A Phase II Trial of Trametinib With Docetaxel in Patients With KRAS Mutation Positive Non-Small Cell Lung Cancer (NSCLC) and Progressive Disease Following One or Two Prior Systemic Therapies
Phase: PHASE2
Conditions: KRAS Gene Mutation, Recurrent Lung Non-Small Cell Carcinoma, Stage IV Lung Non-Small Cell Cancer AJCC v7
Sponsor: National Cancer Institute (NCI)

 
 
 
Version Date:  March 15, 2019 
 
 
 
TO: 
All National Clinical Trials Network (NCTN) Members; CTSU 
 
 
FROM: 
Gretchen Goetz, M.B.A., Lead Protocol Coordinator (Email: ggoetz@swog.org) 
 
 
RE: 
S1507, “A Phase II Trial of Trametinib with Docetaxel in Patients with KRAS Mutation 
Positive Non-Small Cell Lung Cancer (NSCLC) and Progressive Disease Following One or 
Two Prior Systemic Therapies.” Study Chairs: Drs. Shirish M. Gadgeel, Jonathan W. Riess, 
and Philip Mack. 
  
REVISION # 3 
 
Study Chair:  Shirish M. Gadgeel, M.D. 
Phone number:  734/647-6883 
E-mail: sgadgeel@med.umich.edu 
 
IRB Review Requirements 
(√) 
Expedited review allowed 
 
Protocol changes 
(√)  
Informed Consent changes 
(√)  
Patient notification required 
(√)  
Other: Trametinib dimethyl sulfoxide CAEPR update 
 
Sites using the CIRB as their IRB of record:  The protocol and/or informed consent form changes have 
been approved by the CIRB and must be activated within 30 days of the CIRB posting of this notice.  
 
Sites not using the NCI CIRB:  Per CTMB Guidelines, the protocol updates and/or informed consent 
changes must be approved by local IRBs within 90 days of distribution of this notice.  
 
 
 
REVISION #3 
 
This revision has been prepared in response to an RRA from Dr. Helen Chen (helen.chen@nih.gov) 
received on February 22, 2019.  The Action Letter for this RRA is anticipated on March 29, 2019.  The 
above referenced protocol has been revised as follows: 
 
1. 
The Version Date has been revised in the Protocol and the Model Consent Form. 
 
2. 
Section 3.4c.1:  The trametinib CAEPR has been updated from Version 2.4, dated October 7, 
2016 to Version 2.5, dated February 1, 2019.  The CAEPR has been updated as follows: 
 
• The SPEER grades have been updated. 
 
• The section below utilizes CTCAE 5.0 language unless otherwise noted. 

 
S1507 
 
Revision #3 (contd.) 
 
Page 2 
 
 
 
 
 
 
• 
Increase in Risk Attribution: 
o Changed to Rare but Serious from Also Reported on Trametinib dimethyl 
sulfoxide Trials But With Insufficient Evidence for Attribution: Papilledema; 
Thromboembolic event (venous) 
o Changed to Less Likely from Also Reported on Trametinib dimethyl sulfoxide 
Trials But With Insufficient Evidence for Attribution: Nail changes 
 
• 
Deleted Risk:  
o Also Reported on Trametinib dimethyl sulfoxide Trials but With Insufficient 
Evidence for Attribution: Rash pustular; Retinal detachment  
 
• 
Provided Further Clarification:  
o Footnote# 3 “Edema includes edema, lymphedema, and edema limbs.” is now 
reworded as “Generalized edema includes edema, lymphedema, and edema 
limbs.” 
o Footnote# 5 “Skin and subcutaneous tissue disorders - Other (rash) may include 
rash, rash acneiform, rosacea, erythematous rash, genital rash, rash macular, 
exfoliative rash, rash generalized, erythema, rash papular, seborrheic dermatitis, 
dermatitis psoriasiform, rash follicular, and skin fissures.” is now reworded as 
“Skin and subcutaneous tissue disorders - Other (rash) may include rash, 
rosacea, erythematous rash, genital rash, rash macular, exfoliative rash, rash 
generalized, erythema, rash papular, seborrheic dermatitis, dermatitis 
psoriasiform, rash follicular, skin fissures, and skin chapped.”  
o Periorbital edema previously listed under the SKIN AND SUBCUTANEOUS 
TISSUE DISORDERS SOC (CTCAE 4.0 language), is now reported under the 
EYE DISORDERS SOC. 
o Vascular disorders - Other (edema) (CTCAE 4.0 language) is now reported as 
Generalized edema under the GENERAL DISORDERS AND ADMINISTRATION 
SITE CONDITIONS SOC. 
o Skin and subcutaneous tissue disorders - Other (folliculitis) (CTCAE 4.0 
language) is now reported as Folliculitis under the INFECTIONS AND 
INFESTATIONS SOC. 
o Musculoskeletal and connective tissue disorder - Other (rhabdomyolysis) 
(CTCAE 4.0 language) is now reported as Rhabdomyolysis. 
o Enterocolitis is now reported as part of Colitis. 
o Anal hemorrhage, Epistaxis, Lower gastrointestinal hemorrhage, Rectal 
hemorrhage and Upper gastrointestinal hemorrhage are now reported as parts of 
Vascular disorders - Other (hemorrhage). 
o Gastrointestinal disorders - Other (oropharyngeal pain) (CTCAE 4.0 language) is 
now reported as Oropharyngeal pain under the RESPIRATORY, THORACIC 
AND MEDIASTINAL DISORDERS SOC. 
o Investigations - Other (blood lactate dehydrogenase increased) (CTCAE 4.0 
language) is now reported as Blood lactate dehydrogenase increased. 
o Metabolism and nutrition disorders - Other (hyperphosphatemia) (CTCAE 4.0 
language) is now reported as Hyperphosphatemia. 
o Musculoskeletal and connective tissue disorder - Other (muscle spasm) (CTCAE 
4.0 language) is now reported as Muscle cramp. 

 
S1507 
 
Revision #3 (contd.) 
 
Page 3 
 
 
 
 
 
o Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other 
(tumor hemorrhage) (CTCAE 4.0 language) is now reported as Tumor 
hemorrhage. 
o Renal and urinary disorders - Other (dysuria) (CTCAE 4.0 language) is now 
reported as Dysuria. 
o Skin and subcutaneous tissue disorders - Other (skin fissures) is now reported as 
part of Skin and subcutaneous tissue disorders - Other (rash). 
 
3. 
Section 8.1:  This section has been updated to state that CTCAE Version 5.0 will be used for 
Serious Adverse Event (SAE) reporting and CTCAE Version 4.0 will be used for routine toxicity 
reporting. 
 
4. 
Section 16.1i:  This section has been updated to use CTCAE Version 5.0 terminology. 
 
5. 
The model consent form risk profile for trametinib dimethyl sulfoxide has been revised as follows: 
 
• 
Increase in Risk Attribution: 
o Added to Occasional: Change in or loss of some or all of the finger or 
toenails 
o Added to Rare: Blood clot which may cause swelling, pain, shortness of 
breath 
 
• 
Provided Further Clarification:  
o Sores in mouth which may cause difficulty swallowing (under Occasional) is now 
reported as Sores in the mouth which may cause difficulty swallowing (under 
Occasional). 
o High blood pressure (under Occasional) is now reported as High blood pressure 
which may cause headaches, dizziness, blurred vision (under Occasional). 
o Damage to muscle (under Rare) is now reported as Damage to muscle which 
may cause muscle pain, dark red urine (under Rare). 
o Damage of the lungs which may cause shortness of breath (under Rare) is now 
reported as Damage to the lungs which may cause shortness of breath (under 
Rare). 
 
Patient Notification and Regulatory Considerations 
 
Please note that the information provided below regarding patient notification and amendments to local 
consent forms reflects SWOG’s minimum requirements.  Sites should refer to the policies/procedures of 
the IRB of record to determine whether they have any more stringent requirements. 
 
Patient Notification 
 
Patients must be notified of the changes above that are bolded.   
 
Who must be informed?   
 
• 
Patients currently receiving trametinib dimethyl sulfoxide  

 
S1507 
 
Revision #3 (contd.) 
 
Page 4 
 
 
 
 
 
 
How must patients be notified? 
 
• 
Notification must take place either via the attached Consent Addendum or via formal reconsent.  
After the changes have been discussed with the patient, the patient should sign and date either 
the Consent Addendum or the 3/15/19 version of the consent form. 
 
What is the notification deadline and process? 
 
• 
Patients must be notified by their next scheduled visit or within 90 days after CTSU distribution of 
this revision, whichever is sooner. 
• 
Sites using the NCI CIRB as their IRB of record:  CIRB has approved the attached Consent 
Addendum; therefore, the Consent Addendum may be utilized immediately to notify patients of 
these changes.  
 
• 
Sites not using the NCI CIRB as their IRB of record:  This information should be communicated to 
patients already enrolled on study without waiting for IRB review/approval.  This information 
represents a significant new finding(s) that developed during the course of the research that may 
relate to a patient’s willingness to continue participation.  Per the Office for Human Research 
Protections, the regulations do not require IRB review and approval of statements describing 
such significant new findings before they are provided to already enrolled patients.  If  local IRB 
approval of the Consent Addendum is required before sites may utilize it, the site must still notify 
patients verbally prior to the notification deadline and notification must be documented in the 
patient chart.  The site must then obtain patient signature on the Consent Addendum or updated 
consent form once the addendum and/or revised consent is locally approved. 
 
Regulatory Considerations: 
 
Do local consent forms need to be updated?  
 
• 
No, local consent forms need not be updated because this study is closed to accrual. 
 
This memorandum serves to notify the NCI and the SWOG Statistics and Data Management Center. 
 
cc:   
PROTOCOL AND INFORMATION OFFICE 
 

S1507 
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Version Date 3/15/19 
 
 
 
 
 
 
PRIVILEGED COMMUNICATION 
Activation Date July 18, 2016 
FOR INVESTIGATIONAL USE ONLY 
 
 
SWOG 
 
TITLE 
A PHASE II TRIAL OF TRAMETINIB WITH DOCETAXEL IN PATIENTS WITH KRAS MUTATION 
POSITIVE NON-SMALL CELL LUNG CANCER (NSCLC) AND PROGRESSIVE DISEASE FOLLOWING 
ONE OR TWO PRIOR SYSTEMIC THERAPIES 
 
NCT #XXXXX 
 
STUDY CHAIRS: 
AGENTS: 
 
Shirish M. Gadgeel, M.D. (Medical Oncology) 
NCI Supplied Investigational Agents: 
Wayne State University 
Trametinib dimethyl sulfoxide (GSK1120212B) 
Karmanos Cancer Institute 
 
(NSC 763093)  
) 
4100 John R 
 
Detroit, MI 48201-2067 
Commercially Supplied Agent: 
Phone:  313/576-8753 
Docetaxel (NSC 628503) 
FAX:  313/576-8699 
Filgrastim (r-mehHuG-CSF) (Neupogen®) 
E-mail:  gadgeels@karmanos.org 
 
(NSC 614629) 
 
Pegfilgrastim (Neulasta™) (NSC 725961) 
Jonathan W. Riess, M.D. (Medical Oncology) 
 
UC Davis Comprehensive Cancer Center 
BIOSTATISTICIANS: 
4501 X Street, Suite 3016 
 
Sacramento, CA 95817 
James Moon, M.S. 
Phone:  916/734-3772 
Jieling Miao, M.S. 
FAX:  916/734-7946 
SWOG Statistical Center 
E-mail:  jwriess@ucdavis.edu 
1100 Fairview Ave N, M3-C102 
 
P.O. Box 19024 
Philip Mack, Ph.D. (Translational Medicine) 
Seattle, WA 98109-1024 
UC Davis Cancer Center 
Phone:  206/667-4623 
Division of Hematology/Oncology 
FAX:  206/667-4408 
4501 X Street 
E-mail:  jmoon@fredhutch.org 
Sacramento, CA 95817 
E-mail:  jmiao@fredhutch.org 
Phone: 916-734-8022 
 
FAX:  916-734-2361 
 
Email: pcmack@ucdavis.edu 
 
 
PARTICIPANTS 
 
ALLIANCE / Alliance for Clinical Trials in Oncology 
ECOG-ACRIN / ECOG-ACRIN Cancer Research Group 
NRG / NRG Oncology 
SWOG / SWOG 

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TABLE OF CONTENTS 
 
TITLE  .................................................................................................................................... 1 
PARTICIPANTS ........................................................................................................................ 1 
TABLE OF CONTENTS ............................................................................................................. 2 
CANCER TRIALS SUPPORT UNIT (CTSU) ADDRESS AND CONTACT INFORMATION ................... 4 
1.0 
OBJECTIVES ................................................................................................................ 5 
1.1 
Primary Objective ........................................................................................................... 5 
1.2 
Secondary Objectives ..................................................................................................... 5 
1.3 
Translational Medicine Objectives ..................................................................................... 5 
2.0 
BACKGROUND ............................................................................................................. 5 
3.0 
DRUG INFORMATION ...................................................................................................13 
3.1 
Docetaxel (NSC 628503) ................................................................................................14 
3.2 
Filgrastim (r-metHuG-CSF) (Neupogen®) (NSC 614629) .....................................................15 
3.3 
Pegfilgrastim (Neulasta™) (NSC 725961)..........................................................................16 
3.4 
Trametinib Dimethyl Sulfoxide (GSK1120212B) (NSC-763093).............................................18 
4.0 
STAGING CRITERIA .....................................................................................................26 
5.0 
ELIGIBILITY CRITERIA .................................................................................................27 
5.1 
Disease Related Criteria .................................................................................................28 
5.2 
Prior/Concurrent Therapy Criteria.....................................................................................28 
5.3 
Clinical/Laboratory Criteria ..............................................................................................29 
5.4 
Specimen Submission Criteria .........................................................................................30 
5.5 
Regulatory Criteria .........................................................................................................30 
6.0 
STRATIFICATION FACTORS .........................................................................................31 
7.0 
TREATMENT PLAN ......................................................................................................31 
7.1 
Pre-Medication ..............................................................................................................31 
7.2 
Treatment.....................................................................................................................31 
7.3 
Drug Compliance Documentation .....................................................................................33 
7.4 
Full CDUS Reporting Requirement ...................................................................................33 
7.5 
Criteria for Removal from Protocol Treatment.....................................................................33 
7.6 
Discontinuation of Treatment ...........................................................................................33 
7.7 
Follow-Up Period ...........................................................................................................33 
8.0 
TOXICITIES TO BE MONITORED AND DOSE MODIFICATIONS ........................................33 
8.1 
NCI Common Terminology Criteria for Adverse Events........................................................33 
8.2 
General Dose Modification Guidelines ..............................................................................34 
8.3 
Dose Modifications ........................................................................................................34 
8.4 
Dose Modification Contacts .............................................................................................48 
8.5 
Adverse Event Reporting ................................................................................................48 
9.0 
STUDY CALENDAR ......................................................................................................49 
10.0 
CRITERIA FOR EVALUATION AND ENDPOINT ANALYSIS ..............................................53 
10.1 
Measurability of Lesions .................................................................................................53 
10.2 
Objective Status at Each Disease Evaluation .....................................................................54 
10.3 
Best Response..............................................................................................................55 
10.4 
Performance Status .......................................................................................................56 
10.5 
Time to Death ...............................................................................................................56 
10.6 
Progression-Free Survival ...............................................................................................57 
11.0 
STATISTICAL CONSIDERATIONS .................................................................................57 
11.1 
Sample size with Power Justification.................................................................................57 
11.2 
Secondary Objectives ....................................................................................................58 
11.3 
Accrual ........................................................................................................................59 
11.4 
Data and Safety Monitoring .............................................................................................59 
12.0 
DISCIPLINE REVIEW ....................................................................................................59 
13.0 
REGISTRATION GUIDELINES .......................................................................................59 
13.1 
Registration Timing ........................................................................................................59 
13.2 
Investigator/Site Registration ...........................................................................................59 

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13.3 
OPEN Registration Requirements ....................................................................................62 
13.4 
Registration Procedures .................................................................................................63 
13.5 
Exceptions to SWOG registration policies will not be permitted. ............................................63 
14.0 
DATA SUBMISSION SCHEDULE ...................................................................................63 
14.1 
Data Submission Requirement ........................................................................................64 
14.2 
Master Forms................................................................................................................64 
14.3 
Data Submission Procedures ..........................................................................................64 
14.4 
Data Submission Overview and Timepoints .......................................................................66 
15.0 
SPECIAL INSTRUCTIONS .............................................................................................67 
15.1 
Translational Medicine and Banking .................................................................................67 
16.0 
ETHICAL AND REGULATORY CONSIDERATIONS ..........................................................69 
16.1 
Adverse Event Reporting Requirements ............................................................................71 
17.0 
BIBLIOGRAPHY ...........................................................................................................77 
18.0 
APPENDIX ...................................................................................................................81 
18.1 
Intake Calendar - Trametinib ...........................................................................................82 
18.2 
Translational Medicine Methodology .................................................................................83 
18.3 
Bone Marrow Distribution in the Adult ...............................................................................84 
 
 

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CANCER TRIALS SUPPORT UNIT (CTSU) ADDRESS AND CONTACT INFORMATION 
To submit site registration 
documents: 
For patient 
enrollments: 
 
Submit study data: 
 
CTSU Regulatory Office 
1818 Market Street, 
Suite 1100 
Philadelphia, PA19103 
Phone:  866-651-CTSU 
 
Fax: 215-569-0206 
 
Email:  
 
CTSURegulatory@ctsu.coccg.org 
 
(for submitting regulatory documents 
only) 
 
 
Please refer to the patient 
enrollment section of the protocol for 
instructions on using the Oncology 
Patient Enrollment Network (OPEN) 
which can be accessed at 
https://www.ctsu.org/OPEN_SYSTE
M/ or https://OPEN.ctsu.org. 
 
Contact the CTSU Help Desk with 
any OPEN-related questions at 
ctsucontact@westat.com. 
 
 
 
Data collection for this study will be 
done exclusively through Medidata 
Rave.  Please see the data 
submission section of the protocol 
for further instructions.  
 
Other Tools and Reports: Institutions 
participating through the CTSU 
continue to have access to other 
tools and reports available on the 
SWOG Workbench. Access this by 
using your active CTEP-IAM userid 
and password at the following url: 
 
https://crawb.crab.org/TXWB/ctsulog
on.aspx 
The most current version of the study protocol and all supporting documents must be downloaded 
from the protocol-specific Web page of the CTSU Member Web site located at https://www.ctsu.org.  
Access to the CTSU members’ website is managed through the Cancer Therapy and Evaluation Program 
- Identity and Access Management (CTEP-IAM) registration system and requires user log on with CTEP-
IAM username and password. 
  
For patient eligibility questions contact the SWOG Data Operations Center by phone or email: 
 
206-652-2267 
lungquestion@crab.org 
For treatment or toxicity related questions contact Dr. Gadgeel or Dr. Riess. 
 
For questions unrelated to patient eligibility, treatment, or data submission contact the CTSU Help 
Desk by phone or e-mail: 
 
CTSU General Information Line: 
888-823-5923 
ctsucontact@westat.com 
 
All calls and correspondence will be triaged to the appropriate CTSU representative. 
 
The CTSU Web site is located at https://www.ctsu.org 
 

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1.0 
OBJECTIVES 
 
1.1 
Primary Objective 
 
To evaluate the response rate (confirmed and unconfirmed) to trametinib plus docetaxel 
in the entire study population of KRAS mutation positive non-small cell lung cancer 
(NSCLC) patients following one or two prior systemic therapies. 
 
1.2 
Secondary Objectives 
 
a. 
To evaluate if trametinib plus docetaxel is consistent with promise of activity 
measured by the response rate in G12C KRAS mutation positive NSCLC 
patients following one or two prior systemic therapies. 
 
b. 
To assess the response rate of this combination in non-G12C KRAS mutation 
positive NSCLC patients. 
 
c. 
To assess progression-free survival within the G12C and non-G12C KRAS 
positive subgroups and the entire study population. 
 
d. 
To evaluate the toxicity of the regimen. 
 
e. 
To assess overall survival within G12C positive patients, non-G12C positive 
patients, and the entire study population. 
 
1.3 
Translational Medicine Objectives 
 
a. 
To evaluate the response rates in the presence of comutations p53 and LKB1. 
 
b. 
To bank specimens for future research. 
 
 
2.0 
BACKGROUND 
 
KRAS mutation positive NSCLC 
 
In recent years genetic alterations that bestow a selective proliferative and survival advantage (so 
called ‘driver mutations’) have been identified in a subset of cancers, including non-small cell lung 
cancer (NSCLC).  These driver mutations are responsible for both initiation and maintenance of 
the malignant phenotype.  Drugs targeting such driver mutations have led to significant clinical 
benefit in patients with such tumors. 
 
In NSCLC two genetic alterations that have been successfully targeted for therapeutic benefit and 
now have approved drugs are mutations in the tyrosine kinase domain of the EGFR (epidermal 
growth factor receptor) gene and ALK (anaplastic lymphoma kinase) gene rearrangements. (1,2)  
These results have spurred interest in identifying other genetic alterations that can be targeted. 
 
Mutations in the KRAS gene were identified in NSCLCs over 25 years ago. (3) The protein 
encoded by the KRAS gene functions as a guanosine diphosphate (GDP)/ guanosine 
triphosphate (GTP) regulated on-off switch that can activate downstream signaling proteins. (4)  
The GDP/GTP cycling is regulated by guanine nucleotide exchange factors that promote 
formation of active Ras-GTP complex, whereas GTPase activating proteins stimulate GTP 
hydrolysis and lead to the formation of inactive Ras-GDP.  Activated Ras-GTP binds to many 

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effector proteins and activates them and thus the downstream signaling pathways.  Mutated 
KRAS in cancers result in single amino acid substitutions primarily in codons 12, 13 and 61.  
Mutated Ras encodes for protein that is insensitive to GTPase and therefore constantly bound to 
GTP and active, leading to increased activation of downstream signaling proteins.  In non-small 
cell lung cancers, KRAS mutations occur most commonly in adenocarcinomas (25-30%; 
squamous cell < 5%) and they occur primarily in codon 12 and codon 13. (5, 6,7) Also KRAS 
mutations are much more common in smokers (25%) than never smokers (6%). Direct inhibition 
of KRAS for therapeutic benefit has remained elusive.  An alternative approach is to inhibit the 
downstream signaling proteins to effectively inhibit KRAS signaling and thus its oncogenic 
consequences. 
 
Raf1 was the first effector protein of Ras to be identified. Raf1 signals through a pathway that 
involves the ERK-MEK signaling cascade. (8) The ERK-MEK signaling pathway is the primary 
mediator of the oncogenic effects of Ras mutations.  However Ras mutations also activate other 
pathways that are important for its oncogenic effects and one of the most important non-ERK-
MEK pathways to be activated by Ras is the PI3K pathway.  This occurs through the direct 
interaction of Ras and PI3K. (9)  The PI3K is known to play a significant role in cell proliferation 
and survival and it involves the Ser/Thr kinase Akt, protein kinase B and nuclear factor- kappa B 
(NFkB).   
 
Since ERK-MEK pathway is an important mediator of the oncogenic effects of KRAS, MEK 
inhibitors were evaluated for the treatment of patients with KRAS mutation positive tumors 
including NSCLC.  Evidence to date has suggested that the benefits of single agent MEK 
inhibitors are modest. (10,11)  A plausible explanation for the observed modest activity is the 
ability of tumors to sustain the malignant phenotype through other pathways activated by mutated 
KRAS, particularly the PI3K pathway.  Pre-clinical studies have shown that tumor cells with Ras 
or Raf activation resistant to MEK inhibitors have an activated PI3K pathway. (12,13)  In addition, 
pre-clinical studies show that MEK inhibition may release the negative feedback loops, leading to 
activation of AKT and this could limit the anti-tumor effects of MEK inhibitors in KRAS mutation 
positive tumors. (14)   
 
Retrospective clinical data suggest that KRAS-mutation positive NSCLCs are more resistant to 
chemotherapy drugs. (15,16)  In addition data presented by Shepherd, et al suggests that 
benefits of adjuvant chemotherapy may differ based on types of KRAS mutations. Patients with 
codon 13 KRAS mutation positive NSCLCs had worse outcomes with adjuvant chemotherapy. 
(17)  In-vitro studies have shown that addition of MEK inhibitor to chemotherapy can enhance the 
anti-tumor effects of chemotherapy. (18)  Recently Janne, et al reported the results of a 
randomized Phase II study that evaluated the addition of selumitinib (AZD6244), another MEK 
inhibitor, to docetaxel in patients with KRAS mutation positive progressive NSCLC. (19)  The 
addition of AZD6244 led to improved progression free survival (5.3 mo vs. 2.1 mo, p=0.0138) and 
response rate (37.2% vs. 0%, p < 0.0001).  The percentage of patients that were alive and 
progression free at 6 months was also superior in patients who received the combination, 37.1%, 
compared to the patients who received docetaxel alone, 15.8% (p=0.0158).  The overall survival 
was numerically superior with the addition of AZD6244 (9.4 mo vs. 5.2 mo) but this did not reach 
statistical significance (p=0.2069).  Adverse events were also higher among patients who 
received the combination of AZD6244 with docetaxel, particularly neutropenia.  Despite the 
higher rates of adverse events, the patients receiving the combination were able to receive a 
median of 5 cycles compared to patients receiving docetaxel alone, who received a median of 4 
cycles.  These data suggest that MEK inhibitors in combination with chemotherapy, specifically 
docetaxel, have a role in the management of patients with KRAS mutation positive NSCLC.  The 
results of this study have not only generated interest in testing tumors of NSCLC patients for 
KRAS mutations but also interest in evaluating other MEK inhibitor-based strategies for the 
treatment of these patients. 
 
Heterogeneity of KRAS mutation cancers 

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Emerging data suggest that the biologic behavior of KRAS mutation positive tumors is 
heterogeneous. In colon cancer certain studies have suggested that the negative predictive value 
of KRAS mutations for benefit from cetuximab varies according to codon 12 or codon 13 
mutations. (20) As stated earlier a retrospective analyses of adjuvant trials in lung cancer by 
Shepherd, et al showed that patients with codon 13 mutations had worse outcome with adjuvant 
chemotherapy. (21) This was not observed in patients with codon 12 mutations. In this study 10% 
of the KRAS mutation positive patients had codon 13 mutations.  
 
The heterogeneity of KRAS mutations extends to patients’ smoking status. The spectrum of 
KRAS mutations in lung cancer differs between smokers and never smokers and from those 
observed in other tumors. (22,23) The most common KRAS mutation in lung cancer patients, 
who are current or former smokers, is a G to T transversion (43%), with the most common amino 
acid substitution being cysteine (Gly-12Cys or G12C). In contrast, the most common KRAS 
mutation in lung cancer patients who are never smokers is a G to A transition, with the most 
common amino acid substitution being aspartate. In an analysis of patients whose tumors were 
biopsied prospectively on a clinical trial, Ihle, et al reported that patients with Gly-12Cys and Gly-
12Val had worse progression free survival than patients with tumors that had other KRAS 
mutations. (24) In addition, based on in vitro analysis, they found that downstream signaling 
varies based on specific KRAS mutations. Thus, Gly-12Cys and Gly-12Val activated Ral 
signaling, whereas Gly-12Asp activated PI3K and MEK. The importance of specific amino acid 
substitutions, in predicting for benefit from specific targeted agents, is further highlighted by 
recent data from a Phase Ib trial evaluating trametinib, a MEK inhibitor, in combination with 
docetaxel in two different cohorts of advanced NSCLC patients: KRAS mutation positive (N=25 
patients) and KRAS wild type (22 patients). The disease control rate (CR+PR+SD) in both 
cohorts was about 60%. The disease control rate was 80% among patients with tumors that had 
G12C mutations (N=10 patients) but only 47% among patients with tumors that had other KRAS 
mutations (N=15 patients). All patients were treated with granulocyte growth factors since the rate 
of cytopenias, particularly neutropenia, can be high. Even with the use of colony stimulating 
factors 23% of the patients had neutropenia and 4% of the patients had febrile neutropenia. The 
efficacy data suggest that the clinical benefit with a combination of a MEK inhibitor and docetaxel 
is different in patients with KRAS mutation positive NSCLCs based on the specific amino acid 
substitution. (25) 
 
Heterogeneity in biologic behavior of KRAS mutant tumors may also be related to concomitant 
genetic alterations. Over the last few years it has been recognized that KRAS-mutation positive 
NSCLCs could have other genetic alterations, specifically loss of p53 or tumor suppressor gene 
LKB1.  Previous reports suggest that concomitant p53 mutations occur in about 30% of KRAS 
mutation positive NSCLC and that this rate varies according to smoking status, with a higher rate 
observed in patients who are current or recent smokers. (26) LKB1 is a serine/threonine kinase 
that is known to have tumor suppressive effect and is inactivated in about 30% of 
adenocarcinomas. (27) Heterozygous germline mutations in LKB1 predisposes to Peutz-Jeghers 
syndrome. LKB1 through the activation of AMPK regulates mTOR signaling.  In addition LKB1 
regulates the PI3K/AKT pathway through PTEN.  Thus, in tumors with loss of LKB1, the 
PI3K/AKT/mTOR signaling is activated.  In addition, it can be hypothesized that KRAS mutation 
positive tumors with concomitant loss of LKB1 are highly dependent upon PI3K/Akt/mTOR 
signaling.  This hypothesis is supported by pre-clinical evidence that presence of LKB1 loss of 
function mutations predict for anti-tumor activity of PI3K pathway inhibitors. (28) Recently 
Skoulidis, et al presented data showing that concomitant mutations in LKB1 and p53 define two 
non-overlapping subsets of KRAS mutation positive lung adenocarcinomas with distinct intra-
cellular signaling and therefore distinct therapeutic susceptibilities. In addition, they showed that 
KRAS positive NSCLCs that don’t have concomitant mutations in either LKB1 or p53 tend to 
cluster with one of the two subsets. (29) These data suggest that KRAS mutation positive tumors 
that don’t have p53 or LKB1 mutations may also have differential activation of the PI3K pathway. 
 

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Chen, et al conducted a co-clinical trial along with the randomized Phase II study, reported by 
Janne, et al, evaluating the influence of these concomitant genetic alterations on the efficacy of 
docetaxel + MEK inhibitor combination. (30)  In this trial they treated genetically engineered mice 
bearing KRAS-mutation positive NSCLCs with AZD6244 and docetaxel or docetaxel alone. This 
co-clinical trial found that AZD6244, the MEK inhibitor, enhanced the activity of docetaxel in 
KRAS mutant tumors and KRAS mutant tumors with p53 loss but it did not do so in KRAS-
mutation positive tumors with loss of LKB1. These data suggest that the presence of these 
concomitant genetic alterations could influence the efficacy of MEK + docetaxel combination as 
well as the efficacy of MEK + PI3K/AKT pathway inhibitors in KRAS mutation positive NSCLCs. 
 
Trametinib 
 
Trametinib is a potent allosteric and ATP non-competitive inhibitor of MEK1/2. In pre-clinical 
studies the drug inhibited ERK phosphorylation in all cell lines, however the anti-tumor activity 
was most often observed in Braf mutant cells lines, variably in KRAS mutant cell lines and seldom 
in cell lines without Braf or KRAS mutation. The drug has shown clinical activity as a single agent 
in Braf mutant melanoma and modest activity in KRAS mutant pancreatic cancer (2/26) and 
KRAS mutant NSCLC (2/22). Trametinib is metabolized predominantly via deacetylation (non-
cytochrome P450 [CYP450]-mediated) with secondary oxidation or in combination with 
glucuronidation biotransformation pathways. (31) The deacetylation is likely mediated by 
hydrolytic esterases, such as carboxylesterases, or amidases.  Based on in vitro studies, 
trametinib is not an inhibitor of CYP1A2, CYP2A6, CYP2B6, CYP2D6, and CYP3A4.  Trametinib 
has an overall low potential for drug-drug interactions. 
 
In a Phase I trial the MTD (maximum tolerated dose) of trametinib was established as 3 mg every 
day, but the recommended Phase II dose was chosen at 2mg every day based on tolerability of 
repeated cycles. (32) The relationship between dose and tumor biomarkers such as pERK, Ki67, 
and p27, were evaluated in patients with BRAF or NRAS mutation-positive metastatic melanoma. 
(33)  In general, increasing exposures and/or doses provided greater pharmacodynamic effects.  
The median change observed at a dose of 2 mg every day was 62% inhibition of pERK, 83% 
inhibition of Ki67, and a 175% increase in p27. 
 
On May 29, 2013, the U.S. Food and Drug Administration (FDA) approved trametinib for the 
treatment of patients with unresectable or metastatic melanoma with BRAFV600E or BRAFV600K 
mutations as detected by an FDA-approved test. (34)  On January 10, 2014, the Food and Drug 
Administration granted accelerated approval to trametinib and dabrafenib for use in combination 
to treat patients with unresectable or metastatic melanoma with a BRAF V600E or V600K 
mutation as detected by an FDA-approved test. (35) 
 
In a multicenter Phase II study, NSCLC patients with KRAS mutant tumors were randomized 2:1 
to receive trametinib (2 mg every day) or docetaxel (75 mg/m2 IV every 3 weeks). (36) A total of 
134 pts were randomized to trametinib (89) or docetaxel (45); 129 patients had KRAS-mutant 
NSCLC.  The hazard ratio for PFS was 1.14 (95% CI, 0.75-1.75; P=0.5197) with a median PFS of 
11.7 versus 11.4 weeks for trametinib versus docetaxel.  The overall response rate (ORR) was 
12% for trametinib and 12% for docetaxel.  
 
As previously stated encouraging activity in KRAS mutation positive tumors has been reported 
with the combination of trametinib and docetaxel. (37) Cytopenias were common and therefore 
growth factor support was required.  With growth factor support the RP2D is 2 mg daily of 
trametinib and docetaxel at the dose of 75 mg/m2 administered every 21 days.  The toxicities 
observed with this combination were GI toxicities, mucositis and fatigue. Efficacy both in KRAS 
mutation positive and negative tumors was observed with this combination, with preferential 
activity in the G12C KRAS mutation positive patients. 
 

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Trametinib also has been evaluated in other tumors including acute myeloid leukemia/ 
myelodysplastic syndrome and pancreatic cancer both as single agent and in combination with 
chemotherapy drugs. Activity with this drug has been observed in these tumors though further 
studies are required to better define the role of this drug in these tumors.  
 
Based on available AE data from clinical studies involving trametinib to date, the most common 
toxicities are rash and diarrhea.  Rash and diarrhea are common, class-effect toxicities for MEK 
inhibitors.  In addition, visual impairment and left ventricular ejection fraction (LVEF) reduction, 
although observed at lower frequencies, are also considered class-effect toxicities as they have 
been observed with trametinib as well as other MEK inhibitors. 

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Adverse Events (AE) of special interest: 
Rash, diarrhea, visual disorders, hepatic disorders, cardiac-related AEs, and pneumonitis are 
considered AEs of special interest because they are either known class effects (i.e., have been 
observed with other MEK inhibitors) or are potentially life-threatening. (38) The following sections 
provide integrated summaries for these AEs across different clinical trials, with emphasis on trials 
using trametinib as monotherapy, especially at the RP2D of 2 mg. 
 
Rash:  Rash was a common AE observed across different dose levels and in different 
combinations. (39)  At the 2 mg dose, rash was seen in 27% to 78% of patients in different trials.  
Of the approximately 370 subjects with rash AEs at the 2 mg monotherapy dose (including 
crossover subjects) in five studies, the majority of rash AEs were Grades 1 or 2 (24% to 73%); 
0% to 9% of patients experienced Grade 3 rash AEs, and four patients had a Grade 4 rash AE. 
 
In a randomized Phase III trial of trametinib vs. chemotherapy, the overall incidence of skin 
toxicity (including rash, dermatitis, acneiform rash, palmar-plantar erythrodysesthesia syndrome, 
and erythema) was 87% in patients treated with trametinib and 13% in chemotherapy-treated 
patients.  Severe skin toxicity occurred in 12% of patients on the trametinib arm, most commonly 
for secondary infections of the skin  The median time to onset of skin toxicity was 15 days 
(range:  1 to 221 days), and median time to resolution was 48 days (range:  1 to 282 days).  Dose 
reduction was required in 12% for skin toxicities, and permanent discontinuation of trametinib was 
required in 1% of patients.  
 
Diarrhea:  At the 2 mg monotherapy dose, 33% to 58% of patients in five trials had diarrhea. (40)  
Of the approximately 320 subjects (including crossover subjects) with diarrhea at this dose, the 
majority of diarrhea AEs were Grade 1 or 2 in severity (33% to 56% of all study patients); 17 
patients had Grade 3 diarrhea, and none had Grade 4 diarrhea. 
 
Visual disorders:  At the 2 mg monotherapy dose, 4% to 21% of the patients in five trials 
experienced visual disorders. (41)  Of the 85 total subjects (including crossover subjects) 
experiencing visual disorders at this dose level, the majority of visual disorders were Grades 1 or 
2 (4% to 20% of all study patients); six patients experienced Grade 3 visual disorders, and one 
patient experienced a Grade 4 visual disorder. 
 
− 
Retinal Pigment Epithelial Detachment (RPED):  Also known as chorioretinopathy, RPED is a 
visual impairment due to fluid accumulation under the retina and causes blurry vision.  There 
were five cases of RPED, previously termed central serous retinopathy, reported from the 
integrated trametinib safety population consisting of subjects treated with trametinib 2 mg 
once daily from five studies. (42)  As of 23 June 2013, 14 cases of RPED were reported 
across the entire trametinib program amongst subjects treated with trametinib either as 
monotherapy or in combination with other anti-cancer agents (including cases from a 
MEK/BRAF combination study). 
 
Retinal vein occlusion (RVO):  As of 23 June 2013, a total of four cases of RVO were 
reported across the entire trametinib program (including one case from a MEK/BRAF 
combination study). (43) All cases of RVO occurred in one eye only.  Study drug was stopped  
at time of diagnosis in all cases.  There was a decrease of visual acuity in two subjects with 
central RVO (CRVO) while the other two subjects had no meaningful decrease of visual 
acuity.  In the two subjects with CRVO, local treatment with intravitreal injections of anti-
VEGF antibodies was initiated within 2 weeks after RVO diagnosis, and visual acuity 
improved in one subject and restored to baseline conditions in another subject, at the time of 
the data cutoff.  Three of these four cases were considered related to study treatment by the 
investigators. 
 

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Hepatic disorders:  Abnormalities of liver enzymes and bilirubin have been observed with 
administration of trametinib. (44)  However, assessment of these cases was often confounded by 
co-morbid conditions (such as biliary obstruction), concomitant use of other potentially 
hepatotoxic drugs, and liver metastases.  At the 2 mg monotherapy dose, 8% to 34% of patients 
in five trials had LFT abnormalities.  Of the 96 total patients (including crossovers) with LFT 
changes, the majority were Grade 1 or 2 in severity (4% to 20% of all study patients); 26 had 
Grade 3 events, and 6 patients had Grade 4 events. 
  
Cardiac-related AEs:  At the 2 mg monotherapy dose, 3% to 21% of the subjects in six studies 
had cardiac-related AEs. (45)  Of the 65 total subjects (including crossover subjects) 
experiencing cardiac-related AEs at the 2 mg monotherapy dose in five of the studies, the 
majority of cardiac-related AEs were Grades 1 or 2 in severity (0% to 16% of all study subjects); 
18 subjects had Grade 3 cardiac-related AEs, and no subjects had Grade 4 cardiac-related AEs 
in any study.  No subject in one study, which evaluated the effect of repeat oral dosing of 
trametinib 2 mg QD on cardiac repolarization in subjects with solid tumors, had cardiac-related 
AEs.  One study subject receiving trametinib 2 mg QD had Grade 5 (fatal) acute cardiac failure, 
with evidence of massive tumor invasion of the heart; this AE was considered not drug-related by 
the investigator. 
 
In the Phase III trial of trametinib vs. chemotherapy in patients with melanoma (MEK114267), 
cardiomyopathy (defined as cardiac failure, left ventricular dysfunction, or decreased LVEF) 
occurred in 7% (14/211) of patients treated with trametinib, and in no patients in the 
chemotherapy arm.  Cardiomyopathy was identified within the first month of treatment in five of 
these 14 patients; median onset of cardiomyopathy was 63 days (range: 16 to 156 days).  
Cardiomyopathy resolved in 10 of these 14 (71%) patients.  Cardiac monitoring should be 
included in trametinib protocols, to include LVEF assessment by echocardiogram or MUGA scan 
at baseline, one month after initiation of trametinib and then at 2- to 3-month intervals while on 
treatment.  Refer to dose modification guidelines for cardiac AEs in the event of LVEF decline or 
symptomatic cardiac AEs. 
 
Pneumonitis:  At the 2 mg monotherapy dose, 0% to 4% of the subjects in five studies had 
pneumonitis. (46)  Of the nine total subjects (including crossovers) experiencing pneumonitis AEs 
at this dose, three subjects had Grade 1 or 2 pneumonitis and six subjects had Grade 3 
pneumonitis. 
 
Embryofetal toxicity:  Based on its mechanism of action, trametinib can cause fetal harm when 
administered to a pregnant woman.  Trametinib was embryotoxic and abortifacient in rabbits at 
doses greater than or equal to those resulting in exposures approximately 0.3 times the human 
exposure at the recommended clinical dose.  If this drug is used during pregnancy, or if the 
patient becomes pregnant while taking this drug, the patient should be apprised of the potential 
hazard to a fetus. 
 
Incidence of common AEs reported from a Phase III trial of trametinib vs. chemotherapy in 
patients with advanced melanoma: 
 
Patients with abnormal LVEF, history of acute coronary syndrome within 6 months, or current 
evidence of Class II or greater congestive heart failure (New York Heart Association) were 
excluded from this trial.  Selected adverse reactions (AR) occurring in patients receiving 
trametinib as compared to patients in the chemotherapy arm are listed as below: 

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Table:  Selected adverse reactions (ARs) occurring in ≥ 10% of patients receiving trametinib AND 
at a higher incidence than in the chemotherapy arm (high in the trametinib arm compared with 
chemotherapy by ≥ 5% in overall incidence or by ≥ 2% Grade 3 or 4 AEs) 
 
 
Trametinib 
(n=211) 
Chemotherapy 
(n=99) 
Adverse Reactions 
All Grades 
Grades 
3 and 4 
All Grades 
Grades 
3 and 4 
Skin and subcutaneous 
tissue disorders 
 
 
 
 
Rash 
57 
8 
10 
0 
Dermatitis acneiform 
19 
<1 
1 
0 
Dry skin 
11 
0 
0 
0 
Pruritis 
10 
2 
1 
0 
Paronychia 
10 
0 
1 
0 
Gastrointestinal disorders 
 
 
 
 
Diarrhea 
43 
0 
16 
2 
Stomatitis 
15 
2 
2 
0 
Abdominal pain 
13 
1 
5 
1 
Vascular disorders 
 
 
 
 
Lymphedema 
32 
1 
4 
0 
Hypertension 
15 
12 
7 
3 
Hemorrhage 
13 
<1 
0 
0 
 
Table:  Percent-patient incidence of laboratory abnormalities occurring at a higher incidence in 
patients treated with trametinib versus chemotherapy (between-arm difference of ≥ 5% [all 
grades] or ≥ 2% [Grades 3 or 4]) 
 
 
Trametinib 
(n=211) 
Chemotherapy 
(n=99) 
Preferred term 
All Grades 
Grades 
3 and 4 
All Grades 
Grades 
3 and 4 
Increased aspartate 
aminotransferase (AST) 
60 
2 
16 
1 
Increased alanine 
aminotransferase (ALT) 
39 
3 
20 
3 
Hypoalbuminemia 
42 
2 
23 
1 
Anemia 
38 
2 
26 
3 
Increased alkaline 
phosphatase 
24 
2 
18 
3 
 
Other clinically important adverse reactions observed in ≤ 10% of patients (n=329) treated with 
trametinib were: nervous system disorders (dizziness, dysgeusia), ocular disorders (blurred 
vision, dry eye), infections and infestations (folliculitis, rash pustular, cellulitis), cardiac disorders 
(bradycardia), gastrointestinal disorders (xerostomia), and musculoskeletal and connective tissue 
disorders (rhabdomyolysis). 
 
Rationale 
 

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KRAS mutation positive NSCLC is a distinct biologic subset of NSCLC that has eluded effective 
targeted therapy. KRAS mutations occur in about 25% of NSCLCs. At the present time there is 
no approved therapy for this specific NSCLC patient population. In addition, some studies 
suggest that presence of KRAS mutations may predict for poor prognosis and inferior outcomes 
with chemotherapy. It is therefore imperative that novel therapies are evaluated in this specific 
NSCLC patient population. Trametinib may be one of the most effective MEK inhibitors. Though 
another trial has shown improvement in outcomes with the combination of docetaxel and MEK 
inhibitor, this single arm Phase II trial will attempt to assess the activity of the combination of 
docetaxel with trametinib in KRAS mutation positive NSCLC. 
 
An important consideration in evaluating treatment strategies is that KRAS mutation positive 
NSCLCs can have different biologic outcomes and consequence based on the specific KRAS 
mutations due to differential downstream signaling. For example, Gly (12Cys), the most common 
KRAS mutation in patients with lung cancer, is highly associated with tobacco carcinogenesis and 
complex genotypes which result from cigarette smoking and appears to have distinct clinical and 
pathological characteristics.  In this regard, heterogeneity in the biology of KRAS-mutated 
cancers may also occur due to concomitant genetic alterations (co-mutations) such as KB1 loss 
and p53 loss.  Therapeutic strategies based on these factors are therefore of considerable 
interest, and this study will attempt to provide an estimate of efficacy with this combination in the 
different subsets of KRAS mutation positive NSCLC.  
 
Inclusion of Women and Minorities 
 
This study was designed to include women and minorities, but was not designed to measure 
differences of intervention effects.  The anticipated accrual in the ethnicity/race and sex 
categories is shown in the table below.  
DOMESTIC PLANNED ENROLLMENT REPORT 
Racial Categories 
Ethnic Categories 
Total 
Not Hispanic or Latino 
Hispanic or Latino 
Female 
Male 
Female 
Male 
American Indian/ Alaska 
Native 
0 
0 
0 
0 
0 
Asian 
1 
2 
0 
0 
3 
Native Hawaiian or 
Other Pacific Islander 
0 
0 
0 
0 
0 
Black or African 
American 
2 
2 
0 
0 
4 
White 
24 
21 
0 
1 
46 
More Than One Race 
 
 
 
 
 
Total 
27 
25 
0 
1 
53 
 
 
3.0 
DRUG INFORMATION 
 
Investigator Brochures  
 
For information regarding Investigator Brochures, please refer to SWOG Policy 15. 
 
For this study, docetaxel, filgrastim, and pegfilgrastim are commercially available; therefore, 
Investigator Brochures are not applicable for these drugs.  Information about commercial drugs is 
publicly available in the prescribing information and other resources. 
 
For this study, trametinib is investigational and is being provided under an IND held by the 
National Cancer Institute.  The Investigator Brochure may be obtained by contacting the NCI’s 
Pharmaceutical Management Branch (PMB) at 240/276-6575. 

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3.1 
Docetaxel (NSC 628503)  
 
a. 
PHARMACOLOGY 
 
Mechanism of Action: Docetaxel promotes the assembly of microtubules and 
stabilizes their formation by inhibiting depolymerization. This stabilization creates 
a microtubule which is non-functional. Cell death is promoted by the disruption of 
normal cell shape, motility, attachment, and intracellular transport. Docetaxel is 
cytotoxic predominately in the s-phase of the cell cycle. 
 
b. 
PHARMACOKINETICS 
 
1. 
Absorption: Intravenous administration of docetaxel results in 100% 
bioavailability. Area under the curve (AUC) of docetaxel was dose 
proportional following doses of 70 mg/m2 to 115 mg/m2 with infusion 
times of 1 to 2 hours.  
 
2. 
Distribution: The initial rapid decline represents distribution to the 
peripheral compartments and the late (terminal) phase is due, in part, to 
a relatively slow efflux of docetaxel from the peripheral compartment. 
Mean steady state volume of distribution was 113 L. In vitro studies 
showed that docetaxel is about 94% protein bound, mainly to α1-acid 
glycoprotein, albumin, and lipoproteins.  
 
3. 
Metabolism: Docetaxel is primarily metabolized in the liver by 
cytochrome P450 3A4 and 3A5 isoenzymes (CYP3A4/5).  
 
4. 
Elimination:  Docetaxel elimination follows a three compartment model 
with an initial distribution half-life of 3 to 5 minutes, an intermediate 
elimination half-life of 36 to 60 minutes, and a terminal half-life of 10 to 
18 hours. Mean total body clearance was 21 L/h/m2.Approximately 6% of 
unchanged drug is eliminated by the kidney in 24 hours, with the majority 
(80%) of excretion occurring in feces at 7 days.  
 
c. 
ADVERSE EFFECTS  
 
1. 
Possible Side Effects of Docetaxel:  The most common adverse effects 
occurring in > 20% of people receiving docetaxel include: fluid retention, 
alopecia, nail disorders, skin reactions (rash, pruritis), nausea, vomiting, 
diarrhea, constipation, mucositis, infections, anemia, asthenia, 
neutropenia, neuropathy, fever, amenorrhea, erythema of the extremities 
with edema, pain and lacrimation with or without conjunctivitis. 
 
Adverse effects occurring in ≤ 20% of people receiving docetaxel 
include: cutaneous skin reactions, abdominal pain, thrombocytopenia, 
febrile neutropenia, hepatotoxicity, venous thromboembolism, pulmonary 
embolism, myalgia, anorexia, dysgeusia, dyspnea, and cardiac 
dysrhythmias. 
 
Rare (< 3%) but potentially serious adverse effects include:  
hypersensitivity reactions (rash/erythema, hypotension, wheezing, 
shortness of breath, swelling of the face or throat), acute myeloid 
leukemia, and interstitial lung disease or pneumonia.  

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Patients receiving docetaxel infusions may experience alcohol 
intoxication from the ethanol included in the formulation. 
 
Refer to the current FDA-approved package insert for the most 
comprehensive and up to date information on adverse reactions. 
 
2. 
Pregnancy and Lactation: Pregnancy Category D. Excretion in breast 
milk is unknown and breast feeding is not recommended during 
treatment. 
 
3. 
Drug Interactions: Cytochrome P450 3A4/5 inducers, inhibitors, or 
substrates may alter docetaxel metabolism. In patients receiving 
treatment with docetaxel, close monitoring for toxicity and a docetaxel 
dose reduction could be considered if systemic administration of a potent 
CYP3A inhibitor cannot be avoided.  Patients should use caution with 
sleep aids or narcotic analgesics due to possible additive sedation from 
the alcohol present in the docetaxel formulation. Due to potential drug 
interactions, a complete patient medication list, including docetaxel, 
should be screened prior to initiation of and during treatment with 
docetaxel (see Section 8.0). Toxicities to be Monitored and Dosage 
Modifications. 
 
d. 
DOSING & ADMINISTRATION 
 
See treatment plan in Section 7.0. 
 
e. 
HOW SUPPLIED  
 
Docetaxel is commercially available and will not be supplied. Refer to the current 
FDA-approved package insert. 
 
f. 
STORAGE, PREPARATION & STABILITY 
 
Refer to the current FDA-approved package insert. 
 
3.2 
Filgrastim (r-metHuG-CSF) (Neupogen®) (NSC 614629) 
 
a. 
PHARMACOLOGY 
 
Mechanism of Action: Filgrastim stimulates the production, maturation, and 
activation of neutrophils; filgrastim activates neutrophils to increase both their 
migration and cytotoxicity. 
 
b. 
PHARMACOKINETICS 
 
1. 
Absorption: First-order pharmacokinetic modeling with maximum serum 
concentration reached within 2 to 8 hours after subcutaneous injection 
 
2. 
Distribution: Average Vd 150 mL/kg 
 
3. 
Metabolism: Unknown 
 

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4. 
Elimination:  Renal and neutrophil receptor-mediated, elimination half-life 
is approximately 3.5 hours 
 
c. 
ADVERSE EFFECTS  
 
1. 
Possible Side Effects of Filgrastim: Refer to the current FDA-approved 
package insert for the most comprehensive and up to date information 
on adverse reactions. 
 
Most frequent adverse reactions reported are skeletal pain (> 20%). 
 
2. 
Pregnancy and Lactation: Category C, filgrastim should be used during 
pregnancy only if the potential benefit justifies the potential risk to the 
fetus.  Animal studies have demonstrated adverse effects and fetal loss.  
Filgrastim has been shown to cross the placenta in humans.  There are 
no adequate and well-controlled studies in pregnant women. Excretion in 
breast milk unknown/use caution. 
 
3. 
Drug Interactions: Drug interactions between filgrastim and other drugs 
have not been fully evaluated.  Drugs which may potentiate the release 
of neutrophils‚ such as lithium‚ should be used with caution. 
 
Increased hematopoietic activity of the bone marrow in response to 
growth factor   therapy has been associated with transient positive bone-
imaging changes. This should be considered when interpreting bone-
imaging results. 
 
Filgrastim should not be administered on the same day with anticancer 
chemotherapeutic agent(s) with leukocyte suppressive properties.  
 
Filgrastim is contraindicated in patients with hypersensitivity to E.coli-
derived proteins, filgrastim, or any component of the product 
 
d. 
DOSING & ADMINISTRATION 
 
1. 
Dosing – See Section 7.0 Treatment Plan  
 
2. 
Refer to the current FDA-approved package insert for drug 
administration.  
 
e. 
PREPARATION, STORAGE & STABILITY 
 
Refer to the current FDA-approved package insert for storage, stability and 
special handling information. 
 
f. 
HOW SUPPLIED  
 
Filgrastim is commercially available and will not be supplied. Refer to the current 
FDA-approved package insert. 
 
3.3 
Pegfilgrastim (Neulasta™) (NSC 725961) 
 
a. 
PHARMACOLOGY 

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Mechanism of Action: Similar to filgrastim, pegfilgrastim is a colony-stimulating 
factor that acts on hematopoietic cells by binding to specific cell surface 
receptors, thereby stimulating proliferation, differentiation, commitment, and end-
cell functional activation. Studies on cellular proliferation, receptor binding, and 
neutrophil function demonstrate that filgrastim and pegfilgrastim have the same 
mechanism of action. 
 
b. 
PHARMACOKINETICS 
 
1. 
Absorption: Similar to filgrastim, first-order pharmacokinetic modeling is 
expected with maximum serum concentration reached within 2 to 8 hours 
after subcutaneous injection 
 
2. 
Distribution: Similar to filgrastim, volume of distribution of averaged at 
150 mL/kg 
 
3. 
Metabolism: Unknown 
 
4. 
Elimination:  Neutrophil receptor binding is an important component of 
the clearance of pegfilgrastim, and serum clearance is directly related to 
the number of neutrophils. Pegfilgrastim has reduced renal clearance 
and prolonged persistence in vivo as compared with filgrastim. The half-
life of pegfilgrastim ranges from 15 to 80 hours after subcutaneous 
injection. 
 
c. 
ADVERSE EFFECTS  
 
1. 
Possible Side Effects of Pegfilgrastim: Refer to the current FDA-
approved package insert for the most comprehensive and up to date 
information on adverse reactions. Most frequent adverse reactions are 
skeletal pain (< 20%). 
 
2. 
Pregnancy and Lactation: Category C, pegfilgrastim should be used 
during pregnancy only if the potential benefit justifies the potential risk to 
the fetus.  Animal studies have demonstrated adverse effects and fetal 
loss.  Pegfilgrastim has been shown to cross the placenta in humans.  
There are no adequate and well-controlled studies in pregnant women. 
Excretion in breast milk unknown/use caution. 
 
3. 
Drug Interactions: Drug interactions between filgrastim and other drugs 
have not been fully evaluated.  Drugs such as lithium may potentiate the 
release of neutrophils; ensure that patients receiving lithium and 
pegfilgrastim have more frequent monitoring of neutrophil counts. 
 
Pegfilgrastim should not be administered on the same day with 
anticancer chemotherapeutic agent(s) with leukocyte suppressive 
properties.  
 
Pegfilgrastim is contraindicated in patients with hypersensitivity to E.coli-
derived proteins, filgrastim, or any component of the product. 
 
d. 
DOSING & ADMINISTRATION 
 

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1. 
Dosing – See Section 7.0 Treatment Plan  
 
2. 
Refer to the current FDA-approved package insert for drug 
administration.  
 
e. 
PREPARATION, STORAGE & STABILITY 
 
Refer to the current FDA-approved package insert for storage, stability and 
special handling information. 
 
f. 
HOW SUPPLIED  
 
Pegfilgrastim is commercially available and will not be supplied. Refer to the 
current FDA-approved package insert. 
 
3.4 
Trametinib Dimethyl Sulfoxide (GSK1120212B) (NSC-763093)  
 
a. 
PHARMACOLOGY 
 
Mechanism of Action: Trametinib is a reversible, highly selective allosteric 
inhibitor of mitogen-activated extracellular signal regulated kinase 1 (MEK1) and 
MEK2.  Tumor cells commonly have hyperactivated extracellular signal-related 
kinase (ERK) pathways in which MEK is a critical component.  Trametinib 
interferes with cellular signal-transduction and inhibits proliferation by inducing 
cell apoptosis, with selective activity towards B-RAF serine/threonine protein 
kinase (BRAF) and v-ras oncogene homolog GTPase (RAS) mutant cancer cell 
lines and hematopoietic cancer cells from acute myeloid leukemia (AML) and 
chronic myeloid leukemia (CML) origins.  
 
b. 
PHARMACOKINETICS 
 
1. 
Absorption: Peak plasma concentrations are observed at 1.5 hours 
following single dose oral administration of trametinib under fasted 
conditions in humans.  Administration of trametinib with a high-fat, high-
calorie meal resulted in a 70% decrease in the maximum concentration 
(Cmax) and 10% decrease in the area under the concentration curve 
(AUC) compared to fasted conditions.  Therefore, it is recommended that 
trametinib be administered under fasting conditions.  The absolute oral 
bioavailability of a 2 mg tablet is moderate to high (72%) relative to a co-
administered IV microdose (5 micrograms).   
 
2. 
Distribution: Trametinib is highly bound to plasma proteins (97.4%), and 
has a high volume of distribution (Vd) of 1060 L.   
 
3. 
Metabolism: Following single dose oral administration in humans, 
approximately 50% of plasma radioactivity is present as the parent 
compound.  Trametinib is primarily metabolized via deacetylation 
mediated by hydrolytic esterases, such as carboxylesterases or 
amidases, with secondary oxidation or in combination with 
glucuronidation biotransformation pathways.  The high absolute 
bioavailability and low clearance relative to liver blood flow (3.21 L/hr) 
suggest low hepatic extraction of trametinib in addition to low first-pass 
metabolism. 
 

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4. 
Elimination:  Trametinib has a long terminal half-life of 5.3 days and 
accumulates with repeat once daily dosing.  Fecal excretion is the major 
route of elimination accounting for >80% of excreted radioactivity 
recovered.  Urinary excretion accounted for <19% of excreted 
radioactivity recovered (< 10% of the radioactive dose). 
 
c. 
ADVERSE EFFECTS  
 
1. 
Comprehensive Adverse Events and Potential Risks list (CAEPR) 
for Trametinib dimethyl sulfoxide (GSK1120212B, NSC 763093) 
 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) 
provides a single list of reported and/or potential adverse events (AE) 
associated with an agent using a uniform presentation of events by body 
system. In addition to the comprehensive list, a subset, the Specific 
Protocol Exceptions to Expedited Reporting (SPEER), appears in a 
separate column and is identified with bold and italicized text. This 
subset of AEs (SPEER) is a list of events that are protocol specific 
exceptions to expedited reporting to NCI (except as noted below). Refer 
to the 'CTEP, NCI Guidelines: Adverse Event Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/
aeguidelines.pdf for further clarification. Frequency is provided based on 
1111 patients. Below is the CAEPR for Trametinib (GSK1120212B). 
 
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted 
in parentheses next to the AE in the SPEER. If this CAEPR is part of a 
combination protocol using multiple investigational agents and has an AE 
listed on different SPEERs, use the lower of the grades to determine if 
expedited reporting is required. 
 
Version 2.5, February 1, 20191 
 
Adverse Events with Possible  
Relationship to Trametinib (GSK1120212B) 
(CTCAE 5.0 Term) 
[n= 1111] 
 
Specific Protocol 
Exceptions to 
Expedited Reporting
(SPEER)  
Likely 
(>20%) 
Less Likely 
(<=20%) 
Rare but 
Serious (<3%) 
BLOOD AND LYMPHATIC SYSTEM 
DISORDERS 
 
Anemia 
Anemia (Gr 3) 
CARDIAC DISORDERS 
 
Heart failure 
 
Left ventricular 
systolic 
dysfunction 
 
Sinus bradycardia 
EYE DISORDERS 
 
Blurred vision 
 
Dry eye 
 
Eye disorders - 
Other 
(chorioretinopathy 
also known as 
retinal pigment 

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Adverse Events with Possible  
Relationship to Trametinib (GSK1120212B) 
(CTCAE 5.0 Term) 
[n= 1111] 
 
Specific Protocol 
Exceptions to 
Expedited Reporting
(SPEER)  
Likely 
(>20%) 
Less Likely 
(<=20%) 
Rare but 
Serious (<3%) 
epithelial 
detachment) 
 
Eye disorders - 
Other (retinal vein 
occlusion) 
 
Eye disorders - 
Other (visual 
disorders)2 
 
Papilledema 
 
Periorbital edema 
GASTROINTESTINAL DISORDERS 
 
Abdominal pain 
Abdominal pain (Gr 2) 
 
Colitis 
 
Colonic 
perforation 
 
Constipation 
Constipation (Gr 2) 
Diarrhea 
Diarrhea (Gr 3) 
 
Dry mouth 
Dry mouth (Gr 2) 
 
Dyspepsia 
Dyspepsia (Gr 2) 
 
Mucositis oral 
Mucositis oral (Gr 3) 
Nausea 
Nausea (Gr 3) 
 
Vomiting 
Vomiting (Gr 3) 
GENERAL DISORDERS AND ADMINISTRATION 
SITE CONDITIONS 
 
Chills 
Chills (Gr 2) 
 
Edema face 
Fatigue 
Fatigue (Gr 3) 
 
Fever 
Fever (Gr 2) 
Generalized 
edema3 
Generalized edema3 
(Gr 2) 
IMMUNE SYSTEM DISORDERS 
 
Allergic reaction4 
INFECTIONS AND INFESTATIONS 
 
Folliculitis 
Folliculitis (Gr 2) 
 
Lung infection 
 
Paronychia 
Paronychia (Gr 2) 
 
Skin infection 
Skin infection  
(Gr 2) 
INVESTIGATIONS 
 
Alanine 
aminotransferase 
increased 
Alanine 
aminotransferase 
increased (Gr 3) 
 
Alkaline 
phosphatase 
increased 
Alkaline phosphatase 
increased (Gr 2) 

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Adverse Events with Possible  
Relationship to Trametinib (GSK1120212B) 
(CTCAE 5.0 Term) 
[n= 1111] 
 
Specific Protocol 
Exceptions to 
Expedited Reporting
(SPEER)  
Likely 
(>20%) 
Less Likely 
(<=20%) 
Rare but 
Serious (<3%) 
 
Aspartate 
aminotransferase 
increased 
Aspartate 
aminotransferase 
increased (Gr 3) 
 
CPK increased 
 
Ejection fraction 
decreased 
METABOLISM AND NUTRITION DISORDERS 
 
Anorexia 
Anorexia (Gr 3) 
 
Dehydration 
Dehydration (Gr 3) 
 
Hypoalbuminemia 
 
Hypomagnesemia 
Hypomagnesemia (Gr 
2) 
 
Hyponatremia 
Hyponatremia (Gr 3) 
MUSCULOSKELETAL AND CONNECTIVE 
TISSUE DISORDERS 
 
Arthralgia 
 
Back pain 
Back pain (Gr 2) 
 
Pain in extremity 
Pain in extremity (Gr 
2) 
 
Rhabdomyolysis 
NERVOUS SYSTEM DISORDERS 
 
Dizziness 
Dizziness (Gr 2) 
 
Headache 
Headache (Gr 2) 
RESPIRATORY, THORACIC AND MEDIASTINAL 
DISORDERS 
 
Cough 
Cough (Gr 2) 
 
Dyspnea 
Dyspnea (Gr 3) 
 
Pneumonitis 
SKIN AND SUBCUTANEOUS TISSUE 
DISORDERS 
 
Alopecia 
Alopecia (Gr 2) 
 
Dry skin 
Dry skin (Gr 2) 
 
Nail changes 
 
Palmar-plantar 
erythrodysesthesi
a syndrome 
 
Pruritus 
Pruritus (Gr 2)  
Skin and 
subcutaneous 
tissue 
disorders - 
Other (rash)5 
 
Skin and 
subcutaneous tissue 
disorders - Other 
(rash)5  
(Gr 3) 
VASCULAR DISORDERS 
 
Hypertension 
Hypertension  
(Gr 3) 

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

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GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - 
Flu like symptoms; General disorders and administration site conditions - 
Other (axillary pain); Localized edema; Malaise; Non-cardiac chest pain; 
Pain 
HEPATOBILIARY DISORDERS - Cholecystitis; Hepatic failure; Hepatic 
pain; Hepatobiliary disorders - Other (hepatic encephalopathy) 
INFECTIONS AND INFESTATIONS - Biliary tract infection; Catheter 
related infection; Device related infection; Endocarditis infective; 
Enterocolitis infectious; Hepatitis viral; Infections and infestations - Other 
(abscess limb); Infections and infestations - Other (necrotizing fasciitis); 
Infections and infestations - Other (oral infection); Pharyngitis; Sepsis; 
Upper respiratory infection; Urinary tract infection 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - 
Bruising  
INVESTIGATIONS - Blood bilirubin increased; Blood lactate 
dehydrogenase increased; Creatinine increased; Electrocardiogram QT 
corrected interval prolonged; GGT increased; Lipase increased; 
Lymphocyte count decreased; Platelet count decreased; Serum amylase 
increased; White blood cell decreased 
METABOLISM AND NUTRITION DISORDERS - Hyperglycemia; 
Hyperkalemia; Hyperphosphatemia; Hyperuricemia; Hypocalcemia; 
Hypoglycemia; Hypokalemia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - 
Generalized muscle weakness; Muscle cramp; Musculoskeletal and 
connective tissue disorder - Other (compression fracture); Myalgia; Neck 
pain 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL 
CYSTS AND POLYPS) - Tumor hemorrhage; Tumor pain 
NERVOUS SYSTEM DISORDERS - Dysgeusia; Encephalopathy; 
Intracranial hemorrhage; Lethargy; Nervous system disorders - Other 
(diplopia); Seizure; Somnolence; Stroke; Syncope; Transient ischemic 
attacks 
PSYCHIATRIC DISORDERS - Anxiety; Confusion; Delirium; Depression; 
Hallucinations; Insomnia; Personality change 
RENAL AND URINARY DISORDERS - Acute kidney injury; Cystitis 
noninfective; Dysuria; Hematuria; Proteinuria; Urinary incontinence 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Vaginal 
fistula; Vaginal hemorrhage 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - 
Bronchopulmonary 
hemorrhage; 
Hypoxia; 
Laryngeal 
edema; 
Oropharyngeal pain; Pleural effusion; Pneumothorax; Productive cough; 
Pulmonary hypertension; Respiratory failure; Sinus disorder 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Bullous 
dermatitis; Photosensitivity; Purpura; Skin and subcutaneous tissue 
disorders - Other (erythema nodosum); Skin ulceration; Urticaria 
VASCULAR DISORDERS - Hematoma; Hot flashes; Hypotension 
 
Note: Trametinib (GSK1120212B) in combination with other agents 
could cause an exacerbation of any adverse event currently known to be 
caused by the other agent, or the combination may result in events never 
previously associated with either agent. 
 
2. 
Pregnancy and Lactation: There are no adequate and well-controlled 
studies of trametinib in pregnant women.  Animal studies have shown 
reproductive toxicity, decreased maternal and fetal weight, fetal 

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malformations, and early termination of pregnancy.  Therefore, trametinib 
should not be administered to pregnant women. Women of childbearing 
potential should use effective methods of contraception during therapy 
and for 4 months following discontinuation.  If trametinib is used during 
pregnancy, or if the subject becomes pregnant while taking trametinib, 
the subject should be informed of the potential hazard to the fetus. It is 
not known whether trametinib is excreted in human milk.  Because of the 
potential for drugs to be excreted in human milk, the risk to the nursing 
infant cannot be excluded and therefore trametinib should not be 
administered to nursing mothers. 
 
3. 
Drug Interactions: In vitro studies suggest that trametinib may be a 
substrate for CYP3A4 metabolism and consideration should be used 
when trametinib is given in combination with a strong CYP3A4 inducer or 
inhibitor. Trametinib is a weak CYP2C8 inhibitor and may affect 
medications that are substrates of CYP2C8.  Trametinib is not a 
substrate for human P-glycoprotein (Pgp), breast cancer resistance 
protein (BCRP), OATP1B1, or OATP1B2 transporters. 
 
Patients who are taking concomitant medications that have the potential 
to interact with trametinib may continue taking them, but should be 
monitored for additional toxicities. 
 
d. 
DOSING & ADMINISTRATION 
 
1. 
Dosing – See Section 7.0 Treatment Plan 
 
2. 
Administration Instructions:  Administer orally, on an empty stomach, either 
1 hour before or 2 hours after food. 
 
e. 
PREPARATION, STORAGE & STABILITY 
 
Store tablets at 2°C – 8°C in the original bottle(s). Bottle(s) should be protected from 
light and moisture. Shelf life surveillance of the intact bottles is ongoing. 
 
Patient Storage Instructions: 
- 
Study drug can be transported home in the bottle(s) that were dispensed to 
the patient at room temperature.  Avoid exposing the bottle(s) to prolonged 
temperature extremes (ie.do not leave bottle(s) in a hot car while doing 
errands) 
- 
At home, store the study drug in the refrigerator, 2°C – 8°C (36°F - 46°F).  Do 
not freeze the bottles. 
- 
Keep the tablets in the original bottle(s).  Do not remove tablets from the 
bottle(s) and put them in a pill box or daily dispenser. 
- 
Keep desiccant cylinder in the bottles in order to keep tablets dry. 
 
f. 
HOW SUPPLIED 
 
1. 
Novartis supplies and CTEP, NCI, DCTD distributes 0.5 mg and 2 mg (as 
free base) tablets.  
 
Investigationally labeled bottles each contain 32 tablets packaged in high 
density polyethylene bottles with child-resistant closures including an 
induction seal liner. 
 

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The tablet core contains mannitol, microcrystalline cellulose, 
hypromellose, croscarmellose sodium, magnesium stearate (non-
animal), colloidal silicon dioxide and sodium lauryl sulfate.  
 
• 
0.5 mg tablets are yellow, modified oval, biconvex and film-coated. 
Aqueous film coating consists of Opadry Yellow 03B120006 
(hypromellose, titanium dioxide, polyethylene glycol, iron oxide 
yellow). 
 
• 
2 mg tablets are pink, round, biconvex and film-coated. Aqueous 
film coating consists of Opadry Pink YS-1-14762-A 
(hypromellose, titanium dioxide, polyethylene glycol, polysorbate 
80, iron oxide red). 
 
Each commercially-labeled bottle contains 30 tablets with a desiccant. 
 
The tablet core contains mannitol, microcrystalline cellulose, 
hypromellose, croscarmellose sodium, magnesium stearate (non-
animal), colloidal silicon dioxide and sodium lauryl sulfate.  
 
• 
0.5 mg tablets are yellow, modified oval, biconvex and film-coated 
with ‘GS’ debossed on one face and ‘TFC’ on the opposing face. 
Aqueous film coating consists of hypromellose, titanium dioxide, 
polyethylene 
glycol, 
iron 
oxide 
yellow. 
 
• 
2 mg tablets are pink, round, biconvex and film-coated with ‘GS’ 
debossed on one face and ‘HMJ’ on the opposing face. Aqueous 
film coating consists of hypromellose, titanium dioxide, 
polyethylene glycol, polysorbate 80, iron oxide red. 
 
2. 
Supplied by:  Trametinib is an investigational agent supplied to 
investigators by the Division of Cancer Treatment and Diagnosis 
(DCTD), NCI. Trametinib is provided to the NCI under a Collaborative 
Agreement between Novartis and the DCTD, NCI. 
 
3. 
Drug Ordering: NCI supplied agents may be requested by the Principal 
Investigator (or their authorized designee) at each participating 
institution. Pharmaceutical Management Branch (PMB) policy requires 
that agent be shipped directly to the institution where the patient is to be 
treated. PMB does not permit the transfer of agents between institutions 
(unless prior approval from PMB is obtained). The CTEP assigned 
protocol number must be used for ordering all CTEP supplied 
investigational agents. The responsible investigator at each participating 
institution must be registered with CTEP, DCTD through an annual 
submission of FDA form 1572 (Statement of Investigator), Curriculum 
Vitae, Supplemental Investigator Data Form (IDF), and Financial 
Disclosure Form (FDF). If there are several participating investigators at 
one institution, CTEP supplied investigational agents for the study should 
be ordered under the name of one lead investigator at that institution. 
 
Drug may be requested by submitting agent requests through the PMB 
Online Agent Ordering Processing (OAOP) application (https://eapps-
ctep.nci.nih.gov/OAOP/pages/login.jspx). Access to OAOP requires the 
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account (https://eapps-ctep.nci.nih.gov/iam/) and the maintenance of an 
"active" account status and a "current" password. 
 
4. 
Drug Returns: All unused drug supplies should be returned to the PMB. 
When it is necessary to return study drug (e.g. sealed vials remaining 
when expired vials are recovered by the PMB), investigators should 
return the study drug to the PMB using the NCI Return Agent Form 
available on the NCI home page (http://ctep.cancer.gov). 
 
5. 
Drug Accountability: The investigator, or a responsible party designated 
by the investigator, must maintain a careful record of the receipt, 
disposition and return of all drugs received from the PMB using the Drug 
Accountability Record Form available on the NCI home page 
(http://ctep.cancer.gov). 
 
6. 
Contact Information:  Questions about drug orders, transfers, returns or 
accountability should be addressed to the PMB by calling 240/276-6575 
Monday through Friday between 8:30 a.m. and 4:30 p.m. Eastern time or 
by emailing PMBAfterHours@mail.nih.gov anytime. 
 
 
 
4.0 
STAGING CRITERIA 
 
Patients must have recurrent or Stage IV disease as outlined below (AJCC Cancer Staging 
Manual, 7th Edition, 2010): 
 
Stage IV 
Any T Any N M1a 
 
Any T Any N M1b 
 
Primary Tumor (T) 
 
TX 
Primary tumor cannot be assessed, or tumor proven by the presence of malignant cells in 
sputum or bronchial washings but not visualized by imaging or bronchoscopy 
T0 
No evidence of primary tumor 
Tis 
Carcinoma in situ 
T1 
Tumor 3 cm or less in greatest dimension, surrounded by lung or visceral pleura, without 
bronchoscopic evidence of invasion more proximal than the lobar bronchus (i.e., not in 
the main bronchus)* 
T1a 
Tumor 2 cm or less in greatest dimension 
T1b 
Tumor more than 2 cm but 3 cm or less in greatest dimension 

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T2 
Tumor more than 3 cm but 7 cm or less or tumor with any of the following features (T2 
tumors with these features are classified T2a if 5 cm or less); Involves main bronchus, 2 
cm or more distal to the carina; Invades visceral pleura (PL1 or PL2); Associated with 
atelectasis or obstructive pneumonitis that extends to the hilar region but does not involve 
the entire lung 
 
T2a 
Tumor more than 3 cm but 5 cm or less in greatest dimension 
T2b 
Tumor more than 5 cm but 7 cm or less in greatest dimension 
T3 
Tumor more than 7 cm or one that directly invades any of the following:  parietal pleural 
(PL3) chest wall (including superior sulcus tumors), diaphragm, phrenic nerve, 
mediastinal pleura, parietal pericardium; or tumor in the main bronchus (less than 2 cm 
distal to the carina* but without involvement of the carina; or associated atelectasis or 
obstructive pneumonitis of the entire lung or separate tumor nodule(s) in the same lobe 
T4 
Tumor of any size that invades any of the following:  mediastinum, heart, great vessels, 
trachea, recurrent laryngeal nerve, esophagus, vertebral body, carina, separate tumor 
nodule(s) in a different ipsilateral lobe 
 
* 
The uncommon superficial spreading tumor of any size with its invasive component 
limited to the bronchial wall, which may extend proximally to the main bronchus, is also 
classified as T1a. 
 
Regional Lymph Nodes (N) 
 
NX 
Regional lymph nodes cannot be assessed 
N0 
No regional lymph node metastases 
N1 
Metastasis in ipsilateral peribronchial and/or ipsilateral hilar lymph nodes and 
intrapulmonary nodes, including involvement by direct extension 
N2 
Metastasis in ipsilateral mediastinal and/or subcarinal lymph node(s) 
N3 
Metastasis in contralateral mediastinal, contralateral hilar, ipsilateral or contralateral 
scalene, or supraclavicular lymph node(s) 
 
Distant Metastasis (M) 
 
M0 
No distant metastasis 
M1 
Distant metastasis 
M1a 
Separate tumor nodule(s) in a contralateral lobe tumor with pleural nodules or malignant 
pleural (or pericardial) effusion ** 
M1b 
Distant metastasis 
 
** 
Most pleural (and pericardial) effusions with lung cancer are due to tumor.  In a few 
patients, however, multiple cytopathologic examinations of pleural (pericardial) fluid are 
negative for tumor, and the fluid is non-bloody and is not an exudate.  Where these 
elements and clinical judgment dictate that the effusion is not related to the tumor, the 
effusion should be excluded as a staging element and the patient should be classified as 
M0. 
 
 
5.0 
ELIGIBILITY CRITERIA 
 
Each of the criteria in the following section must be met in order for a patient to be considered eligible for 
registration.  Use the spaces provided to confirm a patient's eligibility.  For each criterion requiring test 
results and dates, please record this information on the Onstudy Form and submit via Medidata Rave® 
(see Section 14.0).  Any potential eligibility issues should be addressed to the Data Operations Center in 
Seattle at 206/652-2267 or lungquestion@crab.org prior to registration. 

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In calculating days of tests and measurements, the day a test or measurement is done is considered Day 
0.  Therefore, if a test is done on a Monday, the Monday 4 weeks later would be considered Day 28.  This 
allows for efficient patient scheduling without exceeding the guidelines.  If Day 14 or 28 falls on a 
weekend or holiday, the limit may be extended to the next working day. 
 
5.1 
Disease Related Criteria 
 
a. 
Patients must have pathologically confirmed KRAS mutation (at codon 12, 13 
and 61) positive non-small cell lung cancer (NSCLC) that is Stage IV or 
recurrent.  The specific subtype of KRAS mutation must be known. KRAS 
mutation and subtype testing must have been performed in a CLIA certified 
laboratory. CLIA certified commercially available tests are acceptable. 
 
b. 
Patients must have measurable disease (see Section 10.1) documented by CT 
or MRI within 28 days prior to registration.  The CT f rom a combined PET/CT 
may be used only if it is of diagnostic quality as defined in Section 10.1a. Non-
measurable disease must be assessed within 42 days prior to registration. All 
known sites of disease must be assessed and documented on the Baseline 
Tumor Assessment Form (RECIST 1.1).   
 
c. 
Patients must not have known brain metastases, leptomeningeal carcinomatosis 
or spinal cord compression unless:  (1) metastases have been locally treated 
(including SBRT, WBRT, and surgical resection) and have remained clinically 
controlled and asymptomatic for at least 14 days following treatment and prior to 
registration, AND (2) patient has no residual neurological dysfunction and has 
been off corticosteroids for at least 2 days prior to registration. 
 
5.2 
Prior/Concurrent Therapy Criteria 
 
a. 
Patients must have documented progressive cancer following at least one but no 
more than two prior regimens of systemic therapy for lung cancer, one of which 
must have been platinum based combination chemotherapy. 
 
Treatment with an immune therapy or targeted therapy for advanced disease will 
be considered a separate regimen and will count toward the prior regimens. 
 
Maintenance therapy will not be counted as a separate regimen.    
 
Adjuvant chemotherapy or chemotherapy administered as part of concurrent 
chemotherapy and radiation therapy for the treatment of lung cancer will not 
count as a prior regimen of systemic therapy as long as recurrence of patient’s 
lung cancer occurred more than 12 months after the last day of chemotherapy. 
 
 
b. 
Patients must not have received any chemotherapy, biologic agent, or any 
investigational agent within 14 days prior to registration. Patients must have 
recovered from any adverse events to CTCAE Grade 0-1 prior to registration. 
 
c. 
Prior treatment with an anti-PD-1 or anti-PDL1 is not required.  
 
d. 
Patients must not have received prior docetaxel. Patients must not have received 
therapy with a drug known to be either a MEK inhibitor or a PI3K/AKT/mTOR 
pathway inhibitor. 
 

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e. 
Patients must have recovered from any adverse effects from prior therapy 
(except alopecia) to ≤ CTCAE Grade 1 prior to registration.  
 
f. 
Patients may have had prior radiation therapy as long as it has not affected 
greater than 25% of the bone marrow and at least one measurable lesion is 
outside the area of prior radiation (see Section 18.3). At least 7 days must have 
elapsed since last radiation treatment.  Patients must have recovered from any 
adverse events from prior radiation therapy to ≤ CTCAE Grade 1. 
 
g. 
Patients must not have had a major surgery within 28 days prior to registration. 
Patients must have recovered from any adverse effects of prior surgery to the 
satisfaction of the treating physician. Biopsies and central IV access placement 
are not considered major surgery. 
 
h. 
Because the composition, PK, and metabolism of many herbal supplements are 
unknown, the concurrent use of all herbal supplements is prohibited during the 
study (including but not limited to St. John’s Wort, kava, ephedra [ma huang], 
ginko biloba, dehydroepiandrosterone [DHEA], yohimbe, saw palmetto, or 
ginseng). 
 
5.3 
Clinical/Laboratory Criteria 
 
a. 
Patients must have Zubrod performance status of 0-2 (see Section 10.4 
 
b. 
Patients must have adequate bone marrow function as evidenced by all of the 
following:  ANC ≥ 1500/mcL; platelet count ≥ 100,000/mcL; and hemoglobin ≥ 9 
grams/dl. These results must be obtained within 28 days prior to registration. 
 
c. 
Patients must have adequate liver function as evidenced by the following: total 
bilirubin ≤ 1.5 x institutional upper limit of normal (IULN), and AST and ALT ≤ 2.5 
x IULN (or < 5 x IULN for patients with known liver metastases).  These results 
must be obtained within 28 days prior to registration. 
 
 
d. 
Patients must have adequate renal function as evidenced by ONE of the 
following: serum creatinine ≤ 1.5 x IULN OR measured or calculated creatinine 
clearance ≥ 40 mL/min.  This result must have been obtained within 28 days prior 
to registration. 
 
Calculated creatinine clearance = (140 - age) x wt (kg) x 0.85 (if female) 
 
72 x creatinine (mg/dl) 
 
e. 
Patients must be able to swallow oral medications and must not have a gastro-
intestinal disorder with diarrhea as a major symptom or that may alter absorption 
such as malabsorption syndromes or gastric resection. 
 
f. 
Patient must not have prior history of interstitial lung disease or pneumonitis.  
 
g. 
Patients must not have history of significant co-morbid illness inclusive of but not 
restricted to New York Heart Association Class II, congestive cardiac failure, 
uncontrolled hypertension, history of myocardial infarction, unstable angina, 
coronary angioplasty, stenting or cerebrovascular accident within 6 months prior 
to registration or any other illness that in the assessment of the treating physician 
would compromise the ability of the patient to participate in this study.  
 

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h. 
Patients must have QTC interval ≤ 480 msec (using the Bazett’s formula) on 
electrocardiogram performed within 42 days prior to registration.  History or 
evidence of current clinically significant uncontrolled arrhythmias are not eligible.  
However, patients with controlled atrial fibrillation for > 30 days prior to 
randomization are eligible. Patients must not have atrial fibrillation > Grade 2 on 
the screening ECG.  Patients with CTCAE Grade 1-2 atrial fibrillation on their 
screening ECG must have a second ECG performed prior to registration and 
more than 30 days from the screening ECG (either before or after) with the most 
recent ECG showing stable or improving grade of atrial fibrillation. 
 
i. 
Patients must have a left ventricular ejection fraction (LVEF) ≥ institutional lower 
limit of normal (ILLN) by ECHO or MUGA within 42 days prior to registration. 
 
j. 
Patients must not have untreated or unresolved retinopathy or have a history (or 
current evidence) of retinal vein occlusion determined by an ophthalmology exam 
within 42 days prior to registration. 
 
k. 
Patients must not have an immediate or delayed hypersensitivity reaction or 
idiosyncracy to drugs chemically related to trametinib, or excipients, or to 
dimethyl sulfoxide (DMSO) or other agents used in the study. 
 
l. 
Patients must not have a known history of active hepatitis B or C infection 
(defined as presence of Hep B sAg and/or Hep B DNA and/or Hep C RNA) 
because docetaxel and trametinib can cause hepatotoxicity and can jeopardize 
patients with hepatitis.  Also, because docetaxel and trametinib can cause 
significant cytopenias, patients must not have a known history of HIV 
seropositivity. 
 
m. 
No other prior malignancy is allowed except for the following:  adequately treated 
basal cell or squamous cell skin cancer, in situ cervical cancer, adequately 
treated Stage I or II cancer from which the patient is currently in complete 
remission, or any other cancer from which the patient has been disease free for 
three years.  Patients with localized prostate cancer who are being followed by 
an active surveillance program are also eligible. 
 
n. 
Patients must not be pregnant or nursing due to the risk of fetal or nursing infant 
harm.  Women/men of reproductive potential must have agreed to use an 
effective contraceptive method (hormonal or barrier method of birth control; 
abstinence) prior to study entry, during the study participation and for 4 months 
after the last dose of the drug.  A woman is considered to be of "reproductive 
potential" if she has had menses at any time in the preceding 12 consecutive 
months.  In 
addition 
to 
routine 
contraceptive 
methods, 
"effective 
contraception" also includes heterosexual celibacy and surgery intended to 
prevent pregnancy (or with a side-effect of pregnancy prevention) defined as a 
hysterectomy, bilateral oophorectomy or bilateral tubal ligation.  However, if at 
any point a previously celibate patient chooses to become heterosexually active 
during the time period for use of contraceptive measures outlined in the protocol, 
he/she is responsible for beginning contraceptive measures. 
 
5.4 
Specimen Submission Criteria 
 
a. 
Patients must be offered optional participation in banking of specimens for future 
research as described in Section 15.1. 
 
5.5 
Regulatory Criteria 
 

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a. 
Patients must be informed of the investigational nature of this study and must 
sign and give written informed consent in accordance with institutional and 
federal guidelines 
 
b. 
As a part of the OPEN registration process (see Section 13.3 for OPEN access 
instructions) the treating institution's identity is provided in order to ensure that 
the current (within 365 days) date of institutional review board approval for this 
study has been entered in the system. 
 
 
6.0 
STRATIFICATION FACTORS 
 
Patients will be stratified by type of KRAS mutation: G12C vs non-G12C. 
 
 
7.0 
TREATMENT PLAN 
 
For treatment or dose modification questions, please contact Dr. Shirish M. Gadgeel at 313/576-
8753 or email at gadgeels@karmanos.org or contact Dr. Jonathan Riess at 916/734-3772 or 
jonathan.riess@ucdmc.ucdavis.org.  For dosing principles or questions, please consult the 
SWOG Policy #38 "Dosing Principles for Patients on Clinical Trials" at http://swog.org (then click 
on "Policies and Manuals" under the "Visitors" menu and choose Policy 38). 
 
7.1 
Pre-Medication 
 
Patients receiving therapy with docetaxel must receive appropriate pre-medications 
consisting of dexamethasone and anti-emetics. The exact schedule and dose for these 
pre-medications should be according to local practices. 
 
7.2 
Treatment 
 
Patients will receive the following therapy: 
 
 
Agent 
Dose 
Route 
Day 
Schedule* 
 
Trametinib 
2 mg 
PO 
1-21 
Daily 
 
Docetaxel 
75 mg/m2 
IV 
1 
Each cycle 
 
Pegfilgrastim/filgrastim** 
 
* 1 cycle = 21 days 
** As long as the patient is receiving docetaxel at the dose of 75mg/m2, patient must 
receive pegfilgrastim or filgrastim following each cycle. Dosing and administration 
must be performed in accordance with ASCO and NCCN guidelines. Current 
guidelines from both NCCN and ASCO state that prophylactic use of myeloid growth 
factors is justified if the expected risk of febrile neutropenia is 20%.  In previous 
studies of MEK inhibitors with docetaxel the risk of febrile neutropenia was around 
20%.  
 
Docetaxel treatment will be administered on an outpatient basis. 
 

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On the day of treatment with docetaxel patients must have a neutrophil count of ≥ 
1,500/mcL and platelet count of ≥ 100,000/mcL.  If counts do not recover to required level 
in 21 days then docetaxel must be discontinued. No specific changes are required for 
anemia.  This should be managed according to local guidelines. 
 
Patients must not receive any other therapy for NSCLC while receiving treatment on this 
trial. Patients must not receive any other investigational agent while receiving treatment 
on this trial. Bisphosphonates and denusomab for bone metastases are permitted. 

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7.3 
Drug Compliance Documentation 
 
The study medication will be given in accordance with the protocol and the instructions of 
a site investigator.  Patients will be asked to bring the remaining trial medication at the 
end of each cycle to the investigator site for a compliance check. The remaining tablets 
will be counted by the investigator/site staff and recorded at the investigator site. 
Discrepancies between the number of tablets remaining and the calculated number of 
tablets the patients should have taken must be documented and explained. At the end of 
each cycle, any remaining medication will be collected. If the patient is eligible for further 
treatment, a new bottle of study medication must be dispensed. 
 
Drug compliance will be recorded by patients in the Intake Calendar (see Appendix 18.1).  
Institutional CRAs will review and ascertain patient adherence with protocol therapy at 
the end of treatment for each cycle.  Calendar should be kept in the patient's clinic chart. 
 
7.4 
Full CDUS Reporting Requirement 
 
Because this study contains an investigational drug for which CTEP holds the IND, it falls 
under CTEP requirements for full reporting.  This involves required submission of cycle-
specific toxicity and dose information (see Section 14.4b, the S1507 Treatment Form, 
and the S1507 Adverse Event Form).  A cycle is defined as 21 days. 
 
7.5 
Criteria for Removal from Protocol Treatment 
 
a. 
Progression of disease or symptomatic deterioration (as defined in Section 
10.2e). 
 
b. 
Unacceptable toxicity.  
 
c. 
Delay of both agents > 3 weeks beyond scheduled treatment for any reason. 
 
d. 
The patients may withdraw from the study at any time for any reason. 
 
e. 
The investigator can withdraw a patient from the study in the event of serious and 
persistent non-compliance that jeopardizes the patient’s safety or renders study 
results for this patient unacceptable. 
 
7.6 
Discontinuation of Treatment 
 
All reasons for discontinuation of treatment must be documented in the Off Treatment 
Notice. 
 
7.7 
Follow-Up Period 
 
All patients will be followed until death or 3 years after registration, whichever occurs first. 
 
 
8.0 
TOXICITIES TO BE MONITORED AND DOSE MODIFICATIONS 
 
8.1 
NCI Common Terminology Criteria for Adverse Events 
 
Two different versions of the NCI Common Terminology Criteria for Adverse 
Events (CTCAE) will be used on this study. 
 

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a. 
Serious Adverse Event (SAE) reporting 
 
The CTCAE (NCI Common Terminology Criteria for Adverse Events) Version 5.0 
will be utilized for SAE reporting only.  The CTCAE Version 5.0 can be 
downloaded from the CTEP home page (https://ctep.cancer.gov).  All appropriate 
treatment areas should have access to a copy of the CTCAE Version 5.0. 
 
b. 
Routine toxicity reporting 
 
This study will utilize the CTCAE Version 4.0 for routine toxicity reporting.  A copy 
of the CTCAE Version 4.0 can be downloaded from the CTEP home page 
(https://ctep.cancer.gov).  All appropriate treatment areas should have access to 
a copy of the CTCAE Version 4.0. 
 
8.2 
General Dose Modification Guidelines  
 
a. 
Missed doses are to be omitted rather than made up. 
 
b. 
If multiple toxicities are experienced, dose modifications will be based on the 
toxicity requiring the largest dose reduction. 
 
c. 
The treating physician can reduce the dose of only one of the two drugs if the 
toxicity is felt to be related to only one of the drugs. 
 
d. 
Reductions are based on the dose given in the preceding cycle and are based on 
toxicities observed since the prior toxicity evaluation. 
 
e. 
If both drugs are held > 21 days, patient must be removed from protocol 
treatment. If one drug is held for > 21 days then that drug should be permanently 
discontinued and the other drug could be continued as long as the treating 
physician believes the patient is deriving clinical benefit.  
 
f. 
If trametinib is discontinued due to toxicity, patient may remain on docetaxel as 
long as docetaxel is well tolerated and according to the treating physician the 
patient is still deriving benefit.  If docetaxel is discontinued due to toxicity, patient 
may remain on trametinib as long as trametinib is well tolerated and according to 
the treating physician the patient is still deriving benefit. 
 
8.3 
Dose Modifications 
 
a. 
Dose Modifications for Docetaxel and Trametinib 
 
Trametinib dose levels 
Docetaxel dose levels 
Level 0:  2 mg 
Level 0:  75 mg/m2 
Level -1:  1.5 mg 
Level -1:  60 mg/m2 
Level -2:  1 mg 
Level -2:  50 mg/m2 
 
Note: Except where indicated below, no dose escalations are allowed. 
 
On the day of docetaxel administration patient must not have a > Grade 1 
toxicity attributable to docetaxel. 
 
Maximum of 2 dose reductions for trametinib are allowed. If further dose 
reduction is required the drug must be discontinued.  

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Dose modification and AE guidelines are outlined in the sections below for AEs 
that are deemed possibly related to trametinib or docetaxel: 
 
• 
AEs not otherwise specified 
• 
Rash 
• 
Visual changes 
• 
Diarrhea  
• 
Liver chemistry elevation 
• 
Ejection fraction changes 
• 
Prolonged QTc 
• 
Hypertension 
• 
Nausea and vomiting 
• 
Cytopenias 
• 
Pneumonitis 
 
b. 
Trametinib or Docetaxel Dose Modification for Toxicities Not Specified in 
Subsequent Sections 
 
Trametinib or docetaxel Treatment Modification for Clinically Significant Toxicities 
Deemed Related to the specific drug 
(This section is not for specific AEs such as hypertension, rash, ejection fraction changes, 
pneumonitis, diarrhea, liver chemistry, QTc prolongation, or visual changes.  Refer to 
other sections for these specific AEs). 
CTCAE v4 
Grade 
Management Guideline 
Dose Modification 
Grade 1 
Monitor as clinically 
indicated.  Provide 
supportive care according to 
institutional standards. 
Continue trametinib and docetaxel at 
current dose level. 
Grade 2 
(tolerable) 
• Interrupt treatment until resolution to 
Grade 1 or baseline. If it is clear that 
the toxicity is related to only 1 drug then 
the other drug may be continued.    
• Upon resolution, restart treatment with 
both drugs at current dose level. 
Grade 2 
(intolerable) 
and  Grade 3 
• Interrupt treatment until resolution to 
Grade 1 or baseline.   
• Upon resolution to baseline or Grade 1, 
restart with one level of dose reduction 
for both drugs. 
• If the Grade 3 toxicity recurs, interrupt 
trametinib and/or docetaxel; When 
toxicity resolves to Grade 1 or baseline, 
restart trametinib and/or docetaxel 
reduced by another dose level.  
• If it is clear that the toxicity is from one 
drug then the other drug may be 
continued at the same dose level and 
interruption of the other drug is not 
necessary.  
 
Grade 4 
 
If event resolves to Grade 1 or baseline 
discuss potential continuation of 
trametinib/docetaxel with Medical 
Monitor; if continuation of treatment 

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Trametinib or docetaxel Treatment Modification for Clinically Significant Toxicities 
Deemed Related to the specific drug 
(This section is not for specific AEs such as hypertension, rash, ejection fraction changes, 
pneumonitis, diarrhea, liver chemistry, QTc prolongation, or visual changes.  Refer to 
other sections for these specific AEs). 
CTCAE v4 
Grade 
Management Guideline 
Dose Modification 
agreed then restart trametinib/docetaxel 
at dose reduced by one dose level. 
If event does not resolve, permanently 
discontinue trametinib/docetaxel. 
If it is clear that the toxicity is from one 
drug then the other drug may be 
continued at the same dose level and 
interruption of the other drug is not 
necessary.  
 
c. 
Rash 
 
Rash is a frequent AE observed in patients receiving trametinib. (47) 
Recommendations for supportive care and guidelines for dose modifications for 
rash are based on experience with other MEK inhibitors and EGFR inhibitors. 
(48,49) No modifications in docetaxel dose or schedule are necessary for 
trametinib related rash.  
 
The institutional standards for the management of skin-related AEs can differ 
from these guidelines.  In this case, best clinical judgment should be applied and 
a consultation with the study chair or the CTEP Medical Monitor may be required. 
 
Guidelines for Supportive Care of Rash 
Type of Care 
Action 
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 body areas such as face, chest, and 
upper back.   
• Use mild-strength topical steroid (hydrocortisone 1% 
cream) or topical antibiotic (e.g., clindamycin) or oral 
antibiotics (e.g., doxycycline 100 mg BID, 
minocycline 100 mg BID). 

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Guidelines for Supportive Care of Rash 
Type of Care 
Action 
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 physician 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 
• Use moderate strength topical 
steroid.2 
• Reassess after 2 weeks. 
• Continue trametinib. 
• If rash does not recover to baseline 
within 2 weeks despite best supportive 
care, reduce trametinib by one dose 
level.3 
Grade 2 
 
• Initiate prophylactic and 
symptomatic treatment 
measures.1 
• Use moderate strength topical 
steroid.2 
• Reassess after 2 weeks. 
 
• Reduce trametinib by one dose 
level. 
• If rash recovers to ≤ Grade 1 within 2 
weeks, increase dose to previous dose 
level. 
• If no recovery to ≤ Grade 1 within 2 
weeks, interrupt trametinib until 
recovery to ≤ Grade 1. 
• Restart trametinib at reduced dose 
level.3 
Grade ≥3 
 
• Use moderate strength topical 
steroids PLUS oral methyl-
prednisolone dose pack.2 
• Consult dermatologist. 
• Interrupt trametinib until rash recovers 
to ≤ Grade 1. 
• Restart with trametinib reduced by 
one dose level.3,4 
• 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. 
2.  Moderate-strength topical steroids:  Hydrocortisone 2.5% cream or fluticasone 
propionate 0.5% cream. 
3.  Approval of CTEP Medical Monitor is required to restart study treatment after >4 
weeks of interruption. 
4.  Trametinib may be escalated to previous dose level if no rash is evident 4 weeks after 
restarting study treatment. 
 

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d. 
Visual Changes 
 
Trametinib is known to be associated with visual adverse events.  An 
ophthalmologist should be consulted if changes in vision develop.  However, if 
the visual changes are clearly unrelated to study treatment (e.g., allergic 
conjunctivitis), then monitor closely as it may be reasonable to defer ophthalmic 
examination.  Special attention should be given to retinal findings (e.g., retinal 
pigment epithelial detachment (RPED) or retinovascular abnormalities (i.e., 
branch or central retinal vein occlusions [RVO]).  
 
Guidelines regarding event management and dose reduction for visual changes 
considered to be related to study treatment are provided in the table below. 
 
No modifications in dose or schedule of docetaxel is necessary if patient 
develops visual changes from trametinib. If it is not clear whether docetaxel has 
contributed to the toxicity then the guidelines in Section 8.3b (“Trametinib or 
Docetaxel Dose Modification for Toxicities Not Specified in Subsequent 
Sections”) should be followed. 

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Management and Trametinib Dose Modification for Visual Changes 
and/or Ophthalmic Examination Findings 
Event 
CTCAE Grade 
Management Guideline 
Dose Modification 
Grade 1* 
 
 
• Consult ophthalmologist 
within 7 days of onset. 
 
• If dilated fundus examination cannot be 
performed within 7 days of onset, hold trametinib 
until RPED and RVO can be excluded by retina 
specialist/ophthalmologist. 
• If RPED and RVO excluded, continue/or restart 
trametinib at same dose level. 
• If RPED suspected/diagnosed:  See RPED dose 
modification table below (following this table); 
report as SAE. 
• If RVO diagnosed:  Permanently discontinue 
trametinib and report as SAE. 
Grade 2 and 
Grade 3 
 
• Consult ophthalmologist 
immediately. 
 
• Hold trametinib 
• If RPED or RVO excluded, restart trametinib at 
same dose level after visual AE is < Grade 1.  If 
no recovery within 3 weeks, discontinue 
trametinib 
• If RPED diagnosed:  See RPED dose 
modification table below; report as SAE. 
• If RVO:  Permanently discontinue trametinib 
and report as SAE. 
Grade 4 
 
• Consult ophthalmologist 
immediately. 
• Report as SAE. 
• Hold Trametinib 
• If RPED/RVO excluded, may restart trametinib at 
same or reduced dose after discussion with the 
CTEP Medical Monitor. 
• If RVO or RPED, permanently discontinue 
trametinib. 
Abbreviations: RPED = retinal pigment epithelial detachments; 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. 

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Trametinib Dose Modification for RPED 
Event 
CTCAE Grade 
Action and Dose Modification 
Grade 1 RPED (Asymptomatic; 
clinical or diagnostic observations 
only) 
• Continue treatment with retinal evaluation monthly until 
resolution.  If RPED worsens, follow instructions below. 
Grade 2-3 RPED (Symptomatic with 
mild to moderate decrease in visual 
acuity; limiting instrumental ADL) 
• Interrupt trametinib. 
• Retinal evaluation monthly. 
• If improved to ≤ Grade 1, restart trametinib with one 
dose level reduction (reduced by 0.5 mg) or discontinue 
in patients taking trametinib 1 mg daily. 
• If no recovery within 4 weeks permanently discontinue 
trametinib 
 
e. 
Diarrhea 
 
Episodes of diarrhea have occurred in patients receiving trametinib. (50)  Other 
frequent causes of diarrhea including concomitant medications (e.g., stool 
softeners, laxatives, antacids, etc.), infections by C. difficile or other pathogens, 
or partial bowel obstruction should be clinically excluded. 
 
Guidelines regarding management and dose modification for diarrhea considered 
related to trametinib are provided in the table below. 
 
Diarrhea may also occur with docetaxel. Therefore docetaxel modifications are 
also included in the table below.  
Management and Trametinib/Docetaxel Dose Modification 
Guidelines for Diarrhea 
CTCAE Grade 
Adverse Event Management 
Action and Dose 
Modification 
Uncomplicated 
Diarrhea,1 
Grade 1 or 2 
• Diet:  Stop all lactose containing 
products; eat small meals, BRAT-diet 
(banana, rice, apples, toast) 
recommended. 
• Hydration:  8-10 large glasses of clear 
liquids per day (e.g., Gatorade or 
broth). 
• Loperamide3:  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. 
• Diarrhea >24 hours:  Loperamide 
2 mg every 2 hours; maximum 16 
mg/day.  Consider adding oral 
antibiotics. 
• Diarrhea >48 hous:  Loperamide 2 mg 
every 2 hours; maximum 16 mg/day.  
Add budesonide or other second-line 
therapies (otreotide, or tincture of 
opium) and oral antibiotics. 
 
• Continue 
trametinib/docetaxel. 
• If diarrhea is Grade 2 for 
> 48 h, interrupt 
trametinib and docetaxel 
until diarrhea resolves to 
Grade ≤1. 
• Restart trametinid and 
docetaxel at the same 
dose level 
• If treatment delay is >21 
days, discontinue 
trametinib/docetaxel. 

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Management and Trametinib/Docetaxel Dose Modification 
Guidelines for Diarrhea 
CTCAE Grade 
Adverse Event Management 
Action and Dose 
Modification 
Uncomplicated 
Diarrhea,1 
Grade 3 or 4 
 
Any 
Complicated 
Diarrhea2 
 
• Clinical evaluation mandatory. 
• Loperamide3:  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. 
• 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 
docetaxel until diarrhea 
resolves to ≤ Grade 1. 
• Restart with trametinib 
and docetaxel reduced 
by one dose level.4 
• If 3 dose reductions of 
study treatment are 
clinically indicated, 
permanently 
discontinue trametinib 
and docetaxel. 
• If treatment delay is >21 
days weeks, discontinue 
trametinib and 
docetaxel. 
1.  Uncomplicated diarrhea defined by the absence of symptoms such as cramping, 
nausea/vomiting ≥ Grade 2, decreased performance status, pyrexia, sepsis, 
neutropenia ≥ Grade 3, frank bleeding, and/or dehydration requiring intravenous fluid 
substitution. 
2.  Complicated diarrhea defined by the presence of symptoms such as cramping, 
nausea/vomiting ≥ Grade 2, decreased performance status, pyrexia, sepsis, 
neutropenia ≥ Grade 3, frank bleeding, and/or dehydration requiring intravenous fluid 
substitution. 
3.  Loperamide should be made available prior to start of study treatment so 
loperamide administration can begin at the first signs of diarrhea. 
4.  Escalation of trametinib 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. Escalation of docetaxel is not 
allowed.  
 
f. 
Liver Chemistry Changes 
 
It is recommended that docetaxel modifications be made according to package 
insert and institutional guidelines. A general recommendation is to hold docetaxel 
if the patient has developed Grade 2 elevation in liver enzymes or elevation in 
bilirubin, which is associated with greater than 50% of the bilirubin being direct. 
Restart docetaxel at the next lower dose once the liver enzymes have returned to 
Grade 1 and the direct bilirubin has normalized 

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Trametinib Dose Modification for Liver Function Test Abnormalities 
Event 
Treatment modifications and 
assessment/monitoring 
ALT ≥3x ULN but <5x ULN and TB <2x 
ULN, without symptoms considered related 
to liver injury or hypersensitivity and who 
can be monitored weekly for 4 weeks 
 
• May continue study drug.  
• Report as SAE if CTEP-AERS 
reporting criteria is met. 
• If liver chemistry stopping criteria are 
met any time, proceed as described 
below. 
 
MONITORING: 
Repeat LFT (ALT, AST, ALK, bilirubin) 
until they return to normal/baseline or 
stabilise (LFT may be every 2 weeks 
after 4 weeks if ALT <3x ULN and TB <2 
ULN). 
Criteria for discontinuing study drug:  When 
any of the liver stopping  criteria below is 
met, discontinue trametinib  
 
1. ALT ≥3xULN and bilirubin ≥2x ULN  or 
>35% direct bilirubin 1, 2 
2. ALT ≥ 3xULN and INR >1.5, if INR 
measured2  (INR threshold does not 
apply if patient is on anticoagulant) 
3. ALT ≥5x ULN 
4. ALT ≥3x ULN persists for ≥4 weeks 
5. ALT ≥3x ULN and cannot be monitored 
weekly for 4 weeks 
6. ALT  ≥3x ULN associated with 
symptoms3  (new or worsening) 
believed to be related to  liver injury or 
hypersensitivity 
 
• Immediately discontinue study 
treatment. 
• Do not restart/rechallenge unless 
approved by CTEP trametinib medical 
monitor.   
• Report as SAE if:  1) CTEP-AERS 
reporting criteria are met, or 2) 
patients meet criteria 1-2. 
• Perform liver event ASSESSMENT 
AND WORKUP (see below). 
• Monitor the patient until liver 
chemistries  resolve, stabilize, or 
return to baseline (see MONITORING 
below). 
• If applicable, provide details on 
required follow up assessments (e.g., 
follow up for overall survival or 
disease recurrence or progression).  
 
 
MONITORING: 
In patients stopping for criteria 1-2 (with 
abnormal TB and INR, indicating 
potentially more significant liver 
toxicities): 
• Repeat liver chemistries (ALT, AST, 
ALK, bilirubin) and perform liver event 
follow-up assessments within 24 
hours. 
• Monitor subjects twice weekly until 
LFT return to normal/baseline or 
stabilize. 
• A specialist or hepatology 
consultation is recommended. 
In patients stopping for criteria 2-6: 
• Repeat LFT and perform liver event 
follow up assessments within  24-72 

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Trametinib Dose Modification for Liver Function Test Abnormalities 
Event 
Treatment modifications and 
assessment/monitoring 
hrs  
• Monitor subjects weekly until LFTs 
return to normal/baseline or stabilize. 
 
ASSESSMENT and WORKUP: 
• Viral hepatitis serology.4 
• If possible, obtain blood sample for 
PK analysis.5 
• Serum CPK and LDH. 
• Fractionate bilirubin, if total bilirubin 
≥2x ULN. 
• CBC with differential to assess 
eosinophilia. 
• Record clinical symptoms of liver 
injury, or hypersensitivity on AE CRF. 
• Record concomitant medications 
(including acetaminophen, herbal 
remedies, other over the counter 
medications). 
• Record alcohol use. 
Additional work up for patient stopping 
for criteria 1-2 (with abnormal TB and 
INR, indicating potentially more 
significant liver toxicities): 
• Anti-nuclear antibody, anti-smooth 
muscle antibody, Type 1 anti-liver 
kidney microsomal antibodies, and 
quantitative total immunoglobulin G 
(IgG or gamma globulins). 
• Serum acetaminophen adduct HPLC 
assay (in subjects with likely 
acetaminophen use in the preceding). 
• If there is underlying chronic hepatitis 
B (e.g. positive hepatitis B surface 
antigen):  quantitative hepatitis B DNA 
and hepatitis delta antibody.6 
• Liver imaging (ultrasound, MRI, CT) 
and /or liver biopsy. 
Footnotes: 
1.  Serum bilirubin fractionation should be performed if testing is available. If serum 
bilirubin fractionation testing is unavailable, record presence of detectable urinary 
bilirubin on dipstick, which indicates direct bilirubin elevations and suggesting liver 
injury. 
2.  All events of ALT ≥3xULN and bilirubin ≥2xULN (>35% direct bilirubin) or ALT ≥3x 
ULN and INR >1.5 (if INR measured) may indicate severe liver injury (possible “Hy’s 
Law”).  INR measurement is not required, and the threshold value stated will not apply 
to subjects receiving anticoagulants. 
3.  New or worsening symptoms believed to be related to liver injury (such as fatigue, 
nausea, vomiting, right upper quadrant pain or tenderness, or jaundice) or believed to 
be related to hypersensitivity (such as fever, rash or eosinophilia) 
4.  Includes: Hepatitis A IgM antibody; Hepatitis B surface antigen and Hepatitis B 

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Trametinib Dose Modification for Liver Function Test Abnormalities 
Event 
Treatment modifications and 
assessment/monitoring 
Core Antibody (IgM); Hepatitis C RNA; Cytomegalovirus IgM antibody;  Epstein-Barr 
viral capsid antigen IgM antibody (or if unavailable, obtain heterophile antibody or 
monospot testing);  Hepatitis E IgM antibody  
5.  PK sample is desired if feasible.  Record the date/time of the PK blood sample 
draw and the date/time of the last dose of study treatment prior to blood sample draw 
on the CRF. If the date or time of the last dose is unclear, provide the subject’s best 
approximation. If the date/time of the last dose cannot be approximated OR a PK 
sample cannot be collected in the time period indicated above, do not obtain a PK 
sample.  Not required for single-dose studies 
6.  If hepatitis delta antibody assay cannot be performed, it can be replaced with a 
PCR of hepatitis D RNA virus (where needed) (Le Gal et al., 2005). 
 
g. 
Reduced Left Ventricular Ejection Fraction 
 
Decreases of the left ventricular ejection fraction (LVEF) have been observed in 
patients receiving trametinib.   
 
Therefore, ECHO/MUGAs 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 visit(s). 
 
Trametinib 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 repeat 
ECHO/MUGA 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 CTEP trametinib 
medical monitor and request approval 
for restart. 
− Restart treatment with trametinib at 
reduced dose by one dose level.b 
− Repeat ECHO/MUGA 2, 4, 8, and 12 
weeks after re-start; continue in 
intervals of 12 weeks thereafter. 
• If LVEF does not recover within 4 weeks: 
− Consult with cardiologist. 
− Permanently discontinue trametinib. 
− Report as SAE 
− Repeat ECHO/MUGA after 2, 4, 8, 12, 
and 16 weeks or until resolution. 
− Consult with the CTEP trametinib 
medical monitor.c 
Symptomaticb 
 
• Grade 3:  resting 
LVEF 39-20% or 
>20% absolute 
reduction from 
baseline 
• Permanently discontinue trametinib. 
• Report as SAE. 
• Consult with cardiologist. 
• Repeat ECHO/MUGA after 2, 4, 8, 12, 
and 16 weeks or until resolution. 

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Trametinib Dose Modification Guidelines and Stopping Criteria for LVEF 
Decrease 
Clinic 
LVEF-drop (%) or 
CTCAE grade 
Action and Dose Modification 
• Grade 4:  Resting 
LVEF ≤20%. 
a If ECHO/MUGA does not show LVEF recovery after 2 weeks, repeat ECHO/MUGA 2 
weeks later. 
b Escalation of trametinib to previous dose level can be considered if LVEF remains 
stable for 4 weeks after restarting of trametinib.  Approval from the CTEP trametinib 
medical monitor is required. 
c Symptoms may include: dyspnea, orthopnea, and other signs and symptoms of 
pulmonary congestion and edema. 
 
h. 
QTc Prolongation 
 
Docetaxel may be continued in patients with QTc prolongation.  
 
Trametinib Withholding and Stopping Criteria for QTc Prolongation 
QTc Prolongationa 
Action and Dose Modification 
• QTcB ≥501 msec, or 
• Uncorrected QT >600 
msec, or 
• QTcB >530 msec for 
patients with bundle 
branch block 
 
• Interrupt study treatment until QTcB prolongation 
resolves to Grade 1 or baseline. 
• Test serum potassium, calcium, phosphorus, and 
magnesium.  If abnormal, correct per routine clinical 
practice to within normal limits. 
• Review concomitant medication usage for a prolonged 
QTc. 
• Restart at current dose level.b 
• If the event does not resolve or recurs after 
restarting, permanently discontinue study treatment. 
Abbreviations:  msec = milliseconds; QTcB = QT interval on electrocardiogram corrected 
using Bazett’s formula 
a Based on average QTc value of triplicate ECGs.  For example, if an ECG demonstrates 
a prolonged QT interval, obtain two or more ECGs over a brief period, and then use the 
averaged QTc values of the three ECGs to determine if study treatments should be 
interrupted or discontinued. 
b if the QTc prolongation resolves to Grade 1 or baseline, the patient may resume study 
treatment if the investigator and the CTEP trametinib medical monitor agree that the 
subject will benefit from further treatment. 
 
i. 
Hypertension 
 
Increases in blood pressure (BP) have been observed in patients receiving 
trametinib.  Recommendations for BP monitoring and management are provided 
below. No changes in docetaxel are necessary.  
 

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Management and Trametinib Dose Modification for Hypertension 
Event 
Management Guideline 
Dose Modification 
Definitions used in the table: 
- Persistent hypertension:  Hypertension detected in two separate readings during up to 
three subsequent visits. 
- Well-controlled hypertension:  Blood pressure of SBP ≤140 mmHg and DBP ≤90 
mmHg in two separate readings during up to three subsequent visits. 
- Symptomatic hypertension:  Hypertension associated with symptoms (e.g., headache, 
light-headedness, vertigo, tinnitus, episodes of fainting or other symptoms indicative 
of hypertension) that resolve after the blood pressure is controlled within the normal 
range. 
- Asymptomatic hypertension: SBP >140 mmHg and/or DBP >90 mmHg in the absence 
of the above symptoms. 
(Scenario A) 
Asymptomatic and persistent 
SBP of ≥140 and 
<160 mmHg, or DBP ≥90 
and <100 mmHg,  
or 
Clinically significant increase in 
DBP of 20 mmHg (but still 
below 100 mmHg). 
• Adjust current or initiate new 
antihypertensive medication(s). 
• Titrate antihypertensive 
medication(s) during the next 2 
weeks to achieve well-
controlled BP.  If BP is not well-
controlled within 2 weeks, 
consider referral to a specialist 
and go to scenario (B). 
Continue trametinib at 
the current dose. 
(Scenario B) 
Asymptomatic SBP ≥160 
mmHg, or DBP 
≥100 mmHg,  
or 
Failure to achieve well-
controlled BP within 2 weeks in 
Scenario A. 
• Adjust current or initiate new 
antihypertensive medication(s). 
• Titrate antihypertensive 
medication(s) during the next 2 
weeks to achieve well-
controlled BP. 
• Interrupt trametinib 
if clinically indicated. 
• Once BP is well-
controlled, restart 
trametinib reduced 
by one dose level.a 
(Scenario C) 
Symptomatic hypertension  
or 
Persistent SBP ≥160 mmHg, 
or DBP ≥100 mmHg, despite 
antihypertensive medication 
and dose reduction of 
trametinib 
• Adjust current or initiate new 
antihypertensive medication(s). 
• Titrate antihypertensive 
medication(s) during the next 2 
weeks to achieve well-
controlled BP. 
• Referral to a specialist for 
further evaluation and follow-up 
is recommended. 
• Interrupt trametinib. 
• Once BP is well-
controlled, restart 
trametinib reduced 
by one dose level.a 
(Scenario D) 
Refractory hypertension 
unresponsive to above 
interventions or hypertensive 
crisis. 
Continue follow-up per protocol. 
Permanently 
discontinue 
trametinib. 
a. 
Escalation of trametinib to previous dose level can be considered if BPs remain well 
controlled for 4 weeks after restarting of trametinib.  Approval from Medical Monitor is 
required. 
 

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j. 
Nausea and Vomiting 
 
Appropriate prophylactic anti-emetics should be prescribed.   
 
Nausea and 
Modification 
Vomiting Grade 
 
 
Nausea 1 
Antiemetic treatment*, if deemed necessary by treating physician.  
 
Nausea 2 
Give antiemetic treatment*. Hold trametinib if  
and/or  
Grade 2 vomiting or Grade 2 nausea persists  
Vomiting 1-2 
for 3 or more consecutive days despite optimal 
 
supportive care. Resume treatment at next reduced dose level 
when recovered to ≤ Grade 1. If nausea and vomiting have not 
resolved to Grade 1 in 21 days then trametinib should be 
discontinued (see Section 8.2e). 
 
Vomiting 3 or 4 or  
Give antiemetic treatment*. Hold trametinib  
Nausea 3 or 4 
until recovery to ≤ Grade 1 or baseline then resume treatment at 
next reduced dose level.  If ≥ Grade 3 nausea or vomiting does not 
resolve to ≤ Grade 1 within 21 days of stopping treatment and 
despite optimal supportive care, discontinue trametinib (see 
Section 8.2e). 
*  Antiemetic treatment should follow the recommendations given in the Consensus 
Statement of the Antiemetic Subcommittee of the Multinational Association of 
Supportive Care in Cancer (MASCC): Prevention of chemotherapy- and radiotherapy-
induced emesis: Results of the Perugia Consensus Conference (R06-0986). 
 
k. 
Cytopenias 
 
Patients must receive pegfilgrastim or filgrastim. On the day of treatment with 
docetaxel patients must have a neutrophil count of ≥ 1,500/mcl and platelet 
count of ≥ 100,000/mcL. If counts do not recover to required level in 21 
days then docetaxel must be discontinued. No specific changes are 
required for anemia. This should be managed according to local guidelines.  
 
Neutropenia 
 Modification 
or Thrombocytopenia 
 
 
1 
No change required in trametinib. Reduce docetaxel to next 
dose level if counts have not recovered to required levels by 
Day 1 of next cycle.      
 
2 
Same as Grade 1. Reduce docetaxel and trametinib to next 
dose level if counts have not recovered to required levels by 
Day 1 of next cycle.      
 
3 or 4 
Hold trametinib and docetaxel. Resume treatment at next 
reduced dose level once the toxicity improves to ≤ Grade 2. If ≥ 
Grade 3 neutropenia or thrombocytopenia does not resolve to ≤ 
Grade 2 within 21 days of stopping treatment discontinue 
protocol treatment (see Section 8.2e). 

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l. 
Pneumonitis 
 
Pneumonitis is known to occur with trametinib and docetaxel. Patients should 
undergo appropriate assessment to determine if there is another cause for the 
pneumonitis.  
 
Pnuemonitis Grade  
Guidelines/Modification 
 
 
1 
Continue treatment with both drugs. Patient may need to be 
followed more closely.   
 
2 or 3 
Interrupt both drugs. Once toxicity resolves to ≤ Grade 1 can 
restart both drugs at the next lower dose. If  toxicity does not 
resolve in 21 days then study drugs should be discontinued 
(see Section 8.2e). 
 
4 
Permanently discontinue study therapy. 
 
8.4 
Dose Modification Contacts 
 
For treatment or dose modification questions, please contact Dr. Shirish M. Gadgeel at 
313/576-8753 or email at gadgeels@karmanos.org or contact Dr. Jonathan Riess at 
916/734-3772 or jonathan.riess@ucdmc.ucdavis.org. 
 
8.5 
Adverse Event Reporting 
 
Toxicities (including suspected reactions) that meet the expedited reporting criteria as 
outlined in Section 16.0 of the protocol must be reported to the Operations Office, Study 
Chair and NCI via CTEP-AERS, and to the IRB per local IRB requirements. 
 

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9.0 
STUDY CALENDAR 
 
 
 
 
 
 
 
£ 
 
 
 
REQUIRED STUDIES 
Pre-
Reg 
® 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5 
Cycle 6 
Off  
Protocol 
Treatment 
After off 
treatment, 
prior to 
prog ≠ 
F/U 
after 
prog β 
W 
W 
W 
W 
W 
W 
W W 
W 
W 
W 
W 
W 
W W 
W 
W 
W 
 
 
 
1 
2 
3 
1 
2 
3 
1 
2 
3 
1 
2 
3 
1 
2 
3 
1 
2 
3 
 
 
 
PHYSICAL 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
History and Physical 
Exam 
X 
X 
X 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
X 
Weight and 
Performance Status 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
X 
Toxicity Notation 
 
X 
X 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
 
Pill Count (see Section 
7.3) 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
 
Baseline Abnormalities 
Assessment 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Disease Assessment € 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
Ophthalmology exam ¿ 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
LABORATORY 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CBC/Differential/Platelet
s 
X 
X 
X 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
 
Bilirubin 
X 
X 
X 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
 
AST and ALT 
X 
X 
X 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
 
Serum creatinine / 
Calculated creatinine 
clearance 
X 
X 
X 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
 
SCANS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CT or MRI for disease 
assessment € 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
Electrocardiogram Ω 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Echocardiogram or 
MUGA ۞ 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X
۞ 
 
 
 
 
 
 
 
 

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£ 
 
 
 
REQUIRED STUDIES 
Pre-
Reg 
® 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5 
Cycle 6 
Off  
Protocol 
Treatment 
After off 
treatment, 
prior to 
prog ≠ 
F/U 
after 
prog β 
W 
W 
W 
W 
W 
W 
W W 
W 
W 
W 
W 
W 
W W 
W 
W 
W 
 
 
 
1 
2 
3 
1 
2 
3 
1 
2 
3 
1 
2 
3 
1 
2 
3 
1 
2 
3 
 
 
 
SPECIMEN 
SUBMISSION 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Archived Tissue Ϣ  
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Buffy coat and plasma ¥ 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
TREATMENT 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Trametinib ± 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
  
  
Docetaxel ƻ 
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
 
  
  
Filgrastim or 
Pegfilgrastim ƻ 
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
 
  
  
 
Footnotes 
£ 
Protocol treatment and parameters will continue at the intervals indicated for Cycles 5 and 6 until patient has met any of the criteria in Section 
7.5. 
 
Ω  Electrocardiograms must be done within 42 days prior to registration then the first day of each cycle for the first four cycles, and then as often as 
clinically indicated to assess QT interval (see Section 8.3j). 
 
€  
Disease assessment, including CT or MRI, must be performed after every 6 weeks. 
 
® 
See Section 5.0 for additional information and required values 
 
±  
Daily oral dosing (see Section 7.2) 
 
≠ 
 After off treatment prior to disease progression, scans for disease assessment and physical assessments (with lab tests performed at the 
discretion of the treating investigator) must take place every six weeks until progression. 
 
β 
After off treatment following disease progression, physical assessments (with lab tests performed at the discretion of the treating investigator) 
must take place every six months until three years from the time of registration. 
Ϣ If patient consents, submit within 30 days after registration (see Section 15.1 for details). 
ƻ 
If docetaxel is given at 75 mg/m2, filgrastim or pegfilgrastim administration is mandatory per Section 7.2. 
۞ Echocardiogram or MUGA must be done within 42 days prior to registration then every 12 weeks to assess LVEF.  The same modality (ECHO or 
MUGA) should be used at all timepoints. 
¿ 
Ophthalmology exam must be performed within 42 days prior to registration (see Section 5.3j) and, if clinically indicated (see Section 8.3d), 
during study to assess visual changes.  Ophthalmology exam should include Ocular Coherence Tomography, fundoscopy, tonometry, visual field 
examination, and corrected visual acuity assessments. 

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¥ 
If patient consents, draw blood prior to treatment on Cycle 1 Day 1, at Cycle 3 visit, and when patient is removed from protocol treatment (see 
Section 15.1 for details). 
 

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10.0 
CRITERIA FOR EVALUATION AND ENDPOINT ANALYSIS 
 
10.1 
Measurability of Lesions 
 
a. 
Measurable disease: Measurable disease is defined differently for lymph nodes 
compared with other disease and will be addressed in a separate section below. 
 
 
1. 
Lesions that can be accurately measured in at least one dimension 
(longest diameter to be recorded) as ≥ 2.0 cm  by chest x-ray, by ≥ 1.0 
cm  with CT or MRI scans, or ≥ 1.0 cm with calipers by clinical exam. All 
tumor measurements must be recorded in decimal fractions of 
centimeters (or millimeters). 
 
The defined measurability of lesions on CT scan is based on the 
assumption that CT slice thickness is 0.5 cm or less.  If CT scans have 
slice thickness greater than 0.5 cm, the minimum size for a measurable 
lesion should be twice the slice thickness.   
 
2. 
A malignant lymph node is to be considered pathologically enlarged and 
measurable if it measures ≥ 1.5 cm in SHORT AXIS (greatest diameter 
perpendicular to the long axis of the lymph node) when assessed by 
scan (CT scan slice recommended being no greater than 0.5 cm). 
 
b. 
Non-measurable disease:  All other lesions (or sites of disease), including small 
lesions (longest diameter < 1.0 cm or pathologic lymph nodes with ≥ 1.0 cm to < 
1.5 cm short axis), are considered non-measurable disease.  Bone lesions, 
leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis 
cutis/pulmonitis, inflammatory breast disease, and abdominal masses (not 
followed by CT or MRI), are considered non-measurable as are previously 
radiated lesions that have not progressed. 
 
c. 
Notes on measurability 
 
1. 
For CT and MRIs, the same type of scanner should be used and the 
image acquisition protocol should be followed as closely as possible to 
prior scans.  Body scans should by performed with breath-hold scanning 
techniques, if possible.  
 
2. 
PET-CT:  At present, the low dose or attenuation correction CT portion of 
a PET-CT is not always of optimal diagnostic CT quality for use with 
RECIST measurements.  However, if the site can document that the CT 
performed as part of a PET-CT is of identical diagnostic quality to a 
diagnostic CT, then the CT portion of the PET-CT can be used for 
RECIST measurements and can be used interchangeably with 
conventional CT. 
 
3. 
Ultrasound: Ultrasound is not useful in assessment of lesion size and 
should not be used as a method of measurement. 
 
4. 
Cystic lesions that meet the criteria for radiographically defined simple 
cysts should not be considered as malignant lesions (neither measurable 
nor non-measurable) since they are, by definition simple cysts. 
 

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5. 
If a target lesion becomes very small some radiologists indicate that it is 
too small to measure.  If the lesion is actually still present, a default 
measurement of 0.5 cm should be applied.  If the radiologist believes the 
lesion has gone, a default measurement of 0.0cm should be recorded. 
 
10.2 
Objective Status at Each Disease Evaluation 
 
Objective Status is to be recorded at each evaluation. All measurable lesions up to a 
maximum of 2 lesions per organ 5 lesions in total, representative of all involved organs, 
should be identified as target lesions at baseline. All other lesions (or sites of disease) 
including any measurable lesions over and above the 5 target lesions should be identified 
as non-target lesions.  Measurements must be provided for target measurable lesions, 
while presence or absence must be noted for non-target measurable and non-
measurable disease.   
 
For studies that use disease progression as an endpoint, whole body scanning at specific 
intervals is necessary to determine that progression is NOT present outside of the 
“target” areas. Therefore, in these studies it is not acceptable to image only the “target” 
areas of the body in follow-up scans. For study-specific imaging requirements, see the 
Study Calendar in Section 9.0. 
 
a. 
Complete Response (CR):  Complete disappearance of all target and non-
target lesions (with the exception of lymph nodes mentioned below).  No new 
lesions.  No disease related symptoms.   Any lymph nodes (whether target or 
non-target) must have reduction in short axis to < 1.0 cm.  All disease must be 
assessed using the same technique as baseline. 
 
b. 
Partial Response (PR): Applies only to patients with at least one measurable 
lesion. Greater than or equal to 30% decrease under baseline of the sum of 
appropriate diameters of all target measurable lesions.  No unequivocal 
progression of non-measurable disease.  No new lesions.  All target measurable 
lesions must be assessed using the same techniques as baseline. 
 
c. 
Stable: Does not qualify for CR, PR, Progression or Symptomatic Deterioration.  
All target measurable lesions must be assessed using the same techniques as 
baseline. 
 
d. 
Progression: One or more of the following must occur:  20% increase in the sum 
of appropriate diameters of target measurable lesions over smallest sum 
observed (over baseline if no decrease during therapy) using the same 
techniques as baseline, as well as an absolute increase of at least 0.5 cm.  
Unequivocal progression of non-measurable disease in the opinion of the treating 
physician (an explanation must be provided).  Appearance of any new lesion/site.  
Death due to disease without prior documentation of progression and without 
symptomatic deterioration (see Section 10.2e). 
 
Notes regarding new lesions:  FDG-PET imaging can complement regular scans 
in identifying new lesions according to the following algorithm. 
 
1. 
Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is 
a sign of progression based on a new lesion. 
 
2. 
No FDG-PET at baseline and a positive FDG-PET at follow-up 
corresponding to a potential new site of disease must have a 
confirmation by anatomical assessment (e.g. CT, MRI, x-ray) as new site 

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of disease to be considered progressive disease.  In such a case, the 
date of progressive disease will be the date of the initial abnormal FDG-
PET. 
 
 
e. 
Symptomatic deterioration:  Global deterioration of health status requiring 
discontinuation of treatment without objective evidence of progression.  Efforts 
should be made to obtain objective evidence of progression after discontinuation. 
 
f. 
Assessment inadequate, objective status unknown.  Progression or 
symptomatic deterioration has not been documented, and one or more target 
measurable lesions have not been assessed or inconsistent assessment 
methods were used. 
 
g. 
Objective status notes: 
 
1. 
Non-measurable and non-target measurable disease do not affect 
Objective Status  in determination of CR (must be absent--a patient who 
otherwise has a CR, but who has non-measurable or non-target 
measurable disease present or not assessed, will be classified as having 
a PR). However, non-measurable and non-target lesions are included in 
determination of progression (if new sites of disease develop or if 
unequivocal progression occurs in the opinion of the treating physician). 
 
2. 
An objective status of PR or stable cannot follow one of CR.  Stable can 
follow PR only in the rare case that tumor increases too little to qualify as 
progression, but enough that a previously documented 30% decrease no 
longer holds. 
 
3. 
In cases for which initial flare reaction is possible (hypercalcemia, 
increased bone pain, erythema of skin lesions), objective status is not 
progression unless either symptoms persist beyond 4 weeks or there is 
additional evidence of progression. 
 
4. 
Lesions that appear to increase in size due to presence of necrotic tissue 
will not be considered to have progressed. 
 
5. 
For bone disease documented on bone scan only, increased uptake 
does not constitute unequivocal progression. However, increase in the 
soft tissue component of a lesion as measured by CT or MRI would 
constitute progression. 
 
6. 
Appearance of new pleural effusions does not constitute unequivocal 
progression unless cytologically proven of neoplastic origin, since some 
effusions are a toxicity related to therapy or other medical conditions. 
Increase in the size of an existing effusion does not constitute 
unequivocal progression, since the fluid status of the patient could alter 
the size of the effusion. 
 
7. 
If CR determination depends on a lesion for which the status is unclear 
by the required tests, it is recommended the residual lesion be 
investigated with biopsy or fine needle aspirate. 
 
10.3 
Best Response 
 

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This is calculated from the sequence of objective statuses. 
 
a. 
CR:  Two or more objective statuses of CR a minimum of four weeks apart 
documented before progression or symptomatic deterioration. 
 
 
b. 
PR:  Two or more objective statuses of PR or better a minimum of four weeks 
apart documented before progression or symptomatic deterioration, but not 
qualifying as CR. 
 
c. 
Unconfirmed CR:  One objective status of CR documented before progression or 
symptomatic deterioration but not qualifying as CR or PR. 
 
d. 
Unconfirmed PR:  One objective status of PR documented before progression or 
symptomatic deterioration but not qualifying as CR, PR or unconfirmed CR. 
 
e. 
Stable/no response:  At least one objective status of stable/no response 
documented at least 6 weeks after registration and before progression or 
symptomatic deterioration, but not qualifying as anything else above. 
 
f. 
Increasing disease:  Objective status of progression within 12 weeks of 
registration, not qualifying as anything else above. 
 
g. 
Symptomatic deterioration: Objective status of symptomatic deterioration within 
12 weeks of registration, not qualifying as anything else above.   
 
h. 
Inadequate assessment, response unknown:  Progression or symptomatic 
deterioration greater than 12 weeks after registration and no other response 
category applies. 
 
10.4 
Performance Status 
 
Patients will be graded according to the Zubrod Performance Status Scale. 
 
POINT 
DESCRIPTION 
 
0 
Fully active, able to carry on all pre-disease performance without 
restriction. 
 
1 
Restricted in physically strenuous activity but ambulatory and 
able to carry out work of a light or sedentary nature, e.g., light 
housework, office work. 
 
2 
Ambulatory and capable of self-care but unable to carry out any 
work activities; up and about more than 50% of waking hours. 
 
3 
Capable of limited self-care, confined to bed or chair more than 
50% of waking hours. 
 
4 
Completely disabled; cannot carry on any self-care; totally 
confined to bed or chair. 
 
10.5 
Time to Death 
 

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From date of registration to date of death due to any cause.  Patients last known to be 
alive are censored at date of last contact. 
 
10.6 
Progression-Free Survival 
 
From date of registration to date of first documentation of progression or symptomatic 
deterioration (as defined above), or death due to any cause.  Patients last known to be 
alive without report of progression are censored at date of last disease assessment. 
 
11.0 
STATISTICAL CONSIDERATIONS 
 
11.1 
Sample size with Power Justification 
 
The primary objective of this study is to evaluate the response rate (confirmed and 
unconfirmed complete and partial responses) in all KRAS mutant patients (both those 
with G12C mutations and those with non-G12C mutations). An important secondary 
outcome is to evaluate the response rate in the subset of patients with a G12C mutation. 
It is assumed that this regimen will not warrant further investigation in this setting if the 
true response rate is ≤ 17% and that a true response rate ≥ 37% would be of 
considerable interest.  
 
A two-stage design will be implemented as follows. Initially, 30 patients will be enrolled. If 
necessary, the study may be temporarily closed while response data matures. We will 
test the alternative of a 37% response rate among the first 30 patients enrolled at the 
0.02 level. If five or fewer responses are observed, then we will perform the same test 
within the G12C stratum. The G12C stratum will remain open until at least 9 G12C 
patients have been enrolled. Assuming 15 of the initial 30 patients have a G12C 
mutation, then 0-1 responses are observed among the 15 G12C patients the study will be 
closed to further accrual with the conclusion that this regimen is not active in this setting. 
If 2 or more responses are observed among the 15 G12C patients, but fewer than 5 
responses overall, then the study will be reopened to G12C patients only. However, if at 
least 6 responses are observed among all 30 patients, then the study will be reopened to 
all KRAS mutation patients.  
 
If the second stage is reopened to all KRAS patients, then an additional 15 patients will 
be enrolled for a total accrual of 45 patients. If at least 13 responses are observed, the 
conclusion would be that this regimen warrants further investigation in this setting, 
assuming other factors, such as progression-free survival, overall survival, and toxicity, 
also appear favorable. This design has 90% power (probability of concluding the regimen 
warrants further investigation when the true response rate is 37%) and a type I error of 
3% (probability of concluding the regimen warrants further investigation when the true 
response rate is 17%). 
 
If less than 25 of the total 45 eligible patients enrolled have a G12C mutation, accrual to 
the G12C stratum will be expanded for up to an additional 5 G12C patients for a total 
sample size of 50. If at least 8 responses are observed among the 25 patients in the 
G12C subset, this would be considered evidence that this regimen warrants further 
investigation in the G12C mutation population, regardless of the conclusion in the overall 
population. This subset analysis has 76% power with a type I error of 5%. 
 
If the second stage is reopened to the G12C stratum only, an additional 20 G12C 
patients will be enrolled for a total sample size of 50. Assuming the total number of G12C 
patients is 35, if at least 11 responses are observed this will be considered evidence that 

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this regimen warrant further investigation in the G12C mutation population only. This 
subset analysis has 80% power with a type I error of 3%. 
The following Table illustrates the decisions rules: 
 
N Overall 
(G12C + 
non-G12C) 
CR/PR 
N G12C 
CR/PR 
Decision 
30 
0-5 
15 
0-1 
Close study and conclude regimen 
inactive in this setting 
30 
0-5 
15 
2+ 
Close the study to non-G12C. Enroll 
an additional 20 G12C patients. 
30 
6+ 
 
 
Enroll 15-20 additional patients 
45 
13+ 
 
 
Conclude regimen warrants further 
investigation 
45 
6-12 
25 
8+ 
Conclude regimen warrants further 
analysis, but only in G12C subset 
45 
6-12 
25 
≤ 7 
Conclude regimen inactive in this 
setting 
If second stage only continues in G12C 
 
 
35 
11+ 
Conclude regimen warrants further 
analysis, but only in G12C subset 
 
 
35 
≤  10 
Conclude regimen inactive in this 
setting 
 
11.2 
Secondary Objectives 
 
Progression-Free Survival and Overall Survival estimates will be calculated using the 
method of Kaplan-Meier. 95% confidence for the medians will be constructed using the 
method of Brookmeyer-Crowley. With 50 patients, PFS (or OS) at a particular time point 
(e.g. 6 months) can be estimated to within ± 14% with 95% confidence. With 25 patients 
in each subgroup (G12C and non-G12C), response and PFS and OS at a particular time 
point can be estimated to within ± 20% with 95% confidence. 
 
With 50 patients, any adverse event with at least a 5% chance of occurring is likely to be 
seen at least once (92% probability). Toxicity rates can be estimated to within ± 14% with 
95% confidence. 
 
Translational Medicine Objectives: 
 
The primary translational medicine objectives are to assess: a) if the presence of 
dysfunctional p53 in KRAS mutant tumors will favor responses compared to patients 
without p53 dysfunction, and b) if the presence of LKB1 disruption in KRAS mutant 
tumors is associated with a lower response rate compared with tumors without presence 
of LKB1 disruption. 
 
Assuming 50 eligible patients will be enrolled and that p53 and LKB1 results will be 
available for 80% of the patients, then 40 eligible patients will be included in this analysis. 
It is further assumed that 30% (~12 patients) will be determined to have p53 loss and 
30% (~12 patients) will be determined to have LKB1 loss. 
 
If we assume a 17% response rate in both the G12C and non-G12C groups, and further 
assume no correlation between G12C status and p53 loss (i.e. equal numbers in each 
group), then if the response rate for patients without p53 loss is 10% and the response 

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rate for patients with p53 loss is 55%, we would have 80% power to detect this difference 
using a one-sided binomial test of proportions with an alpha of 0.05. The response rate 
will be estimated by LKB1 disruption status (yes/no), along with 95% confidence intervals 
around the estimated proportions.  This analysis will evaluate if disruption in LKB1 is 
associated with a lower probability of response.  With 12 LKB1+ and 28 LKB1- patients, 
the response rate can be estimated to within at least ±28% and ±19% with 95% 
confidence, respectively. 
 
11.3 
Accrual 
 
Assuming a 5% ineligibility rate, approximately 53 patients will need to be accrued in 
order to enroll 50 eligible patients. Assuming an estimated accrual rate of 6 patients per 
month, and further assuming no temporary closure between the first and second stage of 
accrual, this study would require approximately 9 months to reach full accrual 
 
11.4 
Data and Safety Monitoring 
 
There is no formal data and safety monitoring committee for this study.  Toxicity and 
accrual are primarily monitored by the Study Chair, Study Statistician and the Disease 
Committee Chair.  Endpoint monitoring is done by the Study Statistician and Study 
Coordinator.  The Adverse Event Coordinator at the Operations Office and the SAE 
Physician Reviewer are notified immediately whenever a serious adverse event is 
reported using the NCI CTEP-AERS system (see Section 16.0 for details). The Adverse 
Event Coordinator then provides the Study Chair and Study Statisticians a cumulative 
report of all SAEs within 24 hours with the most recent event highlighted.  Regular 
monitoring of all adverse events is performed monthly by the Study Chair and Study 
Statistician(s).  The Study Chair and Study Statistician(s) receive monthly reports 
summarizing all adverse events and serious adverse events.  In addition, the Study Chair 
and Study Statistician(s) receive a monthly summary of treatment status for patients on 
the study. Accrual reports are generated weekly and formal toxicity reports are available 
to all SWOG group members are generated every 6 months. 
 
 
12.0 
DISCIPLINE REVIEW 
 
There is no discipline review for this study. 
 
 
13.0 
REGISTRATION GUIDELINES 
 
13.1 
Registration Timing 
 
Patients must be registered prior to initiation of treatment (no more than three working 
days prior to planned start of treatment). 
 
13.2 
Investigator/Site Registration 
 
Prior to the recruitment of a patient for this study, investigators must be registered 
members of a Cooperative Group.  Each investigator must have an NCI investigator 
number and must maintain an “active” investigator registration status through the annual 
submission of a complete investigator registration packet to CTEP. 
 
a. 
CTEP Investigator Registration Procedures 
 

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Food and Drug Administration (FDA) regulations and National Cancer Institute 
(NCI) policy require all investigators participating in any NCI-sponsored clinical 
trial to register and to renew their registration annually. 
 
Registration requires the submission of: 
 
• 
a completed Statement of Investigator Form (FDA Form 1572) with an 
original signature 
• 
a current Curriculum Vitae (CV) 
• 
a completed and signed Supplemental Investigator Data Form (IDF) 
• 
a completed Financial Disclosure Form (FDF) with an original 
signature 
 
Fillable PDF forms and additional information can be found on the CTEP website 
at <http://ctep.cancer.gov/investigatorResources/investigator_registration.htm>.   
 
For questions, please contact the CTEP Investigator Registration Help Desk 
by email at <pmbregpend@ctep.nci.nih.gov>. 
 
b. 
CTEP Associate Registration Procedures 
 
The Cancer Therapy Evaluation Program (CTEP) Identity and Access 
Management (IAM) application is a web-based application intended for use by 
both Investigators (i.e., all physicians involved in the conduct of NCI-sponsored 
clinical trials) and Associates (i.e., all staff involved in the conduct of NCI-
sponsored clinical trials). 
 
Associates will use the CTEP-IAM application to register (both initial registration 
and annual re-registration) with CTEP and to obtain a user account. 
 
Investigators will use the CTEP-IAM application to obtain a user account only. 
(See CTEP Investigator Registration Procedures above for information on 
registering with CTEP as an Investigator, which must be completed before a 
CTEP-IAM account can be requested.) 
 
An active CTEP-IAM user account will be needed to access all CTEP and CTSU 
(Cancer Trials Support Unit) websites and applications, including the CTSU 
members’ website. 
 
Additional 
information 
can 
be found on the CTEP website at 
<http://ctep.cancer.gov/branches/pmb/associate_registration.htm>.  
For 
questions, please contact the CTEP Associate Registration Help Desk by 
email at <ctepreghelp@ctep.nci.nih.gov>. 
 
c. 
CTSU Registration Procedures 
 
Each investigator or group of investigators at a clinical site must obtain IRB 
approval for this protocol and submit IRB approval and supporting documentation 
to the CTSU Regulatory Office before they can be approved to enroll patients.  
Study centers can check the status of their registration packets by querying the 
Regulatory Support System (RSS) site registration status page of the CTSU 
members’ website by entering credentials at https://www.ctsu.org. For sites 
under the CIRB initiative, IRB data will automatically load to RSS. 
 

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Note:  Sites participating on the NCI CIRB initiative and accepting CIRB approval 
for the study are not required to submit separate IRB approval documentation to 
the CTSU Regulatory Office for initial, continuing or amendment review.  This 
information will be provided to the CTSU Regulatory Office from the CIRB at the 
time the site’s Signatory Institution accepts the CIRB approval.  The Signatory 
site may be contacted by the CTSU Regulatory Office or asked to complete 
information verifying the participating institutions on the study.  Other site 
registration requirements (i.e., laboratory certifications, protocol-specific training 
certifications, or modality credentialing) must be submitted to the CTSU 
Regulatory Office or compliance communicated per protocol instructions. 
 
1. 
Downloading Site Registration Documents: 
 
Site registration forms may be downloaded from the S1507 protocol 
page located on the CTSU members’ website. 
 
Go to https://www.ctsu.org and log in to the members’ area using 
your CTEP-IAM username and password 
 
Click on the Protocols tab in the upper left of your screen 
 
Click on the By Lead organization folder to expand 
 
Click on the SWOG link to expand, then select S1507.  
 
Click on LPO Documents, select the Site Registration documents 
link, and download and complete the forms provided. 
 
2. 
Requirements for S1507 Site Registration: 
 
 
CTSU IRB Certification (for sites not participating via the NCI CIRB) 
 
CTSU IRB/Regulatory Approval Transmittal Sheet (for sites not 
participating via the NCI CIRB)  
 
3. 
Submitting Regulatory Documents: 
 
Submit completed forms along with a copy of your IRB Approval and 
Model Informed Consent to the CTSU Regulatory Office, where they will 
be entered and tracked in the CTSU RSS.  
 
CTSU Regulatory Office 
1818 Market Street, Suite 1100 
Philadelphia, PA 19103 
Phone: 1-866-651-2878 
Fax: 215-569-0206 
E-mail: CTSURegulatory@ctsu.coccg.org (for regulatory 
document submission only) 
 
4. 
Checking Your Site’s Registration Status: 
 
Check the status of your site’s registration packets by querying the RSS 
site registration status page of the members’ section of the CTSU 
website.  (Note: Sites will not receive formal notification of regulatory 
approval from the CTSU Regulatory Office.) 
 
Go to https://www.ctsu.org and log in to the members’ area using 
your CTEP-IAM username and password 
 
Click on the Regulatory tab at the top of your screen 

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 
Click on the Site Registration tab 
Enter your 5-character CTEP Institution Code and click on Go 
 
13.3 
OPEN Registration Requirements 
 
The individual registering the patient must have completed the appropriate SWOG 
Registration Worksheet.  The completed form must be referred to during the registration 
but should not be submitted as part of the patient data. 
 
Patient enrollment will be facilitated using the Oncology Patient Enrollment Network 
(OPEN).  OPEN is a web-based registration system available on a 24/7 basis.  To access 
OPEN, the site user must have an active CTEP-IAM account (check at < https://eapps-
ctep.nci.nih.gov/iam/index.jsp >) and a 'Registrar' role on either the LPO or participating 
organization roster. 
 
OPEN will also ask additional questions that are not present on the SWOG Registration 
Worksheet.  The individual registering the patient must be prepared to provide answers to 
the following questions: 
 
a. 
Institution CTEP ID 
 
b. 
Protocol Number 
 
c. 
Registration Step 
 
d. 
Treating Investigator 
 
e. 
Credit Investigator 
 
f. 
Patient Initials 
 
g. 
Patient’s Date of Birth 
 
h. 
Patient SSN (SSN is desired, but optional.  Do not enter invalid numbers.) 
 
i. 
Country of Residence 
 
j. 
ZIP Code 
 
k. 
Gender (select one): 
• 
Female Gender 
• 
Male Gender 
 
l. 
Ethnicity (select one): 
• 
Hispanic or Latino 
• 
Not Hispanic or Latino 
• 
Unknown 
 
m. 
Method of Payment (select one): 
• 
Private Insurance 
• 
Medicare 
• 
Medicare and Private Insurance 
• 
Medicaid 
• 
Medicaid and Medicare 
• 
Military or Veterans Sponsored NOS 

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• 
Military Sponsored (Including Champus & Tricare) 
• 
Veterans Sponsored 
• 
Self Pay (No Insurance) 
• 
No Means of Payment (No Insurance) 
• 
Other 
• 
Unknown 
 
n. 
Race (select all that apply): 
• 
American Indian or Alaska Native 
• 
Asian 
• 
Black or African American 
• 
Native Hawaiian or other Pacific Islander 
• 
White 
• 
Unknown 
 
13.4 
Registration Procedures 
 
a. 
All site staff will use OPEN to enroll patients to this study.  OPEN is integrated 
with the CTSU Enterprise System for regulatory and roster data and, upon 
enrollment, initializes the patient in the Rave database.  OPEN can be accessed 
at https://open.ctsu.org, from the OPEN tab on the CTSU members’ side of the 
website at https://www.ctsu.org, or from the OPEN Patient Registration link on 
the SWOG CRA Workbench. 
 
b. 
Prior to accessing OPEN site staff should verify the following: 
 
• 
All eligibility criteria have been met within the protocol stated timeframes and 
the affirmation of eligibility on the Registration Worksheet has been signed by 
the registering investigator or another investigator designate. Site staff 
should refer to Section 5.0 to verify eligibility. 
 
• 
All patients have signed an appropriate consent form and HIPAA 
authorization form (if applicable). 
 
c. 
The OPEN system will provide the site with a printable confirmation of 
registration and treatment information.   Please print this confirmation for your 
records. 
 
d. 
Further instructional information is provided on the OPEN tab on the CTSU 
members’ side of the website at https://www.ctsu.org or at https://open.ctsu.org. 
For any additional questions contact the CTSU Help Desk at 888/823-5923 or 
ctsucontact@westat.com. 
 
13.5 
Exceptions to SWOG registration policies will not be permitted. 
 
a. 
Patients must meet all eligibility requirements. 
 
b. 
Institutions must be identified as approved for registration. 
 
c. 
Registrations may not be cancelled. 
 
d. 
Late registrations (after initiation of treatment) will not be accepted. 
 
 
14.0 
DATA SUBMISSION SCHEDULE 

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14.1 
Data Submission Requirement 
 
Data must be submitted according to the protocol requirements for ALL patients 
registered, whether or not assigned treatment is administered, including patients deemed 
to be ineligible.  Patients for whom documentation is inadequate to determine eligibility 
will generally be deemed ineligible 
 
14.2 
Master Forms 
 
Master forms can be found on the protocol abstract page on the SWOG website 
(www.swog.org) and (with the exception of the sample consent form and the Registration 
Worksheet) must be submitted on-line via the Web; see Section 14.3a for details. 
 
 
 
14.3 
Data Submission Procedures 
 
a. 
Data collection for this study will be done exclusively through the Medidata 
Rave® clinical data management system. Access to the trial in Rave is granted 
through the iMedidata application to all persons with the appropriate roles 
assigned in Regulatory Support System (RSS). To access Rave via iMedidata, 
you must have an active CTEP-IAM account (check at https://eapps-
ctep.nci.nih.gov/iam/index.jsp) and the appropriate Rave role (Rave CRA, Read-
Only, Site Investigator) on either the LPO or participating organization roster at 
the enrolling site. 
 
Upon initial site registration approval for the study in RSS, all persons with Rave 
roles assigned on the appropriate roster will be sent a study invitation e-mail from 
iMedidata. To accept the invitation, site users must log into the Select Login 
(https://login.imedidata.com/selectlogin) using their CTEP-IAM user name and 
password, and click on the “accept” link in the upper right-corner of the iMedidata 
page. Please note, site users will not be able to access the study in Rave until all 
required Medidata and study specific trainings are completed. Trainings will be in 
the form of electronic learnings (eLearnings), and can be accessed by clicking on 
the link in the upper right pane of the iMedidata screen. 
 
Users that have not previously activated their iMedidata/Rave account at the time 
of initial registration approval for the study in RSS will also receive a separate 
invitation from iMedidata to activate their account. Account activation instructions 
are located on the CTSU website, Rave tab under the Rave resource materials 
(Medidata Account Activation and Study Invitation Acceptance). Additional 
information on iMedidata/Rave is available on the CTSU members’ website 
under the Rave tab at www.ctsu.org/RAVE/ or by contacting the CTSU help Desk 
at 888/823-5923 or by e-mail at ctsucontact@westat.com 
 
b. 
You may also access Rave® via the SWOG CRA Workbench.  Go to the SWOG 
web site (http://swog.org) and logon to the Members Area using your SWOG 
Roster ID Number and password. After you have logged on, click on 
Workbenches, then CRA Workbench to access the home page for the CRA 
Workbench and follow the link to Rave® provided in the left-hand navigation 
panel. 
 
To access the CRA Workbench the following must be done (in order): 
 

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1. 
You are entered into the SWOG Roster and issued a SWOG Roster ID 
Number, 
2. 
You are associated as an investigator or CRA/RN at the institution where 
the patient is being treated or followed, 
3. 
Your Web User Administrator has added you as a web user and has 
given you the appropriate system permissions to view data for that 
institution. 
 
For assistance with points 1 and 2 call the Operations Office at 210/614-8808.  
For point 3, contact your local Web User Administrator (refer to the "Who is my 
Web User Administrator?" function on the swog.org Members logon page). 
 
For difficulties with the CRA Workbench, please email  
technicalquestion@crab.org. 
 
c. 
Institutions participating through the Cancer Trials Support Unit (CTSU) please 
refer to the CTSU Participation Table. 

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14.4 
Data Submission Overview and Timepoints  
 
a. 
WITHIN 7 DAYS AFTER REGISTRATION: 
 
Submit the following: 
 
S1507 Onstudy Form 
 Baseline Tumor Assessment Form 
 
Baseline Abnormalities Form 
 
Pathology Report* 
 
KRAS mutation status report (if not part of pathology report)* Report must 
document that KRAS mutation status was determined in a CLIA certified lab. 
 
Submit radiology reports from all scans performed to assess disease at baseline. 
 
* 
NOTE:  Upload these reports via the Source Documentation:  Baseline form 
in Rave®. 
 
b. 
WITHIN 7 DAYS AFTER EACH CYCLE (1 CYCLE = 21 DAYS) OF 
TREATMENT: 
 
Submit the following: 
 
S1507 Treatment Form 
 
S1507 Adverse Event Form 
 
c. 
WITHIN 30 DAYS AFTER REGISTRATION, IF PATIENT CONSENTS: 
 
Submit tissue as described in Section 15.1. 
 
d. 
WITHIN 14 DAYS AFTER EACH DISEASE ASSESSMENT: 
 
Submit the following: 
 
Follow Up Tumor Assessment Form 
 
Radiology reports (Upload these reports via the Source Documentation:  Follow-
Up form in Rave®.) 
 
e. 
WITHIN 14 DAYS AFTER DISCONTINUATION OF TREATMENT: 
 
Submit the following: 
 
Off Treatment Notice 
 
S1507 Treatment Form 
 
S1507 Adverse Event Form  

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f. 
WITHIN 14 DAYS AFTER PROGRESSION/RELAPSE: 
 
Submit the following: 
 
Follow Up Tumor Assessment Form  
 
Lung Carcinoma First Site(s) of Progression or Relapse Form  
 
All radiology reports used to document progression (Upload via the Source 
Documentation: Follow-Up form in Rave)  
 
If the patient was off protocol treatment, also submit the Advanced NSCLS 
Follow-Up Form   
 
g. 
ONCE OFF ALL PROTOCOL TREATMENT, SUBMIT EVERY 6 MONTHS FOR 
UP TO 3 YEARS FROM THE DATE OF REGISTRATION: 
 
Submit the following: 
 
Advanced NSCLC Follow Up Form 
 
Late Effects Form (if prior to treatment for progression or relapse or a second 
primary, and prior to non-protocol treatment, the patient experiences any severe 
[Grade ≥ 3] long term toxicity that has not been previously reported) 
 
h. 
WITHIN 4 WEEKS AFTER KNOWLEDGE OF DEATH: 
 
Submit the Notice of Death. If the patient was still on protocol treatment, also 
submit the forms listed in Section 14.4e.  If the patient was off protocol treatment, 
also submit the Advanced NSCLC Follow-Up Form. 
 
 
15.0 
SPECIAL INSTRUCTIONS 
 
15.1 
Translational Medicine and Banking 
 
Patients must be offered the opportunity to participate in banking of specimens for 
future research. Collection of specimens is critical to the interpretation of this 
study and should be acquired if at all possible. If the patient consents, specimens 
must be submitted as described in this section.  
 
a. 
Archived Tumor Tissue (Optional for patient) 
 
The translational medicine studies described in Section 18.2 will be prioritized for 
the future use of banked speicmens.  Any specimens that remain after the 
completion of these studies will continue to be banked and may be used for other 
future research. 
 
Within 30 days after registration, submit the following: 
 
One or two paraffin-embedded tissue blocks containing formalin fixed tumor or 
needle aspirate slides from time of diagnosis (or subsequent, but prior to 
therapy). It is not necessary to perform an additional biopsy for this purpose. 
Paraffin blocks may be processed according to standard institutional protocols. If 
blocks are unavailable, 6-8 unstained slides are acceptable alternatives. 

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Cytology (i.e., fine-needle aspirations) can be accepted only if they are paraffin 
embedded as cell blocks. 
 
FFPE blocks and slides must be shipped at ambient temperature. 
 
b. 
Buffy Coat and Plasma (Optional for patient) 
 
Buffy coat and plasma will be banked for future research.  
 
Draw approximately 10 mL blood in 1-2 lavender (EDTA) tubes at the following 
three time points:  
 
• 
After registration, prior to treatment on Cycle 1 Day 1 
• 
Cycle 3 visit 
• 
when patient is removed from protocol treatment 
 
Blood should be placed on wet ice immediately after collection and processed as 
soon as possible (preferably within 2 hours). Centrifuge vacutainer tubes at 
approximately 800 x g for 10 minutes (preferably in a refrigerated centrifuge, if 
available).  Immediately after centrifugation, carefully transfer plasma to a new 15 
mL conical tube using a pipette, being careful not to aspirate the interface 
between the plasma and the platelets (buffy coat layer).  Set aside original purple 
top tubes for later processing.  Then centrifuge plasma a second time at 1200 x g 
for 10 minutes.  After the second centrifugation, aliquot plasma in 500 ul aliquots 
into 6-10 labeled 1.8-2.0 ml cryovials, being careful not to disturb the pellet in the 
bottom of the tube.  The buffy coat, a whitish layer of cells between the plasma 
and red blood cell layers, should be collected from the original purple top tube(s) 
and transferred into 2 labeled 1.8-2.0 ml cryovials (contamination with RBC not a 
concern).  Freeze cryovials immediately and store at or below -70° until shipping. 
 
Blood products may be batch shipped.  They must be shipped by overnight 
delivery on dry ice (please do not ship on a Friday).   
 
c. 
Specimen Tracking System 
 
All specimen submissions for this study must be entered and tracked using the 
SWOG online Specimen Tracking system. SWOG members may log on the 
online system via the CRA Workbench. To access the CRA Workbench, go to 
the SWOG Web site (http://swog.org) and logon to the Members Area. After you 
have logged on using your SWOG roster ID number and password, click on the 
CRA Workbench link to access the home page for CRA Workbench website. 
Non- SWOG users may log into SpecTrack using their CTSU UserID and 
password on the SpecTrack login page located at  
https://crawb.crab.org/SpecTrack/Logon.aspx (select the option “SWOG – 
SWOG – CTSU”).  SpecTrack start-up instructions (both written and demo) are 
available after signing in to SpecTrack.  
 
A copy of the Shipment Packing List produced by the online Specimen Tracking 
system should be printed and placed in the pocket of the specimen bag if it has 
one, or in a separate resealable bag. The Specimen Submission Form is NOT 
required when the online system is used. 
 
ALL SPECIMENS MUST BE LOGGED VIA THIS SYSTEM; THERE ARE NO 
EXCEPTIONS. 
 

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To report technical problems with Specimen Tracking, such as database errors 
or connectivity issues, please send an email to technicalquestion@crab.org. For 
procedural help with logging and shipping specimens, there is an introduction to 
the system on the Specimen Tracking main page 
(http://dnet.crab.org/SpecTrack/Documents/Instructions.pdf); or contact the Data 
Operations Center at 206/652-2267 to be routed to the Data Coordinator for 
further assistance. 
 
In the online specimen tracking system, the appropriate SWOG laboratory for 
submission of all specimens for this study is: 
 
Lab #111:  
UC Davis SWOG Translational Medicine Lab 
Phone: 916/734-0821 
Contact:  Leslie Solis, M.S. 
 
 
16.0 
ETHICAL AND REGULATORY CONSIDERATIONS 
 
The following must be observed to comply with Food and Drug Administration regulations for the 
conduct and monitoring of clinical investigations; they also represent sound research practice: 
 
Informed Consent 
 
The principles of informed consent are described by Federal Regulatory Guidelines (Federal 
Register Vol. 46, No. 17, January 27, 1981, part 50) and the Office for Protection from Research 
Risks Reports:  Protection of Human Subjects (Code of Federal Regulations 45 CFR 46).  They 
must be followed to comply with FDA regulations for the conduct and monitoring of clinical 
investigations. 
 
Institutional Review 
 
This study must be approved by an appropriate institutional review committee as defined by 
Federal Regulatory Guidelines (Ref. Federal Register Vol. 46, No. 17, January 27, 1981, part 56) 
and the Office for Protection from Research Risks Reports:  Protection of Human Subjects (Code 
of Federal Regulations 45 CFR 46). 
 
Drug Accountability 
 
An investigator is required to maintain adequate records of the disposition of investigational drugs 
according to procedures and requirements governing the use of investigational new drugs as 
described in the Code of Federal Regulations 21 CFR 312.  
 
Publication and Industry Contact 
 
The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the NCI under 
a Collaborative Agreement (CRADA, CTA, CSA) between the Pharmaceutical Company(ies)  
(hereinafter referred to as "Collaborator(s)") and the NCI Division of Cancer Treatment and 
Diagnosis.  Therefore, the following obligations/guidelines in addition to the provisions in the 
"Intellectual Property Option to Collaborator"  
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm) contained within the 
terms of award apply to the use of the Agent in this study: 
 
1. 
Agent(s) may not be used outside the scope of this protocol, nor can Agent(s) be 
transferred or licensed to any party not participating in the clinical study.  Collaborator(s) 
data for Agent(s) are confidential and proprietary to Collaborator(s) and shall be 

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maintained as such by the investigators.  The protocol documents for studies utilizing 
Agents contain confidential information and should not be shared or distributed without 
the permission of the NCI.  If a copy of this protocol is requested by a patient or patient’s 
family member participating on the study, the individual should sign a confidentiality 
agreement. A suitable model agreement can be downloaded from: http://ctep.cancer.gov. 
 
 
2. 
For a clinical protocol where there is an investigational Agent used in combination with 
(an)other investigational Agent(s), each the subject of different Collaborative 
Agreements, the access to and use of data by each Collaborator shall be as follows (data 
pertaining to such combination use shall hereinafter be referred to as "Multi-Party Data"): 
 
a. 
NCI will provide all Collaborators with written notice regarding the existence and 
nature of any agreements governing their collaboration with NCI, the design of 
the proposed combination protocol, and the existence of any obligations which 
would tend to restrict NCI's participation in the proposed combination protocol. 
 
b. 
Each Collaborator shall agree to permit use of the Multi-Party Data from the 
clinical trial by any other Collaborator solely to the extent necessary to allow said 
other Collaborator to develop, obtain regulatory approval or commercialize its 
own investigational Agent. 
 
c. 
Any Collaborator having the right to use the Multi-Party Data from these trials 
must agree in writing prior to the commencement of the trials that it will use the 
Multi-Party Data solely for development, regulatory approval, and 
commercialization of its own Agent. 
 
3. 
Clinical Trial Data and Results and Raw Data developed under a Collaborative 
Agreement will be made available exclusively to Collaborator(s), the NCI, and the FDA, 
as appropriate and unless additional disclosure is required by law or court order as 
described in the IP Option to Collaborator 
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm).  Additionally, 
all Clinical Data and Results and Raw Data will be collected, used and disclosed 
consistent with all applicable federal statutes and regulations for the protection of human 
subjects, including, if applicable, the Standards for Privacy of Individually Identifiable 
Health Information set forth in 45 C.F.R. Part 164. 
 
4. 
When a Collaborator wishes to initiate a data request, the request should first be sent to 
the NCI, who will then notify the appropriate investigators (Group Chair for Cooperative 
Group studies, or PI for other studies) of Collaborator's wish to contact them. 
 
5. 
Any data provided to the Collaborator(s) for Phase III studies must be in accordance with 
the guidelines and policies of the responsible Data Monitoring Committee (DMC), if there 
is a DMC for this clinical trial. 
 
6. 
Any manuscripts reporting the results of this clinical trial must be provided to 
CTEP by the Group office for Cooperative Group studies or by the principal investigator 
for non-Cooperative Group studies for immediate delivery to Collaborator(s) for advisory 
review and comment prior to submission for publication.  Collaborator(s) will have 30 
days from the date of receipt for review.  Collaborator shall have the right to request that 
publication be delayed for up to an additional 30 days in order to ensure that 
Collaborator's confidential and proprietary data, in addition to the Collaborator(s)'s 
intellectual property rights, are protected.  Copies of abstracts must be provided to CTEP 
for forwarding to Collaborator(s) for courtesy review as soon as possible and preferably 

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at least three (3) days prior to submission, but in any case, prior to presentation at the 
meeting or publication in the proceedings.  Press releases and other media presentations 
must also be forwarded to CTEP prior to release.  Copies of any manuscript, abstract 
and/or press release/media presentation should be sent to: 
 
E-mail:  ncicteppubs@mail.nih.gov 
 
The Regulatory Affairs Branch will then distribute them to the Collaborator(s).  No 
publication, manuscript or other form of public disclosure shall contain any of the 
Collaborator's confidential/proprietary information. 
 
Monitoring 
 
This study will be monitored by the Clinical Data Update System (CDUS) Version 3.0.  
Cumulative protocol and patient-specific CDUS data will be submitted quarterly to CTEP by 
electronic means, either by FTP burst of data or via the CDS web application.  Reports are due 
January 31, April 30, July 31 and October 31.  The SWOG Data Operations center will submit 
data using the CDUS instructions that can be found on the CTEP website  
(http://ctep.cancer.gov/reporting/cdus.html).  
 
Confidentiality 
 
Please note that the information contained in this protocol is considered confidential and should 
not be used or shared beyond the purposes of completing protocol requirements until or unless 
additional permission is obtained. 
 
16.1 
Adverse Event Reporting Requirements 
 
a. 
Purpose 
 
Adverse event data collection and reporting, which are required as part of every 
clinical trial, are done to ensure the safety of patients enrolled in the studies as 
well as those who will enroll in future studies using similar agents. Adverse 
events are reported in a routine manner at scheduled times during a trial. 
(Directions for routine reporting are provided in Section 14.0.) Additionally, 
certain adverse events must be reported in an expedited manner to allow for 
more timely monitoring of patient safety and care. The following guidelines 
prescribe expedited adverse event reporting for this protocol.  
 
b. 
Reporting method 
 
This study requires that expedited adverse events be reported using the Cancer 
Therapy Evaluation Program Adverse Event Reporting System (CTEP-AERS).  
CTEP's guidelines for CTEP-AERS can be found at http://ctep.cancer.gov. A 
CTEP-AERS report must be submitted to the SWOG Operations Office 
electronically via the CTEP-AERS Web-based application located at: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_eve
nts.htm 
 
c. 
When to report an event in an expedited manner 
 
Some adverse events require 24-hour notification (refer to Table 16.1) via CTEP-
AERS.  
 

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When the adverse event requires expedited reporting, submit the report within 
the number of calendar days of learning of the event, as specified in Table 16.1.  
 
In the rare event when internet connectivity is disrupted a 24-hour notification is 
made to NCI by telephone at 301-897-7497.  An electronic report MUST be 
submitted immediately upon re-establishment of internet connection. 
 
Any supporting documentation requested by CTEP should be submitted in 
accordance with instructions provided by the CTEP-AERS system. 
 
d. 
Other recipients of adverse event reports 
 
The SWOG Operations Office will forward reports and documentation to the 
appropriate regulatory agencies and drug companies as required. 
 
Adverse events determined to be reportable to the Institutional Review Board 
responsible for oversight of the patient must be reported according to local policy 
and procedures. 
 
e. 
Expedited reporting for investigational agents 
 
Expedited reporting is required if the patient has received at least one dose of the 
investigational agent(s) as part of the trial. Reporting requirements are provided 
in Table 16.1. The investigational agent used in this study is trametinib.  If there 
is any question about the reportability of an adverse event or if on-line CTEP-
AERS cannot be used, please telephone or email the SAE Specialist at the 
Operations Office, 210/614-8808 or adr@swog.org, before preparing the report. 

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Table 16.1: 
Late Phase 2 and Phase 3 Studies:  Expedited Reporting Requirements for Adverse Events that 
Occur on Studies under a CTEP IND within 30 Days of the Last Administration of the 
Investigational Agent/Intervention1  trametinib 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, 
whether or not they are considered related to the investigational agent(s)/intervention (21 
CFR 312.64) 
 
 An adverse event is considered serious if it results in ANY of the following outcomes:   
1) Death 
2) A life-threatening adverse event  
3) An adverse event that results in inpatient hospitalization or prolongation of existing 
hospitalization for ≥ 24 hours  
4) A persistent or significant incapacity or substantial disruption of the ability to conduct normal 
life functions  
5) A congenital anomaly/birth defect.  
6) 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 subject and may require medical or surgical intervention to prevent 
one of the outcomes listed in this definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the 
NCI via CTEP-AERS within the timeframes detailed in the table below. 
Hospitalization 
Grade 1 
Timeframes 
Grade 2 
Timeframes 
Grade 3 
Timeframes 
Grade 4 & 5 
Timeframes 
Resulting in 
Hospitalization  
≥ 24 hrs 
10 Calendar Days 
24-Hour 5 
Calendar 
Days 
Not resulting in 
Hospitalization  
≥ 24 hrs 
Not required 
10 Calendar 
Days 
NOTE:  Protocol specific exceptions to expedited reporting of serious adverse events are found 
in the Specific Protocol Exceptions to Expedited Reporting (SPEER) portion of the 
CAEPR  
Expedited AE reporting timelines are defined as: 
o “24-Hour; 5 Calendar Days” - The AE must initially be reported via CTEP-AERS within 24 
hours of learning of the AE, followed by a complete expedited report within 5 calendar 
days of the initial 24-hour report. 
 
o “10 Calendar Days” - A complete expedited report on the AE must be submitted within 10 
calendar days of learning of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of 
investigational agent/intervention and have an attribution of possible, probable, or definite 
require reporting as follows:  
 
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
• All Grade 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
• Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization  
• Grade 3 adverse events 
May 5, 2011 

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f. 
Additional Instructions or Exceptions to CTEP-AERS Expedited Reporting 
Requirements for Late Phase 2 and Phase 3 Studies Utilizing an Agent 
under a CTEP IND: 
 
1) 
Group-specific instructions 
 
Submission of the on-line CTEP-AERS report plus any necessary 
amendments generally completes the reporting requirements.  In 
addition, you may be asked to submit supporting clinical data to the 
Operations Offices in order to complete the evaluation of the event.  
If requested, the supporting data should be sent within 5 calendar 
days by fax to 210-614-0006.  Supporting clinical data submitted 
should include: 
• 
Printed copy of the first page of the CTEP-AERS Report. 
• 
Copies of clinical sourced documentation of the event. 
• 
If applicable, and they have not yet been submitted to the 
SWOG Data Operations Center copies of Off Treatment 
Notice and/or Notice of Death. 
 
g. 
Expedited reporting for commercial agents 
 
Commercial reporting requirements are provided in Table 16.2. The commercial 
agent used in this study is docetaxel.  If there is any question about the 
reportability of an adverse event or if on-line CTEP-AERS cannot be used, 
please telephone or email the SAE Program at the Operations Office, 210/614-
8808 or adr@swog.org, before preparing the report. 
 
Table 16.2. Expedited reporting requirements for adverse events 
experienced within 30 days of the last administration of docetaxel 
 
Attribution 
 
Grade 4 
 
Grade 5a 
Unexpected 
Expected 
Unexpected 
Expected 
Unrelated or 
Unlikely 
 
 
CTEP-
AERS 
CTEP-
AERS 
Possible, 
Probable, 
Definite 
CTEP-
AERS 
 
CTEP-
AERS 
CTEP-
AERS 
CTEP-AERS:  Indicates an expedited report is to be submitted via CTEP-AERS within 
10 calendar days of learning of the eventb. 
a This includes all deaths within 30 days of the last dose of treatment with a 
commercial agent(s), regardless of attribution.  Any death that occurs more th an  30 
days after the last dose of treatment with a commercial agent(s) and is attributed 
(possibly, probably, or definitely) to the agent(s) and is not due to cancer recurrence 
must be reported according to the instructions above. 
 
b Submission of the on-line CTEP-AERS report plus any necessary amendments 
generally completes the reporting requirements. You may, however, be asked to 
submit supporting clinical data to the Operations Office in order to complete the 
evaluation of the event. If requested, the specified data should be sent within 5 
calendar days by fax to 210-614-0006.  
 
 

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h. 
Reporting Secondary Malignancy, including AML/ALL/MDS 
 
1. 
A secondary malignancy is a cancer caused by treatment for a previous 
malignancy (e.g., treatment with investigational agent/intervention, 
radiation or chemotherapy).  A secondary malignancy is not considered a 
metastasis of the initial neoplasm. 
 
CTEP requires all secondary malignancies that occur following treatment 
with an agent under an NCI IND to be reported via CTEP-AERS.  Three 
options are available to describe the event. 
 
• 
Leukemia secondary to oncology chemotherapy (e.g., Acute 
Myelocytic Leukemia [AML]) 
 
• 
Myelodysplastic syndrome (MDS) 
 
• 
Treatment-related secondary malignancy 
 
 
Any malignancy possibly related to cancer treatment (including 
AML/MDS) should also be reported via the routine reporting mechanisms 
outlined in each protocol. 
 
Second Malignancy: A second malignancy is one unrelated to the 
treatment of a prior malignancy (and is NOT a metastasis from the initial 
malignancy).  Second malignancies require ONLY routine reporting via 
CDUS unless otherwise specified. 
 
For more information see: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/
aeguidelines.pdf  
 
2. 
Supporting documentation should be submitted to CTEP in accordance 
with instructions provided by the CTEP-AERS system.  A copy of the 
report and the following supporting documentation must also be 
submitted to SWOG Operations Office within 30 days by fax to 210-614-
0006 or mail to the address below: 
 
• 
a copy of the pathology report confirming the AML/ALL /MDS 
diagnosis 
• 
(if available) a copy of the cytogenetics report   
 
SWOG 
ATTN: SAE Program 
4201 Medical Drive, Suite 250 
San Antonio, Texas 78229 
 
NOTE: If a patient has been enrolled in more than one NCI-sponsored 
study, the report must be submitted for the most recent trial. 
 

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i. 
Reporting Pregnancy, Pregnancy Loss, and Death Neonatal 
 
1. 
Pregnancy Study participants who become pregnant while on study; that 
pregnancy should be reported in an expedited manner via CTEP-AERS 
as Grade 3 “Pregnancy, puerperium and perinatal conditions – Other 
(pregnancy)” under the Pregnancy, puerperium and perinatal conditions 
SOC.   
 
Additionally, the pregnancy outcome for patients on study should be 
reported via CTEP-AERS at the time the outcome becomes known, 
accompanied by the same Pregnancy Report Form used for the initial 
report. 
 
2. 
Pregnancy Loss Pregnancy loss is defined in CTCAE as “Death in 
utero.” Pregnancy loss should be reported expeditiously as Grade 4 
“Pregnancy loss” under the Pregnancy, puerperium and perinatal 
conditions SOC.   
 
A Pregnancy loss should NOT be reported as a Grade 5 event under 
the Pregnancy, puerperium and perinatal conditions SOC, as 
currently CTEP-AERS recognizes this event as a patient death. 
 
3. 
Death Neonatal Death neonatal is defined in CTCAE as “Newborn death 
occurring during the first 28 days after birth.  A neonatal death should be 
reported expeditiously as Grade 4 “Death neonatal” under the General 
disorders and administration SOC.   
 
Neonatal death should NOT be reported as a Grade 5 event under the 
General disorders and administration SOC as currently CTEP-AERS 
recognizes this event as a patient death. 
 
NOTE:  When submitting CTEP-AERS reports for “Pregnancy, “Pregnancy loss”, 
or “Neonatal loss”, the Pregnancy Information Form should also be completed 
and faxed with any additional medical information to 301-230-0159.  The 
potential risk of exposure of the fetus to the investigational agent(s) or 
chemotherapy agent(s) should be documented in the “Description of Event” 
section of the CTEP-AERS report. 
 
The Pregnancy Information Form is available at:    
http://ctep.cancer.gov/protocolDevelopment/adverse_effects.htm. 

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17.0 
BIBLIOGRAPHY 
 
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Roberts PJ, Stinchcombe TE, Der CJ, et al. Personalized medicine in non-small cell lung cancer: 
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Hainsworth JD, Cebotaru CL, Kanarev V, et al. A phase II, open-label, randomized study to 
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Wee S, Jagani Z, Xiang KX, et al. PI3K pathway activation mediates resistance to MEK inhibitors 
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Eberhard DA, Johnson BE, Amler MC, et al. Mutations in the epidermal growth factor receptor 
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Winton T, Livingston R, Johnson D, et al. Vinorelbine plus cisplatin vs. observation in resected 
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Holt SV, Logie A, Odedra R, et al. The MEK1/2 inhibitor, selumetinib (AZD6244; ARRY-142886), 
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Le Calvez F, Mukeria A, Hunt JD, et al. TP53 and Kras mutation load and types in lung cancers in 
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Marcus AI, Zhou W. LKB1 regulated pathways in lung cancer invasion and metastasis. J 
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Investigator's Brochure.  (2012a). GSK1120212.  GlaxoSmithKline.  Version 04.  September 5, 
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Balagula Y, Barth Huston K, Busam KJ, et al.  Dermatologic side effects associated with the MEK 
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18.0 
APPENDIX 
 
18.1 
Intake Calendar - Trametinib 
 
18.2 
Translational Medicine Methodology 
 
18.3 
Bone Marrow Distribution in the Adult 

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18.1 
Intake Calendar - Trametinib 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sunday 
Monday 
Tuesday 
Wednesday 
Thursday 
Friday 
Saturday 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Patient Signature: 
 
SWOG Patient ID________  Patient Initials (L, F, M) ________ SWOG Study #S1507  
 
Institution/Affiliate _______________________  Physician _____________________________ 
Instructions for the participant: 
This is a monthly calendar on which you are to record the number of tablets you take each day.  
Be sure you have enough calendars to last until your next appointment.  If you develop any side 
effects from the tablets, mark this on the calendar on the day you note the effect.  Bring your 
calendars with you each time you have an appointment. 
 
If you have questions contact: ____________________ Telephone: _____________________ 
 
Your next appointment is: _______________________ 
Special instructions: 
 
Month: 
 
Year: 
 

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18.2 
Translational Medicine Methodology 
 
p53, STK11 and KRAS mutation analysis:  Tumor TP53, STK11 and KRAS mutation 
status will be determined in all consenting patients with sufficient tumor in real time 
(within 2 weeks of receipt of tissue). Mutation analysis will be performed by Genoptix 
using the Nexcourse NSCLC assay under oversight from the UC Davis Comprehensive 
Cancer Center by Dr. Philip Mack. The Genoptix next-generation sequencing panel uses 
capture-based technology to measure mutations, copy number variance and fusion 
events in 25 NSCLC-specific cancer genes.  Using the Illumina HiSeq2000 platform, 
hybrid-capture–selected libraries are sequenced to high uniform depth (targeting >500× 
coverage by non-PCR duplicate read pairs, with >99% of exons at coverage >100×). 
Protocols and reagents have been optimized to assure even coverage and robust 
performance for a wide variety of specimens. Sequence data are processed using a 
customized analysis pipeline designed to accurately detect multiple classes of genomic 
alterations: base substitutions, indels, focal gene amplifications, homozygous gene 
deletions and selected gene fusions in routine clinical specimens. All testing is done in a 
CLIA-certified, CAP-accredited laboratory.  Overall substitution detection performance is 
high; >99% of base substitutions expected to be present at mutant allele frequencies 
(MAF) ≥ 10% are successfully detected (1,036/1,036), as are 99% of substitutions at 
MAF < 10% (1,013/1,021) In addition, high specificity is maintained with a positive 
predictive value (PPV, the fraction of substitution calls in the pools traceable to a 
substitution in a constituent cell line) >99% (2,577/2,579, with two false-positive calls at 
MAF < 5%).  At 250× median coverage, >99% of base substitutions present at MAF ≥ 
10% are successfully detected (1,035/1,036), as are 98% of substitutions at 5% ≤ MAF ≤ 
10% (601/614). Furthermore, PPV remains high (>99%) across the full coverage range. 
A high correlation between expected and observed MAFs at test sites remains, 
highlighting the quantitative nature of the optimized NGS-based test.  Overall, indel 
detection is also high: 98% (92/94) of indels at MAF ≥ 20% are successfully detected, as 
well as 97% (71/73) of indels at 10% ≤ MAF ≤ 20% and 88% (53/60) of indels at 5% ≤ 
MAF ≤ 10%.  In addition to TP53, STK11 and KRAS, the assay will also interrogate AKT1 
activating mutations and PTEN deleterious abnormalities.  Genoptix operates under strict 
adherence to the WHO’s good clinical laboratory practice (GCLP) guidelines, and all work 
will be performed in their CLIA-licensed CAP-accredited facilities. Additionally, Genoptix 
will perform p53 IHC using their validated commercial assay and a partnership has been 
formed with MolecularMD to evaluate LKB1 (STK11) by IHC. The IHC assays are 
essential to identify abnormalities that result in loss of expression.  Patient specimen 
materials from this trial will not be assayed until CTEP has reviewed all assay 
information. 

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18.3 
Bone Marrow Distribution in the Adult 
 
Anatomic Site 
% Total Red Marrow 
 
Head 
13.1 
 
 Cranium 
12.0 
 Mandible 
   1.1 
 
Upper Limbs 
   8.3 
 
 2 Humerus 
   2.0 
 2 Scapula 
   4.8 
 2 Clavicle 
   1.5 
 
Sternum 
   2.3 
 
Ribs 
   7.9 
 
Vertebrae 
42.3 
 
 Cervical 
   3.4 
 Thoracic 
14.1 
 Lumbar 
10.9 
 Sacrum 
13.9 
 
Lower Limb Girdle 
26.1 
 
 2 Os Coxae 
22.0 
 2 Femoral Head & Neck 
   4.0 
 
 
(Extracted from Phys Med Biol 5:255, 1961)