An Open Label, Two-Part, Phase Ib/II Study to Investigate the Safety, Pharmacokinetics, Pharmacodynamics, and Clinical Activity of the MEK Inhibitor Trametinib and the BCL2-Family Inhibitor Navitoclax (ABT-263) in Combination in Subjects With KRAS or NRAS Mutation-Positive Advanced Solid Tumors
Phase: PHASE1
Conditions: Metastatic Malignant Solid Neoplasm, Refractory Malignant Solid Neoplasm, Unresectable Malignant Solid Neoplasm
Sponsor: National Cancer Institute (NCI)

NCI Protocol #: 9525
Version Date: July 22, 2022
i
 8.1.1
Trametinib dimethyl sulfoxide 
(GSK1120212B) (NSC 763093)
Revised to include: 
Revised “How Supplied” text
This submission is in response to Mr. Howells’ May 23, 2022 notice regarding updates to the 
trametinib tablet formulation pharmaceutical information.
NCT02079740

NCI Protocol #: 9525
Version Date: July 22, 2022
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NCI Protocol #:
9525
Local Protocol #:
13-505
TITLE:  An open label, two-part, phase Ib/II study to investigate the safety, pharmacokinetics, 
pharmacodynamics, and clinical activity of the MEK inhibitor trametinib and the BCL2-family 
inhibitor navitoclax (ABT-263) in combination in subjects with KRAS or NRAS mutation-
positive advanced solid tumors
Coordinating Center:
Dana Farber Harvard Cancer Center (Massachusetts General 
Hospital, Dana Farber Cancer Institute)
*Principal Investigator:
Ryan B. Corcoran, MD PhD
Massachusetts General Hospital Cancer Center
149 13th St, 7th Floor
Boston, MA  02129
Office: 617-726-8599
Fax: 617-724-9648
Email: rbcorcoran@partners.org 
Co-Investigators:
Jeffrey W. Clark, MD
Massachusetts General Hospital Cancer Center
275 Cambridge St.
Boston, MA  02114
Office: 617-643-3415
Fax: 617-724-3166
Email: jclark@partners.org 
Geoffrey I. Shapiro, MD PhD
Dana-Farber Cancer Institute
450 Brookline Avenue
Boston, MA 02215
Office: 617-632-4942
Fax: 617-632-1977
Email: geoffrey_shapiro@dfci.harvard.edu
NCT02079740

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Version Date: July 22, 2022
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Statistician:
Study Coordinators:
Beow Y. Yeap
Linda Rivera, CRA
Massachusetts General Hospital
Massachusetts General Hospital
Biostatistics Center
326 Cambridge Street
50 Staniford St., 5th Floor
Boston, MA 02114
Boston, MA  02114
Office: 617-724-6212
Office: 617-726-7730
Fax: 617-726-4319
Fax: 617-724-9878
Email: Lrivera3@mgh.harvard.edu
Email: byeap@partners.org 
Responsible Research Nurses:
Victoria Turbini, MS, RN 
Yawkey 7
55 Fruit Street
Boston, MA 02114
Office: 617-643-5530
Fax: 617-724-2840
Email: vturbini@mgh.harvard.edu
NCT02079740

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Version Date: July 22, 2022
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NCI Supplied Agent(s):  
Trametinib dimethyl sulfoxide (GSK1120212B) (NSC 763093)
Navitoclax; NSC 750238)
IND#:  119585
IND Sponsor:  DCTD, NCI
Other Agent(s):  N/A
Investigational Agent 
IND#
IND Sponsor 
N/A
Investigational Device 
IDE#
IDE Sponsor 
N/A
Protocol Type / Version # / Version Date: Amendment 21; Version 23, Revised July 22, 2022
NCT02079740

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SCHEMA
Study Design
This study is a two-part Phase 1b/Phase 2 clinical trial of the MEK inhibitor trametinib in 
combination with the BCL2-family inhibitor navitoclax.
In Part 1 (Phase 1b), this study aims to determine the maximal tolerated dose (MTD) of 
trametinib and navitoclax that can be given safely in combination in order to determine a 
recommended phase 2 dose (RP2D).  Patients with advanced or metastatic solid tumors that have 
been determined to harbor KRAS or NRAS mutations by CLIA-approved laboratory assay will 
be eligible. Prior therapy for advanced or metastatic disease will be allowed.   Pharmacokinetic 
(PK) assays will be carried out to assess the interaction of these two drugs, and these data will be 
correlated with clinical toxicities as dose escalation is undertaken.  Paired pre-treatment and on-
treatment tumor biopsies will be obtained to assess the pharmacodynamic response to therapy.
Part 2 is a single-arm Phase 2 study of trametinib in combination with navitoclax at the RP2D 
determined in the Phase 1b trial above.  Patients with KRAS mutation or NRAS mutations 
positive solid tumors will be enrolled into up to 4 different disease-specific expansion cohorts.  
These will include expansion cohorts for patients with KRAS or NRAS mutation-positive: (1) 
Pancreatic cancer, (2) GYN cancer, (3) lung cancer, (4) all other NRAS-mutant solid tumor types 
exclusive of pancreatic, GYN, and lung cancers.
Part 1 (Phase 1b)
Dose Escalation Schedule
Dose
Dose Level
Trametinib
(mg) PO daily
Navitoclax
(mg) PO daily
Level 1 
1
150
Level 2
1.5
150
Level 3
1.5
200
Level 4
2
200
Level 5
2
250
Level 6
2
300
Level 7
2
325

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Part 2 (Phase 2)
  Stage 1:
              Stage 1:   
  Stage 1:
     
           Stage 1:                
  Enroll 12
              Enroll 12
  Enroll 12
 
           Enroll 12
  Patients 
            Patients
  Patients
           Patients
   
Stage 2:
              Stage 2:   
    Stage 2:
            Stage 2:                
Enroll 13
              Enroll 13
    Enroll 13     
            Enroll
Patients 
              Patients
    Patients
            Patients
      N  = 25 total
N  = 25 total      
          N  = 25 total
               N  = 25 total
Patients with KRAS or NRAS mutation 
positive advanced solid tumors
SCREENING
Expansion Cohort #1
Pancreatic cancer
Expansion Cohort #2
GYN Cancer
Expansion Cohort #3
Lung Cancer
Expansion Cohort #4
NRAS-mutant solid 
tumors (excluding 
pancreatic GYN, lung)
*if no responses, stop 
cohort
*if one or more 
responses, proceed to 
stage 2
*if no responses, stop 
cohort
*if one or more 
responses, proceed to 
stage 2
*if no responses, stop 
cohort
*if one or more 
responses, proceed to 
stage 2
*if no responses, stop 
cohort
*if one or more 
responses, proceed to 
stage 2

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TABLE OF CONTENTS
SCHEMA.........................................................................................................................................4
1.
OBJECTIVES......................................................................................................................9
1.1
Primary Objectives...................................................................................................9
1.2
Secondary Objectives...............................................................................................9
2.
BACKGROUND .................................................................................................................9
2.1
Study Diseases .........................................................................................................9
2.2
CTEP IND Agent(s)...............................................................................................10
2.3
Other Agent(s) .......................................................................................................27
2.4
Rationale ................................................................................................................27
2.5
Correlative Studies Background ............................................................................28
3.
PATIENT SELECTION....................................................................................................30
3.1
Eligibility Criteria..................................................................................................30
3.2
Exclusion Criteria ..................................................................................................32
3.3
Inclusion of Women and Minorities ......................................................................35
4.
REGISTRATION PROCEDURES ...................................................................................36
4.1
General Guidelines.................................................................................................36
4.2
Registration Process...............................................................................................36
4.3
Investigator and Research Associated Registration with CTEP............................37
5.
TREATMENT PLAN........................................................................................................38
5.1
Agent Administration.............................................................................................38
5.2
Definition of Dose-Limiting Toxicity....................................................................48
5.3
General Concomitant Medication and Supportive Care Guidelines......................49
5.4
Duration of Therapy...............................................................................................50
5.5
Duration of Follow Up...........................................................................................51
5.6
Criteria for Removal from Study...........................................................................51
6.
DOSING DELAYS/DOSE MODIFICATIONS ...............................................................51
6.1
Trametinib Dose Modifications.............................................................................51
6.2
Navitoclax Dose modifications..............................................................................64
7.
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ............................67
7.1
Comprehensive Adverse Events and Potential Risks Lists (CAEPRs) .................67
7.2
Adverse Event Characteristics...............................................................................73
7.3
Expedited Adverse Event Reporting......................................................................74
7.4
Routine Adverse Event Reporting .........................................................................77
7.5
Secondary Malignancy...........................................................................................77

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7.6
Second Malignancy................................................................................................77
8.
PHARMACEUTICAL INFORMATION..........................................................................77
8.1
CTEP IND Agents .................................................................................................78
8.2
Other Investigational Agent(s)...............................................................................83
8.3
Commercial Agent(s).............................................................................................83
9.
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ........................................83
9.1
Biomarker Studies and Patient Tumor Biopsies....................................................83
9.2
Investigational Device Information .......................................................................87
9.3
Laboratory Correlative Studies..............................................................................88
9.4
Special Studies.......................................................................................................91
10.
STUDY CALENDAR .......................................................................................................91
11.
MEASUREMENT OF EFFECT .....................................................................................104
11.1
Antitumor Effect – Solid Tumors ........................................................................104
11.2
Antitumor Effect – Hematologic Tumors............................................................109
11.3
Other Response Parameters .................................................................................109
12.
DATA REPORTING / REGULATORY REQUIREMENTS.........................................110
12.1
Data Reporting.....................................................................................................110
12.2
CTEP Multicenter Guidelines..............................................................................110
12.3
Collaborative Agreements Language...................................................................110
13.
STATISTICAL CONSIDERATIONS.............................................................................112
13.1
Study Design/Endpoints ......................................................................................112
13.2
Sample Size/Accrual Rate....................................................................................115
13.3
Stratification Factors............................................................................................115
13.4
Analysis of Secondary Endpoints........................................................................116
13.5
Reporting and Exclusions ....................................................................................117
REFERENCES ............................................................................................................................118
APPENDIX A
PERFORMANCE STATUS CRITERIA ................................................123
APPENDIX B
CTEP MULTICENTER GUIDELINES..................................................124
APPENDIX C
PK SAMPLING GUIDELINES ..............................................................126
APPENDIX D
Patient Drug interactions handout and wallet card ..................................131
APPENDIX E
MEDICATION DIARIES .......................................................................134
APPENDIX F
BIOASSAY TEMPLATES .....................................................................135

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1. OBJECTIVES
1.1
Primary Objectives
1.1.1
Part 1 (Phase 1b) Primary objectives
To determine the dose-limiting toxicities of trametinib in combination with 
navitoclax, and the maximal doses at which both drugs can be safely administered 
together.
1.1.2
Part 2 (Phase 2) Primary objectives
To determine the response rate of the combination of trametinib and navitoclax in 
subjects with KRAS or NRAS mutation-positive advanced or metastatic solid 
tumors in disease-specific expansion cohorts.
To confirm the safety and tolerability of trametinib and navitoclax in combination 
at the recommended phase 2 dose (RP2D) determined in the Phase 1b portion.
1.2
Secondary Objectives
1.1.3
Part 1 (Phase 1b) Secondary Objectives
To determine the pharmacokinetics of both drugs administered together. 
To assess for evidence of response to therapy.
To evaluate the pharmacodynamic response to therapy in tumor biopsies
1.1.4
Part 2 (Phase 2) Secondary Objectives
To evaluate the pharmacodynamic response to therapy in tumor biopsies (first 15 
patients enrolled overall)
2. BACKGROUND
2.1
Study Diseases
KRAS and NRAS mutation-positive advanced solid malignancies: RAS family members are the 
most frequently mutated oncogenes in human cancer. KRAS mutations occur in ~20% of all 
cancers, with particularly high frequency in pancreatic (~90%), colorectal (~40%), and lung 

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(~30%) cancers (Malumbres et al., 2003; Montagut et al., 2009).  NRAS mutations are present in 
melanoma (~20%) and colorectal cancer (~10%).  However, no effective therapies exist for 
RAS-mutant cancers, largely because RAS itself has proven difficult to target directly with small 
molecules (Young et al., 2009). Targeting single RAS effector pathways (e.g. MEK) has also 
failed to induce clinical responses (Rinehart et al., 2004; Adjei et al, 2008), likely because RAS 
activates multiple critical effector pathways, such as the MEK-ERK, PI3K-AKT, and NF-κB 
pathways (Montagut et al., 2009).
2.2
CTEP IND Agent(s)
2.2.1
Trametinib Dimethyl Sulfoxide (GSK1120212B)
The RAF-MEK-ERK pathway plays a critical role in multiple cellular functions.  
Activation of the pathway can result from activation/mutations of the upstream receptor 
tyrosine kinases (RTKs) and RAS, or upregulation/mutations in RAF and MEK.  Upon 
activation, RAF acts as the MAPK kinase and activates MAPKK (MEK1/2), which in 
turn catalyze activation of the effectors ERK1/ERK2.  Once activated, ERK1/2 
translocate into the nucleus and phosphorylate a number of effector proteins and 
transcriptional factors that regulate cell proliferation, motility, differentiation, and 
survival.  
Trametinib is one of the several MEK inhibitors in clinical development.  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 (U.S. Food and Drug 
Administration, 2013).  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 (U.S. Food and Drug Administration, 2014).
Experience to date indicates that MEK is a valid target.  In a phase III trial comparing 
trametinib with dacarbazine or paclitaxel in patients with BRAF V600E or V600K 
mutant metastatic melanoma, trametinib demonstrated a significantly better response rate, 
progression-free survival, and overall survival (Flaherty et al., 2012).  However, single 
agent activities are limited.  Extensive research is underway to identify the patient 
selection markers and develop rational combination strategies.  Preclinical studies have 
provided strong rationale and proof of principle for combination of MEK inhibitors with 
RTK inhibitors (EGFR or IGF-1R) (Gopal et al., 2010; Ebi et al., 2011), PI3K/AKT 
inhibitors (Engelman et al., 2008; Hoeflich et al., 2009), and mTOR inhibitors.  On the 
other hand, the optimal dose/schedule and patient selection criteria for combination 
regimens have not been defined.  Phase 1 results for a number of combinations have been 
reported, including AZD6244 + MK2206 (Tolcher et al., 2011) and GDC-0973 + GDC-
094 (MEK + PI3K inhibitor) (Bendell et al., 2011).

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The most up-to-date preclinical and clinical study information for trametinib can be 
found in the GSK1120212 (trametinib) Investigator's Brochure (2013).
2.2.1.1
Mechanisms of Action and Preclinical Data with Trametinib
Trametinib is a dimethyl sulfoxide (DMSO) solvate compound (ratio 1:1) with potent, 
allosteric and ATP non-competitive inhibition of MEK1/2 (IC50 of 0.7 and 0.9 nM 
against MEK1 and MEK2, respectively) (Gilmartin et al., 2011).  Trametinib inhibited 
MEK1/2 kinase activity and prevented RAF-dependent MEK phosphorylation (S217 for 
MEK1), producing prolonged pERK1/2 inhibition.  Trametinib showed better potency 
against unphosphorylated MEK1/2 (u-MEK1/2) when compared with preactivated 
diphosphorylated MEK (pp-MEK), suggesting that u-MEK affords a higher affinity 
binding site for trametinib than does pp-MEK.
The specificity of trametinib was confirmed against a panel of 183 kinases, including 
MEK5 (the closet kinase homolog to MEK1/2), CRAF, BRAF, ERK1, and ERK2 
(Yamaguchi et al., 2011).  Trametinib demonstrated equal potency against activated 
MEK1- and MEK2-mediated phosphorylation of ERK (sequence identity of 85% across 
the whole protein and 100% in the active site for humans).  Trametinib demonstrated 
preferential inhibition of RAF-mediated MEK1 activation (IC50 = 0.60 nM) over pMEK1 
kinase activity (IC50 = 13 nM) (Investigator’s Brochure, 2012a).
BRAF-mutant Colo205, A375P F11s, and HT-29 human tumor xenograft mouse models 
showed the most significant mean tumor growth inhibition (TGI) (80% to 87%) at 3.0 
mg/kg trametinib, with multiple complete and partial tumor regressions.  In the Colo205 
model, tumor regression was observed even at a dose of 0.3 mg/kg (Yamaguchi et al., 
2011).  Two KRAS-mutant xenograft models, HCT-116 and A549, also showed 
significant TGI (83% and 75%) but without significant tumor regressions (Gilmartin et 
al., 2011).  As predicted by cell proliferation assays, tumor xenograft lines with wild-type 
(wt) RAF/RAS (PC3, BxPC3, and BT474) were much less sensitive, showing only 
modest TGI (44-46%) with no tumor regressions.
Pharmacodynamic studies were performed in mice treated with trametinib for 14 days 
(Gilmartin et al., 2011).  In the A375P F11s xenograft model, the first dose of trametinib 
(3 mg/kg) significantly reduced pERK for more than 8 hours on Day 1.  pERK inhibition 
was more sustained (over 24 hours) after the Day 7 dose, probably due to an increase in 
the steady-state levels of trametinib after repeated doses.  The average Cmax in blood was 
1,410 nM on Day 7, with an estimated half-life (t1/2) of 33 hours.  In addition, 
immunohistochemistry (IHC) also confirmed inhibition of cell proliferation (reduced 
Ki67) and G1 cell cycle arrest (elevated p27Kip1/CDKN1B) following 4 days of 
treatment.

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2.2.1.2
Clinical Pharmacokinetics (PK) and Activity of Trametinib
FTIH Phase 1 Trial of Trametinib Monotherapy (MEK111054)
There are 3 parts in this ongoing study.  Part 1:  The dose-escalation portion involves 
administration of trametinib (repeat doses of 0.125 mg to 4.0 mg) to patients with solid 
tumors or lymphoma in one of three schedules - (1) QD for 21 days followed by 7 days 
without drug, (2) loading dose on Day 1 or Day 1-2, followed by QD with the designated 
dose, or (3) QD dosing without a drug holiday.  Part 2:  cohort expansion at the 
recommended phase 2 dose (RP2D) for pancreatic cancer, melanoma, NSCLC, CRC, or 
any BRAF mutation-positive cancer.  Part 3:  expansion to characterize the biologically 
active range of trametinib via analysis of pharmacodynamic biomarkers (biopsies or 
FDG-PET).
The dose escalation part and some of the cohort expansion components have been 
completed.  The MTD of trametinib was established as 3 mg QD, but the recommended 
phase 2 dose (RP2D) was chosen at 2 mg QD based on tolerability of repeated cycles 
(Infante et al., 2010).
PK and metabolism of trametinib:
PK measurements were conducted under fasting conditions.  After a single dose (Day 1), 
AUC0-24 and Cmax values were dose-proportional up to 6 mg, lower than dose 
proportional following 8 mg, and greater than dose proportional following the 10 mg 
dose.  Median Tmax was 1.5 hours.
After repeat doses (Day 15), trametinib accumulated with a mean accumulation ratio of 
6.6 at the RP2D of 2 mg QD.  Between-subject variability in exposure ranged from 27-
50% for Cmax and 20-41% for AUC0-24 across all dosing regimens.  The effective t1/2 was 
approximately 4.5 days, and steady state was reached by approximately Day 15.  
Trametinib had a small peak:trough ratio of ~2 (Infante et al., 2010).  At 2 mg QD on 
Day 15, mean AUC0-24 was 376 ng•h/mL and Cmax 23 ng/mL, and the mean trough 
concentrations ranged from 10.0 to18.9 ng/mL.  The long half-life and small peak:trough 
ratio of trametinib allowed constant target inhibition within a narrow range of exposure.
Drug-drug interactions:
Trametinib is metabolized predominantly via deacetylation (non-cytochrome P450 
[CYP450]-mediated) with secondary oxidation or in combination with glucuronidation 
biotransformation pathways (Investigator’s Brochure, 2012a).  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.
Pharmacodynamic effect and biomarkers:
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 

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(Investigator's Brochure, 2012a).  In general, increasing exposures and/or doses provided 
greater pharmacodynamic effects.  The median change observed at a dose of 2 mg QD 
was 62% inhibition of pERK, 83% inhibition of Ki67, and a 175% increase in p27.
Antitumor Activity of Trametinib Monotherapy
In the FTIH phase 1 trial, 14 patients with BRAF-mutant melanoma received trametinib 
at 2 mg QD (2 mg/day continuously, or 2 mg for 21 days followed by a 1 week break).  
The overall objective response rate (ORR) was 43% (6/14), including 2 complete 
responses (CRs) (Investigator's Brochure, 2012a).  In 9 patients with BRAF wt 
melanoma, 2 patients achieved a partial response (PR), and 3 stable disease (SD) (Infante 
et al., 2010).  In 26 evaluable pancreatic cancer patients, there were 2 PRs (1 PR was 
KRAS mutation-positive) and 11 SD (2 achieved ≥20% tumor reduction) (Messersmith et 
al., 2011).  Among the 27 CRC patients (without selection of RAS or RAF mutations), 8 
SD were observed.
In a phase 3 trial, patients with unresectable stage IIIC or IV cutaneous melanoma with a 
BRAF V600E or V600K mutation were randomized (2:1) to trametinib (2 mg, PO, QD) 
or chemotherapy (dacarbazine or paclitaxel) (Flaherty et al., 2012).  There were 322 
patients in the intention-to-treat (ITT) population, of whom 273 (85%) were in the 
primary efficacy population (patients with BRAFV600E-positive cancer who did not have 
brain metastases at baseline).  In the ITT analyses, the ORR was 22% in the trametinib 
group and 8% in the chemotherapy group; the median duration of PFS was 4.8 months in 
the trametinib group as compared with 1.5 months in the chemotherapy group; and the 6-
month OS rate was 81% in the trametinib group and 67% in the chemotherapy group.
Antitumor Activity of Trametinib in Cancer Other Than Melanoma
In a phase 1/2 monotherapy study, acute myeloid leukemia (AML) or myelodysplastic 
syndrome (MDS) patients were given trametinib at dose levels from 1-2 mg QD.  Drug-
related AEs in 45 patients were similar to that observed in patients with solid tumors, and 
2 mg PO QD was selected for further investigation in this patient population.  Twelve 
patients (23%) withdrew due to an AE, including cardiac failure (2) and infection (2).  
Efficacy was reported in 39 patients (Borthakur et al., 2010).  The best response in 13 
patients with KRAS or NRAS mutations included 3 CRs (23%), 7 SD (54%), and 1 PD 
(progressive disease) (5%).  In 26 patients with wild-type RAS or an unknown mutation, 
there were 2 PRs (8%).
2.2.1.3
Trametinib Safety Profile
A Comprehensive Adverse Events and Potential Risks (CAEPR) list using NCI 
Common Terminology Criteria for Adverse Events (CTCAE 5.0) terms is included in 
Section 7.1 of the protocol.
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 

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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.
AEs 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 
(Investigator’s Brochure, 2013).  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.
Refer to dose modification guidelines for the toxicities for which they are addressed in 
Section 6.
Rash:  Rash was a common AE observed across different dose levels and in different 
combinations (Investigator’s Brochure, 2013).  At the 2 mg dose, rash was seen in 27% to 
78% of patients in different trials.  Of the ~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 3 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 (Investigator’s Brochure, 2013).  Of ~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 (Investigator’s Brochure, 2013).  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 

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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 (Investigator’s 
Brochure, 2013).  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) (Investigator’s Brochure, 2013).  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.
Hepatic disorders:  Abnormalities of liver enzymes and bilirubin have been observed with 
administration of trametinib (Investigator’s Brochure, 2013).  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 (Investigator’s Brochure, 2013).  Of the 65 total subjects 
(including crossover subjects) experiencing cardiac-related AEs at the 2.0 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.

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In the phase 3 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 (Investigator’s Brochure, 2013).  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:
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

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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).  
2.2.1.4
Clinical Experience with the Combination of Trametinib + Dabrafenib
Trametinib has previously been evaluated in combination with other targeted therapies.  
Experience with the combination of trametinib and the BRAF inhibitor dabrafenib is 
summarized below.  Preliminary data on 45 patients participating in the phase 1/2 study 
of dabrafenib and trametinib, BRF113220, have been reported (Infante et al., 2011).
PK:
The plasma levels of dabrafenib were higher in combination with trametinib as compared 
to that with monotherapy.  Geometric mean Day 15 AUC of dabrafenib in combination 
ranged from 3539 to 5187 ng•hr/mL, and the AUC observed in the monotherapy study 
was 2619 ng•hr/mL.  Further data are required to understand this difference.
PK of trametinib did not appear to be affected by the addition of dabrafenib.  Preliminary 
results showed that the geometric mean dose-normalized AUC0-τ (CV%) for trametinib 

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(dose normalized for the 2.0 mg QD dose) in combination with dabrafenib at 150 mg BID 
was 302 ng•hr/mL (n=17; 35%) on Day 15.  Historical PK data from the trametinib FTIH 
study (MEK111054) indicated a mean Day 15 AUC0-τ (CV%) of 360 ng•hr/mL (31%).
Safety and the RP2D for the combination of trametinib and dabrafenib
One DLT of a recurrent grade 2 neutrophilic panniculitis occurred, and pyrexia was 
common (51%).  The RP2D was 150 mg BID dabrafenib plus 2 mg QD trametinib (both 
agents at the RP2D for single agent).  Of the 137 patients enrolled, 32 patients were 
treated at the RP2D.  SAEs experienced by more than one patient include:  pyrexia (5%), 
hypotension (4%), nausea (3%), and 2% of patients had a constellation of AEs including 
vomiting, dehydration, or renal failure.  The only grade 4 AE was a sepsis-like syndrome 
with fever/hypotension.  Grade 3 AEs included generalized rash (n=2, 4%) and 
neutropenia (n=2, 4%).  Skin toxicity (rash) occurred in 9 (20%) patients.  Of note, the 
rate of SCC was 2% in this study.  A single case of grade 5 hyponatremia was reported.  
Other common AEs are listed in the table below.
Summary of selected AEs experienced by ≥5% of patients regardless of causality
in BRF113220 (treated at RP2D)
AE Term
Dose Escalation Cohort
(150mg BID/2 mg QD)
(n=31)
Any AE, n (%)
24 (77)
Pyrexia
10 (32)
Rash
4 (13)
Dermatitis acneiform
1 (3)
Hypotension
4 (13)
Activity
Among 77 evaluable patients with melanoma who had not received prior BRAF 
inhibitors, there were 43 responses (56%), including 4 CRs (5%) and 39 PRs (51%) 
(Weber et al., 2012).  Twenty-nine patients experienced SD, and three patients 
experienced PD.  Patients were treated on four escalating dose levels of 
dabrafenib/trametinib (mg BID/mg QD):  75/1, 150/1, 150/1.5, 150/2.  The confirmed RR 
for each dose level, respectively, was 67% (n=6), 64% (n=22), 48% (n=25), and 54% 
(n=24).  Median PFS (months) for each of the first three dose levels, respectively, was 
8.7, 8.3, and 5.5; PFS data are not mature for the fourth (150/2) dose level.  Overall PFS 
was 7.4 months.
Currently, the randomized phase 2 portion (Part C) of the study of dabrafenib with or 
without trametinib has enrolled 162 patients as of September 1, 2011 (Investigator’s 
Brochure, 2012b).

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2.2.1.5
Clinical Experience with the Combination of Trametinib + GSK2141795 (AKT 
inhibitor) (TAC113886)
Trametinib has previously been evaluated in combination with other targeted therapies.  
Experience with the combination of trametinib and the AKT inhibitor GSK2141795 is 
summarized below.  Twenty-three patients with advanced solid tumors received the 
combination using a zone-based escalation procedure enabling evaluation of multiple 
combination doses in parallel cohorts (Kurzrock et al., 2011).  While the RP2D for single 
agent for single agent trametinib and GSK2141795 are 2 mg/d and 75 mg/d, dose 
reductions were required for the combination.  DLTs include grade 2 AST and ALT 
elevation, and grade 3 chest pain with sustained ventricular tachycardia; all DLTs were 
reversible with drug interruption.  The most common AEs (≥10%) included nausea 
(26%), AST elevation (22%; grade 3/4, 9%), fatigue (22%) and rash (22%).  Three MTDs 
were defined for variable dose ratios:  2 mg trametinib + 25 mg GSK2141795; 0.5 mg 
trametinib + 75 mg GSK2141795; and 1.5 mg trametinib + 50 mg GSK2141795.  Three 
of 13 evaluable patients (unselected) had tumor shrinkage of 8% (ovarian), 16% 
(endometrial), and 17% (ovarian) after 8 weeks on study.  The dose regime of 1.5 mg 
trametinib + 50 mg GSK2141795 will be considered for further development.  Additional 
trials to explore alternate schedules (e.g., intermittent) and pharmacodynamic markers are 
ongoing.
2.2.2
Navitoclax
Navitoclax is a novel small molecule Bcl-2 (B-cell lymphoma-2) family protein inhibitor 
that binds with high affinity to multiple anti-apoptotic Bcl-2 family proteins including 
Bcl-XL (inhibition constant [Ki]<0.5 nM), Bcl-2 (Ki<1.0 nM), Bcl-w (Ki<1.0 nM), and 
Bcl-B (Ki<5.0 nM) (Investigator’s Brochure, 2011).    
The Bcl-2 family of genes encodes a group of closely-related proteins that possess either 
pro-apoptotic or anti-apoptotic activity and share up to four Bcl-2 homology (BH) 
domains (Cory and Adams, 2002; Borner 2003; Cory et al., 2003; Willis et al., 2003).  
The anti-apoptotic family members (Bcl-XL, Bcl-2, Bcl-w, A-1, and Mcl-1) are 
characterized by four BH domains that are designated BH1-4.  The pro-apoptotic proteins 
are subdivided into multidomain proteins (Bax and Bak) and the BH3-only proteins (Bad, 
Bik, Bid, Bim Hrk, Bmf, Noxa, and Puma).  The interplay between these three groups of 
proteins serves as the gateway to the intrinsic apoptosis pathway.
The pro-apoptotic proteins Bax and Bak are direct mediators of apoptosis and are 
absolutely required for the initiation of the mitochondrial apoptosis pathway (Lindsten et 
al., 2000; Wei et al., 2001; Degenhardt et al., 2002).  Anti-apoptotic Bcl-2 family 
proteins (e.g., Bcl-2 and Bcl-XL) inhibit cytochrome c release by blocking Bax/Bak 
activation (Adams and Cory, 2001).  The exact mechanism of action of Bcl-2 and Bcl-XL 
has not been completely elucidated; however, it is known that it requires the ability to 
bind the pro-apoptotic Bcl-2 family members, and that the ratio of pro-apoptotic to anti-

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apoptotic proteins is associated with cell survival (Yang and Korsmeyer, 1996; Fadeel et 
al., 1999; Tsujimoto and Shimizu, 2000).
In contrast to other known oncogenes, Bcl-2 does not stimulate cellular proliferation, but 
rather inhibits programmed cell death by protecting cells from a wide variety of pro-
apoptotic stimuli, including cytokine withdrawal, irradiation, cytotoxic drugs, heat, and 
deregulated oncogenes (Korsmeyer, 1999).  Antiapoptotic Bcl-2 family members are 
associated with tumor initiation, disease progression, and drug resistance, and are 
therefore compelling targets for antitumor therapy.  Over expression of certain 
antiapoptotic Bcl-2 proteins is associated with increased tumor resistance to 
chemotherapy; thus, inhibition of these proteins might enhance response to such therapies 
and overcome resistance.
Based on data from company-sponsored studies in relapsed/refractory lymphoid 
malignancies, SCLC, and other solid tumors, the RP2D for single-agent studies in these 
indications should include a 7-day lead-in of navitoclax 150 mg PO, followed by 325 mg 
on Days 1-21 of a 21-day cycle.  A phase 1 trial in CLL has obtained a RP2D of a 7-day 
lead-in of 100 mg/day followed by 250 mg on Days 1-21 of a 21-day cycle (Roberts et 
al., 2012).  
Nonclinical Efficacy Studies
Preclinical models of therapy-resistant lymphoma support the biologic relevance of the 
Bcl-2 family of proteins in the pathogenesis of B-cell lymphomas.  In three flank models 
of B-cell lymphoma (DoHH-2, WSU-DLCL2, and GRANTA-519) known to express 
high levels of Bcl-2, significant monotherapy activity was noted when navitoclax was 
administered at an oral dose of 100 mg/kg/day, once daily (QD) × 17 days (Investigator’s 
Brochure, 2011).  Tumor growth inhibition in these models ranged from 40% to 54% as 
compared to vehicle treated controls.  The WSU-DLCL2 line had been isolated from a 
patient whose disease progressed following chemotherapy, radiation therapy, and bone 
marrow transplantation, and is reputed to be a model of therapy-resistant lymphoma.  
Navitoclax has been tested in vitro against 68 cell lines spanning diverse tumor types and 
was found to display potent (concentration achieving 50% effect [EC50] <1 μM) single-
agent activity against small cell lung cancer (SCLC), follicular lymphoma, and leukemia-
derived cell lines (Investigator’s Brochure, 2011).  These included 10 of 22 cell lines 
representing multiple leukemia and lymphoma types spanning both B-cell and T-cell 
malignancies, and 7 of 22 SCLC cell lines.  In a panel (n=23) of cell lines examined by 
the Pediatric Preclinical Testing Program (PPTP), IC50 values of <1 M were observed in 
9 cell lines, including 3 acute lymphoblastic leukemia (ALL), 2 rhabdomyosarcoma, and 
1 Ewing’s sarcoma cell line (Lock et al., 2008).  In addition, strong synergism was 
observed with DNA-damaging and antimitotic agents across multiple cell lines and tumor 
types (Investigator’s Brochure, 2011).  Strong synergism with DNA-damaging agents 
(etoposide, carboplatin) as well as with the proteasome inhibitor bortezomib was 

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observed in the A549 non-small cell lung cancer (NSCLC) cell line.  Interestingly, in 
some cases, the degree of synergism was dependent on the ratio of the two compounds.  
For example, the synergism between navitoclax and carboplatin increased as the ratio of 
navitoclax to carboplatin decreased.
To assess the ability of navitoclax to directly induce apoptosis, the time course of 
caspase-3 activation was monitored in H146 cells as a function of navitoclax 
concentration (Investigator’s Brochure, 2011).  Navitoclax induced a concentration-
dependent increase in caspase-3 activation with an EC50 of approximately 100 nM.  
Caspase-3 activity is rapidly induced in response to navitoclax treatment with near 
maximum activity by 6 hours.  This is consistent with the time course for which 
cytotoxicity is observed in this cell line.  Other apoptotic markers (cytochrome c release, 
phosphatidylserine externalization) were elevated in a navitoclax -dose-dependent 
manner, further supporting the hypothesis that navitoclax induces apoptosis, likely 
mediated through Bcl-2 family proteins.
Navitoclax was found to be active in 8 of 9 xenograft models of established SCLC, in 
which tumors were allowed to grow to an average volume of 200 to 250 mm3 prior to 
initiation of therapy (Investigator’s Brochure, 2011).  When delivered at a dose of 100 
mg/kg/day orally (PO) for 21 consecutive days, navitoclax exhibited highly significant 
activity in 3 models (H1963, H889, and H146).  Complete tumor regression was observed 
in half of the mice bearing H146 tumors and all of the mice bearing either H889 or 
H1963 tumors.  Significant antitumor activity, including partial responses (PRs; ≥50% 
shrinkage), was observed in an additional 5 models (H1417, H128, H211, H510, and 
H345).  Using the same dose and schedule, navitoclax was also active against larger (440 
mm3), more vascular H146 tumors, inducing complete tumor regression in 3 of 10 mice 
and 1 confirmed tumor cure.
In panels of murine tumor xenograft models examined by the PPTP, single-agent 
navitoclax prolonged the event-free survival (EFS) period in 5 of 6 ALL models as well 
as in 9 of 35 solid tumor xenograft models examined (Lock et al., 2008).  Complete 
responses (CRs) were seen in a B-precursor ALL xenograft and in both T-cell xenografts.  
Solid tumors that showed improved EFS included 2 of 5 rhabdomyosarcoma, 2 of 5 
osteosarcoma, 2 of 6 neuroblastoma, 1 of 5 Ewing sarcoma, and 1 of 3 Wilms’ tumor 
models, as well as the only ependymoma model tested.
Efficacious doses of navitoclax were determined from dose-response studies in the H146 
SCLC flank tumor model after daily (Days 1-21) PO dosing of navitoclax.  A dose of 50 
mg/kg/day elicited tumor regression in 6 of 9 mice (2 CRs, 4 PRs) and was defined as the 
minimally efficacious dose.  A dose of 100 mg/kg/day induced a high percentage of 
complete tumor regressions and was identified as the target dose.  At the 200 and 300 
mg/kg/day doses, 20% of the mice were cured, as no tumor was evident by 
histopathological examination at 125 days after inoculation.  Plasma and tissue drug 
concentrations were determined following multiple (n = 3) QD PO dosing in the same 
strain of mouse utilized in the efficacy study.  From this study, the minimally efficacious 

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plasma exposure for navitoclax in mice, as expressed by area under the concentration-
time curve (AUC), was 53 μg•hr/mL, and the target AUC was 88 μg•hr/mL.  Based on 
these data and on PK modeling, the predicted efficacious plasma exposure in humans is a 
maximum plasma concentration (Cmax) of 6.5 g/mL.
Nonclinical Toxicology 
The primary effects of navitoclax on the hematopoietic systems of both rats and dogs 
were decreased circulating platelets and lymphocytes (Investigator’s Brochure, 2011).  
These effects were dose-dependent and reversible, as were any effects secondary to 
platelet depletion.  The decreased circulating lymphocytes consisted of CD4 and CD8 T 
cells in rats and dogs, with a primary effect seen on B cells in dogs.  Other observed 
hematopoietic effects included reversible decreases in total white blood cell count and 
eosinophil count, primarily in the rat.
Macroscopic and microscopic changes indicative of lymphoid depletion occurred in 
lymphoid tissues at ≥30 mg/kg/day in rats and at ≥3 mg/kg/day in dogs, and were 
consistent with reductions in circulating lymphocytes (Investigator’s Brochure, 2011).  
Affected lymphoid organs included lymph nodes and spleen (rats and dogs), thymus (rats 
only), and Peyer's patch (dogs only).  Partial to complete reversibility of all effects on 
lymphoid tissue was noted.
Navitoclax had no clear adverse CNS effects in the rat and mouse at an intraperitoneally 
(IP) injected dose of 5 mg/kg (Investigator’s Brochure, 2011).  At doses of 10 mg/kg IP 
and higher, mild to moderate sedation occurred and latency to sleep increased after 
barbital injection.  At doses of 25 mg/kg IP and higher, body temperature decreased as 
sedation became more pronounced.  At 100 mg/kg IP, loss of traction was observed.  
Navitoclax produced no relevant effects on neurobehavioral function through the highest 
dose of 15 mg/kg (plasma concentrations of 137.9  27.5 μg/mL).
Navitoclax does not pose a genotoxic risk, as it was negative in all genetic toxicity 
studies, and no effect on embryo-fetal development in rats or rabbits was observed 
(Investigator’s Brochure, 2011).
In the Segment I male rat fertility study, navitoclax -related changes were limited to small 
and/or soft testes, decreased testis and epididymis weights, hypospermatogenesis, and 
reduced sperm motility and sperm counts at 30 mg/kg/day (top dose) following 
approximately 70 days of once daily oral dosing (Investigator’s Brochure, 2011).  In 
addition, time- and dose-dependent navitoclax -related effects were observed on the rat 
ovary.  Ovarian atrophy (associated with ~58% decreased ovarian weights) was observed 
at the highest dose of 100 mg/kg in the 6-month study, characterized by reduction or 
absence or corpora lutea and reduction in number of developing follicles.  Decreases in 
ovarian weights (up to ~29%) were observed at the lower doses in the 6-month study and 
in the shorter duration studies of 2 and 13 weeks in duration.  These weight changes were 

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considered not to be adverse due to the absence of associated histopathologic findings.  
However, no effect on reproductive performance was observed in male or female rats.  
No impairment of fertility was observed in the female rat Segment I study at up to 100 
mg/kg/day (high dose).  In Segment II embryo-fetal development studies, once daily oral 
doses of navitoclax in time-mated female rats (high dose, 100 mg/kg/day) and rabbits 
(high dose, 200 mg/kg/day) were not teratogenic and did not have any effect on the 
embryo/fetal viability of offspring.
Clinical Safety Profile
Navitoclax is being investigated as a single agent and as a component of combination 
therapy.  Trial M10-454, a biocomparison study, is fully enrolled.  Additionally, three 
phase 1/2a studies have completed and published safety and tolerability data from the 
phase 1 dose-escalation portions of the studies, and have transitioned to the phase 2a 
portions of the study:

M06-814, in patients with relapsed or refractory lymphoid malignancies (Wilson 
et al., 2010).  

M06-822, in patients with small-cell lung cancer (SCLC), pulmonary carcinoid, 
and other solid tumors (phase 1), and in patients with SCLC (phase 2a) (Gandhi et 
al., 2011; Rudin et al., 2012).  

M06-873, in patients with relapsed or refractory chronic lymphocytic leukemia 
(CLL) (Roberts et al., 2012).
Thrombocytopenia has been the primary dose-limiting toxicity (DLT) in the clinical 
development of navitoclax.  This has been observed nonclinically and is thought to be 
due to the pharmacodynamic effect of drug action (inhibition of the platelet-expressed 
homolog Bcl-XL, leading to apoptosis) (Investigator’s Brochure, 2011).  Grade 3/4 
thrombocytopenia was observed in 29 out of 55 patients in trial M06-814 (Wilson et al., 
2010); 5 out of 47 patients in the phase 1 portion of trial M06-822 and 16 out of 39 SCLC 
patients in the phase 2a portion (Gandhi et al., 2011; Rudin et al., 2012); and 8 out of 29 
patients in trial M06-873 (Roberts et al., 2012).  Grade 4 thrombocytopenia and 
neutropenia were reversible via temporary suspension or dose reduction of navitoclax, 
and filgrastim for persistent grade 4 thrombocytopenia.  
In all three trials, platelet count decreases occurred both on an intermittent dosing 
schedule (navitoclax administered PO QD on 14 consecutive days of a 21-day cycle) and 
on a continuous schedule (21 out of 21 days).  Platelet counts reached their nadir soon (1-
3 days) after the first dose of navitoclax, but with a rebound occurring even during the 
dosing period (Wilson et al., 2010; Gandhi et al., 2011).  This recovery is thought to be 
due to a compensatory upregulation of megakaryocyte platelet production.  As a result, 
clinical studies now employ a 7-day lead-in period at a reduced dose of navitoclax prior 
to administration of the full dose in Cycle 1.  Use of the lead-in dose before a continuous 
dosing schedule has helped to reduce acute platelet nadirs and the incidence of grade 4 
thrombocytopenia during the first cycle, allowing higher doses than were obtainable on 

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the intermittent (14/21) schedule (Wilson et al., 2010; Roberts et al., 2012).  However, 
severe thrombocytopenia was observed during later cycles in 4 of 7 patients in the 250 
mg and 300 mg continuous-dosing cohorts; as with thrombocytopenia observed in Cycle 
1, these events were reversible with dose reduction or granulocyte colony-stimulating 
factor (G-CSF) administration (Roberts et al., 2012).  
Other frequently reported AEs include anemia, neutropenia, infection, diarrhea, nausea, 
and fatigue (Investigator’s Brochure, 2011; Wilson et al., 2010; Gandhi et al., 2011; 
Roberts et al., 2012).  Although decreases in circulating neutrophils were not observed in 
nonclinical toxicity studies, neutropenia has been noted in some patients both early 
(Cycles 1-5) and late (Cycles 7-14) in the CLL monotherapy study M06-873 (Roberts et 
al., 2012).  Preliminary analysis of early clinical data demonstrates an apparent trend in 
decreasing baseline-normalized ANC nadirs with increasing navitoclax dose, Cmax, or 
AUC.  As such, neutropenia is considered an adverse drug reaction, attributed to 
navitoclax administration; in the CLL study it was reversible with dose reduction or G-
CSF administration.  
Grade 1 and 2 gastrointestinal AEs may be due to the vehicle used in the liquid 
formulation; nausea and vomiting have been managed with antiemetics, and diarrhea with 
diphenoxylate and atropine (Wilson et al., 2010).  Anorexia is also considered an adverse 
drug reaction as it is consistent with the other identified gastrointestinal toxicities.
Other AEs of interest include elevation in liver enzymes, which has limited some 
subjects' dosing.  As such, liver function tests should be routinely monitored during the 
conduct of navitoclax studies.  
Some investigators have reported QTc prolongation as non serious adverse events 
(Investigator’s Brochure, 2011).  Many of these subjects were heavily pretreated with 
cardiotoxic drugs.  Based on nonclinical evaluation, it is unknown or unlikely that QTc 
prolongation is related to navitoclax administration; however, further clinical QTc 
investigation is planned.  Additionally, metabolic changes such as hyperuricemia, 
hyperkalemia, and increased lactate dehydrogenase (LDH) values have been reported and 
are consistent symptoms of tumor lysis syndrome (TLS).  One serious adverse event of 
TLS was reported; however, with continued treatment with prophylaxis, no further events 
of TLS have been reported.  A treatment management strategy for subjects experiencing 
TLS is discussed in Section 6.  
The following recommended phase 2 doses (RP2D) were independently determined 
based on their respective safety and tolerability results: 

M06-814 (lymphoid malignancies):  7-day lead-in dose of 150 mg/day followed 
by 325 mg QD (21/21 days) (Wilson et al., 2010).  

M06-822 (SCLC and other solid tumors):  7-day lead-in dose of 150 mg/day 
followed by 325 mg QD (21/21 days) (Gandhi et al., 2011).  

M06-873 (CLL):  7-day lead-in dose of 100 mg/day followed by 250 mg QD 

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(21/21 days) (Roberts et al., 2012).
Clinical Pharmacokinetics
Pharmacokinetic (PK) data were obtained for the intermittent (14/21) dosing schedules in 
trials M06-814, M06-822, and M06-873, and for the continuous (21/21) dosing schedule 
in trial M06-873.  M06-814 also tested for food effects on PK parameters.  Overall, the 
absorption of navitoclax after oral dosing was relatively slow, with Cmax achieved around 
6-9 hours after first dose.  Exposure (Cmax and AUC0-24) was approximately dose-
proportional over a range of doses from 10 mg/day through 475 mg/day.  There were no 
significant differences in PK values between disease groups (general lymphoid 
malignancies, SCLC, and CLL) (Investigator’s Brochure, 2011).  Individual study results 
are summarized below.
Trial M06-814:  Peak concentration was observed approximately 9 hours after dosing, 
with a terminal plasma half-life (t1/2) of approximately 17 hours, with first-order 
elimination kinetics (Wilson et al., 2010).  Exposure was dose-proportional over a range 
of 10 mg/day to 440 mg/day, with an interpatient variability in exposure of 40%.  The 
dose-normalized Cmax and AUC0-24 of a non-fasting dose was about 20% higher than a 
fasting dose among subjects in the 10 mg through 440 mg cohorts.  Dosages ≥315 
mg/day met the minimum plasma exposure predicted to be in the therapeutic range based 
on animal models.  After a fasting dose, the oral clearance of navitoclax averaged about 
4.4 L/h across all dose levels (Investigator’s Brochure, 2011).  Navitoclax was not 
detected in urine, indicating little to no renal excretion.
Trial M06-822:  Peak concentration was observed approximately 7 hours after dosing, 
with a t1/2 of approximately 15 hours (Gandhi et al., 2011).  Exposure (Cmax and AUC0-24) 
was dose-proportional over a range of 10 mg/day to 475 mg/day. Interpatient variability 
in dose-normalized Cmax and AUC0-24 was about 40%, and values were similar between 
fasting and non-fasting conditions.  Peak-to-trough plasma concentration ratio was close 
to twofold at steady state.  Dosages ≥225 mg/day met the minimum plasma exposure 
predicted to be in the therapeutic range based on animal models.
Trial M06-873:  Peak concentration was observed approximately 6-8 hours after dosing 
in both the intermittent and continuous dosing cohorts (Roberts et al., 2012).  Exposure 
was dose-proportional over a range of 10 mg/day to 250 mg/day in the intermittent 
cohort, and interpatient variability in AUC was 46% for intermittent and continuous 
cohorts.  No consistent trend was observed in dose-normalized steady-state trough 
concentrations over time.  Navitoclax exposure did not demonstrate any correlation with 
age, sex, body weight, body surface area, renal function, or total bilirubin levels.
Clinical Efficacy
Trial M06-814:  Overall, 21 of 46 patients with assessable adenopathy showed some 
reduction in tumor size (Wilson et al., 2010).  Ten of these patients achieved a PR of at 

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26
least a 50% reduction in tumor size, and these responders had median progression-free 
survival (PFS) of 455 days.  Responses occurred over the entire range of doses, with the 
exception of 20 and 200 mg/day, and in several tumor types.  Responses were recorded 
after a median of 3.5 cycles (range 2–10).  
CLL and small lymphocytic lymphoma (SLL), diseases of B-cell accumulation, showed 
the greatest sensitivity to treatment (Wilson et al., 2010).  Seven patients with leukemic 
counts of >5000 cells/μL achieved at least a 50% reduction in their leukemia cells, and 
eight of 16 patients with measurable adenopathy, including bulky adenopathy, achieved a 
PR of at least a 50% reduction in lymph-node size.  For all 20 patients with CLL or SLL, 
median PFS was 246 days, and median overall survival had not been reached at time of 
the report.  Measurable tumor reduction was also noted in six of 16 patients with 
follicular lymphoma.  Overall, the 16 patients with FL had a median PFS of 88 days, and 
no patient with FL had died at time of the report.
Trial M06-822:  Of the 38 patients who were evaluable for response in the phase 1 
portion (23 with SCLC or pulmonary carcinoid), eight had stable disease (SD; five SCLC 
and three atypical pulmonary carcinoid) and one patient with SCLC remained on study 
for 13 months (Gandhi et al., 2011).  One patient with SCLC had a PR that was sustained 
for longer than 35 months (at the time of report); this patient had a localized recurrence 
after first-line treatment with progressive disease on second-line therapy before study 
entry.  Overall, among patients with disease control, the median number of prior therapies 
was three (range, 1–5 prior therapies).  The majority of patients with disease control were 
those treated at the highest dose levels and the median duration of disease control was 5 
months (range, 2–35 months).
In the phase 2a portion of the trial, out of 39 SCLC patients, only 1 PR (ORR 2.6%) and 
9 SD were observed (Rudin et al., 2012).  Thirteen patients were not evaluable for 
response.  Median PFS was 1.5 months (95% confidence interval [CI], 1.4–1.7) and 
median OS was 3.2 months (95% CI, 2.3–8.1).
Trial M06-873:  Nine of 29 CLL patients achieved a PR (objective response rate [ORR] 
31%), five on the intermittent-dosing (14/21) cohort and four on the continuous-dosing 
cohort (Roberts et al., 2012).  SD was the best response in 18 patients and was sustained 
for at least 6 months in eight patients.  Among the 26 patients who received doses of 
navitoclax sufficient to achieve sustained exposure of biologically active concentrations 
(≥110 mg/day), the ORR was 35%.  Clinical benefit appeared durable, since seven 
patients had SD features for more than 12 months from commencement of therapy.  The 
median PFS and the median time to disease progression were both 25 months.  
Among seven patients with fludarabine-refractory disease receiving ≥110 mg/day, one 
achieved a PR and five had overall SD while demonstrating some antitumor efficacy with 
either a more than 50% reduction in peripheral blood lymphocytosis and/or a substantial 
reduction in lymphadenopathy.  The median PFS of fludarabine-refractory patients was 

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25 months.  Among nine patients with bulky lymphadenopathy receiving navitoclax at 
doses ≥110 mg/day, three achieved a PR and six had SD while demonstrating some 
tumor reduction.  Similarly, three of nine patients with del (17p) CLL treated with 
navitoclax at ≥110 mg/day achieved a PR, and their median PFS has not been reached.
2.3
Other Agent(s)
N/A
2.4
Rationale
Previously, our laboratory and others showed that simultaneous targeting of more than one RAS 
effector pathway (specifically the MEK-ERK (MAPK) and PI3K-AKT pathways) caused 
marked responses in KRAS-driven mouse tumor models (Engelman et al., 2008; She et al., 
2010). While these data support the promise of combination therapy strategies, toxicity has 
prevented dosing both medications at or near their maximally-tolerated doses when used in 
combination (LoRusso et al., 2012; Bedard et al., 2012; Speranza et al., 2012). Thus, potent and 
continuous suppression of the MEK and PI3K pathways may not be possible in patients with 
currently available agents. Furthermore, this approach may be effective only in a subset or 
KRAS-mutant cancers. Consequently, additional effective combination therapy strategies for 
KRAS-mutant cancers are critically needed.
A large-scale screening study of >600 cell lines with >100 targeted compounds identified MEK 
inhibitors as the most effective agents in KRAS-mutant cell lines (Garnett et al., 2012).  
However, while MEK inhibition alone leads to decreased proliferation in most KRAS mutant 
cancers, MEK inhibitors alone typically fail to induce a cell death response (Corcoran et al., 
2013).  This observation likely explains why MEK inhibitors have often led to stable disease in 
KRAS-mutant cancer patients (Infante et al., 2010), but have rarely, if ever, led to true objective 
tumor responses.  Still, because of their potent growth inhibitory effects and their ability to cause 
disease stabilization in patients with KRAS mutant cancers, MEK inhibitors are a promising 
backbone for potential combination strategies for KRAS mutant cancers.  
Recently, we conducted a pooled shRNA-drug screen to identify promising partners for 
combination therapy with MEK inhibitors in KRAS mutant cancers (Corcoran et al., 2013).  The 
top hit from this screen was the anti-apoptotic gene BCL-XL.  Pharmacologic inhibition of BCL-
XL with the BH3 mimetic navitoclax in combination with a MEK inhibitor led to pronounced 
apoptosis in the vast majority of 30 KRAS mutant cancer cell lines from different tumor types 
(pancreas, colorectal, and lung).  Apoptosis induction was significantly greater with this inhibitor 
combination than with either agent alone.  Mechanistically, we observed that MEK inhibition 
alone led to dramatic upregulation of the pro-apoptotic protein BIM.  However, 
immunoprecipitation studies revealed that these increased BIM levels were bound and inhibited 
by BCL-XL.  However, addition of navitoclax blocked the inhibitory interaction of BCL-XL and 

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BIM, thus “freeing” these elevated levels of BIM protein to promote apoptosis.
In vivo, the combination of navitoclax and a MEK inhibitor led to dramatic tumor regressions in 
5 independent KRAS mutant cancer models, and to significantly greater anti-tumor effect than 
either agent alone.  We observed dramatic tumor regressions of established tumors in 3 
independent KRAS mutant tumor xenograft models and in 2 genetically-engineered KRAS-
driven mouse models of lung cancer (one with mutant p53 and one with wild-type p53).  
Analysis of treated tumor tissue showed dramatic induction of cell death only in tumors treated 
with the combination of navitoclax and a MEK inhibitor.  These results represent some of the 
most impressive in vivo preclinical efficacy observed to date with any therapeutic strategy in 
KRAS mutant cancers.
NRAS activates the same key downstream pathways as KRAS, and NRAS mutant cancers also 
represent a molecular subtype with few effective treatments.  NRAS mutant cancers have shown 
increased sensitivity to single-agent MEK inhibitors, when compared to KRAS mutant cancers—
for example, the MEK inhibitor binimetinib recently exhibited a 15% confirmed response rate in 
NRAS mutant melanoma patients and extended survival relative to standard chemotherapy.  Still, 
most patients fail to respond and combination therapy strategies are needed. 
Thus, we hypothesize that the combination of navitoclax and a MEK inhibitor (trametinib) is a 
promising novel targeted therapy combination strategy with the potential to lead to tumor 
responses in patients with KRAS or NRAS mutant cancers of several different tissue types, 
including melanoma, pancreatic, colorectal, GYN, and lung cancers.
2.5
Correlative Studies Background
2.5.1
Pharmacokinetic Studies
While the pharmacokinetics of trametinib and navitoclax given as single agents is well-
understood, this study will evaluate the pharmacokinetics of these agents when given in 
combination.  During the Phase 1b portion of the study, subjects will have blood drawn pre-dose, 
and 2h, 4h, 6h, 8h, and 23h after dosing on (1) day 7 of a 7-day navitoclax single-agent lead-in 
dosing period and (2) again after 14 days of combination dosing.  Pre-dose (0h) levels of 
trametinib and navitoclax will also be measured on day 1 of cycles 2, 4, 8 and 12.  Plasma 
concentrations of trametinib will be determined through established procedures by GSK, and 
concentrations of navitoclax will be determined through established procedures by AbbVie.  
These studies will be used to determine whether trametinib and navitoclax interact from a 
pharmacokinetic standpoint, and will be used to determine the maximum observed plasma drug 
concentration (Cmax), area-under-the concentration-time-curve from zero (pre-dose) to 24 hours 
(AUC(0-24)), pre-dose (trough) drug concentration for trametinib and navitoclax, and t1/2.  
Since it is not yet clear whether the single-agent MTDs of these compounds can reached when 
these agents are dosed in combination, measuring the plasma drug concentrations achieved at 

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each dose level provide a valuable comparison of the drug exposure achieved at a given dose 
level to what is known to be achieved at the single-agent MTD.
2.5.2
Pharmacodynamic Studies
This study will incorporate pharmacodynamic analyses to evaluate the effects of trametinib and 
navitoclax given in combination on key cellular signaling pathways and on the induction of 
apoptosis and inhibition of tumor cell proliferation. Paired pre-treatment and on treatment core 
biopsies will be obtained from all patients in the Phase Ib portion of the trial and the first 15 
patients enrolled on the Phase 2 portion of the trial (minimum of 4 patients from each of cohorts 
1, 2 and 3 will be biopsied), if these patients have lesions that can be safely biopsied without 
unacceptable risk or discomfort to the patient.  Pre-treatment biopsies will be obtained between 
days -21 and -1 of treatment, and the on-treatment biopsy will be obtained on day 22 (+/-7 days) 
for patients in the Phase 1b and Part 2 schedule A, and on day 15 (+/-7 days) for patients in the 
Phase 1b and Part 2 schedule B.  Core biopsies of the same tumor lesion will be obtained at each 
time point.  Both fresh frozen and formalin-fixed paraffin-embedded cores will be obtained at 
each time point.
Paired biopsies will be used to assess the pharmacodynamic response to therapy in these patients.  
Markers to be assessed will include proteins or mRNAs involved in MAPK or BCL2 family 
signaling (e.g. phospho-ERK, phospho-S6, or MAPK phosphatases such as DUSP6/MKP1) to 
evaluate pathway inhibition, markers of tumor cell proliferation (e.g. Ki67), and markers of 
apoptosis and cell death (e.g. Cleaved caspase-3).  For each patient, the change in marker level 
between the pre-treatment and on-treatment (day 15) biopsies will indicate the effects of 
treatment on each marker.  Other potentially important biomarkers identified in emerging 
laboratory investigations may also be evaluated.
Biopsies from patients in the Phase Ib portion of the trial will provide an evaluation of the effects 
of each cohort’s dose level on signaling pathway inhibition, inhibition of tumor cell proliferation, 
and induction of tumor cell death.  This will provide an important metric as to the extent of target 
inhibition at each given dose level.  Paired biopsies obtained from the first 15 patients enrolled in 
the Phase 2 portion of the trial (minimum of 4 patients from each of cohorts 1, 2 and 3 will be 
biopsied) will provide a more detailed assessment of the pharmacodynamic effects of therapy at 
the RP2D and will offer the potential to correlate pharmacodynamic effects with tumor response 
and patient outcome.
2.5.3
Predictive Biomarker Analysis in Pre-Treatment Biopsies
Given the molecular heterogeneity of KRAS and NRAS mutant cancers, no single therapeutic 
regimen is expected to be effective in all patients.  Therefore, molecular characterization of 
archived or pre-treatment tumor biopsy tissue for each patient enrolled on this trial will provide a 
critical opportunity to identify valuable biomarkers to predict which patients are more or less 
likely to respond to treatment.  

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2.5.3.1
Mutational Analysis
Extensive tumor mutational analysis of 1000 genes will be performed for each patient 
using a next-generation genotyping platform employed as part of standard oncology 
care at the Massachusetts General Hospital Cancer Center.  Mutations in key 
pathways that might affect the likelihood of a patient’s tumor to respond to therapy 
(e.g. PIK3CA, PTEN, p53, etc.) will be correlated with objective tumor response or 
PFS.  Additional in-depth genomic analyses, including copy number analyses, may 
also be performed.
2.5.3.2
Biomarker Expression Analysis
We also plan analysis of selected protein and mRNA biomarkers identified in 
previous (and future) laboratory studies.  For example, our initial laboratory studies 
(Corcoran et al., Cancer Cell, 2013) have suggested that KRAS mutant cancers that 
express markers of epithelial differentiation (e.g. E-cadherin) are more likely to 
respond to this therapy that cancers expressing markers of mesenchymal 
differentiation (e.g. vimentin). Thus, E-cadherin and vimentin levels will be assessed 
by immunohistochemistry in archived or pre-treatment biopsies. Also, baseline levels 
of specific BCL2 family apoptotic proteins, including BCL-XL, MCL1, and BIM, 
have also been shown to predict responsiveness to this therapy in laboratory models.  
These markers will also be assessed.  Biomarker levels will be correlated with 
response rate or PFS and may help identify which subpopulation of KRAS or NRAS 
mutant cancer patients are more or less likely to response therapy.
3. PATIENT SELECTION
3.1
Eligibility Criteria 
3.1.1
Patients must have histologically- or cytologically-confirmed diagnosis of KRAS or 
NRAS mutation-positive malignancy that is metastatic or unresectable and for which 
standard curative measures do not exist or are no longer effective.  Patients must have 
activating mutations affecting codons 12, 13, 61, or 146 as determined in a CLIA 
certified lab to be eligible for this study.
3.1.2
Patients must have measurable disease by RECIST, defined as at least one lesion that can 
be accurately measured in at least one dimension (longest diameter to be recorded for 
non-nodal lesions and short axis for nodal lesions) as ≥20 mm by chest x-ray or as ≥10 
mm with CT scan, MRI, or calipers by clinical exam.  See Section 11 for the evaluation 
of measurable disease.

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3.1.3
Participants must have received at least one line of prior systemic chemotherapy and 
must have experienced documented radiographic progression or intolerance on this 
therapy.
3.1.4
Paired pre-treatment and post-treatment biopsies are required for all patients on Part 1 
and first 15 patients in Part 2. Participants must have available archival tumor tissue (at 
least 20 unstained slides.)  If archival tissue is not available or is found not to contain 
tumor tissue, a fresh biopsy is required. If a patient is having a tumor biopsy, less than 20 
unstained slides are acceptable with approval of the PI. Biopsies will only be performed 
in a given patient if they are not deemed to involve unacceptable risk based on the sites of 
disease and other concurrent medical conditions.
3.1.5
Age ≥18 years. 
Because no dosing or adverse event data are currently available on the use of trametinib 
in combination with navitoclax in patients <18 years of age, children are excluded from 
this study, but will be eligible for future pediatric trials.
3.1.6
ECOG performance status ≤1 (see Appendix A).
3.1.7
Life expectancy of greater than 3 months
3.1.8
Able to swallow and retain orally-administered medication and does not have any 
clinically significant gastrointestinal abnormalities that may alter absorption such as 
malabsorption syndrome or major resection of the stomach or bowels.
3.1.9
All prior treatment-related toxicities must be CTCAE v4 grade ≤1 (except alopecia) at 
the time of enrollment. This requirement to return to ≤ grade 1 does not apply to immune 
checkpoint inhibitor related endocrinopathies (e.g. thyroiditis, hypophysitis, etc.) that 
necessitate hormone replacement therapy including, but not limited to levothyroxine, 
cortisol, and testosterone. CTCAE v5.0 will be utilized beginning April 1, 2018.
3.1.10 Patients must have normal organ and marrow function as defined below:  

Leukocytes ≥3,000/mcL

Absolute neutrophil count (ANC) ≥1,200/mcL (subjects may be treated with 
hematopoietic growth factors to achieve or maintain this level)

Hemoglobin ≥9 g/dL

Platelets ≥100x109/L 

Albumin ≥2.5 g/dL

Total bilirubin ≤1.5x institutional ULN (patients with Gilbert’s syndrome may have 
serum bilirubin >1.5×ULN)

Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5x 
institutional ULN

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32

Serum creatinine ≤1.5 mg/dL OR calculated creatinine clearance (Cockroft-Gault 
formula) ≥50 mL/min OR 24-hour urine creatinine clearance ≥50 mL/min

Prothrombin time (PT)/International normalized ratio (INR) and partial 
thromboplastin time (PTT) ≤1.2x institutional ULN

Left ventricular ejection fraction ≥ institutional lower limit of normal (LLN) by 
ECHO or MUGA
3.1.11 The effects of trametinib and navitoclax on the developing human fetus are unknown.  
For this reason, women of child-bearing potential and men with a female partner of child 
bearing potential must agree to use adequate contraception using one of the methods 
listed below prior to study entry, for the duration of study participation, and up to 4 
months following completion of therapy.  

total abstinence from sexual intercourse (minimum one complete menstrual cycle 
prior to study drug administration);

Vasectomized male subject or vasectomized partner of female subjects;

Hormonal contraceptives (oral, parenteral, transdermal or vaginal ring) for at least 
3 months prior to study drug administration; if the subject is currently using a 
hormonal contraceptive, she should also use a barrier method during this study 
and for 1 month after study completion;

intrauterine device (IUD);

double-barrier method: male condom plus diaphragm or vaginal cap with 
spermicide (contraceptive sponge, jellies or creams);
Men with a female partner of childbearing potential must have either had a prior 
vasectomy or agree to use effective contraception. Additionally, male subjects (including 
those who are vasectomized) whose partners are pregnant or might be pregnant must 
agree to use condoms for the duration of the study and for 4 months following 
completion of therapy.
Women of childbearing potential must have a negative serum pregnancy test within 7 
days prior to initiation of treatment.  Women will be considered not of childbearing 
potential if they are surgically sterile (bilateral oophorectomy or hysterectomy) and/or 
post-menopausal (amenorrheic for at least 12 months).
Should a woman become pregnant or suspect she is pregnant while she or her partner is 
participating in this study, she should inform her treating physician immediately.  The 
potential hazard to the fetus should be explained to the patient and partner (as applicable).
3.1.12 Ability to understand and the willingness to sign a written informed consent document.
3.2
Exclusion Criteria

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33
3.2.1
History of another malignancy.
Exception:  Patients who have been disease-free for 3 years, or patients with a history of 
completely resected non-melanoma skin cancer or any carcinoma in situ and/or patients 
with indolent second malignancies, are eligible.  Consult the CTEP Medical Monitor if 
unsure whether second malignancies meet the requirements specified above.
3.2.2
History of interstitial lung disease or pneumonitis.
3.2.3
Any major surgery, extensive radiotherapy (>15 days of treatment), chemotherapy with 
delayed toxicity, biologic therapy, or immunotherapy within 21 days prior to first dose of 
study treatment and/or daily or weekly chemotherapy without the potential for delayed 
toxicity within 14 days prior to first dose of study treatment.
3.2.4
Use of other investigational drugs within 28 days (or five half-lives, whichever is shorter; 
with a minimum of 14 days from the last dose) preceding the first dose of study 
drug(s)and during the study.
3.2.5
Patients with known brain metastases should be excluded from this clinical trial because 
of their poor prognosis and because they often develop progressive neurologic 
dysfunction that would confound the evaluation of neurologic and other adverse events.
Exception: Patients with brain metastases will be allowed on study if they have clinically 
controlled neurologic symptoms, defined as surgical excision and/or radiation therapy 
followed by 21 days of stable neurologic function and no evidence of CNS disease 
progression as determined by CT or MRI within 21 days prior to the first dose of study 
drug.
3.2.6
Have a known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs 
chemically related to trametinib, or excipients or to dimethyl sulfoxide (DMSO), or to 
compounds of similar chemical or biologic composition to navitoclax.
 
3.2.7
Current use of a prohibited medication.  The following medications or non-drug therapies 
are prohibited:

Other anti-cancer therapy while on study treatment.  (note:  megestrol [Megace] if 
used as an appetite stimulant is allowed).

Concurrent treatment with bisphosphonates is permitted; however, treatment must be 
initiated prior to the first dose of study therapy.  Prophylactic use of bisphosphonates 
in patients without bone disease is not permitted, except for the treatment of 
osteoporosis.

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], ginkgo 

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34
biloba, dehydroepiandrosterone [DHEA], yohimbe, saw palmetto, or ginseng).

Due to the expected dose-limiting toxicity of thrombocytopenia, the following 
concomitant medications are not allowed during navitoclax administration:  Warfarin, 
clopidogrel (Plavix), ibuprofen, tirofiban (Aggrastat), and other anticoagulants, drugs, 
or herbal supplements that affect platelet function are excluded, with the exception of 
low-dose anticoagulation medications (such as heparin) that are used to maintain the 
patency of a central intravenous catheter.  Aspirin will not be allowed within 7 days 
prior to the first dose of navitoclax or during navitoclax administration.  However, 
subjects who have previously received aspirin therapy for thrombosis prevention may 
resume a low dose (i.e., maximum 100 mg QD) of aspirin if platelet counts are stable 
(≥50,000/mm3) through 6 weeks of navitoclax administration.  All decisions 
regarding treatment with aspirin therapy will be determined by the investigator in 
conjunction with the medical monitor.
3.2.8
Preclinical studies indicate that navitoclax is metabolized by CYP3A4, is a moderate 
inhibitor of CYP2C8, and is a strong inhibitor of CYP2C9.  Therefore, caution should be 
exercised when dosing navitoclax concurrently with CYP2C8 and CYP2C9 substrates.  
Common CYP2C8 substrates include paclitaxel, statins, and glitazones, whereas 
CYP2C9 substrates include phenytoin and warfarin.  When possible, investigators should 
switch to alternative medications or monitor the patients closely (particularly in the case 
of medications that have a narrow therapeutic window such as warfarin.  Use of warfarin 
is specifically prohibited while on study).  CYP3A inhibitors such as ketoconazole and 
clarithromycin are not allowed 7 days prior to the first dose of navitoclax or during 
navitoclax administration.  
Because the lists of these agents are constantly changing, it is important to regularly 
consult a frequently-updated list such as 
http://medicine.iupui.edu/clinpharm/ddis/table.aspx; medical reference texts such as the 
Physicians’ Desk Reference may also provide this information.  As part of the 
enrollment/informed consent procedures, the patient will be counseled on the risk of 
interactions with other agents, and what to do if new medications need to be prescribed or 
if the patient is considering a new over-the-counter medicine or herbal product.  
Patient instructions and information of possible drug interactions, contained in 
Appendix D, will be given to all patients upon enrollment in this study.
3.2.9
History or current evidence/risk of retinal vein occlusion (RVO).
3.2.10 History or evidence of cardiovascular risk including any of the following:

LVEF<LLN.

A QT interval corrected for heart rate using the Bazett’s formula QTcB ≥480 msec.

History or evidence of current clinically significant uncontrolled arrhythmias 
(exception:  patients with controlled atrial fibrillation for >30 days prior to enrollment 

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are eligible).

History of acute coronary syndromes (including myocardial infarction and unstable 
angina), coronary angioplasty, or stenting within 6 months prior to randomization.

History or evidence of current ≥ Class II congestive heart failure as defined by the 
New York Heart Association (NYHA) functional classification system

Treatment-refractory hypertension defined as a blood pressure of systolic >140 
mmHg and/or diastolic >90 mmHg which cannot be controlled by anti-hypertensive 
therapy.

Known cardiac metastases.

Patients with intra-cardiac defibrillators. 
3.2.11 Known Hepatitis B Virus (HBV), or Hepatitis C Virus (HCV) infection (patients with 
chronic or cleared HBV and HCV infection are eligible).  Patients with Human 
Immunodeficiency Virus (HIV) are not eligible if on anti-retroviral medications.
3.2.12 Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, 
symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or 
psychiatric illness/social situations that would limit compliance with study requirements.
3.2.13 Subject has an underlying condition predisposing them to bleeding or currently exhibits 
signs of clinically significant bleeding.
3.2.14 Subject has a recent history of non-chemotherapy-induced thrombocytopenic-associated 
bleeding within 1 year prior to the first dose of study drug.
3.2.15 Subject has a significant history of cardiovascular disease (e.g., MI, thrombotic or 
thromboembolic event in the last 6 months).
3.2.16 Pregnant women or nursing mothers. Animal reproductive studies have not been 
conducted with trametinib or navitoclax.  Therefore, the study drug must not be 
administered to pregnant women or nursing mothers.  
3.3
Inclusion of Women and Minorities
Both men and women of all races and ethnic groups are eligible for this trial.  
Accrual Targets
Sex/Gender
Ethnic Category
Females
Males
Total
Hispanic or Latino
6
+
5
=
11
Not Hispanic or Latino
61
+
58
=
119
Ethnic Category: Total of all subjects
67
(A1)
+
63
(B1) =
130
(C1)

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Racial Category
American Indian or Alaskan Native
1
+
1
=
2
Asian
7
+
6
=
13
Black or African American
8
+
7
=
15
Native Hawaiian or other Pacific 
Islander
2
+
1
=
3
White
49
+
48
=
97
Racial Category: Total of all subjects
67
(A2)
+
63
(B2) =
130
(C2)
(A1 = A2)
(B1 = B2)
(C1 = C2)
4. REGISTRATION PROCEDURES
4.1
General Guidelines
Dana Farber Harvard Cancer Center (DF/HCC) institutions (Massachusetts General Hospital and 
Dana Farber Cancer Institute) will register eligible participants with the DF/HCC Quality 
Assurance Office for Clinical Trials (QACT) central registration system. Registration must occur 
prior to the initiation of therapy. Any participant not registered to the protocol before treatment 
begins will be considered ineligible and registration will be denied. 
A member of the study team will confirm eligibility criteria and complete the protocol-specific 
eligibility checklist.
 
Following registration, participants may begin protocol treatment. Issues that would cause 
treatment delays should be discussed with the Principal Investigator. If a participant does not 
receive protocol therapy following registration, the participant’s protocol status must be changed. 
Notify the QACT Registrar of participant status changes as soon as possible.
4.2
Registration Process
The QACT registration staff is accessible on Monday through Friday, from 8:00 AM to 5:00 PM 
Eastern Standard Time. In emergency situations when a participant must begin treatment during 
off-hours or holidays, call the QACT registration line at 617-632-3761 and follow the 
instructions for registering participants after hours.
  
The registration procedures are as follows:

NCI Protocol #: 9525
Version Date: July 22, 2022
37
1. Obtain written informed consent from the participant prior to the performance of 
any study related procedures or assessments.
2. Complete the protocol-specific eligibility checklist using the eligibility assessment 
documented in the participant’s medical/research record. To be eligible for 
registration to the study, the participant must meet each inclusion and 
exclusion criteria listed on the eligibility checklist.
 
Reminder: Confirm eligibility for ancillary studies at the same time as eligibility 
for the treatment study. Registration to both treatment and ancillary studies will not 
be completed if eligibility requirements are not met for all studies.
3. Complete the IWRS protocol-specific eligibility checklist online using the 
eligibility assessment documented in the participant’s medical record to generate a 
subject number and a RAVE eCRF page for the patient and receive confirmation 
email.
 
4. Fax the eligibility checklist(s) and all pages of the consent form(s) to the QACT at 
617-632-2295.
 
5. The QACT Registrar will (a) validate eligibility, (b) register the participant on the 
study, and (c) randomize the participant when applicable.
 
6. The QACT Registrar will send an email confirmation of the registration and/or 
randomization to the person initiating the registration immediately following the 
registration and/or randomization.
4.3
Investigator and Research Associated Registration with CTEP
Food and Drug Administration (FDA) regulations require IND sponsors to select qualified 
investigators.  NCI policy requires all persons participating in any NCI-sponsored clinical trial to 
register and renew their registration annually.  To register, all individuals must obtain a CTEP 
Identity and Access Management (IAM) account (https://ctepcore.nci.nih.gov/iam).  In addition, 
persons with a registration type of Investigator (IVR), Non-Physician Investigator (NPIVR), or 
Associate Plus (AP) must complete their annual registration using CTEP’s web-based 
Registration and Credential Repository (RCR) (https://ctepcore.nci.nih.gov/rcr).  Documentation 
requirements per registration type are outlined in the table below.

NCI Protocol #: 9525
Version Date: July 22, 2022
38
Documentation Required
IVR
NPIVR
AP
A
FDA Form 1572


Financial Disclosure Form



NCI Biosketch (education, training, employment, 
license, and certification)



HSP/GCP training



Agent Shipment Form (if applicable)

CV (optional)



An active CTEP-IAM user account and appropriate RCR registration is required to access all 
CTEP and CTSU (Cancer Trials Support Unit) websites and applications.  In addition, IVRs and 
NPIVRs must list all clinical practice sites and IRBs covering their practice sites on the FDA 
Form 1572 in RCR to allow the following:

Act as the site-protocol PI on the IRB approval.
Additional information can be found on the CTEP website at 
<https://ctep.cancer.gov/investigatorResources/default.htm >.  Error! Hyperlink reference not 
valid.For questions, please contact the RCR Help Desk by email at < RCRHelpDesk@nih.gov 
mailto:>.
5. TREATMENT PLAN
5.1
Agent Administration
Treatment will be administered on an outpatient basis.  Reported adverse events and potential 
risks are described in Section 7.  Appropriate dose modifications are described in Section 6.  No 
investigational or commercial agents or therapies other than those described below may be 
administered with the intent to treat the patient's malignancy.  The patient will be requested to 
maintain a medication diary of each dose of medication.  The medication diary will be returned 

NCI Protocol #: 9525
Version Date: July 22, 2022
39
to clinic staff at the end of each course (28-day cycle).
Vomited doses of both trametinib and navitoclax will not be made up. Each medication should 
be taken approximately 24 hours after the time that same medication was taken, with an 
allowable window of +/- 8 hours. Doses of each medication should be taken at least 16 hours 
after the prior day’s dose of that same medication. For days on which subjects will undergo an 
on-treatment biopsy or any other procedure which required the subject to be NPO, Navitoclax 
should be taken in the a.m. with Jello at least two hours before the scheduled procedure. 
Trametinib and navitoclax doses should not be crushed, chewed, or dissolved. 
5.1.1
Treatment plan for Part 1 (Phase 1b)
Dosing levels for Part1 of the study are listed below in Table 5.1 and dose escalation will 
proceed as outlined in Figure 5.1.  Agents will be dosed daily in a 28-day cycle according to the 
description outlined in Table 5.2.  A 28-day cycle has been used in previous combination studies 
with trametinib, such as the study combining trametinib and dabrafenib, summarized in section 
2.2.1.4.  Subjects will be assessed for toxicities and safety at weekly intervals during the first 28-
day cycle, at two week intervals during cycle two, and monthly thereafter.  Subjects will undergo 
radiographic assessments of tumor response every 2 cycles (8 weeks +/- 1 week).  The schema 
for dose escalation is shown below in Table 5.3, utilizing standard Phase 1 cohorts of 3 subjects 
per dose level.  The occurrence of 1 dose limiting toxicity (DLT; defined in Section 5.2) will 
prompt expansion of a given dose level to 6 subjects.  The occurrence of 2 DLTs in a given dose 
level will indicate that the maximal tolerated dose (MTD) has been exceeded, and expansion of 
the prior dose level to 6 subjects will occur, if not already performed. Patients will be replaced if 
they are not evaluable for the DLT window. The dose of each agent to be used for Part 2 (Phase 
2) of the study (the recommended Phase 2 dose (RP2D)) will be the highest dose level at which 
no more than 1 subject out of 6 experiences a DLT.  Dose escalation will proceed until the 
MTD/RP2D have been determined, or until the RP2D of each compound individually (2mg daily 
for trametinib; 325mg daily for navitoclax) is reached (represented by dose level 7).  If the MTD 
is reached before dose level 7, alternative dosing schemes will be considered by the investigators 
in which trametinib is dosed intermittently in an effort to reduce toxicity (denoted as Schedule 
C).  If necessary, the exact details of these alternative dosing schemes will be designed at a 
future date through a protocol amendment.
Table 5.1: Dosing Levels for Part 1 (Phase 1b)
Dose Escalation Levels
Dose
Dose Level
Trametinib
(mg) PO daily
Navitoclax
(mg) PO daily
Level 1 
1
150

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Version Date: July 22, 2022
40
Level 2
1.5
150
Level 3*
1.5
200
Level 4*
2
200
Level 5*
2
250
Level 6*
2
300
Level 7*
2
325
*Dose levels 3-7 will include a 7-day lead-in dosing period for navitoclax at 150 mg PO daily.
Figure 5.1:  Dose Escalation Schema for Part 1 (Phase1b)

NCI Protocol #: 9525
Version Date: July 22, 2022
41
To reduce the incidence of significant thrombocytopenia associated with navitoclax dosing, 
a 7-day lead-in dosing period will be used for dose levels in which the target dose of 
navitoclax is greater than 150 mg daily (dose levels 3-7).  Subjects will begin with 
navitoclax dosed at 150 mg PO daily and will escalate to the navitoclax dose defined in the 
cohort dose level after the 7th day of lead-in dosing if the subject’s platelet count is 
≥50,000/mm3 and the patient has no evidence of clinically significant bleeding, defined as 
grade 2 or higher hemorrhage regardless of platelet count.  If the subject’s platelet count 
on the 7th day of lead-in dosing is <50,000mm3, then the dose of navitoclax will be 
maintained at 150 mg daily for an additional 7 days.  If the platelet count is <50,000mm3 
after 14 days at the lead-in dose, then the lead-in dose will become the subject’s dose for the 
duration of the study.
Two different schedules relating to the lead-in dosing period will be evaluated during Part 1 of 
this study.  Schedule A will administer the 7-day lead-in dosing period of navitoclax as a single 
agent, prior to the initiation of trametinib dosing.  Schedule B will begin the 7-day lead-in dosing 
period of navitoclax simultaneously with the initiation of trametinib dosing.  Since potential drug 
interactions between trametinib and navitoclax are not yet defined, and since it is not yet known 

NCI Protocol #: 9525
Version Date: July 22, 2022
42
whether trametinib might potentiate the thrombocytopenia associated with navitoclax dosing, 
Schedule A (single agent lead-in) provides a potentially safer avenue for initial investigation of 
this combination.  However, since navitoclax has not exhibited convincing single agent activity
in pre-clinical models of KRAS mutant cancers (Corcoran et al., 2013), while trametinib has 
demonstrated activity in patients with KRAS mutant cancers (Infante et al, 2010; Messersmith et 
al., 2011), Schedule B may be preferable from an efficacy standpoint, as it does not delay the 
initiation of trametinib.  Therefore, it will be important to determine if any meaningful 
differences in safety and tolerability exist between Schedules A and B.  Schedule C (alternative 
dosing schedule with intermittent trametinib dosing) will be evaluated if unacceptable toxicity is 
observed during dose escalation on Schedules A or B.  Schedules A, B and C are outlined below:
Schedule A
Cycle 1 ONLY
Treatment day:
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
T
T
T
T
T
T
T
T
T
T
T
T
T
T
T
T
T
T
T
T
T
L
L
L
L
L
L
L
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
Cycle 2 and Subsequent Cycles
Treatment day:
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
T
T
T
T
T
T
T
T
T
T
T
T
T
T
T
T
T
T
T
T
T
T
T
T
T
T
T
T
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
Schedule B
Cycle 1 ONLY
Treatment day:
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
T
T
T
T
T
T
T
T
T
T
T
T
T
T
T
T
T
T
T
T
T
T
T
T
T
T
T
T
L
L
L
L
L
L
L
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N

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Version Date: July 22, 2022
43
Cycle 2 and Subsequent Cycles
Treatment day:
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
T
T
T
T
T
T
T
T
T
T
T
T
T
T
T
T
T
T
T
T
T
T
T
T
T
T
T
T
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
Schedule C
Cycle 1 ONLY
Treatment day:
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
T
T
T
T
T
T
T
T
T
T
T
T
T
T
L
L
L
L
L
L
L
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
Cycle 2 and Subsequent Cycles
Treatment day:
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
T
T
T
T
T
T
T
T
T
T
T
T
T
T
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
T = trametinib dose defined by Phase 1b dose level or RP2D
L = lead-in dose of navitoclax (150 mg daily). 
N = Navitoclax dose defined by Phase 1b dose level or RP2D.  Note: as described above, after 
7 days of navitoclax at the lead-in dose of 150 mg daily (L), dose will be escalated to the 
dose defined by the Phase 1b dose level or the RP2D (A), only if subject’s platelet count is 
≥50,000/mm3 and the patient has no evidence of clinically significant bleeding, defined as 
grade 2 or higher hemorrhage regardless of platelet count.  If the subject’s platelet count 
on the 7th day of lead-in dosing is <50,000mm3, then the dose of navitoclax will be 
maintained at 150 mg daily for an additional 7 days.  If the platelet count is <50,000mm3 
after 14 days at the lead-in dose, then the lead-in dose will become the subject’s dose for the 
duration of the study.
Evaluation of dosing Schedules A and B will be performed according to the schema in Figure 
5.1.  Since it is not yet known whether drug interactions might occur between trametinib and 

NCI Protocol #: 9525
Version Date: July 22, 2022
44
navitoclax or whether trametinib might potentiate the thrombocytopenia associated with 
navitoclax dosing, Schedule A (single agent lead-in) will be evaluated first.  Since the 
thrombocytopenia associated with navitoclax is typically most profound during the first few days 
of dosing, Schedule A represents a safer initial approach.
Dose levels 1-3 will be enrolled according to Schedule A (i.e. dosing cohorts 1A, 2A, 3A).  After 
completion of dose level 3A, if dose escalation is warranted per the criteria outlined in Table 5.3 
above, an investigator meeting will be held with NCI/CTEP and pharmaceutical collaborators to 
review safety data.  Pharmacokinetic data will be reviewed to evaluate for any evidence of drug 
interaction, and adverse event data will be reviewed to evaluate for any potentiation of toxicity 
(in particular, thrombocytopenia) by the combination.  If significant safety concerns are noted, 
dose escalation will proceed for the remainder of the study according to Schedule A (i.e. to 
dosing cohort 4A, 5A, 6A, 7A).  If no significant safety concerns are noted, and it is deemed safe 
to proceed, dosing will return to dose level 1 according to schedule B (i.e. dosing cohort 1B).  
Dose escalation will then proceed according to Schedule B to dosing cohort 3B. Since both dose 
levels 2 and 3 involve beginning with 150 mg navitoclax and 1.5 mg trametinib, it is not 
necessary to evaluate dose levels 2 and 3 both according to schedule B, as both would test the 
safety of initiating navitoclax and trametinib simultaneously at these same doses.  Therefore, 
dose escalation will proceed directly from cohort 1B to cohort 3B.  If >1 DLT is experienced 
within dosing cohort 1B or within 3B, then Schedule B will be abandoned, and dose escalation 
will proceed with dosing cohort 4A.  If dosing cohort 3B is completed with ≤1 DLT, then a 
second investigator meeting will be held with NCI/CTEP and pharmaceutical collaborators to 
review safety data.  Pharmacokinetic data will be reviewed to evaluate for any evidence of drug 
interaction, and adverse event data will be reviewed to evaluate for any potentiation of toxicity 
(in particular, thrombocytopenia) by the combination.  If the investigators and NCI/CTEP and 
pharmaceutical collaborators agree that Schedule B demonstrates a comparable or improved 
safety profile relative to Schedule A, then dose escalation will proceed according to Schedule B 
(i.e. to dosing cohort 4B, 5B, 6B, 7B) until the RP2D is determined.  However, if evidence of 
drug interaction exists, or if the investigators and NCI/CTEP and pharmaceutical collaborators 
agree that Schedule A demonstrates a superior safety profile, particularly as it relates to 
navitoclax-associated thrombocytopenia, then dosing will proceed for the remainder of the study 
according to Schedule A (i.e. to dosing cohort 4A, 5A, 6A, 7A) until the RP2D is determined.  If, 
however, unacceptable toxicity (either >1 DLT or toxicity not meeting criteria for DLT, but 
deemed to be unacceptable by investigators) is observed at a given dose level independent of 
schedule A or B, then and alternative dosing schedule (Schedule C) will be explored with 
intermittent trametinib dosing (days 1-14 only of each 28 day cycle), beginning at the last dose 
level completed. With Protocol Version 10 (dated 8/9/16), there will be no further Dose 
Escalation on Schedule A or B.

NCI Protocol #: 9525
Version Date: July 22, 2022
45
Table 5.2:  Schedule of Agent Administration
Schedule A and B:
Regimen Description
Agent
Premedications; 
Precautions
Dose
Route
Schedule
Cycle 
Length
Trametinib
Take on empty 
stomach, >1 
hour before 
meal or >2 
hours after meal
** 
tablet(s)
PO daily, >1 
hour before 
meal or >2 
hours after meal
Days 1-28
Navitoclax*
Take with food.
**  
tablet(s)
PO in the a.m. 
Days 1-28
28 days 
(4 weeks)
* For days on which subjects will undergo an on-treatment biopsy, Navitoclax should be taken 
in the a.m. with Jello at least two hours before the scheduled biopsy.
**Doses as appropriate for assigned dose level.
Schedule C:
Regimen Description
Agent
Premedications; 
Precautions
Dose
Route
Schedule
Cycle 
Length
Trametinib
Take on empty 
stomach, >1 
hour before 
meal or >2 
hours after meal
**  
tablet(s)
PO daily in the 
p.m.,
 >1 hour before 
meal or >2 
hours after meal
Days 1-14
Navitoclax*
Take with food.
**  
tablet(s)
PO in the a.m. 
Days 1-28
28 days 
(4 weeks)
* For days on which subjects will undergo an on-treatment biopsy, Navitoclax should be taken 
in the a.m. with Jello at least two hours before the scheduled biopsy.
**Doses as appropriate for assigned dose level.
Table 5.3: Dose Escalation Criteria for Part 1 (Phase 1b)
Number of Patients with DLT at a 
Given Dose Level
Escalation Decision Rule

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Version Date: July 22, 2022
46
0 out of 3
Enter 3 patients at the next dose level.
>2
Dose escalation will be stopped.  This dose level will be 
declared the maximally administered dose (highest dose 
administered).  Three (3) additional patients will be 
entered at the next lowest dose level if only 3 patients 
were treated previously at that dose.
1 out of 3
Enter at least 3 more patients at this dose level.
If 0 of these 3 patients experience DLT, proceed to 
the next dose level.
If 1 or more of this group suffer DLT, then dose 
escalation is stopped, and this dose is declared the 
maximally administered dose.  Three (3) additional 
patients will be entered at the next lowest dose level 
if only 3 patients were treated previously at that dose.
<1 out of 6 at highest dose level 
below the maximally administered 
dose
This is generally the recommended phase 2 dose. At 
least 6 patients must be entered at the recommended 
phase 2 dose.
Patients will be replaced if they are not evaluable for the DLT window.
5.1.2
Treatment Plan for Part 2 (Phase 2)
For the Phase 2 portion of the study, patients will be dosed at the RP2D defined in Part 1 of this 
study in 28-day cycles. The patient will be requested to maintain a medication diary of each dose 
of medication.  The medication diary will be returned to clinic staff at the end of each course 
(28-day cycle).  Patients will receive a 7-day lead-in dosing period of navitoclax at 150 mg PO 
daily according the Schedule (Schedule A vs. Schedule B) by which the RP2D was defined, as 
described in the previous subsection.  As in Part 1, subjects will begin with navitoclax dosed at 
150 mg PO daily and will escalate to the navitoclax dose defined in the cohort dose level after 
the 7th day of lead-in dosing if the subject’s platelet count is ≥50,000/mm3 and the patient has no 
evidence of clinically significant bleeding, defined as grade 2 or higher hemorrhage regardless of 
platelet count.  If the subject’s platelet count on the 7th day of lead-in dosing is <50,000mm3, 
then the dose of navitoclax will be maintained at 150 mg daily for an additional 7 days.  If the 
platelet count is <50,000mm3 after 14 days at the lead-in dose, then the lead-in dose will become 
the subject’s dose for the duration of the study.
In Part 2 of the study, patients with KRAS or NRAS mutation-positive advanced solid tumors 
will be enrolled into one of the following four expansion cohorts, according to tumor type:
Expansion cohort #
Description

NCI Protocol #: 9525
Version Date: July 22, 2022
47
Expansion cohort 1
KRAS or NRAS mutation-positive pancreatic cancer
Expansion cohort 2
KRAS or NRAS mutation-positive GYN cancer
Expansion cohort 3
KRAS or NRAS mutation-positive lung cancer
Expansion cohort 4
NRAS mutation-positive solid tumors of all other types
(excluding pancreatic, GYN, and lung)
Patients will be enrolled to each expansion cohort according to the schema below.  A total of 12 
patients will be enrolled in each expansion cohort.  If no objective tumor responses (partial or 
complete responses, as defined in section 11.1.4) are seen in the first 12 patients enrolled in a 
given cohort, the cohort will close.  If at least one objective tumor response is observed in a 
given cohort, an additional 13 patients (for a total of 25 patients) will be enrolled to that cohort.  
Statistical considerations are discussed in more detail in Section 13.  Patients will be assessed 
weekly for toxicity and safety during the first 28-day cycle and monthly thereafter.  Patients will 
undergo radiographic assessment of tumor response every 2 cycles (8 weeks).
Part 2 (Phase 2)
  Stage 1:
              Stage 1:   
  Stage 1:
     
           Stage 1:                
  Enroll 12
              Enroll 12
  Enroll 12
 
           Enroll 12
  Patients 
            Patients
  Patients
           Patients
   
Patients with KRAS or NRAS mutation 
positive advanced solid tumors
SCREENING
Expansion Cohort #1
Pancreatic cancer
Expansion Cohort #2
GYN Cancer
Expansion Cohort #3
Lung Cancer
Expansion Cohort #4
NRAS-mutant solid 
tumors (excluding 
pancreatic GYN, lung)
*if no responses, stop 
cohort
*if one or more 
responses, proceed to 
stage 2
*if no responses, stop 
cohort
*if one or more 
responses, proceed to 
stage 2
*if no responses, stop 
cohort
*if one or more 
responses, proceed to 
stage 2
*if no responses, stop 
cohort
*if one or more 
responses, proceed to 
stage 2

NCI Protocol #: 9525
Version Date: July 22, 2022
48
Stage 2:
              Stage 2:   
    Stage 2:
            Stage 2:                
Enroll 13
              Enroll 13
    Enroll 13     
            Enroll
Patients 
              Patients
    Patients
            Patients
      N  = 25 total
N  = 25 total      
          N  = 25 total
               N  = 25 total
5.1.3
Trametinib
The effect of food on trametinib absorption is unknown.  On PK days, the current 
recommendation is to administer trametinib on an empty stomach 1 hour (+/- 5 minutes) 
before navitoclax (which should be taken with food.) On non-PK days, the medications 
do not necessarily need to be taken in this sequence, but trametinib should always be 
taken on an empty stomach (defined at least one hour +/- 5 minutes before and/or two 
hours after food,) and navitoclax should always be taken with food. However, patients are 
encouraged to keep to the same schedule used on PK days as part of their daily 
administration, if possible. The recommendation to administer trametinib fasting may 
change based on emerging data. 
5.1.4
Navitoclax
The recommended starting dose for combination studies of navitoclax is 150 mg PO 
daily.
5.1.5
Other Agent(s)
N/A
5.1.6
Other Modalities or Procedures
N/A
5.1.7
Investigational Imaging Agent Administration
N/A
5.2
Definition of Dose-Limiting Toxicity
Dose-limiting toxicity (DLT) is based on the CTEP Active Version 4 of the NCI Common 
Terminology Criteria for Adverse Events (CTCAE). CTCAE v5.0 will be utilized beginning April 
1, 2018. DLT refers to toxicities experienced during the first 42 days of treatment. A DLT will be 
defined as follows:

Any grade 4 toxicity

NCI Protocol #: 9525
Version Date: July 22, 2022
49

Grade 3 fatigue, persistent for more than 7 days

Grade ≥ 3 nausea, diarrhea, or vomiting despite maximum supportive care and 
persisting more than 72 hours

Grade ≥ 3 neutropenia with fever > 38.5°C

Grade 3 thrombocytopenia with clinically significant bleeding. Clinically significant 
bleeding will be defined as any bleeding requiring transfusion, hospitalization, or 
medical or surgical intervention.  Clinically significant bleeding will only be 
considered a DLT if it is associated and attributable to study drug induced 
thrombocytopenia.

Ejection fraction < lower limit of normal (LLN) with an absolute decrease of >10% 
from baseline with confirming assessment within 7 days.
Management and dose modifications associated with the above adverse events are outlined in 
Section 6.
Dose escalation will proceed within each cohort according to the scheme shown in Table 5.3 
above.  Dose-limiting toxicity (DLT) is defined above. 
5.3
General Concomitant Medication and Supportive Care Guidelines
5.3.1
Trametinib 
Because there is a low potential for interaction of trametinib with other concomitantly 
administered drugs through the cytochrome P450 system, the case report form must capture the 
concurrent use of all other drugs, over-the-counter medications, or alternative therapies.  The 
Principal Investigator should be alerted if the patient is taking any agent known to affect or with 
the potential to affect selected CYP450 isoenzymes.
5.3.2
Navitoclax
Potential issues with navitoclax include drug-drug interactions and thrombocytopenia.  See the 
navitoclax supportive care guidelines (Section 6) currently included in all company-sponsored 
protocols for managing thrombocytopenia (with platelet transfusion recommendations), 
lymphopenia, and tumor lysis syndrome.
In adult monotherapy clinical studies, reductions in circulating platelet counts were observed in 
an expected, dose-dependent predictable manner, with the nadir occurring 3-5 days after the first 
dose of navitoclax followed by a subsequent recovery during ongoing dosing.  This effect is 
reversible with interruption of study drug.  Platelets recover towards baseline with continued 
dosing, but may not necessarily reach baseline levels.  Therefore, adequate platelet 
monitoring should be obtained, including after initiation of navitoclax therapy and when 
platelet counts are noted to be <50,000/mm3 (see also Section 6.2).  Attenuated lead-in dosing 
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mitigates major swings in circulating platelet counts.
Colony stimulating factors (G-CSF, GM-CSF) or human erythropoietin will be considered 
during administration of navitoclax if deemed necessary by the investigator.  
The following concomitant medications are not allowed during navitoclax administration 
due to mechanistic-based platelet toxicities from navitoclax:  Warfarin, Clopidogrel (Plavix), 
ibuprofen, tirofiban (Aggrastat), and other anticoagulants, drugs, or herbal supplements that 
affect platelet function.  Administration of heparin to keep subject's infusion lines patent is 
allowed.  Low-dose anticoagulation medications that are used to maintain the patency of a 
central intravenous catheter are allowed.
Aspirin will not be allowed within 7 days prior to the first dose of navitoclax or during
navitoclax administration.  However, subjects who have previously received aspirin therapy for 
thrombosis prevention, may resume a low dose (i.e., maximum 100 mg QD) of aspirin if platelet 
counts are stable (≥50,000/mm3) through 6 weeks of navitoclax administration.  All decisions 
regarding treatment with aspirin therapy will be determined by the investigator in conjunction 
with the medical monitor.
Disulfiram is not allowed due to potential drug interactions.
Navitoclax is a moderate inhibitor of the activity of cytochrome P450 (CYP) isoenzyme 
CYP2C8 (IC50 = 3.4 μM or 3.3 μg/mL) and is a potent inhibitor of CYP2C9 activity (IC50 = 1.0 
μM or 0.97 μg/mL).  At the expected biologically effective plasma concentration of about 3 to 5 
μM (3–5 μg/mL), navitoclax is likely to inhibit the metabolism of drugs that are substrates for 
CYP2C8 and CYP2C9.  Clinically relevant CYP2C8 substrates include paclitaxel, statins, and 
glitazones, whereas phenytoin and warfarin are substrates of CYP2C9.  Co-dosing with CYP2C8 
and CYP2C9 substrates should be undertaken with caution.
Navitoclax is metabolized in the liver by CYP3A4.  Strong CYP3A4 inducers/inhibitors are 
NOT allowed. Weak or moderate inhibitors/inducers are allowed, but should be used with 
caution. CYP3A4 inhibitors such as ketoconazole and clarithromycin are not allowed 7 days 
prior to the first dose of navitoclax or during navitoclax administration.
5.4
Duration of Therapy
In the absence of treatment delays due to adverse event(s), treatment may continue until one of 
the following criteria applies:

Disease progression,

Intercurrent illness that prevents further administration of treatment,

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
Unacceptable adverse event(s),

Patient decides to withdraw from the study, or

General or specific changes in the patient's condition render the patient unacceptable 
for further treatment in the judgment of the investigator.

The study reaches its planned stopping date, which will be 2 years after the last 
patient’s first dose of study drugs. However, in the event that a patient or patients 
have an excellent response to therapy that is ongoing at the time of this planned 
stopping date, the possibility of continuing treatment for the patient(s) in question 
will be subject to discussion.
5.5
Duration of Follow Up 
Patients will be followed until the resolution or stabilization of all study-related toxicity and for a 
minimum of 30 days after removal from study or until death, whichever occurs first.  Patients 
removed from study for unacceptable adverse event(s) will be followed until resolution or 
stabilization of the adverse event.
5.6
Criteria for Removal from Study
Patients will be removed from study when any of the criteria listed in Section 5.4 applies.  The 
reason for study removal and the date the patient was removed must be documented in the Case 
Report Form.
6. DOSING DELAYS/DOSE MODIFICATIONS
When a situation arises that requires dose interruption or discontinuation of one of the study 
drugs based on the criteria outlined below, the other study drug should be continued as indicated 
according to the protocol until the patient meets criteria for removal from study as outlined in 
Section 5.4.
6.1
Trametinib Dose Modifications
The table below outlines the dose levels to be used for any necessary trametinib dose 
modifications:
Dose Level
Trametinib Dose/Schedule
0
2 mg QD
-1
1.5 mg QD

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-2
1 mg QD
-3
0.5 mg QD
A maximum of two trametinib dose level reductions are allowed.  If a third dose level reduction 
is required, treatment will be permanently discontinued.
6.1.1
Trametinib Dose Modification for Toxicities Not Specified in Subsequent Sections
Trametinib Treatment Modification for Clinically Significant Toxicities Likely to be Related to Trametinib 
in the judgment of investigator
(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
Continue trametinib at current dose level.
Grade 2
(tolerable)
Interrupt treatment until resolution to grade 1 or baseline.  
Upon resolution, restart treatment 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
If the Grade 3 toxicity recurs, interrupt trametinib; When 
toxicity resolves to Grade 1 or baseline, restart trametinib 
reduced by another dose level
Grade 4
Monitor as clinically indicated.  
Provide supportive care 
according to institutional 
standards
Permanently discontinue trametinib.
Trametinib should be discontinued if treatment delay is >21 days due to toxicities.  If the investigator concludes 
that continued trametinib will benefit a patient, the study chair and CTEP Medical Monitor may be consulted for 
the possibility of resuming trametinib, provided that toxicities have resolved to baseline or grade 1.
* CTCAE v5.0 will be utilized beginning April 1, 2018.
6.1.2
Trametinib Dose Modification for Rash
Rash is a frequent AE observed in patients receiving trametinib (Investigator’s Brochure, 2012a).  
Recommendations for supportive care and guidelines for dose modifications for rash are based 
on experience with other MEK inhibitors and EGFR inhibitors (Balagula et al., 2010; Lacouture 
et al., 2011).
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.

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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).
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

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Trametinib Dose Modification Guidelines and Management for Rash
Rash Severity
Management Guideline
Dose Modification
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 priopionate 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.
6.1.3
Trametinib Dose Modifications for 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)).  For events of 
visual changes (regardless of severity) for which an ophthalmic examination is conducted, a blood sample 
for PK analysis must be drawn as close as possible to the time of the event.
Patients are required to have a standard ophthalmic exam performed by an ophthalmologist at baseline 
and any time patients report visual disturbance.  The exam will include best corrected visual acuity, 
tonometry slit lamp biomicroscopic examination, visual field examination, and indirect fundoscopy with 
special attention to retinal abnormalities. Optical coherence tomography is recommended at scheduled 
visits, and if retinal abnormalities are suspected. Other types of ancillary testing including color fundus 
photography and fluorescein angiography are also recommended if clinically indicated. 
Guidelines regarding management and dose reduction for visual changes and/or ophthalmic examination 
findings considered to be related to study treatment are provided in the tables below.

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Management and Dose Modification Guidelines for Visual Changes and/or Ophthalmic 
Examination Findings
CTCAE 
Gradea
Adverse Event Management
Action and Dose Modification
 
Grade 1b

Consult ophthalmologist within 7 
days of onset

If dilated fundus examination cannot be 
performed within 7 days of onset, 
interrupt trametinib 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 or 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

Interrupt trametinib 

If RPED and 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 diagnosed: Permanently 
discontinue trametinib and report as 
SAE
 
Grade 4

Consult ophthalmologist 
immediately 

Report as SAE

Interrupt trametinib 

If RPED and RVO excluded, may 
consider restarting trametinib at same or 
reduced dose after discussion with 
CTEP medical monitor 

If RVO or RPED diagnosed, 
permanently discontinue trametinib 
Abbreviations:  RPED = retinal pigment epithelial detachment; RVO= retinal vein occlusion; SAE = serious 
adverse event
a:  Refers to CTCAE Version 4.0 ‘Eye disorders – Other, specify’. CTCAE v5.0 will 
be utilized beginning April 1, 2018.

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b:  If visual changes are clearly unrelated to study treatment (e.g., allergic conjunctivitis), monitor closely but 
ophthalmic examination is not required.
Recommended dose modifications for trametinib for retinal pigment epithelial detachments 
(RPED)a
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 at lower dose (reduced by 
0.5 mg) or discontinue in patients 
taking trametinib 1 mg daily

If no recovery within 4 weeks, 
permanently discontinue trametinib.
a:  Refers to CTCAE Version 4.0 ‘Retinopathy’. CTCAE v5.0 will be utilized beginning April 1, 2018.
6.1.4
Trametinib Dose Modification for Diarrhea
Episodes of diarrhea have occurred in patients receiving trametinib (Investigator’s Brochure, 
2012a).  Other frequent causes of diarrhea may include concomitant medications (e.g., stool 
softeners, laxatives, antacids, etc.), infections by C. difficile or other pathogens, or partial bowel 
obstruction.  Those conditions should be excluded.
Guidelines regarding management and dose modification for diarrhea considered related to 
trametinib are provided in the table below.

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Management and Trametinib 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 (bananas, 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 hours:  Loperamide 
2 mg every 2 hours; maximum 16 
mg/day.  Add budesonide or other 
second-line therapies (octreotide, 
or tincture of opium) and oral 
antibiotics.
Continue trametinib.
If diarrhea is grade 2 for > 48 h, 
interrupt trametinib until diarrhea 
resolves to grade ≤1.
Restart trametinib at the same dose 
level
If treatment delay is > 21 days, 
discontinue trametinib.

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Management and Trametinib 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 until diarrhea 
resolves to ≤ grade 1.
Restart with trametinib reduced by 
one dose level.4
If 3 dose reductions of study 
treatment are clinically indicated, 
permanently discontinue 
trametinib.
If treatment delay is >21 days, 
discontinue trametinib.
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.
6.1.5
Trametinib Dose Modification for Liver Chemistry Changes
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 are 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).

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Trametinib Dose Modification for Liver Function Test Abnormalities
Event
Treatment modifications and assessment/monitoring
Criteria for discontinuing 
study drug:  When any of the 
liver stopping criteria below is 
met, discontinue trametinib 
ALT ≥3xULN and bilirubin 
≥2x ULN or >35% direct 
bilirubin 1, 2
ALT  3xULN and INR >1.5, 
if INR measured2 (INR 
threshold does not apply if 
subject is on anticoagulant)
ALT ≥5x ULN
ALT ≥3x ULN persists for 4 
weeks
ALT ≥3x ULN and cannot be 
monitored weekly for 4 weeks
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 subject until liver chemistries resolve, stabilize, or 
return to baseline (see MONITORING below).
[
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 3-6:
Repeat LFT and perform liver event follow up assessments 
within 24-72 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 
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Trametinib Dose Modification for Liver Function Test Abnormalities
Event
Treatment modifications and assessment/monitoring
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 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.  
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).
6.1.6
Trametinib Dose Modification for Pneumonitis
Pneumonitis has been observed in patients receiving trametinib.  To reduce the risk of 
pneumonitis, patients will be monitored closely for symptoms and evaluated with imaging and 
functional tests.  Dose modification and supportive care guidelines for pneumonitis are described 
in the tables below.

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Pneumonitis Guidelines for Trametinib Monotherapy
CTCAE Grade
Adverse Event Management
Action and Dose Modification
Grade 1
CT scan (high-resolution with lung windows) 
recommended.
Work-up for infection.
Monitoring of oxygenation via pulse-oximetry 
recommended.
 Consultation with pulmonologist recommended.
Continue trametinib at current dose.
Grade 2
CT scan (high-resolution with lung windows).
Work-up for infection.
Consult pulmonologist.
Pulmonary function tests:  If < normal, repeat every 8 
weeks until ≥ normal.
Bronchoscopy with biopsy and/or BAL 
recommended.
Symptomatic therapy including corticosteroids if 
clinically indicated.
Interrupt trametinib until recovery 
to grade ≤1.
If AE resolved to grade ≤1 and 
relationship to trametinib is 
equivocal, restarting trametinib 
with one dose reduction may be 
considered, after discussion with 
the medical monitor.  
If treatment delay is > 4 weeks, 
permanently discontinue 
trametinib.
Grade 3
CT scan (high-resolution with lung windows).
Work-up for infection.
Consult pulmonologist.
Pulmonary function tests-if < normal, repeat every 8 
weeks until ≥ normal.
Bronchoscopy with biopsy and/or BAL if possible.
Symptomatic therapy including corticosteroids as 
clinically indicated.
Interrupt trametinib until recovery 
to grade ≤1.
If AE resolved to grade ≤1 and 
relationship to trametinib is 
equivocal, restarting trametinib 
with one dose reduction may be 
considered, after discussion with 
the medical monitor.  
If treatment delay is >4 weeks, 
permanently discontinue 
trametinib.
Grade 4
Same as grade 3.
Permanently discontinue 
trametinib.
Abbreviations:  BAL = bronchoalveolar lavage; CT = computed tomography.
6.1.7
Trametinib Dose Modification for Reduced Left Ventricular Ejection Fraction
Decreases of the left ventricular ejection fraction (LVEF) have been observed in patients 
receiving trametinib.  Therefore, ECHOs or 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).  

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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 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 2, 4, 8 and 12 
weeks after re-start; continue in 
intervals of 12 weeks thereafter.
If LVEF does not recover within 4 
weeks:
Consult with cardiologist.
Permanently discontinue 
trametinib.
Report as SAE
Repeat ECHO after 2, 4, 8, 12, 
and 16 weeks or until resolution.
Consult with the CTEP medical 
monitor.d
Symptomaticc
Grade 3:  resting LVEF 39-20% or 
>20% absolute reduction from 
baseline
Grade 4:  Resting LVEF ≤20%.
Permanently discontinue 
trametinib.
Report as SAE.
Consult with cardiologist.
Repeat ECHO after 2, 4, 8, 12, and 
16 weeks or until resolution.
a If ECHO does not show LVEF recovery after 2 weeks, repeat ECHO 2 weeks later.
b Escalation of trametinib to previous dose level can be considered in LVEF remains stable for 4 weeks after 
restarting of trametinib.  Approval from the CTEP medical monitor is required. 
c Symptoms may include:  dyspnea, orthopenea, and other signs and symptoms of pulmonary congestion and 
edema.
6.1.8
Trametinib Dose Modification for QTc Prolongation
QTc-Prolongationa
Action and Dose Modification

QTcB ≥501 msec or

uncorrected QT>600 msec or

QTcB>530 msec for subjects with bundle 
branch block

Interrupt study treatment until QTcB prolongation 
resolves to Grade 1 or baseline

Test serum potassium, calcium, phosphorus and 
magnesium. If abnormal, correct per routine clinical 
practice to within normal limits.

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
Review concomitant medication usage for a prolonged 
QTc.

Restart at current dose levelb

If event does not resolve or recurs after restarting, 
permanently discontinue study treatment
Abbreviations:  msec = milliseconds; QTcB = QT interval on electrocardiogram corrected using the Bazett’s 
formula
a:    Based on average QTc value of triplicate ECGs.  For example, if an ECG demonstrates a prolonged QT 
interval, obtain two or more ECGs over a brief period (within one hour), 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 subject may resume study treatment if the 
investigator and CTEP medical monitor agree that the subject will benefit from further treatment.
6.1.9
Trametinib Dose Modification for Hypertension
Increases in blood pressure (BP) have been observed in patients receiving trametinib.  
Recommendations for BP monitoring and management are provided below.
Monitoring:  All BP assessments should be performed under the following optimal conditions:

The subject has been seated with back support, ensuring that legs are uncrossed and flat 
on the floor.

The subject is relaxed comfortably for at least 5 minutes.

Restrictive clothing has been removed from the cuff area, and the right cuff has been 
selected.

The subject’s arm is supported so that the middle of the cuff is at heart level.

The subject remains quiet during the measurement.

In subjects with an initial BP reading within the hypertensive range, a second reading 
should be taken at least 1 minute later, with the two readings averaged to obtain a final 
BP measurement.  The averaged value should be recorded in the eCRF.

Visits to monitor increased blood pressure can be scheduled independently from the per-
protocol visits outlined in the study calendar.  Ideally, subsequent blood pressure 
assessments should be performed within 1 week.

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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) 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 study treatment
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 the CTEP medical monitor is required.
6.2
Navitoclax Dose modifications
The table below outlines the dose levels to be used for any necessary navitoclax dose 
modifications:

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65
Dose Level
Navitoclax Dose/Schedule
6
325 mg QD
5
300 mg QD
4
250 mg QD
3
200 mg QD
2
150 mg QD
1
100 mg QD
A maximum of three navitoclax dose level reductions are allowed. If a fourth dose level dose 
reduction is required, navitoclax will be permanently discontinued. 
If navitoclax is held > 21 days, it should be discontinued.
6.2.1
Management of Thrombocytopenia
6.2.1.1
Dose Reduction and Interruption
Navitoclax accelerates apoptosis of circulating platelets, which differs from typical 
chemotherapy-induced thrombocytopenia related to myelosuppression.
All decisions regarding continued navitoclax dosing for individual subjects will be determined 
by the investigator, as appropriate.  These decisions should be guided by the following:
Additional platelet counts should be performed every other day or at the discretion of the 
investigator for a platelet count on any given day that is less than 50,000/mm3.
Administration of navitoclax will be interrupted or discontinued for any pre-dose platelet count 
<25,000/mm3.  A platelet count <25,000/mm3 should be confirmed the same day by a separate 
peripheral blood draw and sent also for a peripheral blood smear.
For any clinically significant bleeding event, defined as grade 2 or higher hemorrhage regardless 
of platelet count, navitoclax should be withheld, and:

Once the toxicity recovers to an acceptable grade level (i.e., grade 1 bleeding 
and/or platelet count is 50,000/mm3 and stable or increasing), navitoclax may be 
restarted at a reduced dose of DL –1.

If the toxicity recurs at the dose levels above, navitoclax should once again be 
interrupted.  Once the toxicity recovers to an acceptable grade level, navitoclax 
may be restarted at reduced dose of DL –2.

If the toxicity recurs at the dose levels above, navitoclax should once again be 
interrupted.  Once the toxicity recovers to an acceptable grade level, navitoclax 
may be restarted at DL –3 or stopped altogether.
After any grade 4 platelet count <25,000/mm3 is observed for the first time per month in a 

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66
subject, serial PK samples will be collected.  PK samples will be collected as soon as possible 
after the grade 4 platelet count is determined and then 24 and 48 hours after the event.
Limited human clinical data are available to understand the response to infusion of exogenous 
platelets in the presence of circulating drug levels.  Data from a single dose and a 28-day 
multiple dose, nonclinical studies in dogs demonstrate that under conditions of navitoclax plasma 
concentrations exceeding concentrations in the clinic (>10 μg/mL) and rapid platelet apoptosis, 
platelet infusions do not have a measurable effect on circulating platelet counts.  However, under 
conditions of lower navitoclax plasma concentrations (<10 μg/mL), platelet infusions do result in 
an increase in circulating platelet counts.  This response appears to be more consistent and of 
greater duration as navitoclax plasma concentrations decline.  Although the administration of 
multiple platelet transfusions may produce a sustained increase in circulating platelets, post-
transfusion platelet kinetics should be monitored when clinically indicated.
If platelet transfusions are required in response to active bleeding, dosing of navitoclax should be 
suspended.  It should be noted that platelet response with transfusions may not follow typical 
platelet kinetics of thrombocytopenia as with typical chemotherapy-induced myelosuppression.  
Procedures consistent with local institutional blood banking guidelines regarding platelet 
transfusions should be followed.
6.2.1.2
Platelet Transfusion Recommendations
If a platelet transfusion is deemed necessary, the investigator should be aware of the following:

Due to the rapid apoptotic effect of navitoclax on mature platelets, the initial 
increase in platelet counts post-transfusion(s) may be smaller and the duration of 
response may be shorter.  For this reason, the most recently collected donor 
platelets should be transfused.

A post-transfusion platelet count should be obtained within 10 to 60 minutes.

Additional transfusions may be necessary to achieve the desired platelet response.
6.2.2
Management of Lymphopenia
There is a potential for lymphopenia in this study.  Anti-infective prophylaxis should be 
implemented at the investigator's discretion, including appropriate prophylaxis for viral, fungal, 
bacterial, or Pneumocystis carinii Pneumonia (PCP) infections.  Potential for drug-drug 
interactions should be considered.  See description of excluded and cautionary medications.  
Given the potential for increased thrombocytopenia associated with many of the agents used for 
PCP prophylaxis, investigators should consult with the principal investigator prior to initiating 
PCP prophylaxis. 
6.2.3
Management of Neutropenia
Standard management practices for neutropenia should be followed.  Preliminary data analysis 
from the ongoing phase 1 studies in subjects with CLL demonstrates an apparent trend in 
decreasing baseline-normalized absolute neutrophil count (ANC) nadir with increasing doses, 

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67
Cmax, or AUC.
6.2.4
Management of Tumor Lysis Syndrome
In subjects with various tumor types, there is a potential for tumor lysis in the presence of risk 
factors such as bulky disease, elevated pre-treatment LDH levels, elevated leukocyte count, and 
dehydration.  Adequate hydration, careful monitoring of laboratory values, and use of an agent to 
reduce the uric acid level should be considered for subjects at high risk in the first 4 weeks.  For 
subjects who are at high risk during subsequent weeks, please consider the same management 
plan.
7. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  AEs will be 
collected and reported from the start of study treatment (first dose of study drug) and until the 
end of the follow up period as defined in section 5.5.  The following list of AEs (Section 7.1) and 
the characteristics of an observed AE (Section 7.2) will determine whether the event requires 
expedited reporting (via CTEP-AERS) in addition to routine reporting.  
7.1
Comprehensive Adverse Events and Potential Risks Lists (CAEPRs)
The Comprehensive Adverse Event 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.  The 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 968 patients. Below is the CAEPR for Trametinib 
dimethyl sulfoxide (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.
7.1.1
CAEPRs for CTEP IND Agents
7.1.1.1
CAEPR for Trametinib 
Comprehensive Adverse Events and Potential Risks list (CAEPR)
for

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Trametinib dimethyl sulfoxide (GSK1120212B, NSC 763093)
The Comprehensive Adverse Event 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 via CTEP-AERS (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 dimethyl 
sulfoxide (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 2.6, October 10, 20191
 Adverse Events with Possible 
 Relationship to Trametinib (GSK1120212B)
 (CTCAE 5.0 Term)
[n= 1111]
Likely (>20%)
Less Likely (<=20%)
Rare but Serious (<3%)
 Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER)
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 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)

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69
 Adverse Events with Possible 
 Relationship to Trametinib (GSK1120212B)
 (CTCAE 5.0 Term)
[n= 1111]
Likely (>20%)
Less Likely (<=20%)
Rare but Serious (<3%)
 Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER)
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)
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

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70
 Adverse Events with Possible 
 Relationship to Trametinib (GSK1120212B)
 (CTCAE 5.0 Term)
[n= 1111]
Likely (>20%)
Less Likely (<=20%)
Rare but Serious (<3%)
 Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER)
Alopecia
Alopecia (Gr 2)
Dry skin
Dry skin (Gr 2)
Nail changes
Palmar-plantar 
erythrodysesthesia syndrome
Pruritus
Pruritus (Gr 2)
Skin and subcutaneous tissue 
disorders - Other (drug reaction 
with eosinophilia and systemic 
symptoms [DRESS])
Skin and subcutaneous tissue 
disorders - Other (rash)5
 
Skin and subcutaneous 
tissue disorders - Other 
(rash)5 (Gr 3)
Stevens-Johnson syndrome6
VASCULAR DISORDERS
Hypertension
Hypertension (Gr 3)
Thromboembolic event 
(venous)
Vascular disorders - Other 
(hemorrhage)7
1This 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.
2Visual 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.  
3Generalized edema includes edema, lymphedema, and edema limbs.
4Hypersensitivity (allergic reactions) may present with symptoms such as fever, rash, increased liver 
function tests, and visual disturbances.
5Skin and subcutaneous tissue disorders - Other (rash) may include rash, rosacea, rash acneiform, 
erythematous rash, genital rash, rash macular, exfoliative rash, rash generalized, erythema, rash papular, 
seborrhoeic dermatitis, dermatitis psoriasiform, rash follicular, skin fissures, and skin chapped.
6Stevens-Johnson syndrome has been observed in patients treated with trametinib and dabrafenib 
combination.
7The 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 

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71
there is insufficient evidence to suggest that there was a reasonable possibility that Trametinib 
dimethyl sulfoxide (GSK1120212B) caused the 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; 
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; 
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 dimethyl sulfoxide (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.

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72
7.1.1.2
CAEPR for Navitoclax
Comprehensive Adverse Events and Potential Risks list (CAEPR)
for 
Navitoclax (ABT-263, NSC 750238)
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 934 patients. Below is the CAEPR for Navitoclax 
(ABT-263).
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 2.6, November 16, 20211
 Adverse Events with Possible 
 Relationship to Navitoclax (ABT-263)
 (CTCAE 5.0 Term)
[n= 934]
 Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER)
Likely (>20%)
Less Likely (<=20%)
Rare but Serious (<3%)
BLOOD AND LYMPHATIC SYSTEM DISORDERS
Febrile neutropenia
GASTROINTESTINAL DISORDERS
Diarrhea
Diarrhea (Gr 2)
Nausea
Nausea (Gr 2)
Vomiting
Vomiting (Gr 2)
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS
Fatigue
Fatigue (Gr 2)
INVESTIGATIONS
Alanine aminotransferase 
increased
Alanine aminotransferase 
increased (Gr 2)
Aspartate aminotransferase 
increased
Lymphocyte count decreased
Neutrophil count decreased
Neutrophil count decreased 
(Gr 2)
Platelet count decreased
Platelet count decreased (Gr 2)
METABOLISM AND NUTRITION DISORDERS
Anorexia
Anorexia (Gr 2)
1This table will be updated as the toxicity profile of the agent is revised.  Updates will be distributed to all 

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73
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.
2Infection may include any of the 75 infection sites under the INFECTIONS AND INFESTATIONS SOC.
3Peripheral neuropathy includes Peripheral motor neuropathy and Peripheral sensory neuropathy under 
the NERVOUS SYSTEM DISORDERS SOC.
Adverse events reported on Navitoclax (ABT-263) trials, but for which there is insufficient 
evidence to suggest that there was a reasonable possibility that Navitoclax (ABT-263) caused the 
adverse event:
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Anemia
CARDIAC DISORDERS - Cardiac arrest; Sinus bradycardia
GASTROINTESTINAL DISORDERS - Abdominal distension; Abdominal pain; Constipation; Dyspepsia; 
Enterocolitis; Flatulence; Mucositis oral; Pancreatitis
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Chills; Edema limbs; Edema 
trunk; Fever; Flu like symptoms; Malaise
HEPATOBILIARY DISORDERS - Hepatic pain
INFECTIONS AND INFESTATIONS - Infections2
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Bruising; Fall
INVESTIGATIONS - Alkaline phosphatase increased; Blood bilirubin increased; Creatinine increased; 
Electrocardiogram QT corrected interval prolonged; Hemoglobin increased; Weight gain; Weight loss; 
White blood cell decreased
METABOLISM AND NUTRITION DISORDERS - Dehydration; Hyperglycemia; Hyperkalemia; 
Hyperuricemia; Hypocalcemia; Hypokalemia; Hypomagnesemia; Hyponatremia
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthralgia; Back pain; Generalized 
muscle weakness; Muscle cramp; Myalgia; Neck pain; Pain in extremity
NERVOUS SYSTEM DISORDERS - Dizziness; Dysgeusia; Headache; Nervous system disorders - Other 
(burning sensation); Nervous system disorders - Other (neuropathy peripheral)3; Stroke; Syncope
PSYCHIATRIC DISORDERS - Anxiety; Insomnia
RENAL AND URINARY DISORDERS - Acute kidney injury
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Cough; Dyspnea; Epistaxis; 
Oropharyngeal pain
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Pruritus; Rash maculo-papular
VASCULAR DISORDERS - Hypotension
Note: Navitoclax (ABT-263) 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.
7.2
Adverse Event Characteristics 

CTCAE term (AE description) and grade:  The descriptions and grading scales 
found in the revised NCI Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.0 will be utilized until March 31, 2018 for AE reporting.  

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CTCAE version 5.0 will be utilized for AE reporting beginning April 1, 2018. All 
appropriate treatment areas should have access to a copy of the CTCAE version 5.0.  
A copy of the CTCAE version 5.0 can be downloaded from the CTEP web site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.  

For expedited reporting purposes only:  
o
AEs for the agent that are bold and italicized in the CAEPR (i.e., those listed in 
the SPEER column, Section 7.1.1) should be reported through CTEP-AERS only 
if the grade is above the grade provided in the SPEER.
o
Other AEs for the protocol that do not require expedited reporting are outlined in 
section 7.3.4.

Attribution of the AE:
o
Definite – The AE is clearly related to the study treatment.
o
Probable – The AE is likely related to the study treatment.
o
Possible – The AE may be related to the study treatment.
o
Unlikely – The AE is doubtfully related to the study treatment.
o
Unrelated – The AE is clearly NOT related to the study treatment.
7.3
Expedited Adverse Event Reporting
7.3.1
Expedited AE reporting for this study must use CTEP-AERS (Cancer Therapy 
Evaluation Program Adverse Event Reporting System), accessed via the CTEP Web site 
(http://ctep.cancer.gov).  The reporting procedures to be followed are presented in the 
“NCI Guidelines for Investigators: Adverse Event Reporting Requirements for DCTD 
(CTEP and CIP) and DCP INDs and IDEs” which can be downloaded from the CTEP 
Web site (http://ctep.cancer.gov).  These requirements are briefly outlined in the tables 
below (Section 7.3.3).
In the rare occurrence when Internet connectivity is lost, a 24-hour notification is to be 
made to CTEP by telephone at 301-897-7497.  Once Internet connectivity is restored, the 
24-hour notification phoned in must be entered electronically into CTEP-AERS by the 
original submitter at the site.
7.3.2
CTEP-AERS is programmed for automatic electronic distribution of reports to the 
following individuals:  Study Coordinator of the Lead Organization, Principal 
Investigator, and the local treating physician.  CTEP-AERS provides a copy feature for 
other e-mail recipients. 
7.3.3
Expedited Reporting Guidelines
Use the NCI protocol number and the protocol-specific patient ID assigned during trial 
registration on all reports.

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Note:  A death on study requires both routine and expedited reporting regardless of 
causality, unless as noted below.  Attribution to treatment or other cause must be 
provided.
Death due to progressive disease should be reported as Grade 5 “Disease Progression” 
in the system organ class (SOC) “General disorders and administration site conditions”.  
Evidence that the death was a manifestation of underlying disease (e.g., radiological 
changes suggesting tumor growth or progression: clinical deterioration associated with a 
disease process) should be submitted. 
Expedited Reporting Requirements for Adverse Events that Occur on Studies under an 
IND/IDE within 30 Days of the Last Administration of the Investigational 
Agent/Intervention 1, 2
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 and Grade 2 Timeframes
Grade 3-5
Timeframes
Resulting in 
Hospitalization 
≥ 24 hrs
10 Calendar Days
Not resulting in 
Hospitalization 
≥ 24 hrs
Not required
24-Hour 5 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 3, 4, and Grade 5 AEs

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Expedited 10 calendar day reports for:

Grade 2 AEs resulting in hospitalization or prolongation of hospitalization
2For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive half-lives, 
rounded UP to the nearest whole day, after the agent/intervention was last administered.  Footnote “1” above 
applies after this reporting period.
Effective Date:  May 5, 2011
7.3.4
Pregnancy, Pregnancy Loss, and Death Neonatal
NOTE:  When submitting CTEP-AERS reports for “Pregnancy”, “Pregnancy loss”, or “Neonatal 
loss”, the Pregnancy Information Form should be completed and faxed along 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.
7.3.4.1
Pregnancy
Patients who become pregnant on study risk intrauterine exposure of the fetus to 
agents which may be teratogenic.  For this reason, 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.
There is a possibility that the sperm of male patients treated on studies involving 
possible teratogenic agents may have been damaged.  For this reason, pregnancy in 
partners of men on study should also be reported and followed as described in this 
section.
Pregnancy should be followed until the outcome is known.
7.3.4.2
Pregnancy Loss
Pregnancy loss is defined in CTCAE as “Death in Utero.”
Any 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.
7.3.4.3
Death Neonatal
Neonatal death, defined in CTCAE as “A disorder characterized by cessation of 
life occurring during the first 28 days of life” that is felt by the investigator to be at 

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least possibly due to the investigational agent/intervention, should be reported 
expeditiously.
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 “Death neonatal” under the General 
disorders and administration SOC, a Grade 5 event.  If reported as such, CTEP-
AERS interprets this as a death of the patient being treated.
7.4
Routine Adverse Event Reporting
All Adverse Events must be reported in routine study data submissions.  AEs reported through 
CTEP-AERS must also be reported in routine study data submissions.
7.5
Secondary Malignancy
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/IDE 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. 
7.6
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. 
8. PHARMACEUTICAL INFORMATION

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A list of the adverse events and potential risks associated with the investigational agents 
administered in this study can be found in Section 7.1.
8.1
CTEP IND Agents
8.1.1
Trametinib dimethyl sulfoxide (GSK1120212B) (NSC 763093)
Chemical Name (IUPAC): equimolecular combination of N-(3-{3-cyclopropyl-5-[(2-fluoro-4-
iodophenyl)amino]-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-
yl}phenyl)acetamide with (methylsulfinyl)methane
Other Names:  trametinib, Mekinist, GSK1120212, JTP-74057, JTP-78296, JTP-75303
CAS Registry Number:  1187431-43-1
Classification:  MEK inhibitor
Molecular Formula:  C26H23FIN5O4 • C2H6OS
M.W.:  693.54 (dimethyl sulfoxide solvate), 615.41 (anhydrous parent)
Approximate Solubility:  Trametinib dimethyl sulfoxide is almost insoluble in water (<0.0001 
mg/mL at 25° C)
Mode of Action:  Trametinib dimethyl sulfoxide is a reversible, highly selective, allosteric 
inhibitor of mitogen-activated extracellular signal regulated kinase 1 (MEK1) and MEK2.  
Tumor cells commonly have hyperactivated extracellular signal-related kinase (ERK) pathways 
in which MEK is a critical component.  Trametinib dimethyl sulfoxide inhibits activation of 
MEK by RAF kinases and MEK kinases.
Description:  Trametinib dimethyl sulfoxide is a white to almost white powder.
How Supplied: Novartis supplies and CTEP, NCI, DCTD distributes trametinib as 0.5 mg and 2 
mg (as free base) tablets. Tablets may be provided in investigationally-labeled bottles or 
commercially-labeled bottles. 
The tablet core contains mannitol, microcrystalline cellulose, hypromellose, 
croscarmellose sodium, magnesium stearate (vegetable source), colloidal silicon dioxide 
and sodium lauryl sulfate.
The aqueous film coating consists of hypromellose, titanium dioxide, polyethylene glycol, 
iron oxide yellow (0.5 mg tablet), iron oxide red (2 mg tablet) and polysorbate 80 (2 mg 
tablet).
Each investigationally-labeled bottle contains 32 tablets with a desiccant:

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
0.5 mg tablets are yellow, modified oval, biconvex and film-coated. 

2 mg tablets are pink, round, biconvex and film-coated. 
Each commercially-labeled bottle contains 30 tablets with a desiccant:

0.5 mg tablets are yellow, modified oval, biconvex, film-coated tablets with ‘GS’ 
debossed on one face and ‘TFC’ on the opposing face. 

2 mg tablets are pink, round, biconvex, film-coated tablets with ‘GS’ debossed on one 
face and ‘HMJ’ on the opposing face. 
Storage:  Store tablets at 2°C - 8°C in the original bottle and dispense unopened bottles.  Do not 
open bottles or repackage tablets or remove desiccant. Bottles should be protected from light and 
moisture.
If a storage temperature excursion is identified, promptly return trametinib to 2°C -
8°C and quarantine the supplies.  Provide a detailed report of the excursion (including 
documentation of temperature monitoring and duration of the excursion) to 
PMBAfterHours@mail.nih.gov for determination of suitability.
Stability:  Stability studies are ongoing. Tablets are only stable for 32 days once bottle has been 
opened. If multiple bottles are dispensed to a patient in the same visit, please advise the patient to 
open only one bottle at a time.
Route of Administration:  Oral. Take by mouth on an empty stomach, either 1 hour before or 2 
hours after a meal.
Potential Drug Interactions
In vitro studies suggest that trametinib dimethyl sulfoxide is not a substrate of CYP enzymes or of 
human Pgp, BCRP, OATP1B1 or OATP1B3 transporters. 
Trametinib dimethyl sulfoxide is a weak CYP2C8 inhibitor and weak CYP3A4 inducer. Drug-
drug interactions with sensitive substrates of 2C8 and 3A4 are not anticipated. 
Availability
Trametinib dimethyl sulfoxide (GSK1120212B) is provided to the NCI under a Collaborative 
Agreement between the Pharmaceutical Collaborator and the DCTD, NCI (see Section 12.3).
8.1.2
Navitoclax (ABT-263; NSC 750238)

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Chemical Name or Amino Acid Sequence: Benzamide, 4-[4-[[2-(4-chlorophenyl)-5,5-dimethyl-
1-cyclohexen-1-yl]methyl]-1-piperazinyl]-N-[[4-[[(1R)-3-(4-morpholinyl)-1-
[(phenylthio)methyl]propyl]amino]-3-[(trifluoromethyl)sulfonyl]phenyl]sulfonyl]
Other Names: ABT-263 
Classification: BCL-2 family protein inhibitor
Molecular Formula: C47H55ClF3N5O6S3
M.W.: 974.61 g/mol
Approximate Solubility: Navitoclax free base is practically insoluble in water 
Mode of Action: Navitoclax is an orally bioavailable BCL-2 family protein inhibitor that binds 
with high affinity to multiple antiapoptotic proteins including BCL-XL, BCL-2, and BCL-W.  
Antiapoptotic BCL-2 family members are associated with tumor initiation, disease progression, and 
drug resistance, and compelling targets for oncology drug development. 
Description:  White to light pink powder.
How Supplied:  AbbVie supplies and the DCTD/NCI distributes navitoclax as 25 mg and 100 mg 
film coated tablets packaged in 28 and 30 count high-density polyethylene (HDPE) bottles, 
respectively.
Navitoclax inactive ingredients are Copovidone, Vitamin E polyethylene glycol succinate, colloidal 
silicon dioxide, croscarmellose sodium, sodium stearyl fumarate (coating, 25 mg:  iron oxide red 
or iron oxide yellow, polyvinyl alcohol, polyethylene glycol 3350, talc, titanium dioxide; and 100 
mg:  iron oxide yellow or oxide red, polyvinyl alcohol, polyethylene glycol 3350, talc, titanium 
dioxide).
Note:  Navitoclax must be dispensed in its original bottle.  If need to dispense the exact count to 
patient, removing extra tablet(s) from the original bottle is allowed. Document the extra tablet(s) 
as wasted in Oral DARF.
Note:  There will be a change of tablet color in future lots of navitoclax in the coming months.  
Previous and Current Lots
Future Lots
25 mg Tablets
Pink
Yellow
100 mg Tablets
Yellow
Pink
Storage:  Store intact bottles of navitoclax at room temperature 150 – 250C (590- 770F), protect from 
light.

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If a storage temperature excursion is identified, promptly return navitoclax 
(ABT-263) to 150 – 250C (590- 770F) and quarantine the supplies.  Provide a 
detailed report of the excursion (including documentation of temperature 
monitoring and duration of the excursion) to PMBAfterHours@mail.nih.gov 
for determination of suitability.
Stability:   Shelf life stability studies for the intact bottles of navitoclax are on-going.
Route(s) of Administration: Oral.
Method of Administration:  Take navitoclax tablets with food.
Potential Drug Interactions: 
CYP-mediated DDI: Navitoclax metabolizes via CYP3A4.  Concomitant use of strong and moderate 
CYP3A4 inhibitors/inducers should be taken with caution. Use alternative medications if possible.  
In vitro studies, navitoclax is a moderate inhibitor of CYP2C8, a strong inhibitor of CYP2C9 and a 
weak inhibitor of CYP2C19, CYP2D6 and CYP3A4 following a 300 mg QD dose. Use caution when 
navitoclax is administered with sensitive substrates of CYP2C8 and CYP2C9.  
Navitoclax is not an inducer of CYP1A2, CYP2B6, CYP2C9 and CYP3A4 and therefore is not 
expected to have any potential for DDI via CYP.  As for M13, it did not increase CYP1A2, 
CYP2B6 and CYP3A4 mRNA expression when tested at concentrations up to 30 μM.
Transporter mediated DDI:  Navitoclax and M13 (navitoclax metabolite) are inhibitors of 
OATP1B1/3, with IC50 values of 2.0 μM (navitoclax) and 20.8 μM (M13) but do not result in DDI 
based on the static model (OATP1B1/1B3, R<1.1).  Navitoclax may inhibit P-gp and BCRP at 
therapeutic doses (Igut/IC50>10).  Both navitoclax and M13 are P-gp and BCRP substrates but are not 
OATP1B1/3 substrates.
Navitoclax and M13 are not inhibitors of OCT1, OCT2, OAT1, OAT3, MATE1 or MATE2K.  
M13 is not an inhibitor of P-gp, BCRP, or BSEP in vesicles or in MDCK cells.
Plasma Protein Binding: Navitoclax was highly bound to plasma proteins across species.  
Protein binding was highest in the human and dog (99.99%) followed by the mouse, rat, and 
monkey (99.98%). For each species studied, the extent of binding was constant over the entire 
drug concentration range (10 to 500 μg/mL) and the
binding was independent of gender. The results indicate that navitoclax will be highly bound 
(99.99%)
to proteins in human plasma at concentrations expected after a therapeutic dosage (Cmax of 6.5 
μg/mL).

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Patient Care Implications:   
Women of child-bearing potential (WOCBP) and men must agree to use adequate contraception 
(hormonal or barrier method of birth control; abstinence) while on treatment with navitoclax 
(ABT-263) and at up to 30 days after the last dose of navitoclax (ABT-263). Male study subjects 
who are sexually active with a WOCBP (woman of child-bearing potential), even if the male 
subject has undergone a successful vasectomy, must agree to use condoms while on treatment 
and through at least 90 days after the last dose of study drug.
It is unknown whether navitoclax is excreted in human milk; thus, breastfeeding is not allowed.
8.1.3
Agent Ordering and Agent Accountability
8.1.3.1
NCI-supplied agents may be requested eligible participating Investigators (or their 
authorized designee) at each participating institution. The CTEP-assigned protocol 
number must be used for ordering all CTEP-supplied investigational agents. The 
eligible participating investigators at each participating institution must be registered 
with CTEP, DCTD through an annual submission of FDA form 1572 (Statement of 
Investigator), NCI Biosketch, Agenda Shipment Form, and Financial Disclosure 
Form (FDF)
Submit agent request through the PMB Online Agent Ordering Processing (OAOP)
application (https://ctepcore.nci.nih.gov/OAOP).  Access to OAOP requires the 
establishment of a CTEP Identity and Access Management (IAM) 
(https://ctepcore.nci.nih.gov/iam) account and the maintenance of an “active” account 
status, a “current” password, and active person registration status.  For questions 
about drug orders, transfers, returns, or accountability, call (240-276-6575) or email 
PMB (PMBAfterHours@mail.nih.gov) any time.  Refer to the PMB’s website for 
specific policies and guidelines related to agent management.”  
8.1.3.2
Agent Inventory Records – The investigator, or a responsible party designated by the 
investigator, must maintain a careful record of the inventory and disposition of all 
agents received from DCTD using the NCI Drug Accountability Record Form 
(DARF).  (See the NCI Investigator’s Handbook for Procedures for Drug 
Accountability and Storage.
8.1.3.3
Brochure Availability – The current versions of the IBs for PMB-supplied agents will 
be accessible to site investigators and research staff through the PMB Online Agent 
Order Processing (OAOP) application.  Access to OAOP requires the establishment 
of a CTEP Identity and Access Management (IAM) account and the maintenance of 
an “active” account status and a “current” password, and active person registration 
status.  Questions about IB access may be directed to the PMB IB coordinator at: 
IBCoordinator@mail.nih.gov

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8.2
Other Investigational Agent(s)
N/A 
8.3
Commercial Agent(s)
N/A
9. BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES
9.1
Biomarker Studies and Patient Tumor Biopsies
9.1.1
Validation of KRAS and NRAS mutations
9.1.1.1
Rationale
To ensure the validity and accuracy of KRAS or NRAS mutations in patients enrolled in this 
study, KRAS and NRAS genotyping will be confirmed centrally at a single institution 
(Massachusetts General Hospital) using a standardized CLIA-approved clinical genotyping 
platform.  For those patients whose KRAS or NRAS status was not determined initially by this 
platform, KRAS or NRAS mutation will be confirmed retrospectively using this standardized 
assay provided that tissue is available for analysis.  However, patients will be allowed to enroll in 
the study prior to retrospective validation, provided they have a documented KRAS or NRAS 
mutation as determined by a CLIA-approved assay.
9.1.1.2
Procedures and Analysis
KRAS or NRAS mutational status will be confirmed using the CLIA-approved standard clinical 
genotyping platform used for routine clinical care at the Massachusetts General Hospital, the 
SNaPshot assay (Dias-Santagata et al, 2010).  SNaPshot assay will be performed in the 
Molecular Pathology Laboratory at the Massachusetts General Hospital Cancer Center.
9.1.2
Pharmacodynamic analyses in paired pre-treatment and on-treatment tumor biopsies.
9.1.2.1
Rationale
This study will incorporate ancillary/exploratory pharmacodynamic analyses to evaluate the 
effects of trametinib and navitoclax given in combination on key cellular signaling pathways and 
on the induction of apoptosis and inhibition of tumor cell proliferation. Paired pre-treatment and 
on treatment (day 22 +/- 7 days) core biopsies will be obtained from all patients in the Phase 1b 

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schedule A portion of the trial, (day 15 +/- 7 days) in the schedule B or C portion, and the first 15 
patients enrolled on the Phase 2 portion of the trial (minimum of 4 patients from each of cohorts 
1, 2 and 3 will be biopsied), if these patients have lesions that can be safely biopsied without 
unacceptable risk or discomfort to the patient.  Biopsies from patients in the Phase 1b portion of 
the trial will provide an evaluation of the effects of each cohort’s dose level on signaling 
pathway inhibition, inhibition of tumor cell proliferation, and induction of tumor cell death.  This 
will provide an important metric as to the extent of target inhibition at each given dose level.  
Paired biopsies obtained from the first 15 patients enrolled in the Phase 2 portion of the trial 
(minimum of 4 patients from each of cohorts 1, 2 and 3 will be biopsied) will provide a more 
detailed assessment of the pharmacodynamic effects of therapy at the RP2D and will offer the 
potential to correlate pharmacodynamic effects with tumor response and patient outcome.
Previous studies incorporating pharmacodynamic analyses of targeted agents (including MEK 
inhibitors) given in combination have shown that the degree of target and/or pathway inhibition 
achieved at doses of targeted agents reachable when given in combination (which are often less 
than the doses achievable when given as single agents, due to additive toxicity) can be 
incomplete, and thus inadequate to promote efficacy (Speranza et al., 2012).  Thus, it will be 
critical to understand the degree of target and/or pathway inhibition achieved at a given dose 
level of the combination and at the RP2D, as this may have important implications on the 
efficacy observed.
9.1.2.2
Procedures and analysis
Given the potential effects of navitoclax on platelets and bleeding risk, platelet count and 
coagulation studies (INR, PTT) will be checked on the same day prior to any research 
biopsies performed while patient is taking study drugs.  A platelet count of >50,000/m3 and 
an INR and PTT in the normal/acceptable range according to institutional guidelines will 
be required for a patient to undergo tumor biopsy.
Pre-treatment biopsies will be obtained between days -21 and -1 of treatment.  When possible, it 
is preferred, but not required, that the pre-treatment biopsy be performed between days -7 and -1 
of treatment in order to most accurately represent the baseline signaling activity prior to 
treatment.  On-treatment biopsies will be obtained after ~2 weeks of combination dosing (day 22 
+/- 7 days for Schedule A dosing, day 15 +/- 7 days for Schedule B or C dosing).  Core biopsies 
of the same tumor lesion will be obtained at each time point.  A minimum of one core will be 
formalin-fixed and paraffin-embedded, and a minimum of one core will be flash frozen.  Both 
formalin-fixed paraffin-embedded and flash frozen tissue will be stored in the pathology 
department at the Massachusetts General Hospital.
Paired biopsies will be used to assess the pharmacodynamic response to therapy in patients 
treated with trametinib and navitoclax.  Markers to be assessed will include proteins or mRNAs 
involved in MAPK or BCL2 family signaling (e.g. phospho-ERK, phospho-S6, or MAPK 
phosphatases such as DUSP6/MKP1) to evaluate pathway inhibition, markers of tumor cell 
proliferation (e.g. Ki67), and markers of apoptosis and cell death (e.g. Cleaved caspase-3).  

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These ancillary/exploratory analyses will be conducted in the Massachusetts General Hospital 
Molecular Pathology Biomarker Laboratory. For each patient, the change in marker level 
between the pre-treatment and on-treatment biopsies will indicate the effects of treatment on 
each marker. Results will be reported as a % increase or decrease in level of a given marker after 
treatment initiation (on-treatment biopsy) relative to before treatment (pre-treatment biopsy).
9.1.2.3
Potential risks to patients
The research biopsies performed on this study do carry a low risk of procedure-related 
complications.  To minimize these risks, biopsies will be performed by personnel who are 
highly-trained and experienced with these procedures (procedures will typically be performed by 
interventional radiology).  In addition, the choice of biopsy site will be based on determination of 
sites that will have the lowest risk of complication based on sites of disease for the individual 
patient.  Adequate measures will be performed to monitor patients undergoing biopsies.  All 
potential risks associated with these research-purpose biopsies will be discussed verbally and in 
writing with the patient during the informed consent process upon study enrollment by the study 
team, and again prior to the procedure by the provider performing the biopsy (typically 
interventional radiology).  Patients will have the choice not to participate in this study if they do 
not wish to undergo research-related biopsies.  Biopsies will only be performed in a given patient 
if they are not deemed to involve unacceptable risk based on the sites of disease and other 
concurrent medical conditions.  Given the potential for thrombocytopenia associated with 
navitoclax, biopsies will only be performed if platelet count is >50,000cells/mm3 and stable 
and coagulation studies (PT/INR and PTT) are in acceptable range, in accordance to 
institutional guidelines.
9.1.3
Identification of potential predictive biomarkers in pre-treatment tumor tissue
9.1.3.1
Rationale
Given the molecular heterogeneity of KRAS and NRAS mutant cancers, no single therapeutic 
regimen is expected to be effective in all patients.  Therefore, molecular characterization of 
archived or pre-treatment tumor biopsy tissue for each patient enrolled on this trial will provide a 
critical opportunity to identify valuable biomarkers to predict which patients are more or less 
likely to respond to treatment.  Initially, these analyses will be exploratory and hypothesis-
generating in nature, but promising biomarker candidates identified in this study can potentially 
be assessed in future clinical studies evaluating this therapeutic regimen.
Initial laboratory studies evaluating the combination of BCL-XL and MEK inhibition in KRAS 
mutant cancer cell lines have identified potential biomarkers of sensitivity.  For example, our 
initial studies (Corcoran et al., 2013) have suggested that KRAS mutant cancers that express 
markers of epithelial differentiation (e.g. E-cadherin) are more likely to respond to this therapy 
than cancers expressing markers of mesenchymal differentiation (e.g. vimentin).  Thus, E-
cadherin and vimentin levels will be assessed by immunohistochemistry in pre-treatment tumor 
tissues of all patients enrolled on this study and correlated with clinical outcome.  Our initial 

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work has shown that E-cadherin and vimentin can be readily assessed in formalin-fixed paraffin-
embedded tissue from KRAS mutant cancer patients (Corcoran et al, 2013).
9.1.3.2
Procedures and analysis
Pre-treatment tumor tissue for analysis will be obtained either from archival tissue remaining 
from a patients’ prior surgery, diagnostic biopsy, or other procedure performed during routine 
clinical care.  These archival tissue blocks will be obtained from the pathology departments of 
the Massachusetts General Hospital or Dana Farber Cancer Institute, or will be provided by the 
pathology department of the institution at which the procedure was performed.  Alternatively, 
tissue derived from the study-related pre-treatment biopsy may also be used for this purpose if 
necessary. At least 20 unstained slides should be obtained. If a patient is having a tumor biopsy, 
less than 20 are acceptable with PI approval. 
9.1.3.3
Mutational analysis
In depth, mutational analysis will be performed using a 1000 gene next-generation sequencing 
platform employed as part of standard oncology care at the Massachusetts General Hospital 
Cancer Center.  Mutations in these 1000 cancer-related genes that might affect the likelihood of a 
patient’s tumor to respond to therapy will be correlated with clinical outcome.  In addition, 
further in-depth genomic analyses, including copy number analysis, may be performed on 
selected specimens.
9.1.3.4
Protein and RNA biomarkers
Selected protein and RNA biomarkers identified in previous (and future) laboratory studies will 
be analyzed in pre-treatment tissues.  Based on initial laboratory studies (Corcoran et al, 2013) 
discussed above, E-cadherin and vimentin protein levels will be assessed by 
immunohistochemistry in formalin-fixed paraffin-embedded tissues.  These analyses will be 
performed using established clinical testing assays by the Clinical Pathology Laboratory at the 
Massachusetts General Hospital.  Analysis of additional protein and RNA biomarkers, such as 
baseline levels of BIM, BCL-XL, MCL1, and other apoptotic proteins, will also be performed.
9.1.3.5
Potential risks to patients
The majority of these analyses will involve archival tissue previously obtained through clinical 
procedures performed as part of routine clinical care.  As such, no additional risks will be posed 
for patients.  In the situation where no archival tissue exists, or if archival tissue is not suitable 
for analysis (e.g. does not contain tumor tissue), then tissue for analysis will be obtained from the 
protocol related pre-treatment biopsy outlined above in Section 9.1.1.  The risks associated with 
these biopsies are outlined in Section 9.1.1.  However, since patients will already be undergoing 
these biopsies as part of the research study plan, no additional risk will be posed by utilizing the 
tissue that is collected for these analyses. 

NCI Protocol #: 9525
Version Date: July 22, 2022
87
9.1.4
Blood collection for cell-free circulating tumor DNA (cfDNA) analysis
9.1.4.1
Rationale
cfDNA analysis represents an increasingly important and noninvasive means of assessing 
mutations in tumor-derived DNA shed into the bloodstream by tumor cells throughout the 
patient’s body.  cfDNA analysis can provide a highly specific means of monitoring tumor burden 
by tracking the abundance of tumor-derived DNA mutations in the blood throughout treatment.  
Sequencing of cfDNA can also provide a non-invasive means of performing targeted or 
comprehensive tumor mutational analysis without the need for a biopsy.
9.1.4.2
Procedures and analyses
20 mL of peripheral blood will be collected in two 10 mL Streck cfDNA tubes at each of the 
timepoints outlined in the study calendar, including pre-treatment, at various intervals during 
treatment and at disease progression.  Streck tubes containing whole blood can be shipped at 
room temperature (within 5 days of draw) to:
Corcoran Laboratory
Massachusetts General Hospital Cancer Center
149 13th St, Room 7330
Charlestown, MA 02129
Cell free plasma will be isolated through two serial centrifugations steps, and plasma and blood 
cell pellet will be aliquoted and frozen.  cfDNA will be isolated from 5 mL using a QIAGEN 
cfDNA kit and will be analyzed by droplet digital PCR (ddPCR) using probes specific to the 
particular KRAS or NRAS mutation present in each patient’s tumor.  Serial measurement of 
KRAS or NRAS mutational abundance in cfDNA throughout treatment will provide a non-
invasive and personalized means of monitoring tumor burden, and the change in mutation levels 
in cfDNA will be correlated with radiographic response.  In select patients of interest, such as 
patients who respond to therapy, but ultimately progress, cfDNA  derived from pre-treatment and 
post-progression plasma may be analyzed by next-generation sequencing methods to identify 
potential mechanisms of acquired resistance.
9.1.4.3
Risks to patients
All blood for cfDNA analysis will be drawn at the time of routine lab draws for other study-
associated blood draws, and thus will not pose significant additional risk to the patient. 
9.2
Investigational Device Information
N/A

NCI Protocol #: 9525
Version Date: July 22, 2022
88
9.3
Laboratory Correlative Studies
9.3.1.1
Pharmacokinetic Studies of navitoclax and trametinib dosed in combination
While the pharmacokinetics (PK) of trametinib and navitoclax given as single agents is well-
understood, this study will evaluate the pharmacokinetics of these agents when given in 
combination.  These studies will be used to determine whether trametinib and navitoclax interact 
from a pharmacokinetic standpoint, and will be used to determine the plasma drug exposures 
achievable at a particular combination dose level and at the maximally-tolerated dose and RP2D.  
The pharmacokinetics and plasma drug levels achieved during combination dosing will have key 
implications on the potential for efficacy at a given dose level.
During Part 1 (the Phase 1b portion) of the study, subjects will have blood drawn pre-dose (0h), 
and 2h, 4h, 6h, 8h, and 23h after dosing of navitoclax on (1) day 7 of a 7-day navitoclax single-
agent lead-in dosing period and (2) again after 14 days of combination dosing.  The exact timing 
of PK blood draws will thus vary depending on whether navitoclax is being given as a single-
agent and whether a subject is following dosing schedule A or B/C (as defined in Section 5.1).  
The exact timing of PK draws are outlined in table format in section 9.3.1.2 below.  Subjects will 
also have PK blood samples drawn pre-dose on day 1 of cycles 2, 4, 8, and 12.
During Part 2 (the Phase 2 portion) of the study, subjects will have PK blood samples drawn pre-
dose on day 1 of cycles 2, 4, 8, and 12.  The exact timing of PK draws are outlined in table 
format in section 9.3.1.2 below. 
PK blood samples will be analyzed by AbbVie (for navitoclax) and GSK (for trametinib) 
according to established procedures, and assessed for the endpoints described in Sections 2.5.1 
and 13.4.1.1.
9.3.1.2
Collection of Specimens
PK blood specimens will be drawn according to the schedules below, which vary depending on 
which study part—Part 1 (Phase 1b) vs. Part 2 (Phase 2)—and which dosing schedule—Schedule 
A vs. B—to which a given subject has been enrolled.
For the purposes of these dosing schedules:
(1) All blood draw times are relative to administration of navitoclax (0h = pre-dose for 
navitoclax).
(2) On PK days, trametinib is to be dosed in the morning on empty stomach ONE HOUR 
(+/- 5 minutes) before navitoclax dose is administered with food.  Thus, when a patient is 
receiving both drugs, an additional trametinib pre-dose (-1h) PK sample will be drawn.
(3) On non-PK days, the medications do not necessarily need to be taken in this sequence, 
but trametinib should always be taken on an empty stomach (defined as at least one hour 
+/- 5 minutes before and/or two hours after food,) and navitoclax should always be taken 
with food. However, patients are encouraged to keep to the same schedule used on PK 

NCI Protocol #: 9525
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89
days as part of their daily administration, if possible. 
Procedures for sample collection are outlined in detail in APPENDIX C.
9.3.1.2.1 Schedule for PK sample collection for Part 1 (Phase 1b) Schedule A
Cycle (C), day (D)
Timing of PK sample blood draws
PK for
C1, D7*
Pre-dose (0h **,) 2h (+/-5 min,) 4h (+/- 
5min,) 6h (+/- 5 min,) 8h (+/-24 min)
 Navitoclax only
C1, D8*
Pre-dose trametinib (will represent 23h 
post dose navitoclax from prior day, +/-1 
hr)
Navitoclax only
C1, D21#
Pre-dose trametinib** (-1h), pre-dose 
navitoclax (0h**,) 2h (+/-5min,) 4h (+/-
5min,) 6h (+/-5min,) 8h (+/-24 min)
Navitoclax and 
trametinib
C1, D22#
Pre-dose trametinib** (-1h)
(will represent 23 h post-dose navitoclax 
from prior day, +/-1hr)
Navitoclax and 
trametinib
C2, D1
Pre-dose trametinib** (single trough 
level)
Navitoclax and 
trametinib
C4, D1
Pre-dose trametinib** (single trough 
level)
Navitoclax and 
trametinib
C8, D1
Pre-dose trametinib** (single trough 
level)
Navitoclax and 
trametinib
C12, D1
Pre-dose trametinib** (single trough 
level)
Navitoclax and 
trametinib
* Navitoclax dosed as single-agent for 7-day lead-in under Schedule A.  Thus, these PK 
assessments will be for navitoclax only.  All other PK assessments will be for navitoclax and 
trametinib.
# Represents 14th day of trametinib dosing under Schedule A
** Pre- dose samples should be drawn within 5 minutes of dosing
9.3.1.2.2 Schedule for PK sample collection for Part 1 (Phase 1b) Schedule B
Cycle (C), day (D)
Timing of PK sample blood draws
PK for
C1, D7
Pre-dose trametinib (-1h)**, pre-dose 
navitoclax (0h)**, 2h (+/-5 min,) 4h 
(+/-5min,) 6h (+/-5 min,) 8h (+/-24 
min)
Navitoclax and 
trametinib
C1, D8
Pre-dose trametinib – (will represent 
23h post-dose navitoclax from prior 
day, +/- 1 hr)
Navitoclax and 
trametinib

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Version Date: July 22, 2022
90
C1, D14#
Pre-dose trametinib (-1h)**, pre-dose 
navitoclax (0h)**, 2h (+/- 5 min,) 4h 
(+/-5 min,) 6h (+/- 5 min,) 8h (+/- 24 
min)
Navitoclax and 
trametinib
C1, D15#
Pre-dose trametinib (-1h)
(will represent 23h post-dose navitoclax 
from prior day, +/- 1 hr)
 Navitoclax and 
trametinib
C2, D1
Pre-dose trametinib** (single trough 
level)
Navitoclax and 
trametinib
C4, D1
Pre-dose trametinib** (single trough 
level)
Navitoclax and 
trametinib
C8, D1
Pre-dose trametinib** (single trough 
level) 
Navitoclax and 
trametinib
C12, D1
Pre-dose trametinib** (single trough 
level)
Navitoclax and 
trametinib
** Pre- dose samples should be drawn within 5 minutes of dosing
# Represents 14th day of trametinib dosing under Schedule B
9.3.1.2.3
Schedule for PK sample collection for Part 1 (Phase 1b) Schedule C
Cycle (C), day (D)
Timing of PK sample blood draws
PK for
C1, D7
Pre-dose navitoclax (0h), 2h (+/-5 min,) 
4h (+/-5min,) 6h (+/-5 min,) 8h (+/-24 
min)
Navitoclax and 
trametinib
C1, D8
Pre-dose navitoclax (0h), (will represent 
24h post-dose from prior day)
Navitoclax and 
trametinib
C1, D14#
Pre-dose navitoclax (0h), 2h (+/- 5 
min,) 4h (+/-5 min,) 6h (+/- 5 min,) 8h 
(+/- 24 min)
Navitoclax and 
trametinib
C1, D15#
Pre-dose navitoclax (0h)
(will represent 23h post-dose navitoclax 
from prior day, +/- 1 hr)
 Navitoclax and 
trametinib
C2, D1
Pre-dose navitoclax (single trough 
level)
Navitoclax and 
trametinib
C4, D1
Pre-dose navitoclax (single trough 
level)
Navitoclax and 
trametinib
C8, D1
Pre-dose navitoclax (single trough 
level)
Navitoclax and 
trametinib
C12, D1
Pre-dose navitoclax (single trough 
level)
Navitoclax and 
trametinib

NCI Protocol #: 9525
Version Date: July 22, 2022
91
# Represents 14th day of trametinib dosing under Schedule C
Trametinib dosing is always in the evenings. Timing is not adjusted on PK days
9.3.1.2.4 Schedule for PK sample collection for Part 2 (Phase 2)
Cycle (C), day (D)
Timing of PK sample blood draws
PK for
C2, D1
Pre-dose trametinib
Navitoclax and trametinib
C4, D1
Pre-dose trametinib
Navitoclax and trametinib
C8, D1
Pre-dose trametinib
Navitoclax and trametinib
C12, D1
Pre-dose trametinib
Navitoclax and trametinib
9.3.1.3
Handling of Specimens
Procedures for specimen handling and processing are defined in APPENDIX C.
9.3.1.4
Shipping of Specimens
Procedures for specimen shipping are defined in APPENDIX C.
9.3.1.5
Sites Performing Correlative Study
Analysis of PK samples will be performed by AbbVie (for navitoclax) and GSK (for trametinib) 
according to established procedures, and assessed for the endpoints described in Sections 2.5.1 
and 13.4.1.1.  Results will be reported to investigators, and data analysis will be performed at 
DF/HCC in cooperation with AbbVie and GSK.
9.4
Special Studies
N/A
10. STUDY CALENDAR
Baseline evaluations are to be conducted within 2 weeks prior to start of protocol therapy.  Scans 
and x-rays, Echocardiogram or MUGA, and ophthalmic examination must be done <4 weeks 
prior to the start of therapy.  In the event that the patient’s condition is deteriorating, laboratory 
evaluations should be repeated within 48 hours prior to initiation of the next cycle of therapy. All 
study visits have a +/- 3 day window after Cycle 2, Day 1. 
Labs obtained on C1, D1 must re-meet eligibility criteria.   

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Version Date: July 22, 2022
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Part 1 (Phase 1b) Schedule A
Pre-
Study
C1D1
C1D7
C1D8
C1D15
C1D21
C1D22
C2D1
C2D15
C3D1, 
C4D1, 
etc..
Off 
Studyq
Trametinib
T
T
T
T
T
T
T
Navitoclax
L
L
N
N
N
N
N
N
 N
Informed consent a
X
 
Demographics
X
Medical history
X
Concurrent meds
X
X---------------------------------------------------------------------------------------------X
Physical exam b
X
X
X
X
X
X
X
X
X
Vital signs c
X
X
X
X
X
X
X
X
X
X
X
Height
X
Weight
X
X
X
X
X
X
X
X
X
Performance status
X
X
X
X
X
X
X
X
X
CBC w/diff, plts
X
X
X
X
X
X
X
X
X
Serum chemistryd
X
X
X
X
X
X
X
X
X
PT/PTT
X
X
X
X
X
X
Tumor Markers e
X
X
X
X
Urinalysis
X
EKG f
X
X
X
X
X
X
X
Echocardiogram or 
MUGA
X
Repeat on C1D28 (up to 5 days prior or on C2D1.) Thereafter, repeat every 12 weeks (use 
same methodology for baseline and follow up). g
Ophthalmology exam
X
Repeated as needed only if patient experiences vision changes
Adverse event evaluation
X---------------------------------------------------------------------------------------------X
X
Radiologic 
evaluation/Tumor 
measurements
X
Radiologic measurements (by CT or MRI) should be performed every 8 weeks following 
Cycle 1 Day 1. Tumor measurements are repeated every 8 weeks.  Documentation 
(radiologic) must be provided for patients removed from study for progressive disease. h
X
B-HCG i
X

NCI Protocol #: 9525
Version Date: July 22, 2022
93
Tumor biopsy
Xj
Xk
PK blood drawl
Xm
Xm
Xn
Xn
Xo
Xl
Archival Tissue
Xp
T:
Trametinib. Dose as assigned; dose first in morning on empty stomach, at least 1 hour before food (there are no hematologic paramaters 
that must be met to continue dosing with trametinib at the beginning of each cycle.)
N:
Navitoclax. Dose as assigned; dose second in morning with food, at least 1 hour after trametinib
L:      Lead-in dose of navitoclax.  150 mg daily in morning for 7 days, dosed as above.
a:        Informed consent can be signed within 28 days of C1D1. 
b:       Complete physical exam required pre-study and on Day 1 of each cycle, including head, eye, ear, nose, throat (HEENT,) cardiovascular, 
dermatological, musculoskeletal, respiratory, gastrointestinal, and neurological systems. Limited or symptom directed physical exam at 
the discretion of the investigator is sufficient at all other visits.
c:       Vitals should include blood pressure, heart rate, respiratory rate, oxygen saturation, and temperature. 
d:       Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, LDH, phosphorus, potassium, 
total protein, SGOT [AST], SGPT [ALT], sodium.
e:      Disease-specific tumor markers as appropriate (e.g. CEA, CA-19-9, CA125) should be drawn at specified times provided the patient has 
elevation of that specific tumor maker prior to study enrollment. Colorectal: CEA; Pancreatic: CEA and CA-19-9; Lung: CEA; Any other 
tumor types: PI with treating MD can advise which tumor markers are appropriate to follow.  
f:       EKGs should be done pre-dose at all required time points. 
g:      ECHO or MUGA to be performed at screening and again on C1D28 (acceptable window C1D23-D29.) Thereafter, exam should be 
repeated every 12 weeks (+/-1 week.) The same modality used during screening should be used for all follow up exams. 
h:      Tumor measurements and radiologic evaluation should occur every 8 weeks +/- 1 week. If a patient is on a dose hold, scans should be 
kept on original schedule and should not be shifted. Patients that have scans which reveal disease progression do not need to repeat end of 
treatment scans. 
i:       Serum pregnancy test (women of childbearing potential) must be done within 7 days of C1D1. 
j:       Pre-study tumor biopsy to occur between days -21 and day-1. When possible, it is preferred, but not required, that the pre-treatment 
biopsy be performed between days -7 and -1 of treatment in order to most accurately represent the baseline signaling activity prior to 
treatment. Platelet count and PT/PTT must be checked prior to procedure according to institutional guidelines, and must be in acceptable 
range as defined in section 9.1.1.2.
k:      On treatment biopsy to occur ~2 weeks after trametinib dosing on C1D22 (+/- 7 days.) Platelet count and PT/PTT must be checked prior 
to procedure on the same day, and must be in acceptable range as defined in section 9.1.1.2.
l:       Complete PK schedule detailed in Section 9.3. Additional PK samples (single trough measurements only) required on day 1 of cycles 4, 8, 
and 12, not represented on this calendar. 
m:     Includes pre-dose (0h), 2h, 4h, 6h, 8h draws on C1D7 and 23h draw (pre-dose) on C1D8. See section 9.3 for details. 
n:      Includes pre- trametinib (-1h), pre navitoclax (0h), and 2h, 4h, 6h, 8h post navitoclax draws on C1D21 and 23h draw (pre- trametinib) on 
C1D22. See section 9.3 for details. 
o:      Single pre-dose (pre- trametinib and navitoclax) trough on C2D1. See Section 9.3 for details. 
p:      At least 20 unstained slides are required. If a patient is having a tumor biopsy, less than 20 is acceptable with PI approval. 
q:      Off study procedures should be performed within 14 days of last dose. Patients will be followed until the resolution or stabilization of all 
study-related toxicity and for a minimum of 30 days after removal from study or until death, whichever occurs first.  Patients removed 
from study for unacceptable adverse event(s) will be followed until resolution or stabilization of the adverse event.

NCI Protocol #: 9525
Version Date: July 22, 2022
94
Part 1 (Phase 1b) Schedule B
Pre-
Study
C1D1
C1D7
C1D8
C1D14
C1D15
C1D22
C2D1
C2D15
C3D1, 
C4D1, 
etc..
Off 
Studyq
Trametinib
T
T
T
T
T
T
T
T
T
Navitoclax
L
L
N
N
N
N
N
N
N
Informed consent a
X
 
Demographics
X
Medical history
X
Concurrent meds
X
X---------------------------------------------------------------------------------------------X
Physical exam b
X
X
X
X
X
X
X
X
X
Vital signs c
X
X
X
X
X
X
X
X
X
X
X
Height
X
Weight
X
X
X
X
X
X
X
X
X
Performance status
X
X
X
X
X
X
X
X
X
CBC w/diff, plts
X
X
X
X
X
X
X
X
X
Serum chemistry d
X
X
X
X
X
X
X
X
X
PT/PTT
X
X
X
X
X
X
X
Tumor Markers e
X
X
X
X
Urinalysis
X
EKG f
X
X
X
X
X
X
X
Echocardiogram or MUGA
X
Repeat on C1D28 (up to 5 days prior or on C2D1.) Thereafter, repeat every 12 weeks (use 
same methodology for baseline and follow up). g
Ophthalmology exam
X
Repeated as needed only if patient experiences vision changes
Adverse event evaluation
X---------------------------------------------------------------------------------------------X
X
Radiologic evaluations/ 
Tumor measurements
X
Radiologic measurements (by CT or MRI) should be performed every 8 weeks following 
Cycle 1 Day 1. Tumor measurements are repeated every 8 weeks.  Documentation 
(radiologic) must be provided for patients removed from study for progressive disease. h
X

NCI Protocol #: 9525
Version Date: July 22, 2022
95
B-HCG
Xi
Tumor biopsy
Xj
Xk
PK blood drawl
Xm
Xm
  Xn
Xn
Xo
Xl
Archival Tissue
Xp
T:
Trametinib. Dose as assigned; dose first in morning on empty stomach, at least 1 hour before food (there are no hematologic paramaters that 
must be met to continue dosing with trametinib at the beginning of each cycle.)
N:
Navitoclax. Dose as assigned; dose second in morning with food, at least 1 hour after trametinib
L:      Lead-in dose of navitoclax.  150 mg daily in morning for 7 days, dosed as above.
a:        Informed consent can be signed within 28 days of C1D1. 
b:       Complete physical exam required pre-study and on Day 1 of each cycle, including head, eye, ear, nose, throat (HEENT,) cardiovascular, 
dermatological, musculoskeletal, respiratory, gastrointestinal, and neurological systems. Limited or symptom directed physical exam at the 
discretion of the investigator is sufficient at all other visits.
c:       Vitals should include blood pressure, heart rate, respiratory rate, oxygen saturation, and temperature. 
d:       Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, LDH, phosphorus, potassium, 
total protein, SGOT [AST], SGPT [ALT], sodium.
e:      Disease-specific tumor markers as appropriate (e.g. CEA, CA-19-9, CA125) should be drawn at specified times provided the patient has 
elevation of that specific tumor maker prior to study enrollment.  Colorectal: CEA; Pancreatic: CEA and CA-19-9; Lung: CEA; Any other 
tumor types: PI with treating MD can advise which tumor markers are appropriate to follow.  
f:       EKGs should be done pre-dose at all required time points. 
g:      ECHO or MUGA to be performed at screening and again on C1D28 (acceptable window C1 D23-D29.) Thereafter, exam should be 
repeated every 12 weeks (+/-1 week.) The same modality used during screening should be used for all follow up exams. 
h:      Tumor measurements and radiologic evaluation should occur every 8 weeks +/- 1 week. If a patient is on a dose hold, scans should be kept 
on original schedule and should not be shifted. Patients that have scans which reveal disease progression do not need to repeat end of 
treatment scans. 
i:       Serum pregnancy test (women of childbearing potential) must be done within 7 days of C1D1. 
j:       Pre-study tumor biopsy to occur between days -21 and day-1. When possible, it is preferred, but not required, that the pre-treatment biopsy 
be performed between days -7 and -1 of treatment in order to most accurately represent the baseline signaling activity prior to treatment. 
Platelet count and PT/PTT must be checked prior to procedure according to institutional guidelines and must be in acceptable range as 
defined in section 9.1.1.2.
k:      On treatment biopsy to occur ~2 weeks after trametinib dosing on day 15 (+/- 7 days.) Platelet count and PT/PTT must be checked prior to 
procedure on the same day, and must be in acceptable range as defined in section 9.1.1.2.
l:       Complete PK schedule detailed in Section 9.3. Additional PK samples (single trough measurements only) required on day 1 of cycles 4, 8, 
and 12, not represented on this calendar. 
m:     Includes pre-dose (0h), 2h, 4h, 6h, 8h draws on C1D7 and 23h draw (pre-dose) on C1D8. See section 9.3 for details. 
n:      Includes pre- trametinib (1h), pre navitoclax (0h), and 2h, 4h, 6h, 8h post navitoclax draws on C1D14 and 23h draw (pre- trametinib) on 
C1D15. See section 9.3 for details. 
o:      Single pre-dose (pre- trametinib and navitoclax) trough on C2D1. See Section 9.3 for details. 
p:      At least 20 unstained slides are required. If a patient is having a tumor biopsy, less than 20 is acceptable with PI approval.
q:      Off study procedures should be performed within 14 days of last dose. Patients will be followed until the resolution or stabilization of all          
study-related toxicity and for a minimum of 30 days after removal from study or until death, whichever occurs first.  Patients removed from 
study for unacceptable adverse event(s) will be followed until resolution or stabilization of the adverse event.
Part 1 (Phase 1b) Schedule C
Pre-
Study
C1D1
C1D7
C1D8
C1D14
C1D15
C1D22
C2D1
C2D15
C3D1, 
C4D1, 
etc..
Off 
Studyq
Trametinib
T
T
T
T
T
T
Navitoclax
L
L
N
N
N
N
N
N
N
Informed consent a
X
 
Demographics
X

NCI Protocol #: 9525
Version Date: July 22, 2022
96
Medical history
X
Concurrent meds
X
X---------------------------------------------------------------------------------------------X
Physical exam b
X
X
X
X
X
X
X
X
X
Vital signs c
X
X
X
X
X
X
X
X
X
X
X
Height
X
Weight
X
X
X
X
X
X
X
X
X
Performance status
X
X
X
X
X
X
X
X
X
CBC w/diff, plts
X
X
X
X
X
X
X
X
X
Serum chemistry d
X
X
X
X
X
X
X
X
X
PT/PTT
X
X
X
X
X
X
X
Tumor Markers e
X
X
X
X
Urinalysis
X
EKG f
X
X
X
X
X
X
X
Echocardiogram or MUGA
X
Repeat on C1D28 (up to 5 days prior or on C2D1.) Thereafter, repeat every 12 weeks (use 
same methodology for baseline and follow up). g
Ophthalmology exam
X
Repeated as needed only if patient experiences vision changes
Adverse event evaluation
X---------------------------------------------------------------------------------------------X
X
Radiologic evaluations/ 
Tumor measurements
X
Radiologic measurements (by CT or MRI) should be performed every 8 weeks following 
Cycle 1 Day 1. Tumor measurements are repeated every 8 weeks.  Documentation 
(radiologic) must be provided for patients removed from study for progressive disease. h
X
B-HCG
Xi
Tumor biopsy
Xj
Xk
PK blood drawl
Xm
Xm
  Xn
Xn
Xo
Xl
Archival Tissue
Xp
cfDNA blood draw
X
X
X
X

NCI Protocol #: 9525
Version Date: July 22, 2022
97
T:
Trametinib. Dose as assigned; dose in the evening on empty stomach, at least 1 hour before or two hours after food (there are no 
hematologic paramaters that must be met to continue dosing with trametinib at the beginning of each cycle.)
N:
Navitoclax. Dose as assigned; dose in morning with food
L:      Lead-in dose of navitoclax.  150 mg daily in morning for 7 days, dosed as above.
a:        Informed consent can be signed within 28 days of C1D1. 
b:       Complete physical exam required pre-study and on Day 1 of each cycle, including head, eye, ear, nose, throat (HEENT,) cardiovascular, 
dermatological, musculoskeletal, respiratory, gastrointestinal, and neurological systems. Limited or symptom directed physical exam at the 
discretion of the investigator is sufficient at all other visits.
c:       Vitals should include blood pressure, heart rate, respiratory rate, oxygen saturation, and temperature. 
d:       Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, LDH, phosphorus, potassium, 
total protein, SGOT [AST], SGPT [ALT], sodium.
e:      Disease-specific tumor markers as appropriate (e.g. CEA, CA-19-9, CA125) should be drawn at specified times provided the patient has 
elevation of that specific tumor maker prior to study enrollment.  Colorectal: CEA; Pancreatic: CEA and CA-19-9; Lung: CEA; Any other 
tumor types: PI with treating MD can advise which tumor markers are appropriate to follow.  
f:       EKGs should be done pre-dose at all required time points. 
g:      ECHO or MUGA to be performed at screening and again on C1D28 (acceptable window C1 D23-D29.) Thereafter, exam should be 
repeated every 12 weeks (+/-1 week.) The same modality used during screening should be used for all follow up exams. 
h:      Tumor measurements and radiologic evaluation should occur every 8 weeks +/- 1 week. If a patient is on a dose hold, scans should be kept 
on original schedule and should not be shifted. Patients that have scans which reveal disease progression do not need to repeat end of 
treatment scans. 
i:       Serum pregnancy test (women of childbearing potential) must be done within 7 days of C1D1. 
j:       Pre-study tumor biopsy to occur between days -21 and day-1. When possible, it is preferred, but not required, that the pre-treatment biopsy 
be performed between days -7 and -1 of treatment in order to most accurately represent the baseline signaling activity prior to treatment. 
Platelet count and PT/PTT must be checked prior to procedure according to institutional guidelines and must be in acceptable range as 
defined in section 9.1.1.2.
k:      On treatment biopsy to occur ~2 weeks after trametinib dosing on day 15 (+/- 7 days.) Platelet count and PT/PTT must be checked prior to 
procedure on the same day, and must be in acceptable range as defined in section 9.1.1.2.
l:       Complete PK schedule detailed in Section 9.3. Additional PK samples (single trough measurements only) required on day 1 of cycles 4, 8, 
and 12, not represented on this calendar. 
m:     Includes pre-dose (0h), 2h, 4h, 6h, 8h draws on C1D7 and 24h draw (pre-dose) on C1D8. See section 9.3 for details. 
n:      Includes pre navitoclax (0h), and 2h, 4h, 6h, 8h post navitoclax draws on C1D14 and 24h draw on C1D15. See section 9.3 for details. 
o:      Single pre-dose (pre-navitoclax) trough on C2D1. See Section 9.3 for details. 
p:      At least 20 unstained slides are required. If a patient is having a tumor biopsy, less than 20 is acceptable with PI approval.
q:      Off study procedures should be performed within 14 days of last dose. Patients will be followed until the resolution or stabilization of all 
study-related toxicity and for a minimum of 30 days after removal from study or until death, whichever occurs first.  Patients removed from 
study for unacceptable adverse event(s) will be followed until resolution or stabilization of the adverse event.      

NCI Protocol #: 9525
Version Date: July 22, 2022
98
 
 
Part 2 (Phase 2) Schedule A
(To be used if RP2D is to be given by Schedule A)
Pre-
Study
C1D1
C1D8
C1D15
C1D22
C2D1
C2D15
C3D1, C4D1, 
etc..
Off Studyp
Trametinib
T
T
T
T
T
T
Navitoclax
L
N
N
N
N
N
N
Informed consent a
X
 
Demographics
X
Medical history
X
Concurrent meds
X
X----------------------------------------------------------------------------------X
Physical exam b
X
X
X
X
X
X
X
X
X
Vital signs c
X
X
X
X
X
X
X
X
X
Height
X
Weight
X
X
X
X
X
X
X
X
X
Performance status
X
X
X
X
X
X
X
X
X
CBC w/diff, plts
X
X
X
X
X
X
X
X
X
Serum chemistry d
X
X
X
X
X
X
X
X
X
PT/PTT
X
X
X
X
X
X
Tumor Markerse
X
X
X
X
Urinalysis
X
EKG f
X
X
X
X
X
X
X
Echocardiogram or MUGA
X
Repeat on C1D28 (up to 5 days prior or on C2D1.) Every 12 weeks (use same 
methodology for baseline and follow up). g
Ophthalmology exam
X
Repeated as needed only if patient experiences vision changes
Adverse event evaluation
X----------------------------------------------------------------------------------
X
Radiologic evaluation/Tumor 
measurements
X
Radiologic measurements (by CT or MRI) should be performed every 8 weeks 
following Cycle 1 Day 1. Tumor measurements are repeated every 8 weeks.  
Documentation (radiologic) must be provided for patients removed from study 
X

NCI Protocol #: 9525
Version Date: July 22, 2022
99
for progressive disease. h
B-HCG
Xi
Tumor biopsy
Xj,k
Xj,l
PK blood drawm
Xn
Xm
Archival Tissue
Xo
T:
Trametinib. Dose as assigned; dose first in morning on empty stomach, at least 1 hour before food (there are no hematologic paramaters 
that must be met to continue dosing with trametinib at the beginning of each cycle.)
N:
Navitoclax. Dose as assigned; dose second in morning with food, at least 1 hour after trametinib
L:      Lead-in dose of navitoclax.  150 mg daily in morning for 7 days, dosed as above.
a:        Informed consent can be signed within 28 days of C1D1. 
b:       Complete physical exam required pre-study and on Day 1 of each cycle, including head, eye, ear, nose, throat (HEENT,) cardiovascular, 
dermatological, musculoskeletal, respiratory, gastrointestinal, and neurological systems. Limited or symptom directed physical exam at 
the discretion of the investigator is sufficient at all other visits.
c:       Vitals should include blood pressure, heart rate, respiratory rate, oxygen saturation, and temperature. 
d:       Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, LDH, phosphorus, potassium, 
total protein, SGOT [AST], SGPT [ALT], sodium.
e:      Disease-specific tumor markers as appropriate (e.g. CEA, CA-19-9, CA125) should be drawn at specified times provided the patient has 
elevation of that specific tumor maker prior to study enrollment.  Colorectal: CEA; Pancreatic: CEA and CA-19-9; Lung: CEA; Any 
other tumor types: PI with treating MD can advise which tumor markers are appropriate to follow.   
f:       EKGs should be done pre-dose at all required time points. 
g:      ECHO or MUGA to be performed at screening and again on C1D28 (acceptable window C1 D23-D29.) Thereafter, exam should be 
repeated every 12 weeks (+/-1 week.) The same modality used during screening should be used for all follow up exams. 
h:      Tumor measurements and radiologic evaluation should occur every 8 weeks +/- 1 week. If a patient is on a dose hold, scans should be 
kept on original schedule and should not be shifted. Patients that have scans which reveal disease progression do not need to repeat end 
of treatment scans. 
i:       Serum pregnancy test (women of childbearing potential) must be done within 7 days of C1D1. 
j:      Tumor biopsies to be performed only in first 15 patients enrolled in Part 2. 
k:      Pre-study tumor biopsy to occur between days -21 and day-1. When possible, it is preferred, but not required, that the pre-treatment 
biopsy be performed between days -7 and -1 of treatment in order to most accurately represent the baseline signaling activity prior to 
treatment. Platelet count and PT/PTT must be checked prior to procedure according to institutional guidelines, and must be in acceptable 
range as defined in section 9.1.1.2.
l:      On treatment biopsy to occur ~2 weeks after trametinib dosing on C1D22 (+/- 7 days.) Platelet count and PT/PTT must be checked prior 
to procedure on the same day, and must be in acceptable range as defined in section 9.1.1.2.
m:     Complete PK schedule detailed in Section 9.3. Additional PK samples (single trough measurements only) required on day 1 of cycles 4, 
8, and 12, not represented on this calendar. 
n:      Single pre-dose (pre-trametinib and navitoclax) trough on C2D1. 
o:      At least 20 unstained slides are required. If a patient is having a tumor biopsy, less than 20 is acceptable with PI approval.
p:      Off study procedures should be performed within 14 days of last dose. Patients will be followed until the resolution or stabilization of all 
study-related toxicity and for a minimum of 30 days after removal from study or until death, whichever occurs first.  Patients removed 
from study for unacceptable adverse event(s) will be followed until resolution or stabilization of the adverse event.
 

NCI Protocol #: 9525
Version Date: July 22, 2022
100
Part 2 (Phase 2) Schedule B
(To be used if RP2D is to be given by Schedule B)
Pre-
Study
C1D1
C1D8
C1D15
C1D22
C2D1
C2D15
C3D1, C4D1, etc…
Off Studyp
Trametinib
T
T
T
T
T
T
T
Navitoclax
L
N
N
N
N
N
N
Informed consent a
X
 
Demographics
X
Medical history
X
Concurrent meds
X
X---------------------------------------------------------------------------------------------X
Physical exam b
X
X
X
X
X
X
X
X
X
Vital signs c
X
X
X
X
X
X
X
X
X
Height
X
Weight
X
X
X
X
X
X
X
X
X
Performance status
X
X
X
X
X
X
X
X
X
CBC w/diff, plts
X
X
X
X
X
X
X
X
X
Serum chemistryd
X
X
X
X
X
X
X
X
X
PT/PTT
X
X
X
X
X
X
X
Tumor Markers e
X
X
X
Urinalysis
X
EKG f
X
X
X
X
X
X
X
Echocardiogram or MUGA
X
Repeat on C1D28 (up to 5 days prior or on C2D1.) Thereafter, repeat every 12 
weeks (use same methodology for baseline and follow up). g
Ophthalmology exam
X
Repeated as needed only if patient experiences vision changes

NCI Protocol #: 9525
Version Date: July 22, 2022
101
Adverse event evaluation
X---------------------------------------------------------------------------------------------X
X
Radiologic 
Evaluations/Tumor 
measurements
X
Radiologic measurements (by CT or MRI) should be performed every 8 weeks 
following Cycle 1 Day 1. Tumor measurements are repeated every 8 weeks.  
Documentation (radiologic) must be provided for patients removed from study for 
progressive disease. h
X
B-HCG
Xi
Tumor biopsy
Xj,k
Xj,l
PK blood drawm
Xn
Xm
Archival Tissue
Xo
T:
Trametinib. Dose as assigned; dose first in morning on empty stomach, at least 1 hour before food (there are no hematologic paramaters 
that must be met to continue dosing with trametinib at the beginning of each cycle.)
N:
Navitoclax. Dose as assigned; dose second in morning with food, at least 1 hour after trametinib
L:      Lead-in dose of navitoclax.  150 mg daily in morning for 7 days, dosed as above.
a:        Informed consent can be signed within 28 days of C1D1. 
b:       Complete physical exam required pre-study and on Day 1 of each cycle, including head, eye, ear, nose, throat (HEENT,) cardiovascular, 
dermatological, musculoskeletal, respiratory, gastrointestinal, and neurological systems. Limited or symptom directed physical exam at 
the discretion of the investigator is sufficient at all other visits.
c:       Vitals should include blood pressure, heart rate, respiratory rate, oxygen saturation, and temperature. 
d:       Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, LDH, phosphorus, potassium, 
total protein, SGOT [AST], SGPT [ALT], sodium.
e:      Disease-specific tumor markers as appropriate (e.g. CEA, CA-19-9, CA125) should be drawn at specified times provided the patient has 
elevation of that specific tumor maker prior to study enrollment. Colorectal: CEA; Pancreatic: CEA and CA-19-9; Lung: CEA; Any 
other tumor types: PI with treating MD can advise which tumor markers are appropriate to follow.   
f:       EKGs should be done pre-dose at all required time points. 
g:      ECHO or MUGA to be performed at screening and again on C1D28 (acceptable window C1 D23-D29.) Thereafter, exam should be 
repeated every 12 weeks (+/-1 week.) The same modality used during screening should be used for all follow up exams. 
h:      Tumor measurements and radiologic evaluation should occur every 8 weeks +/- 1 week. If a patient is on a dose hold, scans should be 
kept on original schedule and should not be shifted. Patients that have scans which reveal disease progression do not need to repeat end 
of treatment scans. 
i:       Serum pregnancy test (women of childbearing potential) must be done within 7 days of C1D1. 
j:     Tumor biopsies to be performed only in first 15 patients enrolled in Part 2.
k:     Pre-study tumor biopsy to occur between day -21 and day -1. When possible, it is preferred, but not required, that the pre-treatment 
biopsy be performed between days -7 and -1 of treatment in order to most accurately represent the baseline signaling activity prior to 
treatment. Platelet count and PT/PTT must be checked prior to procedure according to institutional guidelines, and must be in acceptable 
range as defined in section 9.1.1.3.
l:      On-treatment tumor biopsy to occur after ~14 days of trametinib dosing on day 15 (+/- 7 days). Platelet count and PT/PTT must be 
checked prior to procedure on same day, and must be in acceptable range as defined in section 9.1.1.3.
m:    Complete PK schedule detailed in Section 9.3.  Additional PK samples (single trough measurement only) required on day 1 of cycles 4, 
8, and 12, not represented on this calendar
n:   Single pre-dose (pre-trametinib and navitoclax) trough on C2D1.  See Section 9.3 for details.
o:      At least 20 unstained slides are required. If a patient is having a tumor biopsy, less than 20 is acceptable with PI approval.
p:      Off study procedures should be performed within 14 days of last dose. Patients will be followed until the resolution or stabilization of all 
study-related toxicity and for a minimum of 30 days after removal from study or until death, whichever occurs first.  Patients removed 
from study for unacceptable adverse event(s) will be followed until resolution or stabilization of the adverse event.

NCI Protocol #: 9525
Version Date: July 22, 2022
102
 
Part 2 (Phase 2) Schedule C
(To be used if RP2D is to be given by Schedule C)
Pre-
Study
C1D1
C1D8
C1D15
C1D22
C2D1
C2D15
C3D1, C4D1, etc…
Off Studyp
Trametinib
T
T
T
T
Navitoclax
L
N
N
N
N
N
N
Informed consent a
X
 
Demographics
X
Medical history
X
Concurrent meds
X
X---------------------------------------------------------------------------------------------X
Physical exam b
X
X
X
X
X
X
X
X
X
Vital signs c
X
X
X
X
X
X
X
X
X
Height
X
Weight
X
X
X
X
X
X
X
X
X
Performance status
X
X
X
X
X
X
X
X
X
CBC w/diff, plts
X
X
X
X
X
X
X
X
X
Serum chemistryd
X
X
X
X
X
X
X
X
X
PT/PTT
X
X
X
X
X
X
X
Tumor Markers e
X
X
X
Urinalysis
X
EKG f
X
X
X
X
X
X
X
Echocardiogram or MUGA
X
Repeat on C1D28 (up to 5 days prior or on C2D1.) Thereafter, repeat every 12 
weeks (use same methodology for baseline and follow up). g

NCI Protocol #: 9525
Version Date: July 22, 2022
103
Ophthalmology exam
X
Repeated as needed only if patient experiences vision changes
Adverse event evaluation
X---------------------------------------------------------------------------------------------X
X
Radiologic 
Evaluations/Tumor 
measurements
X
Radiologic measurements (by CT or MRI) should be performed every 8 weeks 
following Cycle 1 Day 1. Tumor measurements are repeated every 8 weeks.  
Documentation (radiologic) must be provided for patients removed from study for 
progressive disease. h
X
B-HCG
Xi
Tumor biopsy
Xj,k
Xj,l
PK blood drawm
Xn
Xm
Archival Tissue
Xo
cfDNA blood draw
X
X
X
T:
Trametinib. Dose as assigned; dose in evening on empty stomach, at least 1 hour before or two hours after food (there are no 
hematologic paramaters that must be met to continue dosing with trametinib at the beginning of each cycle.)
N:
Navitoclax. Dose as assigned; dose in morning with food
L:      Lead-in dose of navitoclax.  150 mg daily in morning for 7 days, dosed as above.
a:        Informed consent can be signed within 28 days of C1D1. 
b:       Complete physical exam required pre-study and on Day 1 of each cycle, including head, eye, ear, nose, throat (HEENT,) cardiovascular, 
dermatological, musculoskeletal, respiratory, gastrointestinal, and neurological systems. Limited or symptom directed physical exam at 
the discretion of the investigator is sufficient at all other visits.
c:       Vitals should include blood pressure, heart rate, respiratory rate, oxygen saturation, and temperature. 
d:       Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, LDH, phosphorus, potassium, 
total protein, SGOT [AST], SGPT [ALT], sodium.
e:      Disease-specific tumor markers as appropriate (e.g. CEA, CA-19-9, CA125) should be drawn at specified times provided the patient has 
elevation of that specific tumor maker prior to study enrollment. GYN: CA-125; Pancreatic: CEA and CA-19-9; Lung: CEA; Any other 
tumor types: PI with treating MD can advise which tumor markers are appropriate to follow.   
f:       EKGs should be done pre-dose at all required time points. 
g:      ECHO or MUGA to be performed at screening and again on C1D28 (acceptable window C1 D23-D29.) Thereafter, exam should be 
repeated every 12 weeks (+/-1 week.) The same modality used during screening should be used for all follow up exams. 
h:      Tumor measurements and radiologic evaluation should occur every 8 weeks +/- 1 week. If a patient is on a dose hold, scans should be 
kept on original schedule and should not be shifted. Patients that have scans which reveal disease progression do not need to repeat end 
of treatment scans. 
i:       Serum pregnancy test (women of childbearing potential) must be done within 7 days of C1D1. 
j:     Tumor biopsies to be performed only in first 15 patients enrolled in Part 2.
k:     Pre-study tumor biopsy to occur between day -21 and day -1. When possible, it is preferred, but not required, that the pre-treatment 
biopsy be performed between days -7 and -1 of treatment in order to most accurately represent the baseline signaling activity prior to 
treatment. Platelet count and PT/PTT must be checked prior to procedure according to institutional guidelines, and must be in acceptable 
range as defined in section 9.1.1.3.
l:      On-treatment tumor biopsy to occur after ~14 days of trametinib dosing on day 15 (+/- 7 days). Platelet count and PT/PTT must be 
checked prior to procedure on same day, and must be in acceptable range as defined in section 9.1.1.3.
m:    Complete PK schedule detailed in Section 9.3.  Additional PK samples (single trough measurement only) required on day 1 of cycles 4, 
8, and 12, not represented on this calendar
n:      Single pre-dose (pre-navitoclax) trough on C2D1.  See Section 9.3 for details.
o:      At least 20 unstained slides are required. If a patient is having a tumor biopsy, less than 20 is acceptable with PI approval.

NCI Protocol #: 9525
Version Date: July 22, 2022
104
p:      Off study procedures should be performed within 14 days of last dose. Patients will be followed until the resolution or stabilization of all 
study-related toxicity and for a minimum of 30 days after removal from study or until death, whichever occurs first.  Patients removed 
from study for unacceptable adverse event(s) will be followed until resolution or stabilization of the adverse event.
 
11. MEASUREMENT OF EFFECT
11.1
Antitumor Effect – Solid Tumors
For the purposes of this study, patients should be re-evaluated for response every 8 weeks.  In 
addition to a baseline scan, confirmatory scans should also be obtained at least 4 weeks 
following initial documentation of objective response.
Response and progression will be evaluated in this study using the new international criteria 
proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline 
(version 1.1) [Eur J Ca 45:228-247, 2009].  Changes in the largest diameter (unidimensional 
measurement) of the tumor lesions and the shortest diameter in the case of malignant lymph 
nodes are used in the RECIST criteria.
11.1.1 Definitions
Evaluable for toxicity.  All patients will be evaluable for toxicity from the time of their 
first treatment with navitoclax and/or trametinib.
Evaluable for objective response.  Only those patients who have measurable disease 
present at baseline, have received at least one cycle of therapy, and have had their disease 
re-evaluated will be considered evaluable for response.  These patients will have their 
response classified according to the definitions stated below.  (Note:  Patients who exhibit 
objective disease progression prior to the end of cycle 1 will also be considered 
evaluable.)
Evaluable Non-Target Disease Response.  Patients who have lesions present at baseline 
that are evaluable but do not meet the definitions of measurable disease, have received at 
least one cycle of therapy, and have had their disease re-evaluated will be considered 
evaluable for non-target disease.  The response assessment is based on the presence, 
absence, or unequivocal progression of the lesions. 
11.1.2 Disease Parameters
Measurable disease.  Measurable lesions are defined as those that can be accurately 
measured in at least one dimension (longest diameter to be recorded) as ≥20 mm by chest 
x-ray or as ≥10 mm with CT scan, MRI, or calipers by clinical exam.  All tumor 

NCI Protocol #: 9525
Version Date: July 22, 2022
105
measurements must be recorded in millimeters (or decimal fractions of centimeters).
Note:  Tumor lesions that are situated in a previously irradiated area might or might not 
be considered measurable.  If the investigator thinks it appropriate to include them, the 
conditions under which such lesions should be considered must be defined in the 
protocol.
Malignant lymph nodes.  To be considered pathologically enlarged and measurable, a 
lymph node must be ≥15 mm in short axis when assessed by CT scan (CT scan slice 
thickness recommended to be no greater than 5 mm).  At baseline and in follow-up, only 
the short axis will be measured and followed.
Non-measurable disease.  All other lesions (or sites of disease), including small lesions 
(longest diameter <10 mm or pathological lymph nodes with ≥10 to <15 mm short axis), 
are considered non-measurable disease.  Bone lesions, leptomeningeal disease, ascites, 
pleural/pericardial effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, 
and abdominal masses (not followed by CT or MRI), are considered as non-measurable.
Note:  Cystic lesions that meet the criteria for radiographically defined simple cysts 
should not be considered as malignant lesions (neither measurable nor non-measurable) 
since they are, by definition, simple cysts.
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if non-
cystic lesions are present in the same patient, these are preferred for selection as target 
lesions.
Target lesions.  All measurable lesions up to a maximum of 2 lesions per organ and 5 
lesions in total, representative of all involved organs, should be identified as target 
lesions and recorded and measured at baseline.  Target lesions should be selected on the 
basis of their size (lesions with the longest diameter), be representative of all involved 
organs, but in addition should be those that lend themselves to reproducible repeated 
measurements.  It may be the case that, on occasion, the largest lesion does not lend itself 
to reproducible measurement in which circumstance the next largest lesion which can be 
measured reproducibly should be selected.  A sum of the diameters (longest for non-
nodal lesions, short axis for nodal lesions) for all target lesions will be calculated and 
reported as the baseline sum diameters.  If lymph nodes are to be included in the sum, 
then only the short axis is added into the sum.  The baseline sum diameters will be used 
as reference to further characterize any objective tumor regression in the measurable 
dimension of the disease.
Non-target lesions.  All other lesions (or sites of disease) including any measurable 
lesions over and above the 5 target lesions should be identified as non-target lesions and 
should also be recorded at baseline.  Measurements of these lesions are not required, but 

NCI Protocol #: 9525
Version Date: July 22, 2022
106
the presence, absence, or in rare cases unequivocal progression of each should be noted 
throughout follow-up. 
11.1.3 Methods for Evaluation of Measurable Disease
All measurements should be taken and recorded in metric notation using a ruler or 
calipers.  All baseline evaluations should be performed as closely as possible to the 
beginning of treatment and never more than 4 weeks before the beginning of the 
treatment.
The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up. Imaging-based 
evaluation is required in this study.
Conventional CT:  This guideline has defined measurability of lesions on CT scan based 
on the assumption that CT slice thickness is 5 mm or less.  If CT scans have slice 
thickness greater than 5 mm, the minimum size for a measurable lesion should be twice 
the slice thickness. CT is the preferred imaging modality in this study and should be used 
as the primary method of disease assessment unless otherwise measurable lesions are not 
able to be adequately assessed by CT scan, in which case one of the following imaging 
modalities can be used instead.  However, the same imaging modality used at baseline 
should be used for evaluation of measurable disease throughout the study.
MRI:  Use of MRI is acceptable in situations in which lesions are not adequately 
assessable by conventional CT scanning.  Use of MRI remains a complex issue.  MRI has 
excellent contrast, spatial, and temporal resolution; however, there are many image 
acquisition variables involved in MRI, which greatly impact image quality, lesion 
conspicuity, and measurement.  Furthermore, the availability of MRI is variable globally.  
As with CT, if an MRI is performed, the technical specifications of the scanning 
sequences used should be optimized for the evaluation of the type and site of disease.  
Furthermore, as with CT, the modality used at follow-up should be the same as was used 
at baseline and the lesions should be measured/assessed on the same pulse sequence.  It is 
beyond the scope of the RECIST guidelines to prescribe specific MRI pulse sequence 
parameters for all scanners, body parts, and diseases.  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 be performed with breath-hold scanning techniques, if 
possible.
PET-CT:  At present, the low dose or attenuation correction CT portion of a combined 
PET-CT is not always of optimal diagnostic CT quality for use with RECIST 
measurements.  However, if the site can document that the CT performed as part of a 
PET-CT is of identical diagnostic quality to a diagnostic CT (with IV and oral contrast), 
then the CT portion of the PET-CT can be used for RECIST measurements and can be 
used interchangeably with conventional CT in accurately measuring cancer lesions over 

NCI Protocol #: 9525
Version Date: July 22, 2022
107
time.  Note, however, that the PET portion of the CT introduces additional data which 
may bias an investigator if it is not routinely or serially performed.  
11.1.4 Response Criteria
11.1.4.1
Evaluation of Target Lesions
Complete Response (CR):  Disappearance of all target lesions.  Any pathological 
lymph nodes (whether target or non-target) must have reduction in short axis to <10 
mm.
Partial Response (PR):  At least a 30% decrease in the sum of the diameters of target 
lesions, taking as reference the baseline sum diameters.
Progressive Disease (PD):  At least a 20% increase in the sum of the diameters of 
target lesions, taking as reference the smallest sum on study (this includes the 
baseline sum if that is the smallest on study).  In addition to the relative increase of 
20%, the sum must also demonstrate an absolute increase of at least 5 mm.  (Note:  
the appearance of one or more new lesions is also considered progressions).
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum diameters while on 
study.
11.1.4.2
Evaluation of Non-Target Lesions
Complete Response (CR):  Disappearance of all non-target lesions and normalization 
of tumor marker level.  All lymph nodes must be non-pathological in size (<10 mm 
short axis).
Note:  If tumor markers are initially above the upper normal limit, they must 
normalize for a patient to be considered in complete clinical response.
Non-CR/Non-PD:  Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal limits.
Progressive Disease (PD):  Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target lesions.  Unequivocal progression 
should not normally trump target lesion status.  It must be representative of overall 
disease status change, not a single lesion increase.    
Although a clear progression of “non-target” lesions only is exceptional, the opinion 
of the treating physician should prevail in such circumstances, and the progression 
status should be confirmed at a later time by the review panel (or Principal 

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108
Investigator).
11.1.4.3
Evaluation of Best Overall Response
The best overall response is the best response recorded from the start of the treatment 
until disease progression/recurrence (taking as reference for progressive disease the 
smallest measurements recorded since the treatment started).  The patient's best 
response assignment will depend on the achievement of both measurement and 
confirmation criteria.
For Patients with Measurable Disease (i.e., Target Disease)
Target 
Lesions
Non-Target 
Lesions
New 
Lesions
Overall 
Response
Best Overall Response when 
Confirmation is Required*
CR
CR
No
CR
≥4 wks. Confirmation**
CR
Non-CR/Non-
PD
No
PR
CR
Not evaluated
No
PR
PR
Non-CR/Non-
PD/not 
evaluated
No
PR
≥4 wks. Confirmation**
SD
Non-CR/Non-
PD/not 
evaluated
No
SD
Documented at least once ≥4 
wks. from baseline**
PD
Any
Yes or No
PD
Any
PD***
Yes or No
PD
Any
Any
Yes
PD
no prior SD, PR or CR

See RECIST 1.1 manuscript for further details on what is evidence of a new lesion.
**        Only for non-randomized trials with response as primary endpoint.
***      In exceptional circumstances, unequivocal progression in non-target lesions may be
            accepted as disease progression.
Note:  Patients with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be 
reported as “symptomatic deterioration.”  Every effort should be made to document the 
objective progression even after discontinuation of treatment.
For Patients with Non-Measurable Disease (i.e., Non-Target Disease)
Non-Target Lesions
New Lesions
Overall Response
CR
No
CR

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109
Non-CR/non-PD
No
Non-CR/non-PD*
Not all evaluated
No
not evaluated
Unequivocal PD
Yes or No
PD
Any
Yes
PD

‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is 
increasingly used as an endpoint for assessment of efficacy in some trials so to assign 
this category when no lesions can be measured is not advised
11.1.5 Duration of Response
Duration of overall response:  The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first 
date that recurrent or progressive disease is objectively documented (taking as reference 
for progressive disease the smallest measurements recorded since the treatment started).
The duration of overall CR is measured from the time measurement criteria are first met 
for CR until the first date that progressive disease is objectively documented.
Duration of stable disease:  Stable disease is measured from the start of the treatment 
until the criteria for progression are met, taking as reference the smallest measurements 
recorded since the treatment started, including the baseline measurements. 
11.1.6 Progression-Free Survival
PFS is defined as the duration of time from start of treatment to time of progression or 
death, whichever occurs first.
11.1.7 Response Review
For Part 2 (the phase 2 portion) of the study, an expert(s) independent of the study will 
review all responses at the study’s completion. 
11.2
Antitumor Effect – Hematologic Tumors
N/A
11.3
Other Response Parameters
N/A

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110
12. DATA REPORTING / REGULATORY REQUIREMENTS
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7.0 
(Adverse Events: List and Reporting Requirements).
12.1
Data Reporting
12.1.1 Method
This study will be monitored by the Clinical Trials Monitoring Service (CTMS).  
Information on CTMS reporting is available at http://www.theradex.com/CTMS.  Data 
will be submitted to CTMS at least once every two weeks on the NCI/DCTD case report 
form or the electronic case report form (ACES).
12.1.2 Responsibility for Data Submission
N/A 
12.2
CTEP Multicenter Guidelines
N/A
12.3
Collaborative Agreements Language
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(s) in this study:
1. Agent(s) may not be used for any purpose 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 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.

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111
2. For a clinical protocol where there is an investigational Agent used in combination with 
(an)other 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 prior 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 that 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 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 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 Collaborator(s) for Phase 3 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 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 at least three (3) days prior to submission, but in 

NCI Protocol #: 9525
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112
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:
Email: ncicteppubs@mail.nih.gov
The Regulatory Affairs Branch will then distribute them to Collaborator(s).  No publication, 
manuscript or other form of public disclosure shall contain any of Collaborator’s confidential/ 
proprietary information.
13. STATISTICAL CONSIDERATIONS
13.1
Study Design/Endpoints
13.1.1 Part 1 (Phase 1b)
Part 1 (Phase 1b) of this study aims to determine the maximal tolerated dose (MTD) of 
trametinib and navitoclax that can be given safely in combination in order to determine a 
recommended phase 2 dose (RP2D).  Patients with advanced or metastatic solid tumors that have 
been determined to harbor KRAS or NRAS mutations by CLIA-approved laboratory assay will 
be eligible. Prior therapy for advanced or metastatic disease will be allowed.   Pharmacokinetic 
(PK) assays will be carried out to assess the interaction of these two drugs, and these data will be 
correlated with clinical toxicities as dose escalation is undertaken.  Paired pre-treatment and on-
treatment (day 15) tumor biopsies will be obtained to assess the pharmacodynamic response to 
therapy.  Adverse events and DLT will be reported as defined in Sections 7 and 5.2, respectively.  
Evaluation of response rate will be performed as defined in Section 11.
Dose escalation will be conducted as outline in Section 5.1.  The following table shows the 
probability of escalating the dose for various true, but unknown, rates of unacceptable toxicity.
True DLT Rate
Probability of Dose 
Escalation
10%
91%
20%
71%
30%
49%
40%
31%
50%
17%
60%
8%

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113
13.1.1.1
Primary Objective      

To determine the dose-limiting toxicities of trametinib in combination with 
navitoclax, and the maximal doses at which both drugs can be safely 
administered together.
13.1.1.2
Primary Endpoint 

Adverse events
13.1.1.3
Secondary Objectives

To determine the pharmacokinetics of both drugs administered in 
combination.

To assess for evidence of response to therapy.

To evaluate the pharmacodynamic response to therapy in tumor biopsies.
13.1.1.4
Secondary Endpoints

Pharmacokinetic Endpoints
o
Maximum observed plasma drug concentration (Cmax)
o
Area-under-the concentration-time-curve from zero (pre-dose) to 24 
hours (AUC(0-24)) for trametinib and navitoclax when administered in 
combination.
o
pre-dose (trough) drug concentration at the end of the dosing interval 
for trametinib and navitoclax when administered in combination.
o
t1/2 of trametinib and navitoclax when administered in combination.

Response rate (partial response [PR] + complete response [CR])

Pharmacodynamic Endpoints: Change in levels (between pre-treatment and 
day 15 tumor biopsies) of proteins/mRNAs implicated in MAPK or BCL2 
family signaling, proliferation markers (Ki67), or apoptosis markers (Cleaved 
caspase-3)
13.1.2 Part 2 (Phase 2)
Part 2 is a single-arm Phase 2 study of trametinib in combination with navitoclax at the RP2D 
determined in the Phase 1b trial above.  Patients with KRAS or NRAS mutation-positive solid 
tumors will be enrolled into up to 4 different disease-specific expansion cohorts.  These will 
include expansion cohorts for patients with KRAS or NRAS mutation-positive: (1) Pancreatic 
cancer, (2) GYN cancer, (3) lung cancer, (4) all other solid tumor types exclusive of pancreatic, 
GYN, and lung cancers.  Part 2 aims to evaluate the efficacy of this regimen in the tumor types 
above and to further evaluate the safety and toxicity profile of this regimen at the RP2D defined 
in Part 1 of the study.  Paired pre-treatment and on-treatment (day 15) tumor biopsies will be 
obtained on the first 15 patients enrolled in Part 2 (minimum 4 patients biopsied in each of 
expansion cohorts 1, 2, and 3) to assess the pharmacodynamic response to therapy.  Adverse 
events will be reported as defined in Section 7.  Evaluation of response rate will be performed as 
defined in Section 11.  PFS will be determined as defined in Section 11.1.6.

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The primary goal of Part 2 is to evaluate the efficacy of this regimen in patients with various 
KRAS or NRAS mutation-positive solid tumor.  Based on traditional response rates to standard 
second line chemotherapy in the tumor types being studied (Guglielmi et al, 2007; Conroy et al, 
2011), we conclude that a response rate of 15-20% or greater in a given expansion cohort would 
deem this regimen worthy of further study in that specific patient population.  In part 2, patients 
will be enrolled in 4 expansion cohorts by a two-stage design, as outlined in Section 5.1.  
Initially 12 patients will be enrolled to each cohort in Stage 1.  If no responses are observed in a 
given cohort among the first 12 patients, then that cohort will be stopped for futility. However, if 
one or more responses are observed in a given cohort, the cohort will proceed to Stage 2, and an 
additional 13 patients will be enrolled for a total of 25 patients in that cohort.  If at least three 
responses are observed within a completed cohort of 25 patients, the regimen will be considered 
promising for treating the specific tumor type.  This design has a 11% false-positive and a 22% 
false-negative error rate for testing a 17% vs. a 5% response rate.  The probability of early 
stopping is 54% if the underlying response rate were truly only 5%.  In the event that the number 
of responses observed in a given cohort does not meet the pre-established response criteria 
defined above, but promising anti-tumor activity is observed (such as prolonged stable disease or 
tumor regressions that fall short of the RECIST cutoff for partial response), the possibility of 
further evaluating of this regimen in the specific patient population can be explored through a 
joint discussion between the investigators, pharmaceutical collaborators, and the NCI-CTEP.
13.1.2.1
Primary Objectives

To determine the response rate of the combination of trametinib and 
navitoclax in subjects with KRAS or NRAS mutation-positive advanced or 
metastatic solid tumors in disease-specific expansion cohorts.

To confirm the safety and tolerability of trametinib and navitoclax in 
combination at the RP2D determined in the Phase 1b portion.
13.1.2.2
Primary Endpoints

Response rate (partial response [PR] + complete response [CR])

Progression-free survival (PFS)

Adverse events
13.1.2.3
Secondary Objective

To evaluate the pharmacodynamic response to therapy in tumor biopsies (first 
15 patients enrolled overall, minimum 4 patients biopsied in each of 
expansion cohorts 1, 2, and 3)
13.1.2.4
Secondary Endpoints

Pharmacodynamic Endpoints: Change in levels (between pre-treatment and 
day 15 tumor biopsies) of proteins/mRNAs implicated in MAPK or BCL2 
family signaling, proliferation markers (Ki67), or apoptosis markers (Cleaved 
caspase-3)

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13.2
Sample Size/Accrual Rate
13.2.1 Part 1 (Phase 1b)
Depending on whether enrollment also occurs to the B dosing cohorts for dose levels 1-3, overall 
accrual to Part 1 of this study will likely be between 21-30 patients.  It is estimated that between 
3-5 patients will be enrolled per month to the phase 1b portion of the study, resulting in an 
accrual time of between 6-9 months.
13.2.2 Part 2 (Phase 2)
Part 2 of the study will involve four expansion cohorts each enrolling a maximum of 25 patients.  
Each cohort will enroll a minimum of 12 patients, and will enroll an additional 13 patients (for 
25 total patients) if at least one objective tumor response is observed among the first 12 patients 
(as described above).  Therefore, a minimum of 48 patients and a maximum of 100 patients will 
be enrolled to this part of the study.  Based on past accrual rates at DF/HCC for patients with 
KRAS or NRAS mutation-positive solid tumors, we estimate that between 8-10 patients will be 
enrolled per month to the phase 2 portion of the study, resulting in an anticipated maximum 
accrual time of 10-12 months.
13.2.3 Accrual Targets
Accrual Targets
Sex/Gender
Ethnic Category
Females
Males
Total
Hispanic or Latino
6
+
5
=
11
Not Hispanic or Latino
61
+
58
=
119
Ethnic Category: Total of all subjects
67
(A1)
+
63
(B1) =
130
(C1)
Racial Category
American Indian or Alaskan Native
1
+
1
=
2
Asian
7
+
6
=
13
Black or African American
8
+
7
=
15
Native Hawaiian or other Pacific 
Islander
2
+
1
=
3
White
49
+
48
=
97
Racial Category: Total of all subjects
67
(A2)
+
63
(B2) =
130
(C2)
(A1 = A2)
(B1 = B2)
(C1 = C2)
13.3
Stratification Factors

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N/A
13.4
Analysis of Secondary Endpoints
13.4.1 Secondary Endpoints for Part 1 (Phase 1b)
13.4.1.1
Pharmacokinetic Endpoints
The following pharmacokinetic endpoints will be measured and reported for navitoclax and 
trametinib.

Maximum observed plasma drug concentration (Cmax)

Area-under-the concentration-time-curve from zero (pre-dose) to 24 hours 
(AUC(0-24)) for trametinib and navitoclax when administered in 
combination.

pre-dose (trough) drug concentration at the end of the dosing interval for 
trametinib and navitoclax when administered in combination.

t1/2 of trametinib and navitoclax when administered in combination.
In particular, in dose levels 1A and 2A, the Cmax and AUC(0-24) for navitoclax will be assessed 
pre-trametinib (e.g. day 7 of lead-in dose in Schedule A) and after 2 weeks of trametinib co-
administration (day 21 of schedule A, 14th day of trametinib dosing) to determine if any increase 
or decrease in navitoclax levels are observed following initiation of trametinib (indicative of 
drug interaction).
13.4.1.2
Response Rate
Response rate will be defined and reported as outlined in Sections 11 and Section 13.5.2 below.
13.4.1.3
Pharmacodynamic Endpoints
Change in levels (between pre-treatment and post-treatment tumor biopsies) of proteins/mRNAs 
implicated in MAPK or BCL2 family signaling (e.g. phosphorylated ERK (P-ERK)), 
proliferation markers (Ki67), or apoptosis markers (Cleaved caspase-3) will be evaluated in 
paired tumor biopsies obtained.  Results will be reported as a % increase or decrease in level of a 
given marker after treatment initiation (day 15 biopsy) relative to before treatment (pre-treatment 
biopsy).  For example, the % increase or decrease in the H-score of P-ERK, Ki67, or Cleaved 
caspase-3 will be reported relative to the pre-treatment biopsy.
13.4.2 Secondary Endpoints for Part 2 (Phase 2)
13.4.2.1 
Pharmacodynamic Endpoints
Change in levels (between pre-treatment and post treatment tumor biopsies) of proteins/mRNAs 

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implicated in MAPK or BCL2 family signaling (e.g. phosphorylated ERK (P-ERK)), 
proliferation markers (Ki67), or apoptosis markers (Cleaved caspase-3) will be evaluated in 
paired tumor biopsies obtained.  Results will be reported as a % increase or decrease in level of a 
given marker after treatment initiation (post treatment biopsy) relative to before treatment (pre-
treatment biopsy).  For example, the % increase or decrease in the H-score of P-ERK, Ki67, or 
Cleaved caspase-3 will be reported relative to the pre-treatment biopsy.
13.5
Reporting and Exclusions
13.5.1 Evaluation of Toxicity
All patients will be evaluable for toxicity from the time of their first treatment with 
navitoclax and/or trametinib.
13.5.2 Evaluation of Response
All patients included in the study must be assessed for response to treatment, even if there 
are major protocol treatment deviations or if they are ineligible.  Each patient will be 
assigned one of the following categories:  1) complete response, 2) partial response, 3) 
stable disease, 4) progressive disease, 5) early death from malignant disease, 6) early 
death from toxicity, 7) early death because of other cause, or 9) unknown (not assessable, 
insufficient data).  [Note:  By arbitrary convention, category 9 usually designates the 
“unknown” status of any type of data in a clinical database.]
All of the patients who met the eligibility criteria (with the possible exception of those 
who received no study medication) should be included in the main analysis of the 
response rate.  Patients in response categories 4-9 should be considered to have a 
treatment failure (disease progression).  Thus, an incorrect treatment schedule or drug 
administration does not result in exclusion from the analysis of the response rate.  Precise 
definitions for categories 4-9 will be protocol specific. 
All conclusions should be based on all eligible patients.  Sub analyses may then be 
performed on the basis of a subset of patients, excluding those for whom major protocol 
deviations have been identified (e.g., early death due to other reasons, early 
discontinuation of treatment, major protocol violations, etc.).  However, these sub 
analyses may not serve as the basis for drawing conclusions concerning treatment 
efficacy, and the reasons for excluding patients from the analysis should be clearly 
reported.  The 95% confidence intervals should also be provided. 

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Biochem Sci.  26:61-66.
Borner, C.  (2003).  The Bcl-2 protein family: sensors and checkpoints for life-or-death 
decisions.  Mol Immunol.  39:615-647.
Cory, S., and J.M. Adams.  (2002).  The Bcl2 family: regulators of the cellular life-or-death 
switch.  Nat Rev Cancer.  2:647-656.
Cory, S., D.C. Huang, and J.M. Adams.  (2003).  The Bcl-2 family: roles in cell survival and 
oncogenesis.  Oncogene.  22:8590-8607.
Degenhardt, K., R. Sundararajan, T. Lindsten, et al.  (2002).  Bax and Bak independently 
promote cytochrome C release from mitochondria.  J Biol Chem.  277:14127-14134.
Fadeel, B., B. Zhivotovsky, and S. Orrenius.  (1999).  All along the watchtower: on the 
regulation of apoptosis regulators.  Faseb J.  13:1647-1657.
Gandhi, L., D.R. Camidge, M.R. de Oliveira, et al.  (2011).  Phase I study of navitoclax (ABT-
263), a novel Bcl-2 family inhibitor, in patients with small-cell lung cancer and other solid 
tumors.  J Clin Oncol.  29:909-916.
Investigator's Brochure.  (2011).  ABT-263.  8th Edition, November 2011.  Abbott Laboratories, 
Abbott Park, IL.
Korsmeyer, S.J.  (1999).  BCL-2 gene family and the regulation of programmed cell death.  
Cancer Res.  59:1693s-1700s.
Lindsten, T., A.J. Ross, A. King, et al.  (2000).  The combined functions of pro-apoptotic Bcl-2 
family members bak and bax are essential for normal development of multiple tissues.  Mol Cell.  
6:1389-1399.
Lock, R., H. Carol, P.J. Houghton, et al.  (2008).  Initial testing (stage 1) of the BH3 mimetic 
ABT-263 by the pediatric preclinical testing program.  Pediatr Blood Cancer.  50:1181-1189.
Roberts, A.W., J.F. Seymour, J.R. Brown, et al.  (2012).  Substantial susceptibility of chronic 
lymphocytic leukemia to BCL2 inhibition: Results of a phase I study of navitoclax in patients 
with relapsed or refractory disease.  J Clin Oncol.  30:488-496.
Rudin, C.M., C.L. Hann, E.B. Garon, et al.  (2012).  Phase 2 study of single agent navitoclax 
(ABT-263) and cancer biomarker correlates in patients with relapsed small cell lung cancer.  
Clin Cancer Res.  18:3163-3169.

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Tsujimoto, Y., and S. Shimizu.  (2000).  Bcl-2 family: life-or-death switch.  FEBS Lett.  466:6-
10.
Wei, M.C., W.X. Zong, E.H. Cheng, et al.  (2001).  Pro-apoptotic BAX and BAK: a requisite 
gateway to mitochondrial dysfunction and death.  Science.  292:727-730.
Willis, S., C.L. Day, M.G. Hinds, and D.C. Huang.  (2003).  The Bcl-2-regulated apoptotic 
pathway.  J Cell Sci.  116:4053-4056.
Wilson, W.H., O.A. O’Connor, M.S. Czuczman, et al.  (2010).  Navitoclax, a targeted high-
affinity inhibitor of BCL-2, in lymphoid malignancies: A phase 1 dose-escalation study of safety, 
pharmacokinetics, pharmacodynamics, and antitumour activity.  Lancet Oncol.  11:1149-1159.
Yang, E., and S.J. Korsmeyer.  (1996).  Molecular thanatopsis: a discourse on the BCL2 family 
and cell death.  Blood.  88:386-401.
Malumbres, M., Barbacid, M. (2003). RAS oncogenes: the first 30 years. Nat. Rev. Cancer 3, 
459-465.
Montagut, C., Settleman, J. (2009). Targeting the RAF-MEK-ERK pathway in cancer therapy. 
Cancer Lett. 283, 125-134.
Young, A., Lyons, J., Miller, A.L., Phan, V.T., Alarcón, I.R., McCormick, F. (2009). Ras 
signaling and therapies. Adv. Cancer Res. 102, 1-17.
Rinehart, J., Adjei, A.A., Lorusso, P.M., Waterhouse, D., Hecht, J.R., Natale, R.B., Hamid, O., 
Varterasian, M., Asbury, P., Kaldjian, E.P., et al. (2004). Multicenter phase II study of the oral 
MEK inhibitor, CI-1040, in patients with advanced non-small-cell lung, breast, colon, and 
pancreatic cancer. J. Clin. Oncol. 22, 4456-4462.
Adjei, A.A., Cohen, R.B., Franklin, W., Morris, C., Wilson, D., Molina, J.R., Hanson, L.J., Gore, 
L., Chow, L., Leong, S., et al. (2008). Phase I pharmacokinetic and pharmacodynamic study of 
the oral, small-molecule mitogen-activated protein kinase 1/2 inhibitor AZD6244 (ARRY-
142886) in patients with advanced cancers. J. Clin. Oncol. 26, 2139-2146.
Engelman, J.A., Chen, L., Tan, X., Crosby, K., Guimares, A.R., Upadhyay, R., Maira, M., 
McNamara, K., Perera, S.A., Song, Y., et al. (2008). Effective use of PI3K and MEK inhibitors to 
treat mutant Kras G12D and PIK3CA H1047R murine lung cancers. Nat. Med. 14, 1351-1356.
She, Q.B., Halilovic, E., Ye, Q., Zhen, W., Shirasawa, S., Sasazuki, T., Solit, D.B., Rosen, N. 
(2010). 4E-BP1 is a key effector of the oncogenic activation of the AKT and ERK signaling 
pathways that integrates their function in tumors. Cancer Cell 18, 39-51.

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LoRusso, P., Shapiro, G., Pandya, S.S., Kwak, E.L., Jones, C., Belvin, M., Musib, L.C., de 
Crespigny, A., McKenzie, M., Gates, M.R., et al. (2012). A first-in-human phase Ib study to 
evaluate the MEK inhibitor GDC-0973, combined with the pan-PI3K inhibitor GDC-0941, in 
patients with advanced solid tumors. J. Clin. Oncol. 30 (suppl; abstr 2566).
Bedard, P., Tabernero, J., Kurzrock, R., Britten, C.D., Stathis, A., Perez-Garcia, J.M., Zubel, A., 
Le, N.T., Carter, K., Bellew, K.M., et al. (2012). A phase Ib, open-label, multicenter, dose-
escalation study of the oral pan-PI3K inhibitor BKM120 in combination with the oral MEK1/2 
inhibitor GSK1120212 in patients with selected advanced solid tumors. J. Clin. Oncol. 30 (suppl; 
abstr 3003).
Speranza, G., Kinders, R.J., Khin, S., Weil, M.K., Do, K.T., Horneffer, Y., Juwara, L., Allen, D., 
Williams, P.M., Lih, C.J., et al. (2012). Pharmacodynamic biomarker-driven trial of MK-2206, 
and AKT inhibitor, with AZD6244 (selumetinib), a MEK inhibitor, in patients with advanced 
colorectal carcinoma. J. Clin. Oncol. 30 (suppl; abstr 3529).
Garnett, M.J., Edelman, E.J., Heidorn, S.J., Greenman, C.D., Dastur, A., Lau, K.W., Greninger, 
P., Thompson, I.R., Luo, X., Soares, J., et al. (2012). Systematic identification of genomic 
markers of drug sensitivity in cancer cells. Nature 483, 570-575.
Infante, J.R., Fecher, L.A., Nallapareddy, S., Gordon, M.S., Flaherty, K.T., Cox, D.S., DeMarini, 
D.J., Morris, S.R., Burris, H.A., Messersmith, W.A. (2010). Safety and efficacy results from the 
first-in-human study of the oral MEK 1/2 inhibitor GSK1120212. J. Clin. Oncol. 28, 15s (suppl; 
abstr 2503).
Corcoran RB, Cheng KA, Ebi H, Hata A, Faber AC, Coffee EM, Greninger P, Brown RD, 
Godfrey JT, Cohoon TJ, Song Y, Lifshits E, Hung KE, Shioda T, Dias-Santagata D, Singh A, 
Settleman J, Benes CH, Mino-Kenudson M, Wong KK, Engelman JA.  (2013). Synthetic lethal 
interaction of combined BCL-XL and MEK inhibition promotes tumor regressions in KRAS 
mutant cancer models. Cancer Cell

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APPENDIX A
PERFORMANCE STATUS CRITERIA
ECOG Performance Status Scale
Karnofsky Performance Scale
Grade
Descriptions
Percent
Description
100
Normal, no complaints, no evidence 
of disease.
0
Normal activity.  Fully active, able 
to carry on all pre-disease 
performance without restriction.
90
Able to carry on normal activity; 
minor signs or symptoms of disease.
80
Normal activity with effort; some 
signs or symptoms of disease.
1
Symptoms, but ambulatory.  
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).
70
Cares for self, unable to carry on 
normal activity or to do active work.
60
Requires occasional assistance, but 
is able to care for most of his/her 
needs.
2
In bed <50% of the time.  
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities.  Up and about 
more than 50% of waking hours.
50
Requires considerable assistance and 
frequent medical care.
40
Disabled, requires special care and 
assistance.
3
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours.
30
Severely disabled, hospitalization 
indicated.  Death not imminent.
20
Very sick, hospitalization indicated. 
Death not imminent.
4
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair.
10
Moribund, fatal processes 
progressing rapidly.
5
Dead.
0
Dead.

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APPENDIX B
CTEP MULTICENTER GUIDELINES
If an institution wishes to collaborate with other participating institutions in performing a 
CTEP sponsored research protocol, then the following guidelines must be followed.
Responsibility of the Protocol Chair 

The Protocol Chair will be the single liaison with the CTEP Protocol and Information 
Office (PIO).  The Protocol Chair is responsible for the coordination, development, 
submission, and approval of the protocol as well as its subsequent amendments.  The 
protocol must not be rewritten or modified by anyone other than the Protocol Chair.  
There will be only one version of the protocol, and each participating institution will use 
that document.  The Protocol Chair is responsible for assuring that all participating 
institutions are using the correct version of the protocol.

The Protocol Chair is responsible for the overall conduct of the study at all participating 
institutions and for monitoring its progress.  All reporting requirements to CTEP are the 
responsibility of the Protocol Chair. 

The Protocol Chair is responsible for the timely review of Adverse Events (AE) to assure 
safety of the patients.

The Protocol Chair will be responsible for the review of and timely submission of data 
for study analysis.
Responsibilities of the Coordinating Center

Each participating institution will have an appropriate assurance on file with the Office 
for Human Research Protection (OHRP), NIH.  The Coordinating Center is responsible 
for assuring that each participating institution has an OHRP assurance and must maintain 
copies of IRB approvals from each participating site. 

Prior to the activation of the protocol at each participating institution, an OHRP form 310 
(documentation of IRB approval) must be submitted to the CTEP PIO.

The Coordinating Center is responsible for central patient registration.  The Coordinating 
Center is responsible for assuring that IRB approval has been obtained at each 
participating site prior to the first patient registration from that site.

The Coordinating Center is responsible for the preparation of all submitted data for 
review by the Protocol Chair.

The Coordinating Center will maintain documentation of AE reports.  There are two 
options for AE reporting: (1) participating institutions may report directly to CTEP with a 
copy to the Coordinating Center, or (2) participating institutions report to the 
Coordinating Center who in turn report to CTEP.  The Coordinating Center will submit 
AE reports to the Protocol Chair for timely review.

Audits may be accomplished in one of two ways: (1) source documents and research 
records for selected patients are brought from participating sites to the Coordinating 
Center for audit, or (2) selected patient records may be audited on-site at participating 
sites.  If the NCI chooses to have an audit at the Coordinating Center, then the 
Coordinating Center is responsible for having all source documents, research records, all 

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IRB approval documents, NCI Drug Accountability Record forms, patient registration 
lists, response assessments scans, x-rays, etc. available for the audit.
Inclusion of Multicenter Guidelines in the Protocol

The protocol must include the following minimum information: 
The title page must include the name and address of each participating institution and 
the name, telephone number and e-mail address of the responsible investigator at each 
participating institution.
The Coordinating Center must be designated on the title page.
Central registration of patients is required.  The procedures for registration must be 
stated in the protocol.
Data collection forms should be of a common format.  Sample forms should be 
submitted with the protocol.  The frequency and timing of data submission forms to 
the Coordinating Center should be stated.
Describe how AEs will be reported from the participating institutions, either directly 
to CTEP or through the Coordinating Center.
Describe how Safety Reports and Action Letters from CTEP will be distributed to 
participating institutions.
Agent Ordering

Except in very unusual circumstances, each participating institution will order DCTD-
supplied investigational agents directly from CTEP.  Investigational agents may be 
ordered by a participating site only after the initial IRB approval for the site has been 
forwarded by the Coordinating Center to the CTEP PIO. 

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APPENDIX C
PK SAMPLING GUIDELINES
1) TRAMETINIB PK
PK studies will be done to assess the biodistribution of trametinib.
Plasma concentrations of trametinib will be measured under the direction of GSK.   Analysis will 
be performed by GSK and the results made available to the investigators. 
Specimen Collection
(Details are provided in the “Pharmacokinetic Laboratory Manual” supplied by GSK.  Note:  
This will be disseminated with the clinical protocol and is also available to investigators on 
request from the coordinating center.)
Specimen Collection Schedule (an example of timepoints of collection is listed below.) 

At each time point, collect 2 mL whole blood PK sample into a properly labeled 2 mL 
K2EDTA evacuated blood collection tube.  Record the date and time each sample is 
collected.  Note the sampling time and volume of blood collection may differ with 
specific protocols and/or regimens.  (In general, separate aliquots are required 
for PK studies of individual drugs)

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Schedule for Part 1 (Phase 1b) Schedule A
(All times relative to navitoclax dose, per Section 9.3)
Day of Collection
Planned Collection Time (hr) 
C1D7
Pre-dose (0h,) 2hr, 4h, 6h, 8h (for 
navitoclax only)
C1D8
Pre-dose trametinib (represents 23 hr 
from prior day for navitoclax only)
C1D21
Pre-trametinib (-1h), pre-navitoclax 
(0h), 2h, 4h, 6h, 8h (for both 
navitoclax and trametinib)
C1D22
Pre-trametinib (represents 23h draw, 
for both navitoclax and trametinib)
C2D1
Pre-trametinib (for both navitoclax and 
trametinib)
C4D1
Pre-trametinib (for both navitoclax and 
trametinib)
C8D1
Pre-trametinib (for both navitoclax and 
trametinib)
C12D1
Pre-trametinib (for both navitoclax and 
trametinib)
Schedule for Part 1 (Phase 1b) Schedule B
(All times relative to navitoclax dose, per Section 9.3)
Day of Collection
Planned Collection Time (hr) 
C1D7
Pre-trametinib (-1h), pre-navitoclax 
(0h), 2h, 4h, 6h, 8h (for both 
navitoclax and trametinib)
C1D8
Pre-trametinib (represents 24h draw, 
for both navitoclax and trametinib)
C1D14
Pre-trametinib (-1h), pre-navitoclax 
(0h), 2h, 4h, 6h, 8h (for both 
navitoclax and trametinib)
C1D15
Pre-trametinib (represents 24h draw, 
for both navitoclax and trametinib)
C2D1
Pre-trametinib (for both navitoclax and 
trametinib)
C4D1
Pre-trametinib (for both navitoclax and 
trametinib)
C8D1
Pre-trametinib (for both navitoclax and 

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trametinib)
C12D1
Pre-trametinib (for both navitoclax and 
trametinib) 
Schedule for Part 1 (Phase 1b) Schedule C
(All times relative to navitoclax dose, per Section 9.3)
Day of Collection
Planned Collection Time (hr) 
C1D7
Pre-navitoclax (0h), 2h, 4h, 6h, 8h 
(for both navitoclax and trametinib)
C1D8
Pre-navitoclax (for both navitoclax and 
trametinib)
C1D14
Pre-navitoclax (0h), 2h, 4h, 6h, 8h 
(for both navitoclax and trametinib)
C1D15
Pre-navitoclax (for both navitoclax and 
trametinib)
C2D1
Pre-navitoclax (for both navitoclax and 
trametinib)
C4D1
Pre-navitoclax (for both navitoclax and 
trametinib)
C8D1
Pre-navitoclax (for both navitoclax and 
trametinib)
C12D1
Pre-navitoclax (for both navitoclax and 
trametinib)
Schedule for Part 2 (Phase 2) 
Day of Collection
Planned Collection Time (hr) 
C2D1
Pre-navitoclax (for both navitoclax and 
trametinib)
C4D1
Pre-navitoclax (for both navitoclax and 
trametinib)
C8D1
Pre-navitoclax (for both navitoclax and 
trametinib)
C12D1
Pre-navitoclax (for both navitoclax and 
trametinib)

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Specimen Processing Procedures
Immediately after collection, gently invert (do not shake) the evacuated blood collection 
tube 8-10 times to mix the K2EDTA anticoagulant with the whole blood.  Blood samples 
MUST be placed on wet ice immediately after mixing the blood with the anticoagulant.  
Blood samples should be processed into plasma within 15 minutes of collection (30 
minutes maximum).  Centrifuge samples at 2500 to 3000 rpm for 10 to 15 minutes at 4°C 
to achieve a clear plasma layer over the red cells.  The speed and time may be varied 
according to the make and model of centrifuge used.  Immediately transfer plasma into 
two 1.0 mL Matrix TrackMate ScrewTop tubes (each containing approximately 0.75 mL 
of plasma) and store at -20°C until shipped.  Ship all frozen plasma samples on dry ice, 
overnight.
Specimen Shipping Instructions
Ship PK samples to:  
Covance Laboratories Inc. 
3301 Kinsman Boulevard
Madison, WI 53704   
Tel 608.241.4471
FAX 608.242.7978 
2) NAVITOCLAX (ABT-263) PK
PK studies will be done to assess the biodistribution of navitoclax.
Plasma concentrations of navitoclax will be measured under the direction of AbbVie.   Analysis 
will be performed by AbbVie and the results made available to the investigators. 
Navitoclax (ABT-263) PK Samples
The processing of PK samples should be performed as described below:
1. Collect 3 mL blood in a K2EDTA collection tube.    
2. Immediately invert tube 8-10 times and place in ice bath or cryoblock until ready to 
centrifuge.
3. Centrifuge within 1 hour of collection at approximately 1100-1600xg for approximately 10 
minutes in a refrigerated centrifuge.
4. Transfer plasma into an appropriately labeled screw-capped polypropylene tube using a plastic 

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pipette. 
5. Freeze at –20°C or colder completing process within 2 hours of collection.
6. Store samples at –20 °C or colder until shipment
Shipping of Specimen(s)
The frozen plasma samples for Navitoclax will be packed in dry ice sufficient to last during 
transport for 3 days and shipped from the study site to AbbVie according to instructions from 
AbbVie. An inventory of the samples included will accompany the package. Arrangements will 
be made with AbbVie for the shipment of samples to:
AbbVie Sample Receiving
R43F/AP13A-2 Room 2310
c/o: Delivery Services
1150 S. Northpoint Blvd.
Waukegan, IL 60085
Telephone: 847-937-0889
Telefax:      847-938-9898
E-mail: sample.receiving@abbvie.com

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APPENDIX D
PATIENT DRUG INTERACTIONS HANDOUT AND WALLET 
CARD
Information for Patients, Their Caregivers and Non-Study Healthcare Team on Possible 
Interactions with Other Drugs and Herbal Supplements
Patient 
Name:
     
Diagnosis: 
     
Trial #:
     
Study 
Doctor:
     
Study Doctor 
Phone #: 
     
Study 
Drug(s)
:
Navitoclax (ABT-
263)
Study 
Doctor:
     
Study Doctor 
Phone #: 
     
Study 
Drug(s)
:
Navitoclax (ABT-
263)
Please show this paper to all your healthcare providers (doctors, physician assistants, nurse 
practitioners, pharmacists), and tell them you are taking part in a clinical trial sponsored by the 
National Cancer Institute. 
These are the things that your healthcare providers need to know:
Navitoclax (ABT-263) interacts with certain specific enzyme(s) in your liver or other tissues like 
the gut.
Explanation
CYP 
isoenzymes
The enzymes in question are CYP2C8, CYP2C9, and CYP3A4. Navitoclax 
(ABT-263) is a moderate inhibitor of CYP2C8 and strong inhibitor of 
CYP2C9.  Substrates of CYP2C8 or CYP2C9 with a narrow therapeutic 
window should be used with caution.  Navitoclax (ABT-263) is metabolized 
by CYP3A4 to some extent.  Use caution when coadministered with any 
medications that are considered strong or moderate CYP3A4 inhibitors or 
inducers.                                                                                                   .
These are the things that you need to know:
The study drug navitoclax (ABT-263), may interact with other drugs which can cause side 
effects. For this reason, it is very important to tell your doctors about all your medicines, 
including: (a) medicines you are taking before this clinical trial, (b) medicines you start or stop 
taking during this study, (c) medicines you buy without a prescription (over-the-counter remedy), 
(d) herbals or supplements (e.g. St. John’s Wort). It is helpful to bring your medication bottles or 
an updated medication list with you. 
Before you enroll onto the clinical trial, your study doctor will work with your regular health 
care providers to review any medicines and herbal supplements that are considered substrates of 
CYP2C8 or CYP2C9 with a narrow therapeutic window, and strong or moderate 
inhibitors/inducers of CYP3A4.

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Please be very careful!  Over-the-counter drugs (including herbal supplements) may 
contain ingredients that could interact with your study drug.  Speak to your doctors or 
pharmacist to determine if there could be any side effects. 
Make sure your doctor knows to avoid certain prescription medications. 
Your regular health care provider should check a frequently updated medical reference or 
call your study doctor before prescribing any new medicine or discontinuing any 
medicine.  
Version Aug/2020
(Next page: Patient Drug Interaction Wallet Card)

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133
EMERGENCY 
INFORMATION
DRUG INTERACTIONS 
Show this card to all of your 
healthcare providers. Keep it 
with you in case you go to the 
emergency room.
Tell your doctors before you start or 
stop any medicines.
Check with your doctor or 
pharmacist if you need to use an 
over-the-counter medicine or herbal 
supplement!
Carry this card with you at all times  
Navitoclax (ABT-263) interacts with specific enzymes called CYP3A4, CYP2C8 
and CYP2C9 and must be used very carefully with other medicines.
Patient Name:      
Diagnosis:      
Study Doctor:      
Study Doctor Phone #:      
Your healthcare providers should be aware of any medicines that are strong or 
moderate inhibitors / inducers of CYP3A4, or substrates of CYP2C9 or 
CYP2C8 with a narrow therapeutic window, which should be used with 
caution.
NCI Trial #:      
Before prescribing new medicines, your health care provider should check a 
frequently-updated medical reference for a list of drugs to avoid or contact 
your study doctor.
Study Drug(S): Navitoclax (ABT-263)
Use caution and avoid the 
following drugs if possible: 

No St. John’s Wort, 
grapefruit or grapefruit 
juice can be consumed 
while taking navitoclax 
(ABT-263).

Tell your doctor if you’re 
taking ibuprofen or aspirin.
             Version AUG/2020
For more information: 1-800-4-CANCER
For more information: 1-800-4-CANCER
For more information: 1-800-4-
CANCER
For more information: 1-800-4-CANCER
cancer.gov | clinicaltrials.gov
cancer.gov | clinicaltrials.gov
cancer.gov | clinicaltrials.gov
cancer.gov | clinicaltrials.gov

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APPENDIX E
MEDICATION DIARIES
Please provide attached medication diaries to participants as appropriate.

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135
APPENDIX F
BIOASSAY TEMPLATES
Please include all applicable bioassays.