2020 
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d. 
Symptomatic hypertension defined as hypertension aggravated by symptoms (e.g., headache, light - 
headedness, vertigo, tinnitus, episodes of fainting) that resolve after the blood pressure is controlled 
within the normal  range. 
 
 
 
12.0 
CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT 
 
The same method of assessment (i.e. CT or MRI) and the same technique (i.e. with or without 
contrast) should be used to characterize each identified and reported lesion at baseline and every 
two cycles (+/- 1 week). A designated radiologist at MSKCC will interpret the study CTs or MRIs 
according to RECIST 1.1 criteria. The same radiologist/physician should perform the evaluation 
for the entire duration of the study. 
Tumor response will be assessed using RECIST 1 and confirmation of PR and CR is required. A 
CT scan of the chest +/- abdomen/pelvis will be performed to demonstrate all known areas of 
measurable disease. The baseline study will occur no more than 4 weeks prior to first study drug 
administration. A CT scan with contrast will be the preferred method and modality of imaging. A 
CT scan without contrast or MRI can be used in patients with contraindications to radiographic 
contrast media used in CT scans. All patients must have at least one measurable disease lesion 
by CT or MRI. 
All measurable lesions, up to a maximum of 5 lesions total, representative of all involved organs 
should be identified as target lesions and recorded and measured at baseline. Target lesions 
should be selected on the basis of their size, should be representative of all involved organs, and 
should lend themselves to reproducible repeat measurements. All other lesions (or sites of 
disease) should be identified as non-target lesions and should also be recorded at baseline. 
Definitions of response in target and non-target lesions are described in table 12.1. Table 12.2 
provides overall responses for all possible combination of tumor responses in target and non- 
target lesions. 
 
Table 12.1 Evaluations of Target Lesions 
Complete response (CR): 
Disappearance of all target lesions 
Partial Response (PR): 
At least a 30% decrease in the sum of the 
diameters of the target lesions 
Progressive Disease (PD): 
At least a 20% increase in the sum of the 
diameters of the target lesions or the 
appearance of one or more new lesions 
Stable Disease (SD): 
Neither sufficient shrinkage or qualify to PR 
nor sufficient increase to qualify for PD 
 
Table 12.2 Evaluations of Non-Target Lesions 
Complete response (CR): 
Disappearance of all non-target lesions 
Incomplete response/stable disease (SD): 
Persistence of one or more non-target 
lesions 
Progressive Disease (PD): 
Appearance of one or more new lesions 
and/or unequivocal progression of existing 
non-target lesion 


Memorial Sloan Kettering Cancer Center 
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Administrative Update 1 : 10-Mar-2020 
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Table 12.3 Best Overall Response 
Target Lesions 
Non-Target Lesions 
New Lesions 
Overall 
Response 
CR 
CR 
No 
CR 
CR 
Incomplete/SD 
No 
PR 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
 
Discontinuation of treatment: Early death is defined as having no repeat tumor assessments 
following initiation of study therapy resulting from death of the patient due to disease or treatment. 
Patients with global deterioration of health status requiring discontinuation of treatment without 
objective disease progression will be recorded as "symptomatic deterioration". Every effort will be 
made to document objective progression after discontinuation of treatment. 
Evaluation of Best Overall Response: The best overall response is the best response recorded 
from the start of treatment until disease progression, as defined in Table 12.3. Patients who 
remain on trial will be followed for 6 months to determine best overall response rate 
Evaluation of Toxicity: All patients who receive at least one dose of treatment with Trametinib 
and Ponatinib will be evaluable for toxicity. 
Progression Free Survival (PFS): Duration of time from first treatment to time of progression or 
death, whichever occurs first. 
Overall Survival (OS): Duration of time from first treatment to time of death 
 
 
13.0 
CRITERIAFOR REMOVAL FROM STUDY 
 
Patients may withdraw from the study at any time. Patients who discontinue early should return 
within 30 days of the last dose of the study drugs for a follow-up evaluation (+/- 14 days). Any 
assessments listed for the final visit in Table 10.1 will be performed at that time. 
Patients will be discontinued from treatment and from the study should they experience any of the 
following 
• 
Dose limiting toxicity in the phase 1 portion 
• 
disease progression (defined by RECIST 1.1) 
 
Other reasons for study discontinuation include but are not limited to: 


Memorial Sloan Kettering Cancer Center 
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• 
change in patient eligibility 
• 
non-compliance with defined treatment plan 
• 
protocol violation 
• 
Investigator's decision based on patient's best interest 
• 
Withdrawal of consent 
• 
Severe, unexpected toxicities/side effects 
• 
lost follow up 
 
Patients who are discontinued from the phase I portion for reasons other than DLT without 
completing at least 21 of 28 days of therapy will be replaced. 
 
 
14.0 
BIOSTATISTICS 
Phase 1: 
Primary Objective: 
 
To determine maximum tolerated dose of combination of Ponatinib and Trametinib in patients with 
KRAS mutated non-small cell lung cancer (NSCLC). 
Endpoints: maximum tolerated doses for combination. The MTD will be defined as the dose that 
does not exceed an acceptable threshold of toxicity. Dose limiting toxicity is a binary outcome 
where a patient either experiences a DLT or not. DLT is defined as any of the toxicity described in 
Section 9 of the attached protocol that occurs during the first cycle of treatment with Trametinib 
and Ponatinib. 
Methods: A standard 3+3 design will be used to find the maximum tolerated dose (MTD). Patients 
who are discontinued before completing at least 21 out of 28 days of therapy for reasons other 
than development of a DLT (progression of disease or withdrawal of consent) will be replaced. 
There will be three set dose levels using the FDA approved dose of Trametinib with escalating 
dose (33%, 66%) of the FDA approved dose of Ponatinib (45mg once daily). In addition, three 
doses of Trametinib (75%, 50% and 25% of FDA approved dose) are reserved for de-escalation 
is dose level 1 is determined to be too toxic. 
 
Dose levels 
Trametinib Dose 
Ponatinib Dose 
Dose level -3 
0.5mg PO q daily 
15mg PO q daily 
Dose Level -2 
1.0 mg PO q daily 
15mg PO q daily 
Dose Level -1 
1.5mg PO q daily 
15mg PO q daily 
Dose Level 1 
2 mg PO q daily 
15mg PO q daily 
Dose Level 2 
2 mg PO q daily 
30mg PO q daily 
 
 
The dose escalation scheme is as follows: 
 
1. If none of the initial three patients at a given dose level experience DLT, the next dose level 
will be studied. 


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2. If one of the initial three patients at a given dose level experiences DLT, three additional 
patients will be treated at the same dose level. Escalation will continue only if there was been 
no additional DLT observed. 
3. If two or more patients experience DLT at a given dose, the previous dose will be declared the 
MTD. Should two or more patients experience the DLT at dose level 1, the dose level -1 will 
be studied. 
4. If only three patients were treated at a dose under consideration as the MTD, an additional 
three patients will be treated at that level to confirm previous results. 
The MTD will be the phase 2 recommended dose. However, if the target toxicity level is not 
exceeded at the dose level 2, then the dose level 2 will be used at the phase II recommended 
dose. At the completion of the phase 1 portion, 6 patients will have been treated at the MTD. 
Considering the doses reserved for de-escalation, a minimum of 8 and a maximum of 30 patients 
will be included. If only does levels 1-2 are used, the maximum number of patients is 12. Given an 
expected accrual rate of 2 patients per month, the phase I portion of the study will be completed  
in about 9 months if no de-escalation doses are used and in a maximum of 18 months otherwise. 
Following the completion of this phase, individual toxicities will be tabulated and the information 
will be summarized using descriptive statistics. 
Phase 2: 
 
Primary Objective: To determine the ORR of the combination of Trametinib and Ponatinib in 
patients with KRAS mutant lung cancer. 
 
Secondary  Objective: To  determine  the  progression  free  survival  and  overall  survival  and 
determine the safety and tolerability of the combination. 
Methods: A Simon optimal two-stage trial design will be utilized to assess the primary endpoint of 
response rate (RECIST 1.1 CR+PR). This study will test the null hypothesis of 10% response rate 
against the alternative hypothesis of 30% response rate for patients with progressive disease 
following at least two prior lines of therapy.  A null hypothesis of 10% was chosen as this 
represents the established response rate for second line chemotherapy (Docetaxel2,20) in this 
setting. Subsequently, an alternative hypothesis of 30% was chosen for this study. The design 
chosen has a 10% type I error (falsely accepting a non-promising therapy), 10% type II error 
(falsely rejecting a promising therapy), for 90% power. The study would enroll 15 patients in the 
first stage.  If one or more responses are seen, then the study would expand to 25 patients.  To 
declare Ponatinib and Trametinib at this dose and schedule as promising, there would need to be 
at least 5 confirmed partial responses in 25 response evaluable patients. Patients must receive at 
least 21 days of therapy to be considered evaluable for response. Patients discontinued from the 
study before 6 month after treatment initiation without observed response (CR/PR) will be counted 
as non-responders. Overall survival and progression free survival will be estimated using the 
Kaplan-Meier method, with the follow-up starting at the initiation of therapy. Patients will be 
censored at the time of the last on-study evaluation if they do not experience the event of interest. 
Safety and tolerability will be summarized using descriptive statistics. The toxicities and the 
adverse events will be assessed for each patient according to the NCI CTCAE version 4.1 criteria. 
All correlative aims are exploratory and will be hypothesis-generating only. 


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Up to 6 patients treated at MTD in phase I, if evaluable for response, will be included in the phase 
II part. Therefore, 9 or 19 additional patients are needed for phase II. Given an expected accrual 
rate of 2 patients per month, the accrual to the phase 2 portion of the study will be completed in 
about 10 months. 
Correlative analysis: 
 
Serial biopsies will be performed in the pre-treatment phase, 4 weeks after starting therapy, and 
at the time of progression (3 biopsies per patient) for patients enrolled in the Phase II portion of 
the study. Levels of pERK will be assessed by immunohistochemistry (IHC) to evaluate degree of 
MAPK pathway inhibition.   pAKT will be assessed by IHC as a marker of PI3K pathway inhibition. 
pFRS2 will also be assessed by IHC as a marker of FGFR1 inhibition.  Plasma testing for ddPCR 
testing of presence of KRAS ctDNA (continuous measure) will be collected at the time of each 
radiographic assessment for patients in both the Phase I and Phase II portion of the study. The 
longitudinal measures of these biomarkers and their changes over time will be summarized by 
medians and ranges. The individual patient measures will be plotted to reveal any trends. The 
presence of concurrent genetic alterations identified on routine molecular profiling will also be 
described by response status using 2-by-2 tables. Correlative studies will be performed only on 
patients in the Phase II portion. Sample size of the correlative studies will therefore include a 
maximum of 19 patients since 6 patients treated at the MTD in the Phase I portion will not have 
the necessary studies performed. 
 
 
15.1 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES 
 
15.2 
Research Participant Registration 
 
Confirm eligibility as defined in the section entitled Inclusion/Exclusion Criteria. Obtain 
informed consent, by following procedures defined in section entitled Informed Consent 
Procedures. During the registration process registering individuals will be required to 
complete a protocol specific Eligibility Checklist. The individual  signing the Eligibility 
Checklist is confirming whether or not the participant is eligible to enroll in the study. Study 
staff are responsible for ensuring that all institutional requirements necessary to enroll a 
participant to the study have been completed. See related Clinical Research Policy and 
Procedure #401 (Protocol Participant Registration). 
15.3 
Randomization 
 
No randomization will occur. 
 
16.1 
DATA MANAGEMENT ISSUES 
 
A Research Study Assistant (RSA) will be assigned to the study. The responsibilities of the 
RSA include project compliance, data collection, abstraction and entry, data reporting, 
regulatory monitoring, problem resolution and prioritization, and coordinate the activities of 
the protocol study team. The data collected for this study will be entered into a secure 
database (Clinical Research Database CRDB).  Source documentation will be available  to 


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support the computerized patient record. The principal investigator will maintain ultimate 
responsibility for the clinical trial. 
 
16.2 
Quality Assurance 
 
Weekly meetings will occur to monitor patient accrual and completeness of registration data. 
Routine data quality reports will be generated to assess missing data and inconsistencies. 
Accrual rates and extent and accuracy of evaluations and follow up will be monitored 
periodically throughout the study  period and potential problem will be brought to the 
attention of the study team for discussion and action. Random sample data quality and 
protocol compliance audits will be conducted by the study team, at a minimum of two times 
a year, and more frequently if indicated. 
 
 
16.3 
Data and Safety Monitoring 
 
The Data and Safety Monitoring (DSM) Plans at Memorial Sloan-Kettering Cancer Center 
were approved by the National Cancer Institute in September 2001. The plans address the 
new policies set forth by the NCI in the document entitled “Policy of the National Cancer 
Institute for Data and Safety Monitoring of Clinical Trials” which can be found at:  
http://cancertrials.nci.nih.gov/researchers/dsm/index.html. The  DSM  Plans  at  MSKCC 
were established and are monitored by the Office of Clinical Research. The MSKCC Data 
and 
Safety 
Monitoring 
Plans 
can 
be 
found 
on 
the 
MSKCC 
Intranet 
at:  
http://mskweb2.mskcc.org/irb/index.htm 
 
There are several different mechanisms bywhich clinical trials are monitored for data, safety 
and quality. There are institutional processes in place for quality assurance (e.g., protocol 
monitoring, compliance and data verification audits, therapeutic response, and staff 
education on clinical research QA) and departmental procedures for quality control, plus 
there are two institutional committees that are responsible for monitoring the activities of our 
clinical trials programs. The committees: Data and Safety Monitoring Committee (DSMC) 
for Phase I and II clinical trials, and the Data and Safety Monitoring Board (DSMB) for Phase 
III clinical trials, report to the Center’s Research Council and Institutional Review Board. 
 
During the protocol development and review process, each protocol will be assessed for its 
level of risk and degree of monitoring required. Every type of protocol (e.g., NIH sponsored, 
in-house sponsored, industrial sponsored, NCI cooperative group, etc.) will be addressed 
and the monitoring procedures will be established at the time of protocol activation. 


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17.1 
PROTECTION OF HUMAN SUBJECTS 
 
Prior to the enrollment of each patient, the risks, benefits, and objectives of the study will be 
reviewed with the participant, including a discussion of the possible toxicities and side  
effects. Alternative,  non-protocol, treatment options will be discussed with the patient. It will 
be reviewed that participation in this clinical trial is voluntary and that the patient may 
withdraw consent at any time. The study is designed with careful safety monitoring for toxicity 
including physician visits. Specific guidelines for symptom management are in place to 
protect the study participants. 
Human Subjects Involvement and Characteristics: All patients at MSKCC who meet the 
inclusion criteria will be eligible to enroll. Patients eligible will be 18 years of age or older with 
a KPS of 70% or greater. Both men and women and members of all ethnic groups will be 
eligible for this trial. Pregnant and breast feeding women are excluded from this study. This 
protocol does not include children because the number of children is expected to be limited 
for the patient population expected to be accrued onto this study. Also the majority of  
children are already accessed by a nationwide pediatric cancer research network. This 
statement is based on exclusion 4b of the NIH policy and guidelines on the Inclusion of 
Children as Participants in Research Involving Human Subjects. 
Consent process: All patients at MSKCC who meet the inclusion criteria will be eligible. 
Participation in the trial is voluntary. All patients will be required to sign a statement of 
informed consent, which must conform to IRB guidelines. The informed consent procedure is 
described in Section 18.0. 
Possible Toxicities: There are risks associated with treatment as described in Section 11.0. 
 
Benefits: The combination of Trametinib and Ponatinib has the potential to be effective and 
induce tumor response in patients with KRAS mutant NSCLC. 
Costs: Patients will be charged (insurance billed) for physician visits, routine laboratory 
tests, and radiologic studies required for monitoring their condition. The patients will not be 
billed for the study drugs, Trametinib or Ponatinib. The research studies will be covered with 
separate research funding and no charges associated with research will be billed to the 
patient. Repeat biopsy on day 28 and progression of disease on study will not be charged to 
the patient. 
Alternatives: The alternative to this trial would be treatment with chemotherapy or 
participation in an alternative clinical trial. 
Confidentiality: Every effort will be made to maintain patient confidentiality. Research and 
hospital records are confidential. Patients’ names and any other identifying information will 
not be used in reports or publications resulting from this study. Other authorized agencies 
and appropriate internal personnel (e.g. qualified monitors from MSKCC) and external 
personnel, its authorized agents, the FDA (and/or other governmental agencies) may review 
patient records as required. 


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Administrative Update 1 : 10-Mar-2020 
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Patient Safety: Patients are monitored by physicians and oncology nurses who are very 
familiar with clinical trials. In the case of an adverse reaction, immediate medical attention is 
available. In the evenings and weekends, we have a 24 hour urgent care facility for 
outpatients. The PI or co-PI will also be available at all times to organize any necessary 
intervention. 
Monitoring of data to ensure safety: The study is to be monitored by the institutional IRB. 
This incorporates an independent data and safety monitoring board established by 
arrangement with the National Cancer Institute. The analysis of safety will include all 
patients. Adverse events, including all toxic effects of treatment, will be tabulated individually 
and summarized by severity and causality. 
17.2 
Privacy 
 
MSK’s Privacy Office may allow the use and disclosure of protected health information 
pursuant to a completed and signed Research Authorization form. The use and disclosure of 
protected health information will be limited to the individuals described in the Research 
Authorization form. A Research Authorization form must be completed by the Principal 
Investigator and approved by the IRB and Privacy Board (IRB/PB). 
The consent indicates that individualized  de identified information collected for the purposes 
of this study may be shared with other qualified researchers. Only researchers who have 
received approval from MSK will be allowed to access this information which will not include 
protected health information, such as the participant’s name, except for dates. It is also 
stated in the Research Authorization that their research data may be shared with other 
qualified  researchers. 
17.3 
Serious Adverse Event (SAE) Reporting 
 
An adverse event is considered serious if it results in ANY of the following outcomes: 
• 
Death 
• 
A life-threatening adverse event 
• 
An adverse event that results in 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 (IME) that may not result in death, be life threatening, or 
require hospitalization may be considered serious when, based upon medical judgment, 
they may jeopardize the patient or participant and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition 
 
 
Note: Hospital admission for a planned procedure/disease treatment is not considered an SAE. 


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Administrative Update 1 : 10-Mar-2020 
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SAE reporting is required as soon as the participant starts investigational treatment/intervention. 
SAE reporting is required for 30-days after the participant’s last investigational 
treatment/intervention. Any event that occur after the 30-day period that is unexpected and at 
least possibly related to protocol treatment must be reported. 
 
 
Please note: Any SAE that occurs prior to the start of investigational treatment/intervention and 
is related to a screening test or procedure (i.e., a screening biopsy) must be reported. 
 
 
All SAEs must be submitted in PIMS. If an SAE requires submission to the HRPP office per IRB 
SOP RR-408 ‘Reporting of Serious Adverse Events’, the SAE report must be submitted within 5 
calendar days of the event.  All other SAEs must be submitted within 30 calendar days of the 
event. 
 
 
The report should contain the following information: 
• 
The date the adverse event occurred 
• 
The adverse event 
• 
The grade of the event 
• 
Relationship of the adverse event to the treatment(s) 
• 
If the AE was expected 
• 
Detailed text that includes the following 
o An explanation of how the AE was handled 
o A description of the participant’s condition 
o Indication if the participant remains on the study 
• 
If an amendment will need to be made to the protocol and/or consent form 
• 
If the SAE is an Unanticipated Problem 
 
 
n 
17.3.1 Novartis reporting 
 
All Serious Adverse Events (“SAE”) required to be reported pursuant to the Protocol shall be 
provided to Novartis and its representatives by Institution or Principal Investigator within 24 
hours of learning of the event as well as provide any additional reports agreed upon by the 
Institution or Principal Investigator and Novartis contact below. The Institution or Principal 
Investigator will have the primary responsibility of reporting adverse events (“AE”) to 
regulatory authorities. 
 
Copies of IND Safety reports submitted to the FDA by the institution under the Institution’s 
IND will be shared with the contact below so that these reports can be evaluated and 
included in the package insert or Novartis IND safety submissions as required to ensure 
safety of other patients who are receiving the product form Novartis for sponsored trials. 


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IRB Number: 17-297 A(7) 
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Administrative Update 1 : 10-Mar-2020 
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The principal investigator has the obligation to report all serious adverse events to the FDA (if 
applicable), IRB, and Novartis Pharmaceuticals Drug Safety and Epidemiology Department 
(DS&E) (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 30 days after the patient has stopped 
study treatment must be reported to Novartis within 24 hours of learning of its occurrence. 
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 fax cover sheet 
to the Novartis Oncology Drug Safety and Epidemiology (DS&E) department by fax (fax: 
877-778-9739) 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 30-day safety evaluation follow-up 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 
Drug Safety and Epidemiology (DS&E) 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. 
17.2.1.1 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 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 Oncology Drug Safety and 
Epidemiology Department (DS&E) by fax (fax: 877-778-9739). 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. 
 
 
17.3.2 Takeda Reporting 


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All Serious Adverse Events (“SAE”) are also required to be reported pursuant to the Protocol 
shall be provided to Takeda and its representatives by Institution or Principal Investigator 
within 24 hours of learning of the event as well as provide any additional reports agreed upon 
by the Institution or Principal Investigator and Takeda contact above. The Institution or 
Principal Investigator will have the primary responsibility of reporting adverse events (“AE”) to 
regulatory authorities. 
 
Copies of IND Safety reports submitted to the FDA by the institution under the Institution’s 
IND will be shared with the contact below so that these reports can be evaluated and 
included in the package insert or Takeda IND safety submissions as required to ensure 
safety of other patients who are receiving the product form Takeda for sponsored trials. 
 
Adverse Events may be spontaneously identified by the patient and/or in response to an 
open question from study personnel or revealed by observation, physical examination, or 
other diagnostic procedures.  Any clinically relevant deterioration in laboratory assessments 
or other clinical finding is considered an AE.  When possible, signs and symptoms indicating 
a common underlying pathology should be noted as one comprehensive event. 
Adverse Events which are serious must be reported to Takeda Pharmacovigilance (or 
designee) from the first dose of ponatinib up to and including 30 days after administration of 
the last dose of ponatinib. Any SAE that occurs at any time after completion of ponatinib 
treatment or after the designated follow-up period that the sponsor-investigator and/or sub- 
investigator considers to be related to any study drug must be reported to Takeda 
Pharmacovigilance (or designee).  In addition, new primary malignancies that occur during 
the follow-up periods must be reported, regardless of causality to study regimen, for a 
minimum of three years after the last dose of the investigational product, starting from the 
first dose of study drug. All new cases of primary malignancy must be reported to Takeda 
Pharmacovigilance (or designee). 
Planned hospital admissions or surgical procedures for an illness or disease that existed 
before the patient was enrolled in the trial are not to be considered AEs unless the condition 
deteriorated in an unexpected manner during the trial (e.g., surgery was performed earlier or 
later than planned).  All SAEs should be monitored until they are resolved or are clearly 
determined to be due to a patient’s stable or chronic condition or intercurrent illness (es). 
Since this is an investigator-initiated study, the principal investigator Dr. Arbour also referred 
to as the sponsor-investigator, is responsible for reporting serious adverse events (SAEs) to 
any regulatory agency and to the sponsor- investigator’s EC or IRB. 
Regardless of expectedness or causality, all SAEs must also be reported in English to 
Takeda Pharmacovigilance or designee: 
Fatal and Life Threatening SAEs within 24 hours of the sponsor-investigator’s 
observation or awareness of the event 
All other serious (non-fatal/non-life threatening) events within 4 calendar days of the 
sponsor-investigator’s observation or awareness of the event 
The Sponsor will send all SAE reports to Takeda Pharmacovigilance (or designee) within 24 
hours but no later than 4 calendar days as per any agreements. 
Follow-up information on the SAE may be requested by Takeda Pharmacovigilance (or 
designee). 


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In the event that this is a multisite study, the sponsor-investigator is responsible to ensure 
that the SAE reports are sent to Takeda Pharmacovigilance (or designee) from all sites 
participating in the study.  Sub-investigators must report all SAEs to the sponsor-investigator 
so that the sponsor-investigator can meet his/her foregoing reporting obligations to the 
required regulatory agencies and to Takeda Pharmacovigilance, unless otherwise agreed 
between the sponsor-investigator and sub-investigator(s). 
Relationship to all study drugs for each SAE will be determined by the investigator or sub- 
investigator by responding yes or no to the question: Is there a reasonable possibility that the 
AE is associated with the study drug(s)? 
 
 
US and Canada 
 
Toll-Free Fax #: 1-800-963-6290 
 
E-mail:  takedaoncocases@cognizant.com 
 
All other countries (Rest of World) 
 
Fax #: 1 202 315 3560 
 
For IND/IDE protocols: The SAE report should be completed as per above instructions. If 
appropriate, the report will be forwarded to the FDA by the IND Office. 
 
 
 
17.2.2.1 Product Complaints or Medication Errors (Including Overdose) 
A product complaint  is a verbal, written,  or electronic  expression that implies  dissatisfaction 
regarding the identity,  strength, purity,  quality,  or stability of a drug product.  Individuals  who 
identify a potential product complaint  situation should immediately contact Takeda 
Pharmacovigilance  or designee  (see below) and report the event. Whenever possible, the 
associated product should be maintained  in accordance with the label instructions  pending further 
guidance  from a Takeda Quality representative. 
 
A medication error is a preventable event that involves an identifiable patient and that leads to 
inappropriate medication use, which may result in patient harm. While overdoses and underdoses 
constitute medication errors, doses missed inadvertently by a patient do not. Investigators must 
record all medication errors (including overdose) on the appropriate form. Individuals who identify 
a potential medication error situation should immediately contact Takeda (see below) and report the 
event. 
 
 
For Product Complaints or Medication Errors (Including Overdose), contact Takeda 
Pharmacovigilance 
For ADCETRIS or PIPELINE Products: 
Phone:  1-844-ONC-TKDA(1-844-662-8532) 
Email:  GlobalOncologyMedInfo@takeda.com 


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Product complaints  in and of themselves  are not AEs.  If a product complaint  results in an SAE, an 
SAE form should be completed and sent to Takeda Pharmacovigilance  (refer to Section 17.2.2). 
17.2.2.2 Procedures for Reporting Drug Exposure During Pregnancy and Birth Events 
If a female patient becomes pregnant or suspects that she is pregnant while participating in this 
study, she must inform the investigator immediately and permanently discontinue study drug. 
The sponsor-investigator must fax a completed Pregnancy Form to the Takeda 
Pharmacovigilance or designee immediately (see Section 17.2.1).  The pregnancy must be 
followed for the final pregnancy outcome (i.e., delivery, still birth, miscarriage) and Takeda 
Pharmacovigilance or designee will request this information from the sponsor-investigator. 
 
Suggested Pregnancy Reporting Form: 
Pregnancy Report Form (a sample will be provided by Takeda) 
 
 
Safety contact: 
 
The Principal Investigator will provide Novartis or its contacts above with copies of the IND 
safety report every 6 months in the format of a line listing with details regarding the reports 
that were submitted to the FDA. Individual submissions will be provided to Novartis upon 
request. 
The Principal Investigator will also provide Takeda or its contacts above with copies of the 
IND safety report every 6 months in the format of a line listing with details regarding the 
reports that were submitted to the FDA. Individual  submissions will be provided to Takeda 
upon request. 
18.1 
INFORMED CONSENT PROCEDURES 
 
Before protocol-specified procedures are carried out, consenting professionals will explain  
full details of the protocol and study procedures as well as the risks involved to participants 
prior to their inclusion in the study. Participants will also be informed that they are free to 
withdraw from the study at any time. All participants must sign an IRB/PB-approved consent 
form indicating their consent to participate. This consent form meets the requirements of the 
Code of Federal Regulations and the Institutional Review Board/Privacy Board of this Center. 
The consent form will include the following: 
1. The nature and objectives, potential risks and benefits of the intended study. 
2. The length of study and the likely follow-up required. 
3. Alternatives to the proposed study. (This will include available standard and 
investigational therapies. In addition, patients will be offered an option of supportive 
care for therapeutic studies.) 
4. The name of the investigator(s) responsible for the protocol. 
5. The right of the participant to accept or refuse study interventions/interactions and to 
withdraw from participation at any time. 
Fax: 1-800-881-6092, Hours Mon – Fri, 9 a.m. – 7 p.m. ET 


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Before any protocol-specific procedures can be carried out, the consenting professional will 
fully explain the aspects of patient privacy concerning research specific information.  In 
addition to signing the IRB Informed Consent, all patients must agree to the Research 
Authorization component of the informed consent form. 
Each participant and consenting professional will sign the consent form. The participant must 
receive a copy of the signed informed consent form. 
 
 
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20.0 
APPENDICES 
 
20.1 Trametinib Prescribing Information 
 
20.2 Ponatinib Prescribing Information