Clinical trial NCT03428126
Conditions: Malignant Neoplasms of Digestive Organs Colorectal Cancer Colon Cancer
Keywords: Malignant neoplasms of digestive organs Colorectal Cancer Colon Cancer Durvalumab MEDI4736 Trametinib GSK1120212
Sponsor: M.D. Anderson Cancer Center
Start date: 2018-03-21; Completion date: 2022-05-05
Enrollment: 29 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The goal of this clinical research study is to learn if durvalumab and trametinib can help to control microsatellite stable (MSS) colorectal cancer. The safety of these drugs will also be studied.

This is an investigational study. Durvalumab is FDA approved and commercially available for the treatment of previously treated advanced bladder cancer. Trametinib is FDA approved in combination with another drug called dabrafenib for the treatment of unresectable or metastatic melanoma with BRAF V600E or BRAF V600K.

It is investigational to use durvalumab and trametinib to treat MSS colorectal cancer.

Up to 56 participants will be enrolled in this study. All will take part at MD Anderson.

Detailed description:
Study Drug Administration:

Each cycle is 28 days.

Participant will take trametinib tablets by mouth every day with at least 8 ounces of water. Each dose should be taken at about the same time each day, 1 hour before or 2 hours after a meal. Participant should not crush, cut, or chew the tablets. If participant misses a dose of trametinib, participant may take the tablets as soon as participant remembers but only if participant's next scheduled dose is at least 12 hours later. If participant's next scheduled dose is less than 12 hours, participant should wait and take participant's next dose as scheduled.

Participant will take trametinib alone for the first 7 days of the study and then participant will begin receiving it in combination with durvalumab.

Every 4 weeks, participant will receive durvalumab by vein over about 60 minutes.

Length of Treatment:

Participant will be able to receive the study drugs for as long as the doctor thinks it is in participant's best interest. Participant no longer will take the study drugs if intolerable side effects occur or if the study doctor decides that the drugs are no longer working.

It is expected that participation in this study may last about 12 months.

Participation in this study will be over after follow-up.

Study Visits:

On Day 1 of Weeks 0, 2, 4, 6, 12, and then every 4 weeks after that (Weeks 16, 20, 24, and so on):

* Participant will have a physical exam.
* Blood (about 6 tablespoons) will be drawn for routine tests, immune system testing, and biomarker testing.
* If participant had a biopsy at screening, participant will have another biopsy during Week 4 to check the status of the disease and for biomarker testing. Depending on when participant joins the study, this biopsy may be optional.

On Day 1 of Week 8:

* Participant will have a physical exam.
* Blood (about 6 tablespoons) will be drawn for routine tests, immune system testing, and biomarker testing.
* Participant will have a CT scan.

On Day 1 of Week 16 and then every 8 weeks after that (Weeks 24, 32, 40, and so on), participant will have a CT scan.

End-of-Treatment:

About 28 days after participant's last dose of study drugs, participant will have a physical exam.

Follow-Up:

After participant's end-of-treatment visit, participant will be called by the study staff every 3 months for up to 18 months to ask how participant is doing. Each call should last about 5-10 minutes.

Arms: arm 1: Participants take Trametinib tablets by mouth every day. Trametinib taken alone for the first 7 days of the study then participants begin receiving it in combination with Durvalumab.

Participants receive Durvalumab by vein every 4 weeks.

Each cycle is 28 days.
Interventions: intervention 1: Durvalumab intervention 2: Trametinib
Intervention descriptions: intervention 1: Dose Escalation and Dose Expansion Dose: 1500 mg by vein every 4 weeks in a 28 day cycle. intervention 2: Dose Escalation Starting Dose: 2mg by mouth daily in a 28 day cycle.

Dose Expansion Dose: MTD from Dose Escalation.

Protocol documents:
Prot_SAP_000.pdf: 
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i 
TITLE: Phase II Study of Durvalumab (MEDI4736) (anti-PD-L1) and Trametinib 
(MEKi) in MSS Metastatic Colon Cancer. 
 
Coordinating Center: 
University of Texas MD Anderson Cancer Center 
 
Principal Investigator: 
Michael Overman, MD 
 
Department of Cancer Medicine 
 
1515 Holcombe Blvd, Unit 1360 
 
Houston, TX 77030 
 
Telephone: (713) 792-2828 
 
Fax: 713-745-1163 
 
moverman@mdanderson.org 
 
 
Agent(s)/Supplier: 
Medimmune(AstraZeneca)/Novartis 
 
 
Version: 2 dated December 19, 2017  
 


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TABLE OF CONTENTS 
 
Page 
 
ABBREVIATIONS…………………………………………………………………………………………………………………….1 
 
1. OBJECTIVES ............................................................................................................................... 2 
1.1 
Primary Objectives/Endpoints 
1.2 
Secondary Objectives/Endpoints 
 
2. BACKGROUND .......................................................................................................................... 2 
2.1 
Study Disease 
2.2 
Investigational Agents 
2.3 
Rationale 
 
3. PATIENT SELECTION ............................................................................................................... 20 
3.1 
Eligibility Criteria  
3.2 
Exclusion Criteria 
 
4. REGISTRATION PROCEDURES ................................................................................................. 23 
 
5. TREATMENT PLAN .................................................................................................................. 23 
5.1  
Study Design and Duration 
5.2  
Definition of Dose-Limiting Toxicity and Maximum Tolerated Dose 
5.3  
General Concomitant Medication and Supportive Care Guidelines 
5.4  
Restrictions for Patients on Study 
5.5 
Duration of Therapy 
5.6 
Duration of Follow Up 
 
6. DOSING DELAYS/DOSE MODIFICATIONS ............................................................................... 25 
 
7. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ................................................. 36 
7.1  
Definition of Adverse Event 
7.2  
Definition of Adverse Event of Special Interest 
7.3  
Recording of Adverse Events 
7.4  
Reporting of Serious Adverse Events 
7.5 
Definitions and Other Events Requiring Immediate Reporting 
 
 
 
8. PHARMACEUTICAL INFORMATION ........................................................................................ 80 
8.1  
Identity of Investigational Products  
 
9. CORRELATIVE/SPECIAL STUDIES ............................................................................................ 85 


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9.1 
Laboratory Correlative Studies 
 
10. STUDY CALENDAR ................................................................................................................... 92 
 
11. MEASUREMENT OF EFFECT……………………………………………………………………………………………….92 
 
12. DATA REPORTING REQUIREMENTS / STUDY AND DATA MANAGEMENT ......................... 96
 
 
12.1 
Monitoring of the Study 
12.2 
Study Timetable and End of Study 
12.3 
Data Management 
12.4 
AstraZeneca / MedImmune Coverage 
 
13. STATISTICAL CONSIDERATIONS ........................................................................................... 102 
 
13.1 
Endpoints 
 
13.2 
Sample Size Justification 
 
13.3 
Interim Monitoring 
 
13.4 
Analysis Plan 
 
 
 
REFERENCES 
 
APPENDICES 
 
APPENDIX 1 
Performance Status Criteria 
 
APPENDIX 2 
 
 
NIAID and Food Allergy & Anaphylaxis Network guidance for Anaphylaxis Diagnosis .........
 
 
 
 
 


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1
 
 
ABBREVIATIONS 
 
ACS 
 
American Cancer Society 
AE  
 
adverse event 
ALT 
 
alanine aminotransferase 
AST 
 
aspartate aminotransferase 
BUN 
 
blood urea nitrogen 
CEA 
 
carcinoembryonic antigen (CEA) 
CFR 
 
Code of Federal Regulations 
CRC 
 
colorectal cancer 
CRF 
 
case report form 
CTCAE  
Common Terminology Criteria for Adverse Events 
DLT 
 
dose limiting toxicity 
ECOG   
Eastern Cooperative Oncology Group 
ECG 
 
electrocardiogram 
FDA 
 
United States Food and Drug Administration  
ICH 
 
International Committee on Harmonisation 
IP  
 
Investigational Product 
IRB  
 
Institutional Review Board 
MG 
 
Milligram 
MTD  
maximum tolerated dose 
PD  
 
progressive disease 
PFS 
 
progression-free survival 
OTC 
 
over-the-counter 
OS  
 
overall survival  
RBC 
 
red blood cells 
RECIST  
Response Evaluation Criteria In Solid Tumors 
RR  
 
response rate 
SAE 
 
serious adverse event 
HNSCC   
head and neck squamous cell carcinoma 
UG  
 
Microgram 
WBC  
white blood cell 
 
 
 
 
 
 
 
 


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1. OBJECTIVES 
 
1.1. Primary Objective/Endpoint 
1.1.1. Objective 
1.1.1.1. 
To determine efficacy of this combination as assessed by the immune-related 
response rate 
1.1.2. Endpoint 
1.1.2.1. 
Best overall response rate (CR+PR) by immune-related response rate. 
 
1.2. Secondary Objectives/Endpoints 
1.2.1. Objectives 
1.2.1.1. 
To assess the safety and tolerability of the combination in this population. 
1.2.1.2. 
Additional efficacy assessments of treatment activity  
1.2.1.3. 
To evaluate the immune microenvironment and systemic changes as a result of 
treatment. 
1.2.2. Endpoints 
1.2.2.1. 
To assess the safety and tolerability of the combination in this population. 
1.2.2.2. 
Progression free survival as determined by irRC 
1.2.2.3. 
Time to treatment failure by irRC 
1.2.2.4. 
Disease control rate and duration of stable disease 
1.2.2.5. 
Overall survival 
1.2.2.6. 
Change in immune cell composition as determined by comparative analysis of 
pre- and post-treatment tumor biopsies, and peripheral blood samples.  
1.2.2.7. 
Exploratory analysis of efficacy endpoints according to CMS subtype 
 
2. BACKGROUND 
 
2.1  
Study Disease 
 
 
2.1.1 
Colon Cancer Background and Treatment Options 
Colorectal cancer (CRC) is the third most common cancer in the United States with an 
estimated 136,830 new cases and 50,310 deaths in 2014 [1].  Approximately 20-25% of CRC 
patients will have distant metastatic disease at the time of diagnosis, and an additional 40-
50% of patients will eventually develop CRC liver metastases (CRCLM) [2].  While treatment 
of early stage disease is highly successful with 5-year survival rates over 70%, this rate drops 
to approximately 10% in the metastatic setting. Front-line treatment options for metastatic 


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disease typically involve 5-FU based regimens along with oxaliplatin, irinotecan, 
bevacizumab, cetuximab, and durvalumab. Patient can achieve excellent disease control in 
the first and second line settings with various combination regimens. Unfortunately, 
patients will typically progress after their tumors become resistant to these therapies. There 
are currently two approved agents in the 3rd line setting, regorafenib and TAS-102, but 
these are typically either poorly tolerated or are of limited benefit. 
 
 
2.1.2 
Colorectal cancer and Immune function 
Significant progress has been made in the characterization of colorectal tumor micro-
environment, and there is evidence that CRC is an immune sensitive malignancy. Regulatory 
T cells accumulate in CRC and as a consequence suppress cytotoxic and helper T-cell activity 
[Svensson 2012]. More importantly, there is strong evidence that the presence of immune 
cells in CRC is predictive of patient outcomes. Intratumoral density of T cells including 
cytotoxic (CD8+) and memory (CD45RO+) has been shown to negatively correlate with risk 
of recurrence in early stage CRC [Pages 2009]. In any stage of disease, decreased density of 
CD8+ lymphocytic infiltrate is associated with primary tumor growth and metastatic 
progression [Mlecnik 2011, Pages 2005]. Efforts by Galon and colleagues have shown than 
an immune score based on T-cell infiltration significantly predicts disease-free and overall 
survival. Further, T-cell infiltration of liver metastases is common, and positively correlates 
with survival [Katz 2013]. Improved survival is significantly associated with number of CD4+ 
and a higher proportion of CD8+ T-cells, while worse outcomes are seen with greater 
proportions of Treg cells. There is a strong association between the presence of a cytotoxic 
infiltrate and disease control at any stage and at metastatic sites of disease. 
 
 
2.1.3 
Immune Checkpoint Inhibition in CRC 
Checkpoint blockade has already been found to be successful in treating mismatch repair 
deficient CRC. The initial results from the first study of PD-1 blockade with the antibody 
pembrolizumab report excellent disease control in this population [Le 2015]. 78% of 
patients demonstrated immune-related progression free survival and 40% had an immune-
related objective response. Within the same study, all patients with microsatellite stable 
disease progressed on therapy. This suggests that there are important difference between 
the MSI and MSS populations, and that checkpoint blockade monotherapy is likely to be 
insufficient to generate a response in the majority of MSS patients. 
 
2.2  
Investigational Agents 
 


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2.2.1 Durvalumab Background 
Durvalumab is a human immunoglobulin G (IgG)1 kappa mAb directed against human 
PD-L1. Durvalumab is expressed in Chinese hamster ovary cells and has an overall molecular 
weight of approximately 149 kDa. Durvalumab selectively binds with high affinity to human 
PD-L1 and blocks its ability to bind to the PD-1 and CD80 receptors, respectively. The 
fragment crystallizable (Fc) domain of durvalumab contains a triple mutation in the 
constant domain of the IgG1 heavy chain that reduces binding to the complement 
component C1q and the Fc gamma receptors responsible for mediating antibody-
dependent cell-mediated cytotoxicity (ADCC) [38]. 
 
2.2.2 Durvalumab Pre-Clinical Experience 
Programmed cell death 1 (CD279) is a member of the immunoglobulin superfamily of 
molecules involved in regulation of T-cell activation. It is found on T cells, B cells, 
macrophages, NK cells, dendritic cells, and mast cells. It has also been described on 
peripheral tissues including cardiac endothelium, lung, small intestine, keratinocytes, islet 
cells of the pancreas, and syncytiotrophoblasts in the placenta as well as a variety of tumor 
cell types [39-45]. Programmed cell death ligand 1 (CD274, B7-H1) is constitutively 
expressed on many hematopoietic cells, but may be upregulated in hematopoietic and non-
hematopoietic cells. Regulation of PD-L1 is mediated, in part, by type I and type II interferon 
(IFN). Programmed cell death ligand 2 (PD-L2; B7-DC) was identified in 2001 [43, 46]. Its 
expression is far more restricted and is confined to hematopoietic cells. Engagement of PD-
1 on T cells inhibits activation with downstream effects on cytokine production, 
proliferation, cell survival, and transcription factors associated with effector T-cell function 
[47-52]. 
 
Durvalumab has shown the following activity as an anti-PD-L1 molecule: 
• Durvalumab binds to PD-L1 and blocks its interaction with PD-1 and CD80. 
• Durvalumab can relieve PD-L1-mediated suppression of human T-cell activation in vitro. 
• Durvalumab inhibits tumor growth in a xenograft model via a T-cell-dependent 
mechanism. 
• A surrogate anti-mouse PD-L1 antibody resulted in improved survival in a syngeneic tumor 
model as monotherapy and resulted in complete tumor regression in > 50% of treated 
mice when given in combination with chemotherapy. 
• In the same study, anti-mouse PD-L1 antibody-treated mice were completely tumor free 3 
months after tumor implantation and demonstrated long-term immunity during re-
challenge. 
• In a subsequent study in the same syngeneic model, the combination of an anti-mouse 
PD-L1 antibody and anti-CTLA-4 antibody resulted in complete tumor regression in all 
mice treated. 


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• Prevalence of PD-L1 expression on the surface of human tumors, ranging from 
approximately 0% to 35%, was demonstrated in a broad survey of samples derived from 
tumor types of interest. 
 
The cynomolgus monkey is considered to be the only relevant nonclinical species for 
evaluation of local and systemic toxicities of Durvalumab. In addition, in vivo in cynomolgus 
monkeys, Durvalumab suppresses soluble programmed cell death ligand 1 (sPD-L1) in serum 
and fully occupies membrane PD-L1 on various leukocyte subsets at doses equal to or more 
than 0.1 mg/kg (lowest dose tested) with a dose-related duration of suppression and 
occupancy. 
 
In general, there were no Durvalumab-related adverse effects in toxicology studies 
conducted in cynomolgus monkeys with Durvalumab that were of relevance to humans. 
Adverse findings in the non-Good Laboratory Practice (GLP) pharmacokinetic 
(PK)/pharmacodynamic and dose range-finding study (4 doses over 5 weeks), and a GLP 4-
week repeat-dose toxicity study were consistent with antidrug antibody (ADA)-associated 
morbidity and mortality in individual animals. The spectrum of findings, especially the 
clinical signs and microscopic pathology, in a single animal in the GLP, 4-week, repeat-dose 
study was also consistent with ADA immune complex deposition, and ADA:Durvalumab 
immune complexes were identified in a subsequent non-GLP, investigative 
immunohistochemistry (IHC) study. Similar observations have been reported by 
MedImmune in cynomolgus monkeys administered human mAbs unrelated to Durvalumab. 
Given that immunogenicity of human mAbs in nonclinical species is not generally predictive 
of responses in humans, the ADA-associated morbidity and mortality were not taken into 
consideration for the determination of the no-observed-adverse-effect level (NOAEL) of 
Durvalumab. Interim audited data from the dosing phase of the pivotal 3-month GLP 
toxicity study with Durvalumab in cynomolgus monkeys showed that subchronic dosing of 
Durvalumab was not associated with any adverse effects. Therefore, the NOAEL of 
Durvalumab in all the general toxicity studies was considered to be 100 mg/kg, the highest 
dose tested in these studies. In addition to the in vivo toxicology data, no unexpected 
membrane binding of Durvalumab to human or cynomolgus monkey tissues was observed 
in GLP tissue cross-reactivity studies using normal human and cynomolgus monkey tissues. 
Finally, in vitro cytokine release studies showed that Durvalumab did not induce cytokine 
release in blood from any donor. 
 
2.2.3 Durvalumab Clinical Experience 
As of July 12, 2016, across the entire clinical development program, an estimated 4067 
patients have been exposed to 1 or more doses of durvalumab in ongoing AstraZeneca 


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sponsored Phase I to III studies, either as monotherapy or in combination and 5911 patients 
where the treatment arm is blinded. Additionally, approximately 4000 patients have been 
exposed to 1 or more doses of durvalumab in ESR/IITs. Estimates of overall cumulative 
patient exposure based on actual exposure data from any completed clinical trials and the 
enrolment/randomisation schemes for ongoing open label and blinded trials are: 3723 
patients received durvalumab monotherapy and 3372 patients received durvalumab in 
combination with tremelimumab. No AstraZeneca or MedImmune studies have been 
completed and no study has terminated prematurely due to toxicity. The total post-
marketing exposure to durvalumab from May 2017 to the 12 July 2017 was estimated to be 
approximately 1.46 patient-years. 
 
Study CD-ON-MEDI4736-1108: NSCLC: As of 24 October 2016, 304 NSCLC patients had 
received durvalumab monotherapy of whom 272 comprised the full analysis set (FAS, 
defined as all patients who had measurable disease at baseline per blinded independent 
central review [BICR] and who had an opportunity to be followed for at least 24 weeks by 
the DCO date of the 24 October 2016. The objective response rate (ORR), was 22.6% and 
4.6% in PD-L1 positive (defined as having tumour cells [TX] ≥25%) and negative patients, 
respectively. The 12-month OS rate was 55.8% and 38.8% in PD-L1 positive and negative 
patients, respectively. HNSCC: As of 29 April 2016, 62 patients with recurrent/metastatic 
SCCHN had received durvalumab monotherapy. Among seven responders, six patients had a 
DOR for ≥12 months with longest DOR being 19.8 months. Six and 12 month OS is 62% and 
42%, respectively. Urothelial Carcinoma: As of DCO on 24 October 2016, 191 patients had 
been enrolled into the urothelial cell cohort. The ORR was numerically higher in the PD-L1 
high (TC ≥25% or IC ≥25%) subgroup (27.6%) compared with the PD-L1 low/negative (TC 
<25% and IC <25%) subgroup (5.1%); and 17.8% overall regardless of PDL1 expression. The 
median TTR was 1.41 months (range 1.2 to 7.2); the median DOR has not yet been reached 
(range 0.9+ to 19.9+). At the DCO, 26 of 34 responders (76.5%) had an ongoing response; 17 
patients had a DOR ≥ 6 months and 10 patients had a DOR ≥9 months. The disease control 
rate (DCR, defined as any complete response (CR)/partial response (PR) or stable disease 
(SD) >6 weeks) by BICR assessment was 36.6% (95% CI: 29.8, 43.9). The median PFS by BICR 
assessment was 1.5 months (95% CI: 1.4, 1.9). The PFS rate at 6 months was 21.7% (95% CI: 
15.8, 28.3). The median OS was 18.2 months (95% CI: 8.1, not estimable); the OS rate at 6, 9 
and 12 months was 64.0% (95% CI: 56.2, 70.9), 57.5% (95% CI: 47.2, 66.5), and 55.0% (95% 
CI: 43.9, 64.7), respectively. Results for all efficacy endpoints were similar between the UC 
cohort (As-treated Population) and the 2L+ post-platinum UC subgroup (As-treated 
Population). HCC: Of the 970 patients in the total 10 mg/kg group, 40 had HCC and were 
included in the HCC cohort, which was analyzed for efficacy using a DCO of the 24 October 


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2016. ORR, based on RECIST v1.1 was 10% (95% CI: 2.8, 23.7). The median PFS was 2.7 
months (95% CI: 1.4, 5.3). The PFS rate at 12 months was 20.7% (95% CI: 9.2, 35.3). The 
median OS was 13.2 months (95% CI: 6.3, 21.1); the OS rate at 6, 9 and 12 months was 
76.5% (95% CI: 59.6, 87.0), 62.3% (95% CI: 44.7, 75.8) and 56.1% (95% CI: 38.4, 70.5), 
respectively. Other indications: In PD-L1 unselected patients, the ORR, based on investigator 
assessment per RECIST v1.1, ranged from 0% in uveal melanoma to 17.4% in advanced 
cutaneous melanoma, and DCR-24w ranged from 4.2% in TNBC to 39.1% in advanced 
cutaneous melanoma. Across the PD-L1 high tumours, ORR was >10% for advanced 
cutaneous melanoma (33.3%). In the PD-L1 positive subset, DCR-24w was >10% in advanced 
cutaneous melanoma (66.7%). 
 
Study D4190C00007: As of the DCO of 03 May 2016 among the 40 patients with MDS 
treated in Study D4190C00007, the best overall responses were mCR in 13 patients (32.5%); 
SD in 6 patients (15.0%); and PD in 12 patients (30.0%). The remaining 9 patients (22.5%) 
did not meet the criteria for complete remission, mCR, partial remission, SD, or PD at the 
date of assessment. 
 
ATLANTIC: A total of 444 patients were enrolled and treated in ATLANTIC (111 in Cohort 1 
[EGFR/ALK+], 265 in Cohort 2 [ERK/ALK wild type] and 68 in Cohort 3 [ERK/ALK wild 
type] [TC ≥90%]). Of these 444 patients, 28 (6.3%) patients were still on treatment at the 
time of the 03 June 2016 DCO, and 78 (17.6%) patients had completed 12 months of 
treatment. Durvalumab demonstrated good clinical activity based on ORR in patients with 
locally advanced or metastatic NSCLC who had received at least 2 prior systemic treatment 
regimens across various subgroups. In the PD-L1 unselected patients (ie, pre-enrichment) in 
the EGFR/ALK wild type/unknown Cohort 2, the ORR was 10.4% (95% CI: 6.2, 16.2). The 
response rate in Cohort 2 was numerically higher in the PD-L1 high (TC ≥25%) patients 
compared with PD-L1 low/negative patients (16.4%, 95% CI: 10.8, 23.5; versus 7.5%, 95% CI: 
3.1, 14.9). In all cohorts, the response rate was similar between the non-squamous patients 
and the full population with the same PD-L1 expression cut off. The response rate was 
numerically higher with the higher PD-L1 cut off (TC ≥90%): 30.9% (95% CI: 20.2, 43.3) in 
Cohort 3 (TC ≥90%) and 23.2% (95% CI: 16.4, 31.1) in the combined Cohorts 2 and 3 with 
PD-L1 TC ≥90%. Responses were observed in the EGFR/ALK+ Cohort 1, but the rate was 
generally lower than the other cohorts (12.2%, 95% CI: 5.7, 21.8 for the PD-L1 high [TC 
≥25%] group; 3.6%, 95% CI: 0.1, 18.3 for the PD-L1 low/negative group). Good durability 
was seen across responders. For patients who responded, the response was durable across 
various subgroups (median DOR in Cohort 2, which had 12 months of follow up: not reached 
for the PD-L1 unselected group; 12.3 months in the PD-L1 high [TC ≥25%] group; and not 


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reached for the PD-L1 low/negative group). However, the data were limited by the length of 
follow-up for Cohort 1 (EGFR/ALK+) and Cohort 3 (TC ≥90%), which had at least 6 months of 
follow-up. The median OS was highest in the PD-L1 high (TC ≥25%) patients with the OS rate 
at 6 and 12 months of 67.4% and 47.7%, respectively, in Cohort 2. For the PD-L1 unselected 
patients, the OS rate at 6 and 12 months was 58.4% and 37.9%, respectively. For the PD-L1 
low/negative patients, the OS rate at 6 and 12 months was 60.3% and 34.5%, respectively. 
 
PACIFIC: As of the DCO, 13 February 2017, 476 and 237 patients with NSCLC were 
randomized to the durvalumab and placebo arms respectively. The median PFS by BICR was 
significantly longer with durvalumab treatment (16.8 months [95% CI: 13.0, 18.1]) 
compared with placebo (5.6 months [95% CI: 4.6, 7.8]); stratified hazard ratio for disease 
progression or death, 0.52; 95% CI: 0.42, 0.65; p<0.001. The 12 month PFS rate was 55.9% 
(95% CI: 51.0, 60.4) with durvalumab vs 35.3% (95% CI: 29.0, 41.7) with placebo and the 18 
month PFS rate was 44.2% (95% CI: 37.7, 50.5) with durvalumab vs 27.0% (95% CI: 19.9, 
34.5) with placebo. PFS improvement with durvalumab was demonstrated across all pre-
specified subgroups and irrespective of pre-cCRT PD-L1 expression (hazard ratios, 0.59; 95% 
CI: 0.43, 0.82 for TC <25%, and 0.41; 95% CI: 0.26, 0.65 for TC ≥25%). 
 
ORR was 28.4% (126/443 patients; 95% CI: 24.3, 32.9) in the durvalumab group compared 
with 16.0% (34/213 patients; 95% CI: 11.3, 21.6) in the placebo group. OS data were 
considered immature at the time of analysis. 
 
The median DOR was longer in the durvalumab group; 72.8% vs 46.8% of patients had 
ongoing response at 18 months compared with placebo. The median time to death or 
distant metastasis was longer with durvalumab than with placebo (23.2 months vs 14.6 
months; P<0.001). 
 
HAWK: As of the DCO, 31 March 2017, 111 patients with HNSCC were treated with 
durvalumab, had measurable disease at baseline and were evaluable. Durvalumab 
demonstrated clinically meaningful antitumour activity in patients with PD-L1 high (≥25% 
TC) HNSCC. ORR, based on BICR assessment using RECIST v1.1 was 16.2% (95% CI: 9.90, 
24.41). The median duration of treatment was 3.45 months (range 0.3 to 12.2 months) and 
the median time to onset of response was 2.0 months (range 1.64 to 9.20 months). 
Responses appeared durable with 55% of patients having ongoing responses at the DCO. 
The median PFS was 2.1 months (95% CI: 1.9, 3.7). The median OS was 7.1 months (95% CI: 
4.9, 9.9); the OS rate at 12 months was 33.6% (95% CI: 24.8, 42.7). 
 


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Study CD-ON-MEDI4736-1161: Of the 68 patients with metastatic or unresectable 
melanoma treated with the combination of durvalumab and BRAFi/MEKi, 65 patients were 
evaluable for response (DCO 21 August 2015). A total of 37 patients (54.4%) had a best 
overall response of confirmed or unconfirmed CR and PR. The confirmed DCR (CR + PR + SD) 
for ≥12 weeks was 73.5%. 
 
All 67 patients who have been treated in Study CD-ON-MEDI4736-1161 had at least 1 AE 
(Table 34). Overall, the most frequently reported (>10% patients) AEs (all grades, regardless 
of causality) in order of decreasing frequency were diarrhea (58.2%); fatigue (47.8%); 
pyrexia (41.8%); vomiting (37.3%); chills and nausea (32.8% each); decreased appetite 
(31.3%); arthralgia and rash (28.4% each); pruritus (26.9%); asthenia and edema peripheral 
(25.4% each); constipation, cough and headache (23.9% each); dry mouth (22.4%); 
dyspnoea (20.9%); anemia, blood creatine phosphokinase increased and dermatitis 
acneiform (19.4% each); abdominal pain and rash maculo-papular (17.9% each); AST 
increased, folliculitis and myalgia (16.4% each); ALT increased, hyperhidrosis and insomnia 
(14.9% each); dizziness and pain in extremity (13.4%); back pain, influenza-like symptoms 
and night sweats (11.9%); and alopecia and hypertension (10.4%). 
 
Thirty-four of 67 treated patients (50.7%) reported SAEs. SAEs occurring in >1 patient by 
order of decreasing frequency were: pyrexia (6 patients); vomiting (4 patients); atrial 
fibrillation, diarrhea, ejection fraction decreased and nausea (3 patients each); anemia, 
asthenia, gastrointestinal hemorrhage, thrombosis and transaminases increased (2 patients 
each). 
 
Ten patients (14.9%) permanently discontinued treatment with investigational products due 
to AEs. These events included choroidal effusion, GGT increased, infusion-related reaction, 
ILD, liver function test increased, platelet count decreased, oedema, paraesthesia, 
tubulointerstitial nephritis and transaminases increased (1 patient each). Three deaths have 
been reported in this study. One death from Cohort A resulted from an event of metastases 
to meninges, 1 death from Cohort B resulted from an event of cardiopulmonary failure and 
the other death from Cohort C resulted from an event of pyrexia. None of the events were 
considered related to investigational product. A total of 61 patients (91.0%) treated with 
study drugs experienced at least 1 AESI (Table 35). The most common AESI was (grouped 
term) diarrhea (39 patients [58.2%]). Other common AESIs (grouped term) were: rash (35 
patients [52.2%]); dermatitis (28 patients [41.8%]); select hepatic events (16 patients 
[23.9%]); and select renal events (9 patients [13.4%]). There was an increased incidence of 


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10
events in the diarrhea, rash, dermatitis and select renal events categories compared to the 
durvalumab monotherapy pool. 
 
The PK profiles of durvalumab as monotherapy and in combination with tremelimumab are 
described based on data from key studies. Based on population PK 
modelling, the estimated half-life of durvalumab is approximately 17 days following 10 
mg/kg Q2W dose. Durvalumab monotherapy (Study CD-ON-MEDI4736-1108): As of 24 
October 2016, PK data were available for 993 patients who have been treated with 
durvalumab 0.1 to 10 mg/kg Q2W or 15 mg/kg Q3W (dose escalation), 10 mg/kg Q2W 
(dose-expansion), and 20 mg/kg Q4W (dose-exploration) durvalumab administered as an iv 
infusion over 60 minutes. Following the first iv dose, durvalumab exhibited nonlinear PK at 
doses <3 mg/kg Q2W likely due to saturable target-mediated CL and exhibited linear PK at 
doses ≥3 mg/kg Q2W. The AUC0-14 increased dose-proportionally at doses of 3 to 20 mg/kg 
and more than dose proportionally at doses of <3 mg/kg, likely due to saturable target-
mediated CL. Cmax increased in a dose-proportional manner within the dose range 
examined. The steady state was achieved at approximately Week 16. Accumulation of 
durvalumab was observed following repeated dosing. Mean AR ranged from 0.64 to 1.87 
and 3.16 to 4.93 for Cmax and Ctrough, respectively. 
 
The ADA profiles of durvalumab as monotherapy and in combination with tremelimumab 
are described based on data from key studies. Durvalumab monotherapy (Study CD-ON-
MEDI4736-1108): As of 24 October 2016, a total of 835 patients provided samples for ADA 
analysis. Only 26 of 835 patients (3.1%) were ADA positive. Three patients were nAb 
positive. Based on population PK covariate analysis, ADA positive status was not associated 
with a clinically relevant reduction of exposure to durvalumab. At the 10 mg/kg Q2W dose, 
sPD-L1 suppression in ADA positive patients was similar to that observed in ADA negative 
patients. The relevance of ADA on safety and efficacy is unknown given the small number of 
ADA positive patients. Details on the safety and efficacy profile of durvalumab monotherapy 
and in combination with BRAF/MEKi are listed above. Refer to the current durvalumab 
Investigator’s Brochure (v11) for a complete summary of non-clinical and clinical 
information including safety, efficacy and pharmacokinetics. 
 
 
2.2.4 Trametinib background 
Trametinib (GSK/NOVARTIS1120212) is a selective MEK1 and MEK2 inhibitor with selective 
activity towards BRAF and RAS mutant cancer cell lines and hematopoietic cancer cells from 
AML and CML origins.  Trametinib inhibited the proliferation of most of the BRAF mutant 


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melanoma cell lines tested (22 of 25), and it effectively inhibited the growth of BRAF mutant 
melanoma xenografts in vivo alone or in combination with dabrafenib.  It causes inhibition 
of ERK phosphorylation leading to G1 cell cycle arrest and tumor xenograft growth 
inhibition in vivo following oral dosing. 
 
2.2.4.1  
Biochemical characterization 
The in vitro activity of trametinib was evaluated using recombinant kinase domains of 
various kinases to determine the potency and selectivity of the compound.  Trametinib was 
shown to be a potent and selective allosteric inhibitor of MEK1 and MEK2 (MEK1/MEK2).  In 
a 3 protein coupled-enzyme system using BRAFV600E or truncated c-RAF and inactive MEK1 
or MEK2 and inactive ERK, trametinib strongly inhibited the phosphorylation of ERK (IC50s 
3.5 to 11 nM). Further investigations demonstrated the ability of trametinib to block BRAF 
catalyzed MEK1/MEK2 activation by binding to the unphosphorylated MEK1/MEK2 (IC50 
=0.7 and 0.9 nM, respectively) as well as its ability to inhibit the kinase activity of 
phosphorylated MEK1/MEK2 (IC50=13.2 and 10.7 nM, respectively).  Additional studies 
showed that trametinib strongly bound to the unphosphorylated MEK1 and had a very slow 
off-rate.  Phospho-mapping by liquid chromatography with mass spectrometry (LC-MS) 
identified that trametinib blocks phosphorylation of Ser218 and not Ser222 on MEK1 by 
BRAFV600E.  Inhibition by trametinib was noncompetitive with ATP.   
 
Trametinib was evaluated to see if it had any direct action on molecules up-stream of 
MEK1/MEK2 in the MAP kinase pathway.  Trametinib did not inhibit BRAF or CRAF kinase 
activity, as it did not affect the phosphorylation of myelin basic protein (MBP) mediated by 
BRAF or CRAF at concentrations up to 10 μM.  
 
Trametinib was inactive against 44 other kinases screened at GSK/NOVARTIS (IC50>10 M) 
and against 131 additional kinases tested at Institutes for Pharmaceutical Discovery, 
Branford, CT at a single concentration (inhibition <50% at 10 μM). It did not affect specific 
ligand bindings to 23 receptors or 7 non-kinase enzymes, indicating a high degree of 
selectivity.  This property is explained by the fact that trametinib is a non-ATP competitive, 
allosteric binding inhibitor, and hence does not share the promiscuity observed with ATP-
competitive kinase inhibitors.  Therefore, trametinib is highly specific for the MEK1 and 
MEK2 kinases (Section 1.5.21.5.2) and is unlikely to have any significant off-target 
pharmacological activity. 
 
In summary, trametinib is a potent and selective inhibitor of MEK1 and MEK2 kinase 
activity. 


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12
 
2.2.5 Trametinib Pre-Clinical Experience 
 
2.2.5.1  
Safety Pharmacology 
In an exploratory modified neurobehavioral screen, a single oral dose of 100 mg/kg 
trametinib was administered to male rats.  Subsequent studies showed that this dose leads 
to morbidity and mortality.  Inhibition of body weight gain, diarrhea, prone position, 
blepharoptosis, piloerection, reduced spontaneous locomotion and mydriasis, were 
observed between 2 and 24 hours post dose.  Comparable findings have not been observed 
in repeat dose toxicity studies at significantly lower, tolerated doses in rats and dogs, 
therefore, at relevant tolerated doses, trametinib is not considered to have any significant 
effects on general behavior, physiologic function or acute neurotoxicity. 
 
No significant respiratory effects were seen in rats following single doses up to 0.125 mg/kg 
trametinib as assessed by measurement of ventilatory function and airway resistance.  A 
dose of 0.125 mg/kg produced a mild, transient decrease in body temperature (up to 0.8°C) 
at 1 hour post dose, which by itself does not appear to result in significant toxicity.  
However, this dose was not tolerated in repeat dose studies in rats due to significant dermal 
toxicity.   
 
Trametinib inhibited hERG channel repolarization in HEK293 cells with an IC50 of 1.54 μM 
(950 ng/mL).  To determine the potential effect of hERG inhibition, a rabbit left ventricular 
wedge assay was performed, which demonstrated that trametinib had no significant effect 
on QT interval at concentrations up to 30 μM (18450 ng/mL; limit of solubility).  However, 
significant decreases in isometric contractile force occurred at concentrations of 10 μM 
(6150 ng/mL) and 30 μM. Trametinib also decreased the Tp-e interval at a concentration of 
30 μM.  These effects occurred at concentrations which far exceed clinical exposures (Cmax 
of 22 ng/mL) at the therapeutic dose of 2 mg/day. 
 
In an exploratory assessment of potential effects of trametinib on cardiovascular function, a 
single intravenous infusion of trametinib in dogs at 1 mg/kg (a dose that when given orally 
produced acute, severe morbidity) over 10 minutes (Cmax of 2.5 μM or 1500 ng/mL) 
produced no changes in electrocardiogram (ECG) parameters, blood pressure or heart rate 
during the 30 minute measurement period.  In the definitive oral cardiovascular safety 
pharmacology study in dogs, single oral doses up to 0.075 mg/kg in dogs (a dose that 
produced morbidity following repeat dosing) produced no changes in arterial blood 
pressure, heart rate, body temperature or ECG intervals, including QTc. 


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In summary, while trametinib demonstrated effects on cardiac electrophysiology in vitro, 
the concentrations at which these effects were observed far exceed the free fraction 
concentrations of tolerated exposures in repeat dose toxicity studies in rats and dogs and 
steady state exposures in subjects at the proposed clinical dose of 2 mg/day.  To date, there 
have been few significant clinical QTc or ECG effects observed in subjects taking trametinib. 
 
2.2.5.2  
Pharmacokinetics and Product Metabolism in Animals 
The nonclinical pharmacokinetics of trametinib were similar across the species (mouse, rat, 
dog and monkey).  Low plasma clearance relative to liver blood flow and generally long half-
lives likely contribute to the accumulation upon repeat dosing which is consistent with 
observations in humans.  Upon achieving steady-state, by 7 days for mice and by 3 weeks 
for rats and dogs (based on sparse sampling study design), the exposure of trametinib 
generally increased dose proportionally, which is consistent with observations in humans 
(steady state appeared to be achieved by Day 15).  
 
The volume of distribution of trametinib was generally greater than total body water for all 
species, consistent with the observed wide distribution to tissues in the rat. There was no 
selective association of drug-related material with melanin containing tissues. Plasma 
protein binding was high in nonclinical species and humans (>95%).  In vitro blood cell 
association in humans was concentration dependent with a high blood to plasma ratio 
(ranged from 3 to 8) at the clinically relevant trametinib concentrations of 1 and 10 ng/mL.  
Nonclinical species, including rats and dogs, showed protracted elimination of DRM (Drug 
Related Material) consistent with a high volume of distribution, long half-life, and the PK 
data of trametinib in subjects with solid tumors. 
 
Absorption and systemic availability in nonclinical species and humans was moderate to 
high (>40% to approximately 100%).  After absorption, the fecal route of elimination was 
the major excretory pathway in humans, rats and dogs.  In humans, trametinib is eliminated 
predominantly by hydrolytic deacetylation, either deacetylation alone (M5) or in 
combination with mono-oxygenation (M7). The enzymes involved are likely hydrolytic 
enzymes, such as esterases or amidases that are not generally associated with drug 
interaction risks.   
 
For the nonclinical species, trametinib was the major circulating component (> 60% of DRM) 
in plasma at all sampling time points.  In humans, trametinib partitions in red blood cells 
and the majority of the circulating radioactivity is present as trametinib in blood (78-95% of 


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DRM). Three minor metabolites M5, M6 and M7 were identified with the deacetylated 
metabolite (M5), which was shown to have similar in vitro pharmacological activity as 
parent, accounting for ≤11% of plasma (rat and dog) or blood DRM (human).  In an earlier 
investigation of plasma metabolites in humans following repeat dosing, the metabolites do 
not appear to accumulate to the same degree as parent.  Qualitatively, all of the major 
metabolites of trametinib observed in humans have been detected in the nonclinical 
species. 
 
Based on in vitro studies, trametinib is not an inhibitor of CYP1A2, CYP2A6, CYP2B6, CYP2D6 
and CYP3A4.  Although trametinib was found to be an in vitro inhibitor of CYP2C8, CYP2C9 
and 2C19, inducer of CYP3A4 and inhibitor of the transporters (OATP1B1, OATP1B3, Pgp and 
BCRP), its low efficacious dose, and low clinical systemic concentration (22.2 ng/mL or 0.04 
μM at 2 mg) relative to the in vitro inhibition/induction potency suggests an overall low 
potential for drug-drug interactions.   
 
2.2.5.3  
Toxicology 
The nonclinical toxicology findings associated with trametinib administration to mice, rats 
and dogs are consistent with pharmacologically mediated changes as a result of 
MEK1/MEK2 inhibition and disruption of MAPK signaling pathways.  Trametinib caused 
adverse effects in a variety of tissues and systems (skin, gastrointestinal tract, phosphate 
homeostasis, liver, ovary, bone and hematological tissues) mainly at doses ≥0.03 
mg/kg/day.  The majority of the findings in mice and dogs appeared to be related to effects 
within the gastrointestinal tract, where in mice, effects were observed at or above clinical 
exposures and primarily consisted of perforation of the colon with secondary peritonitis and 
degeneration/necrosis of the glandular mucosa of the stomach, and in dogs presented 
clinically as decreased body weight, decreased food consumption and/or fecal 
abnormalities and occurred at subclinical exposures. In rats, tolerability was more 
dependent on changes occurring in skin over time and its effect on impaired barrier 
function.  These findings may be related to those seen in the clinic in the form of skin rashes 
and diarrhea.  Rats were more sensitive to trametinib with liver, phosphate homeostasis, 
soft tissue mineralization, bone, hematopoietic and ovary effects occurring at ≥0.016 
mg/kg/day.  Hepatic toxicity in rats given trametinib consisted of increased serum 
transaminases and, in mice and rats at higher doses, hepatocellular necrosis.  
Hyperphosphatemia and physeal thickening occurred in rats given trametinib and is likely 
caused by inhibition of MEK-dependent FGF signaling in kidney and bone, respectively.  
Hematological changes consisted of decreased bone marrow cellularity and, at higher 
doses, hematopoietic cell necrosis.  While minor hematology changes have been observed 


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15
in the clinic, subjects taking trametinib have not demonstrated increased serum 
phosphorus. 
 
In 13 week studies, systemic exposures (AUC) at the MTD in rats or NOAEL in dogs, which 
was also the MTD, were 0.3- and 0.4-times clinical steady state AUC, respectively.  In the 26 
week mouse study, the MTD was 0.1 mg/kg/day which was 1.0-times clinical steady state 
AUC. 
 
Trametinib may impair female fertility in humans based on the reduction of corpora lutea in 
rats (0.3-times clinical steady state AUC).  There were no effects on male reproductive 
organs in toxicology studies in rats or dogs, indicating that trametinib is unlikely to affect 
male fertility.  In embryofetal development studies, maternal toxicity and developmental 
toxicity, including total loss of pregnancy and post-implantation loss, were observed in rats 
and/or rabbits given trametinib (0.3- and 0.1-times clinical steady state AUC, respectively).  
These effects are consistent with literature reports that inhibition of MEK1/MEK2 activity 
impacts granulosa cell survival and folliculogenesis, while genetic ablation of MEK1, ERK2 or 
skin-restricted MEK1/MEK2 has been shown to cause embryolethality and decreased 
progeny size.  Taken together, trametinib treatment may result in adverse effects on 
pregnancy.  There are no adequate and well-controlled studies of trametinib in pregnant 
women.  Women of childbearing potential should be advised to avoid becoming pregnant 
while receiving treatment with trametinib. It is not known if trametinib is excreted in milk. 
 
The principal effects of trametinib in juvenile rats were on growth (body weight and long 
bone length) and in bone, phosphate homeostasis, eye, skin, liver, heart and female 
reproductive system effects, consisting of a delay in a physical landmark of sexual maturity 
and mammary gland development, lower corpora lutea and lower ovarian weights.  All of 
the female reproductive effects were reversible.  With the exception of corneal 
mineralization/dystrophy and increased heart weight, similar effects have been observed in 
adult animals given trametinib.   
 
The genotoxicity assessments conducted indicate that trametinib does not present a 
genotoxic hazard to humans. The requirement for male patients taking trametinib to use 
contraception with female partners of child bearing potential is not recommended based on 
absence of genotoxicity, no effects on male reproductive tissues in nonclinical toxicity 
studies, and the minimal potential for trametinib  exposure of females via semen.   
 
Although the concentration of trametinib in semen is unknown in humans and animals, 


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trametinib was non-genotoxic in preclinical in vivo and in vitro genotoxicity studies 
suggesting that the human risk to induce transmissible genetic damage via sperm from male 
subjects to female partners is low.   The risk for exposure to a female partner of a man 
receiving trametinib therapy is also considered to be low based of the following assessment.   
At a daily dose of 2 mg, the estimated Cmax is 22 ng/mL.  Assuming a similar disposition into 
semen, the estimated daily dose of trametinib to a pregnant partner via semen (assuming 2 
ejaculations/day and 5 mL/ejaculation) would be 220 ng.  The mean trametinib Cmax 
following an IV microtracer dose of 5 ug in humans was determined to be 0.105 ng/mL 
[Study MEK115064: Determination of the Absolute Bioavailability of Trametinib Following a 
Single Oral Dose Co-Administered with an Intravenous Radiolabelled Microdose of 
Trametinib in Subjects with Solid Tumors].  Assuming dose-exposure proportionality via 
intravenous administration, an intravenous dose of 220 ng would result in a Cmax of 
0.00462 ng/mL.  In pregnant rats, the no observed adverse effect level (NOAEL) for embryo 
fetal development effects was 0.016 mg/kg/day (mean AUC of 52.3 ng.h/mL and Cmax of 
2.79 ng/mL), however in pregnant rabbits a NOAEL was not determined with the lowest 
observed adverse effect level (LOAEL) for maternal and embryo fetal development effects 
being 0.039 mg/kg/day (mean AUC of 31.9 ng.h/mL and Cmax of 2.10 ng/mL).  Based on 
these data and assuming 100% absorption of trametinib from semen, the estimated 
exposure via semen would be approximately 1/450th the oral exposure (0.00462 ng/mL/ 
2.10 ng/mL) achieved at the LOAEL dose for rabbit maternal and embryofetal toxicity and 
approximately 1/600th the oral exposure (0.00462 ng/mL/ 2.79 ng/mL) achieved at the 
NOAEL dose in pregnant rats.  Taken together, this would suggest that the risk of 
embryofetal developmental toxicity as a consequence of exposure to female pregnant 
partners is very low.  
 
In conclusion, the toxic potential of trametinib has been characterized in a comprehensive 
battery of preclinical studies.  The effects observed in preclinical studies were generally, 
either directly or indirectly, associated with the pharmacologic inhibition of MEK1/MEK2 by 
trametinib and generally consistent with adverse effects observed in cancer patients.  The 
data from these preclinical studies support the clinical use of trametinib under the proposed 
dose regimen. 
 
2.2.6 Trametinib Clinical Experience 
The effect of trametinib in subjects with a variety of refractory cancers is currently under 
evaluation in 9 clinical studies which are ongoing and 13 completed studies as of the IB 
cutoff date.  Trametinib has been administered as monotherapy in 12 of these studies, and 
as combination therapy in the other 10 studies.  Two additional ongoing studies are part of 


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17
a compassionate use program.  
 
Trametinib pharmacokinetics were determined after single- and repeat-dose oral 
administration of trametinib tablets in subjects with solid tumors.  Trametinib is absorbed 
rapidly with median Tmax generally occurring 1.50 hours after single oral administration of 
trametinib under fasting conditions.  The absolute oral bioavailability of a single trametinib 
2.0 mg tablet is moderate to high (72%) relative to a co-administered IV microdose. Single-
dose administration of trametinib with a high-fat, high-calorie meal resulted in a 70% 
decrease in maximum observed concentration (Cmax), a 24% decrease in area under the 
concentration-time curve from time zero (pre-dose) to last time point (AUC(0-t)) and a 10% 
decrease in AUC extrapolated to infinity (AUC(0-τ)) compared to fasted conditions. 
 
Following repeat-dosing the mean area under the curve (AUC0-τ) and maximum 
concentrations (Cmax) increased in an approximately dose proportional manner.  
Trametinib accumulates with repeat dosing with a mean accumulation ratio at the 
recommended dose of 2 mg once daily of 5.97 and a terminal half-life of 5.3 days 
determined after single dose administration.  Steady state appears to be achieved by Day 
15, with little difference in pre-dose (trough) concentration at the end of the dosing interval 
(Cτ), Cmax and area under the concentration-time curve from time zero (pre-dose) to 24 hrs 
(AUC(0-24)) between Days 15 and 21.   
 
Trametinib is a low extraction ratio drug based on plasma IV clearance of 3.21 L/hr, which 
represents approximately 1% of liver blood flow.  Trametinib has a high volume of 
distribution (Vd) of 1060 L determined following an IV microdose.   
 
Fecal excretion is the major route of elimination after [14C] trametinib oral dose, accounting 
for >80% of excreted radioactivity recovered (or 39.2 and 35.0% of the radioactive dose in 2 
subjects) while urinary excretion accounted for <19% of excreted radioactivity recovered 
(<10% of the radioactive dose).  Following a single dose of [14C]-trametinib, approximately 
50% of circulating radioactivity is represented as the parent compound. However, based on 
metabolite profiling after repeat dosing of trametinib, ≥75% of drug-related material in 
plasma is the parent compound. 
 
In vitro and in vivo data suggest that trametinib is unlikely to affect the PK of other drugs 
and that the PK of trametinib is unlikely to be affected by other drugs.  Trametinib is 
metabolized predominantly via deacetylation which is likely mediated by hydrolytic 
esterases which are not generally associated with drug interaction risk, nor is it a substrate 


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18
of P-gp or BCRP. 
 
Based on the adverse events (AEs) observed in the dose escalation phase of the first-time-
in-human (FTIH) study MEK111054, the maximum tolerated dose was established at 3.0 mg 
once daily, and the recommended Phase II dose (RP2D) of trametinib was identified as 2.0 
mg once daily. 
 
In the 12 monotherapy studies of trametinib for which data are available, all studies except 
one had AEs. In the studies with AEs, 50% to 100% of all subjects in any dose group had at 
least 1 AE, and 0% to 70% of all subjects in any dose group had at least 1 SAE.  Of the studies 
with discontinuations or withdrawals, 3% to 26% of subjects receiving trametinib 
permanently discontinued study treatment or withdrew due to AEs. 
 
Of the >700 subjects (including crossover subjects) in the 2.0 mg dose group, in 8 
monotherapy studies with AEs, 50% to 100% of subjects had at least 1 AE, and 0% to 70% of 
all subjects had SAEs.  Of the studies with discontinuations or withdrawals, 3% to 24% in the 
2.0 mg does group permanently discontinued study treatment or withdrew from the study 
due to AEs. 
 
In the 2.0 mg dose group across all 8 monotherapy studies with AEs, the most common AEs 
had were rash, diarrhea, fatigue, peripheral edema, nausea, acneiform dermatitis, vomiting, 
constipation, anemia, pruritus, alopecia, hypertension, decreased appetite, dyspnea and dry 
skin.  
 
Of the >700 subjects in the 10 combination therapy studies of trametinib, 97% to 100% of 
subjects in any trametinib dose group had at least 1 AE, and 33% to 53% of subjects in any 
trametinib dose group had at least 1 SAE, and 5% to 26% permanently discontinued study 
treatment or withdrew due to AEs. In the combination trials for which data are available, 
the most common AEs had were fatigue, diarrhea, mucosal inflammation, 
thrombocytopenia, nausea, vomiting, rash, pyrexia, neutropenia, decreased appetite, 
acneiform dermatitis, anemia, peripheral edema, constipation, and stomatitis. 
 
Table 1.3: Selected Adverse Reactions Occurring in >10% of Patients Receiving Trametinib. 
Patients with BRAF V600E or V600K mutation-positive metastatic melanoma received either 
2 mg trametinib orally once daily or chemotherapy with either dacarbazine 1000 mg/m2 
every 3 weeks or paclitaxel 175 mg/m2 every 3 weeks. In this study, 9% of patients receiving 
trametinib experienced adverse reactions resulting in permanent discontinuation of trial 


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medication. The most common adverse reactions resulting in permanent discontinuation of 
trametinib were decreased left ventricular ejection fraction (LVEF), pneumonitis, renal 
failure, diarrhea, and rash. Adverse reactions led to dose reductions in 27% of patients 
treated with trametinib. Rash and decreased LVEF were the most common reasons cited for 
dose reductions of trametinib. 
 
Trametinib  (n=211) 
Chemotherapy (n=99) 
Any Grade, 
n(%) 
Grade 3-4, 
n (%) 
Any Grade, 
n(%) 
Grade 3-4, 
n (%) 
GASTROINTESTINAL DISORDERS 
 
 
 
 
   Diarrhea 
43 
0 
16 
2 
   Stomatitis 
15 
2 
2 
0 
   Abdominal pain 
13 
1 
5 
1 
INVESTIGATIONS 
 
 
 
 
   Increased Aspartate aminotransferase 
60 
2 
16 
1 
   Increased Alanine aminotransferase 
39 
3 
20 
3 
   Hypoalbuminemia 
42 
2 
23 
1 
   Anemia 
38 
2 
26 
3 
   Increased Alkaline phosphatase 
24 
2 
18 
3 
SKIN AND SUBCUTANEOUS TISSUE 
DISORDERS 
 
 
 
 
   Rash 
57 
8 
10 
0 
   Acneiform dermatitis 
19 
<1 
1 
0 
   Dry skin 
11 
0 
0 
0 
   Pruritis 
10 
2 
1 
0 
   Paronychia 
10 
0 
1 
0 
VASCULAR DISORDERS 
 
 
 
 
   Lymphedema 
32 
1 
4 
0 
   Hypertension 
15 
12 
7 
3 
   Hemorrhage 
13 
<1 
0 
0 
 
 
 
 
2.3  
Rationale 
We hypothesize that the efficacy of immune-checkpoint inhibitors in microsatellite stable 
(MSS) CRC can be enhanced by better priming and T-cell activation of the intratumoral 
environment. We believe that combining systemic administration of MEK inhibition with an 
anti PD-L1 antibody will augment this T-cell activation in metastatic, MSS CRC. 
Tregs accumulate in CRC and, as a consequence, suppress cytotoxic and helper T-cell activity. 
Improved survival is significantly associated with number of CD4+ and a higher proportion of 
CD8+ T-cells, while worse outcomes are seen with greater proportions of Treg cells. 
Importantly, while CRC has a relatively high degree of mutational heterogeneity [4], TCGA 


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data suggests that fewer neo-epitopes are observed than expected [5]. These findings suggest 
that immune stimulation in combination with checkpoint blockade inhibition may be more 
effective than checkpoint blockade monotherapy. 
To activate the immune response in MSS disease, a different strategy is needed. Genetic 
differences between mismatch repair proficient and deficient patients correlate with 
differences in the tumor immune microenvironment that impact sensitivity to checkpoint 
blockade therapy. Llosa and colleagues [Llosa 2015] interrogated the immune 
microenvironment between a subset of CRC primary tumors that were either micro-satellite 
high or stable. They convincingly demonstrate that tumor immune microenvironment is 
distinct between these populations. Specifically, relative to MSS disease, MSI-high CRC is 
characterized by increased infiltration by T-cells with both cytotoxic and Th1 phenotypes, 
but also expression of high levels of inhibitory immune surface markers such as PD-1, PD-L1, 
CLTA-4. 
 
MEK inhibition has been shown to alter the immune microenvironment in tumors. In pre-
clinical models, Trametinib has been shown to have anti-tumor effects on the CT26 tumor 
model. This murine colorectal tumor cell line contains homozygous KRAS G12D mutation 
and MAPK1/MET amplifications [Castle 2014]. Liu et al showed that while Trametinib has 
modest suppression of tumors in vivo, this effect is enhanced by combination with PD-1 or 
PD-L1 blockade [Liu 2015]. Survival was also improved with combination therapy over either 
agent in monotherapy. Further, when timed with a 1-week lead in with Trametinib, a 
significant improvement in survival was observed. 
 
A preliminary phase 1 study (n=20) utilizing a different PD1 and MEK inhibitor demonstrated 
efficacy of this combination with a 20% response rate in KRAS mutant CRC (all partial 
responses) [Bendall et al, 2016 ASCO Annual Meeting]. An additional 20% of patients 
experienced stable disease (lasting >6 months in 3 patients). No DLTs were observed. 
Further, these agents in combination had no therapy related grade 4 AEs and a 35% rate of 
grade 3 AEs, including diarrhea (9%), fatigue (4%), rash (4%), nausea (4%), maculopapular 
rash (4%), AST increase (4%), and vomiting. These were mostly attributable to the MEKi, 
with a 17% discontinuation rate for the MEKi. The most common AEs included diarrhea 
(70%), fatigue (52%), dermatitis acneiform (44%), rash (35%), nausea (26%), maculopapular 
rash (26%), pruritis (26%), AST increase (22%), creatinine increase (22%), peripheral edema 
(17%), stomatitis (17%), and vomiting (17%). 
 


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We believe that the combination of Durvalumab (a PD-L1 antibody) with Trametinib (MEK 
inhibitor) will be effective and safe in patients with metastatic MSS colorectal cancer. 
 
Rationale for fixed dosing 
 
A population PK model was developed for durvalumab using monotherapy data from a 
Phase I study (study 1108; N=292; doses= 0.1 to 10 mg/kg Q2W or 15 mg/kg Q3W; solid 
tumors). Population PK analysis indicated only minor impact of body weight (WT) on the PK 
of durvalumab (coefficient of ≤ 0.5). The impact of body WT-based (10 mg/kg Q2W) and 
fixed dosing (750 mg Q2W) of durvalumab was evaluated by comparing predicted steady 
state PK concentrations (5th, median and 95th percentiles) using the population PK model. 
A fixed dose of 750 mg was selected to approximate 10 mg/kg (based on median body WT 
of ~75 kg). A total of 1000 subjects were simulated using body WT distribution of 40–120 
kg. Simulation results demonstrate that body WT-based and fixed dosing regimens yield 
similar median steady state PK concentrations with slightly less overall between-subject 
variability with fixed dosing regimen.  
 
Similar findings have been reported by others (32-35). Wang and colleagues investigated 12 
monoclonal antibodies and found that fixed and body size-based dosing perform similarly, 
with fixed dosing being better for 7 of 12 antibodies (34)]. In addition, they investigated 18 
therapeutic proteins and peptides and showed that fixed dosing performed better for 12 of 
18 in terms of reducing the between-subject variability in pharmacokinetic/ 
pharmacodynamics parameters (36).  
 
A fixed dosing approach is preferred by the prescribing community due to ease of use and 
reduced dosing errors. Given expectation of similar pharmacokinetic exposure and 
variability, we considered it feasible to switch to fixed dosing regimens. Based on average 
body WT of 75 kg, a fixed dose of 1500 mg Q4W durvalumab (equivalent to 20 mg/kg Q4W) 
is included in the current study. 
 
 


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22
 
 
3. PATIENT SELECTION 
 
3.1  
Eligibility Criteria 
 
3.1.1 Patients must have histologically or cytologically confirmed metastatic 
colorectal cancer.  
 
3.1.2 Patients must have measurable disease per RECIST v1.1 criteria.  
 
3.1.3 Patients must have had at least prior treatment with a fluoropyrimidine and 
either oxaliplatin or irinotecan. 
 
3.1.4 Age >18 years.  Because no dosing or adverse event data are currently 
available on the use of this combination in patients <18 years of age, children 
are excluded from this study. 
 
3.1.5 Body weight > 30kg. 
 
3.1.6 Life expectancy of greater than 6 months. 
 
3.1.7 ECOG performance status 0-1 (Karnofsky >70%; see Appendix 1). 
 
3.1.8 Patients must have normal organ and marrow function as defined below: 
 
- 
Leukocytes 
 
 
 
 
>3,000/mcL 
- 
Absolute neutrophil count 
>1,500/mcL 
- 
Hemoglobin 
 
 
 
 
> 9.0g/dL 
- 
Platelets  
 
 
 
 
>75,000/mcL 
- 
Total bilirubin  
 
 
 
< 1.5 X institutional normal limits (subjects 
with known Gilbert syndrome are eligible 
with total bilirubin < 3.0 mg/dL) 
- 
AST(SGOT)/ALT(SGPT) 
 
< 2.5 X institutional ULN (< 5 if liver 
metastases present) 
- 
Creatinine  
 
 
 
 
within normal institutional limits 
OR 
- 
Creatinine clearance  
 
> 40mL/min by Cockcroft-Gault or 24h urine 
collection. 
 
 
3.1.9 Known MSS status by either IHC or PCR. Known or evaluable BRAF and KRAS 
status. 


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23
 
 
3.1.10 Evidence of post-menopausal status or negative urinary or serum pregnancy 
test for female pre-menopausal subjects. Women will be considered post-
menopausal if they have been amenorrheic for 12 months without an 
alternative medical cause. The following age-specific requirements apply: 
 
 
 
-- Women <50 years of age would be considered post-menopausal if they 
have been amenorrheic for 12 months or more following cessation of 
exogenous hormonal treatments and if they have luteinizing hormone and 
follicle-stimulating hormone levels in the post-menopausal range for the 
institution or underwent surgical sterilization (bilateral oophorectomy or 
hysterectomy).  
 
 
 
-- Women ≥50 years of age would be considered post-menopausal if they 
have been amenorrheic for 12 months or more following cessation of all 
exogenous hormonal treatments, had radiation-induced menopause with 
last menses >1 year ago, had chemotherapy-induced menopause with last 
menses >1 year ago, or underwent surgical sterilization (bilateral 
oophorectomy, bilateral salpingectomy or hysterectomy). 
 
3.1.11 Women of child-bearing potential and men must agree to use adequate 
contraception (hormonal or barrier method of birth control; abstinence) 
prior to study entry and for the duration of study participation.  Should a 
woman become pregnant or suspect she is pregnant while participating in 
this study, she should inform her treating physician immediately and will be 
removed from the study. 
 
3.1.12 Ability to understand and the willingness to sign a written informed consent 
document. 
 
3.1.13 Willingness to have 2 tumor biopsies; the first before and the second while 
on therapy (optional for all patients and may become mandatory in order to 
ensure 15 patients at MTD have paired biopsies). 
 
 
3.2  
Exclusion Criteria 
 
3.2.1 Patients who have had chemotherapy within 2 weeks prior to first dose of 
study drug. 
 


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3.2.2 Any unresolved toxicity NCI CTCAE Grade ≥2 from previous anticancer 
therapy with the exception of alopecia, vitiligo, and the laboratory values 
defined in the inclusion criteria: 
 
 
-- Subjects with Grade ≥2 neuropathy will be evaluated on a case-by-case 
basis after consultation with the Principal investigator. 
 
 
-- Subjects with irreversible toxicity not reasonably expected to be 
exacerbated by treatment with durvalumab may be included only after 
consultation with the Principal investigator. 
 
3.2.3 Patients may not be receiving any other investigational agents. 
 
3.2.4 Major surgical procedure (as defined by the Investigator) within 28 days prior 
to the first dose of study medication. Note: Local sugery of isolated lesions 
for palliative intent is acceptable. 
 
3.2.5 Patients with known brain metastases or leptomeningeal carcinomatosis will 
be excluded from this clinical trial. Patients with suspected brain metastases 
at screening should have an MRI (preferred) or CT each prefereably with IV 
contrast of the brain prior to study entry. 
 
3.2.6 Mean QT interval corrected for heart rate (QTc) ≥ 470 ms calculated from 3 
electrocardiograms (ECGs) using Fridericia’s Correction. 
 
3.2.7 History of pneumonitis or interstitial lung disease (ILD). 
 
3.2.8 History of allogenic organ transplantation. 
 
3.2.9 Subjects with active, known, or suspected autoimmune disease including 
patients with a history of inflammatory bowel disease (ulcerative colitis or 
Crohn’s disease); patients with a history of symptomatic disease (e.g., 
rheumatoid arthritis, systemic sclerosis [scleroderma], systemic lupus 
erythematosus, autoimmune vasculitis (e.g., Wegener’s granulomatosis), and 
central nervous system or motor neuropathy considered of autoimmune 
origin (e.g., Guillain-Barre Syndrome, myasthenia gravis, multiple sclerosis).  
Subjects with vitiligo, type I diabetes mellitus, Grave’s disease, Hashimoto 
thyroiditis, psoriasis, and other mild autoimmune disease not requiring 
systemic treatment are permitted to enroll at the discretion of the 
investigator. 
 
3.2.10 Subjects with a condition requiring systemic treatment with either 
corticosteroids (>10 mg daily prednisone equivalents) or other 
immunosuppressive medications within 14 days of study drug 


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25
administration.  Inhaled or topical steroids and adrenal replacement doses > 
10 mg daily prednisone equivalents are permitted in the absence of active 
autoimmune disease. 
 
3.2.11  Receipt of live attenuated vaccine within 30 days prior to the first dose of IP. 
Note: Subjects, if enrolled, should not receive live vaccine whilst receiving IP 
and up to 30 days after the last dose of IP. 
 
3.2.12 Prior exposure to T cell checkpoint inhibitor therapies. 
 
3.2.13 Uncontrolled intercurrent illness including, but not limited to, ongoing or 
active infection, symptomatic congestive heart failure, unstable angina 
pectoris, cardiac arrhythmia, interstitial lung disease, serious chronic 
gastrointestinal conditions associated with diarrhea, or psychiatric 
illness/social situations that would limit compliance with study requirements, 
substantially increase risk of incurring AEs or compromise the ability of the 
patient to give written informed consent. 
 
3.2.14 History of active primary immunodeficiency. 
 
3.2.15 Active infection including tuberculosis (clinical evaluation that includes 
clinical history, physical examination and radiographic findings, and TB 
testing in line with local practice for patients suspected of having active 
infection), hepatitis B (known positive HBV surface antigen (HBsAg) result), 
hepatitis C, or human immunodeficiency virus (positive HIV 1/2 antibodies). 
Subjects with a past or resolved HBV infection (defined as the presence of 
hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible. 
Subjects positive for hepatitis C (HCV) antibody are eligible only if 
polymerase chain reaction is negative for HCV RNA. 
 
3.2.16 Female subjects who are pregnant or breastfeeding or male or female 
subjects of reproductive potential who are not willing to employ effective 
birth control from screening to 90 days after the last dose of study 
medications. 
 
3.2.17 Known allergy or hypersensitivity to any of the study drugs or any of the 
study drug excipients. 
 
 
4. REGISTRATION PROCEDURES 
 


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26
This is a single institution study. It will be publically registered on the national clinic trial 
database online at https://clinicaltrials.gov/ 
 
5. TREATMENT PLAN 
 
5.1  
Study Design 
 
This study is an open-label, single center phase 2 trial assessing the efficacy and safety of 
combination intravenous durvalumab with oral trametinib. At trial initiation, the first 
patients will be enrolled at the target doses for the combination durvalumab and trametinib 
identified in earlier melanoma trials as safe and well tolerated; durvalumab at 1500mg q4w 
with trametinib 2mg PO daily. De-escalation doses will be available if this dose proves toxic 
in the colon population (figure 1). After study initiation, up to 6 patients will be enrolled and 
if the number of DLTs <2, this will be considered the MTD of the combination. If the number 
of DLTs>/=2, additional 6 patients will be treated at the lower dose level. The dose level 
with <2 DLTs out of 6 patients will be deemed as the MTD for the combination.  
 
 
Figure 1: Dose Levels 
 
After the MTD of the doublet is confirmed, additional patients will be enrolled at the MTD, 
with a maximum of 44 patients at that dose (including the 6 patients treated during safety 
lead-in). After the MTD is confirmed, patients will be eligible for trametinib dose reductions 
as described in section 6. As described below, early stopping criteria will be used to 
terminate the trial if there is strong evidence of futility. Using a Simon’s 2-stage design 
(figure 2), we will enroll 29 patients. If there is evidence of 2 or more patients with 
response, we will enroll the remaining 15. We believe that a larger first stage is justified 
because an existing PD-L1/MEK trial has shown efficacy (as described in rationale) in a 
similar mCRC population. 
 


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27
 
Figure 2: Study design 
 
We will have a lead in period with trametinib alone for 1 weeks (figure 3) for the dual 
purpose of 1) providing a window to identify toxicities that are related to this agent in 
monotherapy, and 2) to provide a priming effect before the addition of checkpoint 
blockade. As described in the background, there is preclinical evidence that better tumor 
control and survival is achieved with a 1 week trametinib lead in. 
 
 
 
 
Figure 3: Study dosing schedule 
 
In all patients pre- and on-treatment biopsies will be optional and may become mandatory 
in order to ensure 15 patients at MTD have paired biopsies. Additionally, peripheral blood 
will be collected at baseline, day 0, and then approximately every 4 weeks on treatment to 
examine changes in peripheral immune cells and cytokines. These correlative studies are 
fundamentally important to identify immunologic changes associated with treatment. A 
deeper understanding of the cellular and immunologic changes with this combination 
therapy offers the 1) ability to correlate pre-existing tumor features with response to 
therapy; 2) ability to quantify changes in the tumor microenvironment with treatment; and 
3) opportunity to identify therapeutically relevant difference between patients that may 


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28
inform future trials.  
 
Patients will receive restaging imaging every 8 weeks while on therapy, or sooner if deemed 
appropriate by the investigator. Patients will be eligible to remain on therapy if they 
demonstrate either response or stable disease as defined by immune-related response 
criteria. If at the first restaging scan, the patient has progressed, but in the opinion of the 
investigator shows evidence of clinical benefit and good tolerance of therapy, they may 
receive an additional cycle of therapy with restaging in 4 weeks. 
 
Study Schematic 
 
 
5.1.1 Screening visit. 
If a patient is thought to be a potential candidate for the trial then he/she can be 
offered participation and, if agreeable, will undergo screening procedure outlined below 
from D-21 to D-8. 
 
Table 5.1-1: 
Screening Procedural Outline 
Procedure 
Screening 
Visit 
From D-21 
to D-8 
Notes 
 
Eligibility Assessments 
 
Informed Consent 
X 
Original IC in screening for protocol participation; 
 
Inclusion/Exclusion 
Criteria 
X 
All inclusion/exclusion criteria should be assessed at 
screening and confirmed prior to first dose. 
Medical History 
X 
 
Tumor Tissue Sample  
X 
Confirm diagnosis of colorectal adenocarcinoma. 
MSI Status 
X 
MSI status must be confirmed; if not available it may 
be obtained either from archived tissue.  
Prior Medications 
X 
Prior exposure to checkpoint inhibitor therapy 
excluded 
ECOG Performance 
Status 
X 
Within 14 days prior to first dose 
Safety Assessments 


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Table 5.1-1: 
Screening Procedural Outline 
Procedure 
Screening 
Visit 
From D-21 
to D-8 
Notes 
 
Physical Examination 
X 
 
Vital Signs & Oxygen 
Saturation 
X 
Including BP, HR, temperature and oxygen saturation 
by pulse oximetry (at rest). Obtain vital signs at the 
screening visit and within 72 hours prior to first dose. 
Physical Measurements 
X 
Height and Weight. Within 14 days prior to first dose 
Assessment of Signs 
and Symptoms 
X 
Within 14 days prior to first dose 
ECG 
X 
Within 14 days prior to first dose.  
Concomitant 
Medication Collection 
X 
Within 14 days prior to first dose 
Laboratory Tests 
X 
CBC w/differential and platelet count, 
Chemistry panel including: LDH, AST, ALT, Alk Phos, 
T.Bili, Comprehensive metabolic panel, magnesium 
CEA, amylase, lipase, TSH, Free T4, Free T3, HIV Ab, 
Hepatitis B surface antigen (HBV sAg), and hepatitis C 
antibody (HCV Ab) or Hepatitis C RNA (HCV RNA), 
within 14 days prior to starting trametinib 
Pregnancy Test 
(WOCBP only) 
X 
Serum or urine to be done at screening visit and 
repeated within 72h of first dose of study therapy 
Efficacy Assessment 
 
 
Baseline Tumor 
Imaging Assessment 
X 
CT of the C/A/P with contrast within 28 days of starting 
trametinib 
Previous collected 
tumor tissue 
X 
Request previously collected paraffin embedded tumor 
tissue 
Baseline Tumor biopsy 
X 
Biopsy of tumor tissue at baseline is optional for all but 
will be mandatory to ensure 15 patients at MTD have 
paired biopsies. 
 
 
5.1.2 Treatments 
 


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30
5.1.2.1 Durvalumab 
Durvalumab is a human IgG1κ mAb directed against PD-L1.  It will be given at a fixed 
dose of 1500mg IV over approximately 1 hour on day 1 of each cycle.  No 
premedications are needed.  Pharmaceutical details and preparation are provided in 
section 8. No dose modifications are permitted for this agent. Management of adverse 
events related to this agent and treatment delays should follow recommendations in 
section 7.7. 
 
5.1.2.2 Trametinib 
Trametinib (GSK/NOVARTIS1120212) is a selective MEK1 and MEK2 inhibitor. It will be 
taken orally daily at a dose between 1-2mg starting 7 days prior to the first dose of 
durvalumab. In absence of toxicity, trametinib will be taken daily at approximately the 
same time each day including on the day of durvalumab infusion. It should be taken 1 
hour before or 2 hours after a meal. Do not take a missed dose of trametinib within 12 
hours of the next dose of trametinib. 
 
Individual dose reductions for trametinib are permitted. Management of and dose 
modifications in response to adverse events related to study medications are outlined in 
section 6 below as described in version 8 of the trametinib IB. 
 
 
5.1.3 Treatment and Follow Up visits 
Once enrolled on trial, subjects will have the following visits/events.  The study calendar 
in section 10 mirrors the events listed below.  Please note preferred scans are CT but 
MRI is allowed as well.  In addition, approximately 24 hours of steroid therapy such as 
prednisone prior to CT scan due to a contrast allergy is allowed. 
 
 
5.1.3.1  Week -1 (can be up to 7 days prior) 
• Special labs for Immunogenicity assessment (up to 8 tubes x 10 mL each) 
 
 
     5.1.3.2 Week 0 (Cycle 1, Day 1) 
• Clinic visit with targeted physical examination, vital signs, oxygen saturation, 
assessment of performance status, and review of concomitant medication 
• Assess tolerance of and adherence with trametinib therapy 
• Lab tests including CBC with differential and CMP 
• Special labs for Immunogenicity assessment (up to 8 tubes x 10 mL each) 
• Durvalumab cycle 1 in outpatient infusion suite 
 
 
5.1.3.3 Week 2 +/- 3 days 
• Clinic visit with targeted physical examination, vital signs, oxygen saturation, 
assessment of performance status, and review of concomitant medication 
• Assess tolerance of and adherence with trametinib therapy 


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• Lab tests including CBC with differential and CMP 
 
 
5.1.3.4 Week 4 +/- 3 days (+/-7 day window to complete biopsy) 
• Clinic visit with targeted physical examination, vital signs, oxygen saturation, 
assessment of performance status, and review of concomitant medication 
• Assess tolerance of and adherence with trametinib therapy 
• Lab tests including CBC with differential and CMP, CEA, TSH, and FT4 
• Special labs for Immunogenicity assessment (up to 8 tubes x 10 mL each) 
• Durvalumab cycle 2 in outpatient infusion suite 
• Tumor biopsy in interventional radiology (within +/- 7 days of C2D1). Optional 
but mandatory for 15 at MTD. 
 
 
5.1.3.5 Week 6 +/- 3 days 
• Clinic visit with targeted physical examination, vital signs, oxygen saturation, 
assessment of performance status, and review of concomitant medication 
• Assess tolerance of and adherence with trametinib therapy 
• Lab tests including CBC with differential and CMP 
 
 
5.1.3.6 Week 8 +/- 3 days (1-week window to complete tests) 
• Clinic visit with targeted physical examination, vital signs, oxygen saturation, 
assessment of performance status, and review of concomitant medication 
• Special labs for Immunogenicity assessment (up to 8 tubes x 10ml each) 
• Lab tests including CBC with differential, CMP, lipase, amylase, CEA, TSH, and 
FT4. 
• Durvalumab cycle 3 in outpatient infusion suite 
• CT scan of the C/A/P with IV contrast 
• Tumor measurements 
 
 
5.1.3.7 Week 12 +/- 3 days (repeating every 4 weeks while on study) 
• Clinic visit with targeted physical examination, vital signs, oxygen saturation, 
assessment of performance status, and review of concomitant medication 
• Assess tolerance of and adherence with trametinib therapy 
• Lab tests including CBC with differential and CMP 
• Special labs for Immunogenicity assessment (up to 8 tubes x 10 mL each) (week 
12 only and at progression) 
• Durvalumab in outpatient infusion suite 
 
 
5.1.3.8 Week 16 +/- 7 days(repeating every 8 weeks while on study) 
• CT scan of the C/A/P with IV contrast 
• Tumor measurements 
• CEA, TSH, and FT4 


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5.2  
Definition of Dose-Limiting Toxicity and Maximum Tolerated Dose: 
 
5.2.1 Dose-Limiting Toxicity (DLT):  
DLT is defined as any: 
• Any adverse event (AE) of severity grade 3 or 4 (including serious or life-
threatening) considered possibly, probably or definitely related to the 
combination of durvalumab and trametinib (CTCAE v4.0). Any grade 4 immune-
realted AE (irAE). The following caveats are listed below:  
• If a grade 3 event is felt to be secondary to durvalumab or trametinib alone than 
this will not be considered a DLT and treatment can be delayed as per 7.7. If 
toxicity occurs during trametinib lead-in OR is felt to be secondary to trametinib 
alone, the investigator can dose reduce as per 7.7. 
• Only grade 3 lab abnormality that the PI or attending physician feels is clinically 
significant. 
• Grade 3 irAE, excluding colitis or pneumonitis, that does not downgrade to Grade 
2 within 3 days after onset of the event despite optimal medical management 
including systemic corticosteroids or does not downgrade to ≤ Grade 1 or baseline 
within 14 days 
• Any clinically grade 3 or 4 non-hematologic toxicity as defined in the NCI CTC v4.0, 
expected and believed to be related to the combination of durvalumab and 
Trametinib (except nausea and vomiting, diarrhea and electrolyte imbalances 
responsive to appropriate regimens, alopecia or fatigue lasting less than 7 days). 
• Any grade 4 neutropenia (with or without fever and/or sepsis) or 
thrombocytopenia (with or without bleeding) lasting at least 1 week or longer (as 
defined by the NCI-CTC v4.0). 
• Any of the Grade 4 hematologic adverse events for >5 days. 
 
• Any grade 3 or 4 nausea or vomiting lasting more than 5 days despite anti-emetics 
regimens or grade 3 or 4 diarrhea refractory to anti-diarrhea medications. 
 
• Any grade ≥ 3 colitis. 
 
• Any Grade 2 pneumonitis that does not resolve to ≤ Grade 1 within 3 days of the 
initiation of maximal supportive care. 


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33
 
• Liver transaminase elevation > 8 × ULN or total bilirubin > 5 × ULN. 
 
The definition excludes the following conditions:  
• Grade 3 fatigue lasting ≤ 7 days 
• Grade 3 endocrine disorder (thyroid, pituitary, and/or adrenal insufficiency) that is 
managed with or without systemic corticosteroid therapy and/or hormone replacement 
therapy and the subject is asymptomatic 
• Grade 3 inflammatory reaction attributed to a local antitumor response (eg, inflammatory 
reaction at sites of metastatic disease, lymph nodes, etc) 
• Concurrent vitiligo or alopecia of any AE grade 
• Grade 3 infusion-related reaction (first occurrence and in the absence of steroid 
prophylaxis) that resolves within 6 hours with appropriate clinical management 
 
5.2.2 Maximum Tolerated Dose (MTD):  
Maximum Tolerated Dose (MTD) is defined: 
• Highest dose level with less than 2 patients with DLT out of at least six patients in 
the cohort. Management and dose modifications associated with adverse events 
are outlined in below table. 
Number of Patients with DLT* at a Given 
Dose Level 
 
Escalation Decision Rule 
 
 1 out of 3 
 
Enter at least 3 more patients at this dose 
level.  
If 0 of these 3 patients experience DLT, 
continue enrollment at current dose level 
dose level.  
If 1 or more of this group suffer DLT this 
dose is declared the maximally 
administered dose. Three additional 
patients will be entered at the next lowest 
dose level if 3 patients were treated 


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34
previously at that dose. 
>2 out of 3 
Dose escalation will be stopped. This dose 
level will be declared the maximally 
administered dose (highest dose 
administered). Three additional patients 
will be entered at the next lowest dose 
level if 3 or fewer patients were treated 
previously at that dose. 
< =1 out of 6 at highest dose level 
below the maximally administered 
dose 
 
This is generally the MTD. At least 6 
patients must be entered at the MTD. 
*The time window for DLT evaluation among the first 6 patients is 28 days (one cycle) 
All patients will be treated at the highest current dose level. All enrolled participants 
will be considered in the DLT analysis. If patients experiencing DLTs related to 
trametinib, they can continue combination therapy at the next lowest dose as 
described in section 6. 
 
5.3  
General Concomitant Medication and Supportive Care Guidelines 
 
Concommitant medications will be recorded in the medical record only. 
 
Table 1 Supportive Medications 
Supportive medication/class of drug: 
Usage: 
Concomitant 
medications 
or 
treatments 
(eg, acetaminophen or diphenhydramine) deemed 
necessary to provide adequate prophylactic or 
supportive care, except for those medications 
identified as “prohibited,” as listed above  
To be administered as prescribed by the 
Investigator 
Best 
supportive 
care 
(including 
antibiotics, 
nutritional support, correction of metabolic 
disorders, optimal symptom control, and pain 
management [including palliative radiotherapy to 
non-target lesions, etc]) 
Should be used, when necessary, for all 
subjects 
Inactivated viruses, such as those in the influenza 
vaccine 
Permitted 


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Excluded concomitant medications 
Table 1. Prohibited Concomitant Medications 
Prohibited medication/class of drug: 
Usage: 
Any investigational anticancer therapy 
other than those under investigation in this 
study 
Should not be given concomitantly whilst the 
patient is on study treatment 
mAbs against CTLA-4, PD-1, or PD-L1 other 
than those under investigation in this study 
Should not be given concomitantly whilst the 
patient is on study treatment 
Any 
concurrent 
chemotherapy, 
radiotherapy, immunotherapy, or biologic 
or hormonal therapy for cancer treatment 
other than those under investigation in this 
study 
Should not be given concomitantly whilst the 
patient is on study treatment. (Concurrent use of 
hormones for non-cancer-related conditions 
[eg, insulin 
for 
diabetes 
and 
hormone 
replacement therapy] is acceptable. Local 
treatment of isolated lesions, excluding target 
lesions, for palliative intent is acceptable [eg, by 
local surgery or radiotherapy]) 
Immunosuppressive 
medications 
including, but not limited to, systemic 
corticosteroids at doses exceeding <<10 
mg/day>> of prednisone or equivalent, 
methotrexate, azathioprine, and tumor 
necrosis factor-α blockers 
Should not be given concomitantly, or used for 
premedication prior to the I-O infusions. The 
following are allowed exceptions: 
·      Use of immunosuppressive medications for the 
management of IP-related AEs, 
·      Use in patients with contrast allergies. 
·      In addition, use of inhaled, topical, and intranasal 
corticosteroids is permitted. 
A temporary period of steroids will be allowed if 
clinically indicated and considered to be essential 
for the management of non-immunotherapy 
related events experienced by the patient (eg, 
chronic obstructive pulmonary disease, radiation, 
nausea, etc). 
Drugs with laxative properties and herbal 
or natural remedies for constipation 
Should be used with caution through to 90 days 
after the last dose of fixed during the study. 
Sunitinib 
Should not be given concomitantly or through 90 
days after the last dose of tremelimumab (acute 
renal failure has been reported with combination 
therapy of tremelimumab and sunitinib) 


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36
Prohibited medication/class of drug: 
Usage: 
EGFR TKIs <<unless the study is assessing 
the combination of an EGFR TKI and 
durvalumab>> 
Should not be given concomitantly. 
Should be used with caution in the 90 days post 
last dose of durvalumab. 
Increased incidences of pneumonitis (with third 
generation EGFR TKIs) and increased incidence of 
transaminase increases (with 1st generation EGFR 
TKIs) has been reported when durvalumab has 
been given concomitantly. 
Live attenuated vaccines 
Should not be given through 30 days after the last 
dose of IP (including SoC) 
Herbal and natural remedies which may 
have immune-modulating effects 
Per investigator discretion but in general not 
recommend to be given concomitantly. 
Durvalumab and trametinib have been studied in ongoing trial in metastatic 
melanoma. Among 20 metastatic melanoma patients treated with the combination, 
all experienced AEs of at least grade 1 or higher [Ribas et al, ASCO AM 2015]. A dose-
limiting toxicity of reversible choroidal effusion was observed in one patient. The 
most common AEs (by percent patients) were diarrhea (50%), rash (35%), fatigue 
(30%), and folliculitis (25%). 
 
 
 
5.4  
Restrictions for Patients on Study 
The following restrictions apply while the patient is receiving study treatment and 
for the specified times before and after: 


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37
 
Female patient of child-bearing potential: 
─ Females of childbearing potential who are sexually active with a non-sterilized 
male partner must use at least 1 highly effective method of contraception (Table 5.) 
from the time of screening and must agree to continue using such precautions for 
180 days after the last dose of durvalumab + any drug combination therapy or 
90 days after the last dose of durvalumab monotherapy. Non-sterilized male 
partners of a female patient must use male condom plus spermicide throughout this 
period. Cessation of birth control after this point should be discussed with a 
responsible physician. Not engaging in sexual activity for the total duration of the 
drug treatment and the drug washout period is an acceptable practice; however, 
periodic abstinence, the rhythm method, and the withdrawal method are not 
acceptable methods of birth control. Female subjects should also refrain from 
breastfeeding throughout this period. 
Male subjects with a female partner of childbearing potential: 
─ Non-sterilized males who are sexually active with a female partner of childbearing 
potential must use a male condom plus spermicide from screening through 180 days 
after receipt of the final dose of durvalumab + any drug combination therapy or 
90 days after receipt of the final dose of durvalumab monotherapy. Not engaging in 
sexual activity is an acceptable practice; however, occasional abstinence, the rhythm 
method, and the withdrawal method are not acceptable methods of contraception. 
Male subjects should refrain from sperm donation throughout this period. 
─ Female partners (of childbearing potential) of male subjects must also use a highly 
effective method of contraception throughout this period (Table 5.).  
Females of childbearing potential are defined as those who are not surgically sterile 
(ie, bilateral tubal ligation, bilateral oophorectomy, or complete hysterectomy) or 
post-menopausal.  
Women will be considered post-menopausal if they have been amenorrheic for 12 
months without an alternative medical cause. The following age-specific 
requirements apply:  
Women <50 years of age would be considered post-menopausal if they have been 
amenorrheic for 12 months or more following cessation of exogenous hormonal 
treatments and if they have luteinizing hormone and follicle-stimulating hormone 
levels in the post-menopausal range for the institution or underwent surgical 
sterilization (bilateral oophorectomy or hysterectomy).  
Women ≥50 years of age would be considered post-menopausal if they have been 
amenorrheic for 12 months or more following cessation of all exogenous hormonal 


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38
treatments, had radiation-induced menopause with last menses >1 year ago, had 
chemotherapy-induced menopause with last menses >1 year ago, or underwent 
surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or 
hysterectomy). 
Highly effective methods of contraception, defined as one that results in a low 
failure rate (ie, less than 1% per year) when used consistently and correctly are 
described in Table 5.. Note that some contraception methods are not considered 
highly effective (eg male or female condom with or without spermicide; female cap, 
diaphragm, or sponge with or without spermicide; non-copper containing 
intrauterine device; progestogen-only oral hormonal contraceptive pills where 
inhibition of ovulation is not the primary mode of action [excluding 
Cerazette/desogestrel which is considered highly effective]; and triphasic combined 
oral contraceptive pills). 
Table 5.2. Highly Effective Methods of Contraception (<1% Failure Rate) 
• Barrier/Intrauterine methods 
• Hormonal Methods 
• Copper T intrauterine device 
• Levonorgestrel-releasing 
intrauterine system (eg, 
Mirena®)a 
 
• Implants: Etonogestrel-releasing implants: 
e.g. Implanon® or Norplan®  
• Intravaginal: 
Ethinylestradiol/etonogestrel-
releasing intravaginal devices: e.g. NuvaRing®   
• Injection: Medroxyprogesterone injection: 
e.g. Depo-Provera®   
• Combined Pill: Normal and low dose 
combined oral contraceptive pill 
• Patch: 
Norelgestromin/ethinylestradiol-
releasing transdermal system: e.g. Ortho 
Evra®    
• Minipillc: Progesterone based oral 
contraceptive pill using desogestrel: 
Cerazette® is currently the only highly 
effective progesterone based  
a 
This is also considered a hormonal method 
 
Blood donation 
Subjects should not donate blood while participating in this study, or for at least 90 
days following the last infusion of durvalumab or tremelimumab or 90 days after 
receipt of the final dose of durvalumab. 
 


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39
5.5  
Duration of Therapy 
 
In the absence of treatment delays due to adverse events, treatment may continue 
until one of the following criteria applies: disease progression, intercurrent illness 
that prevents further administration of therapy, unacceptable adverse events, 
patient decides to withdraw from study, or general or specific changes in the 
patient’s condition that render the patient unacceptable for further treatment in the 
judgement of the investigator. 
 
5.6 
Duration of Follow Up 
 
Patients will be followed for 1.5 years after completion of active treatment from 
study or until death, whichever occurs first.  Patients removed from study for 
unacceptable adverse events will be followed until resolution or stabilization of the 
adverse event. 
 
 
6. DOSING DELAYS/DOSE MODIFICATIONS 
 
Adjustments for Durvalumab and Trametinib will follow the guidelines and 
recommendations noted below. Based on the mechanism of action of Durvalumab and 
Trametinib leading to T-cell activation and proliferation, the occurrence of irAEs that are 
either overlapping or greater than each of these drugs when used as monotherapy is 
possible though considered unlikely. Adjustments can be made to both drugs or each drug 
independently if a toxicity is felt to be specifically related to one of the drugs.  For specific 
non-immune related toxicities that are expected with trametinib alone, trametinib 
modification should follow table 6.3.  If one study agent is discontinued due to toxicity then 
the patient may continue on protocol with the other agent if it is felt in the patients best 
interest by the treating physician.  The decision to dose adjustment should be based upon 
investigator determined attribution as at least possibly related to trametinib.  
 
Potential irAEs may include[29, 32, 33, 57]: 
 
• Gastrointestinal events including colitis, intestinal perforation, abdominal 
pain, dehydration, nausea and vomiting, and decreased appetite (anorexia) 
• Dermatitis including urticaria, skin exfoliation, and dry skin 
• Endocrinopathies including hypophysitis, adrenal insufficiency, and hyper and 
hypothyroidism 
• Hepatitis including autoimmune hepatitis, and increased serum alanine 
aminotransferase and aspartate aminotransferase 
• Pancreatitis including autoimmune pancreatitis, and lipase and amylase 
elevation 


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• Respiratory tract events including pneumonitis and interstitial lung disease 
• Nervous system events including encephalitis, peripheral motor and sensory 
neuropathies, Guillain-Barre and myasthenia gravis (the latter reported with 
combination of tremelimumab and Durvalumab) 
• Cytopenias including thrombocytopenia, anemia and neutropenia 
• Infusion-related reactions, anaphylaxis, and serious allergic reactions 
• Headache, fatigue, and pyrexia 
• Serious infections 
•Immune complex disease. 
 
 
Subjects should be monitored for signs and symptoms of irAEs. In the absence of an 
alternate etiology (eg, infection or PD), an immune-related etiology should be considered 
for signs or symptoms of enterocolitis, pneumonitis, dermatitis, hepatitis, neuropathy, and 
endocrinopathy. In addition to the treatment modifications shown in Table 6.4/6.5 it is 
recommended that management of irAEs follow the guidelines outlined for ipilimumab [58]. 
These guidelines recommend the following: 
1. Subjects should be evaluated to identify any alternative etiology. 
2. In the absence of a clear alternative etiology, all events of an inflammatory nature 
should be considered to be immune-related. 
3. Symptomatic and topical therapy should be considered for low-grade events. 
4. Systemic corticosteroids should be considered for a persistent low-grade event or for 
a severe event. 
5. More potent immunosuppressives should be considered for events not responding to 
systemic steroids (eg, infliximab, mycophenolate, etc). 
 
All toxicities will be graded according to NCI CTCAEv4.03. In case of doubt, the investigator 
should consult with the AstraZeneca / MedImmune .If the investigator has any question in 
regards to an AE being an irAE, the investigator should immediately contact the AstraZeneca 
/ MedImmune . Treatment modifications will not be required for AEs that are clearly not 
attributed to Durvalumab or Trametinib (such as an accident) or for laboratory 
abnormalities that are not deemed to be clinically significant. 
 
Dose reductions of Durvalumab are not permitted. Dose reductions of trametinib are 
permitted as in table 6.2 
 
Treatment modifications may be required for Durvalumab and Trametinib in the event of 
treatment-related toxicity. General guidelines regarding treatment modification are 
provided in the following tables. 
-Table 6.1 Recommended dose level reductions for Trametinib 
-Table 6.2 Trametinib specific dose modification schedule 


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41
-Table 6.3 Predominantly trametinib specific toxicity: dose modification schedule for 
trametinib and durvalumab 
-Table 6.4 Durvalumab dose modification schedule 
-Table 6.5 Adverse events of special interest (AESI): durvalumab and trametinib dose 
adjustment schedule. 
 
 
 
Table 6.1 Recommended dose level reductions for Trametinib 
 
 
Table 6.2 Trametinib dose modification schedule 
 
 
 
Table 6.3 Predominantly trametinib specific toxicity: dose modification schedule for 
trametinib and durvalumab 
 
CTCAE v4.0 
Trametinib 
Durvalumab 
Adverse Event 
Cardiac Disorders 
  
LV systolic dysfunction 
Also refer to “Decreased ejection fraction” in Investigations 
Grade 3 
Permanently discontinue trametinib; consider 
evaluation by a cardiologist. 
Continue durvalumab at same dose 
level 
Grade 4 
Continue to monitor the LVEF at 2 weeks, 4 
weeks, and then every 4 weeks through week 16 
or until resolution 


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CTCAE v4.0 
Trametinib 
Durvalumab 
Adverse Event 
Hypertension 
–     Continue trametinib at same dose level. 
Continue durvalumab at same dose 
level 
Grade 1 
Grade 2 
•         Continue trametinib at the current dose  
Continue durvalumab at same dose 
level 
•         Adjust current or initiate new 
antihypertensive medication 
•         Titrate antihypertensive medication(s) 
during the next 2 weeks as indicated to achieve 
well-controlled BP 
•         If BP is not well controlled within 2 weeks, 
consider referral to a specialist and manage as for 
Grade 3. 
Grade 3 
•         If symptomatic, interrupt trametinib. If 
asymptomatic, consider interrupting trametinib if 
clinically indicated 
Continue durvalumab at same dose 
level 
•         Adjust current or initiate new 
antihypertensive medication(s) 
•         Titrate antihypertensive medication(s) 
during the next 2 weeks to achieve well-controlled 
BP 
•         If symptomatic or persistent Grade 3 
hypertension despite antihypertensive 
medications and dose reduction of trametinib, 
recommend referral to a specialist for further 
evaluation and follow-up 
•         Once BP is well controlled, restart 
trametinib reduced by one dose level 
Grade 4 
Permanently discontinue trametinib 
Continue durvalumab at same dose 
level 
ECG QT corrected interval 
prolonged 
Continue trametinib at same dose level. 
Continue durvalumab at same dose 
level. 
Grade 1 
Grade 2 
Grade 3 
Note regarding Grade 3:  If an ECG demonstrates a 
prolonged QT interval, obtain 2 more ECGs over a 
brief period and average the QTc values of the 3 
ECGs.  Based on the average QTc value of triplicate 
ECGs (confirmed via manual over-read), modify 
therapy as outlined below. 
  
•   If QTcf > 501 msec or uncorrected QT 


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43
CTCAE v4.0 
Trametinib 
Durvalumab 
Adverse Event 
> 600 msec or QTcf > 530 msec for subjects 
with bundle branch block, interrupt therapy. 
Continue durvalumab at same dose 
level. 
•   If the QTc prolongation resolves to ≤ 480 
msec, trametinib therapy may be resumed at the 
same dose level, if the investigator and 
AstraZeneca / MedImmune  agree that the patient 
could benefit from further treatment. 
•   If the event recurs, permanently discontinue 
trametinib. 
Grade 4 
Permanently discontinue trametinib. 
Permanently discontinue 
durvalumab. 
Ejection fraction ↓ 
For instructions for patients with symptomatic ↓ in 
LVEF, 
  
  
refer to “Left ventricular systolic dysfunction” in Cardiac 
Disorders 
Grade 2 
•         Interrupt trametinib and repeat 
ECHO/MUGA within 2 weeks. If not recovered, 
repeat again in 2 weeks. 
Continue durvalumab at same dose 
level. 
  
•         If the LVEF recovers within 4 weeks 
(defined as LVEF ≥LLN and absolute decrease 
≤10% compared to baseline)  
  
• Consult with the AstraZeneca / 
MedImmune  and request approval to restart 
trametinib. 
  
• Restart treatment with trametinib 
reduced dose by one dose level 
  
• Repeat ECHO/MUGA 2, 4, 8, and 12 
weeks after restart; continue in intervals of 12 
weeks thereafter.  
  
• If LVEF remains stable for 4 weeks 
after restarting trametinib, may request approval 
from AstraZeneca / MedImmune  to reescalate to 
previous dose level. 
  
•         If  LVEF does not recover within 4 weeks 
  
• Consult with cardiologist 
  
• Permanently discontinue 
trametinib  
  
• Report as SAE 
  
• Repeat ECHO/MUGA after 2, 4, 8, 
12, and 16 weeks or until resolution 
  
• Consult with AstraZeneca / MedImmune  


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44
CTCAE v4.0 
Trametinib 
Durvalumab 
Adverse Event 
Grade 3 
If symptomatic, permanently discontinue 
trametinib.   
Continue durvalumab at same dose 
level. 
If asymptomatic, follow instructions for Grade 2 ↓ 
in ejection fraction. 
Grade 4 
Permanently discontinue trametinib. 
Permanently discontinue 
durvalumab. 
Eye Disorders 
  
Retinopathy and Other 
Eye Disorders  
If visual changes are clearly not due to retinal or 
retinal vein abnormalities or are clearly 
unrelated to study drug (e.g., allergic 
conjunctivitis), continue trametinib with close 
observation. 
Continue durvalumab at same dose 
level 
Grade 1 
If etiology is unclear, immediately refer patient 
for ophthalmic exam; if dilated fundus exam 
cannot be performed within 7 days, interrupt 
trametinib until exam is performed. 
  
If RPED or RVO excluded, continue (or restart) 
trametinib at same dose level. 
  
If RVO diagnosed, permanently discontinue 
trametinib. 
  
If RPED suspected or diagnosed and 
asymptomatic, continue trametinib with monthly 
retinal exam until resolution. If symptomatic or 
grade 1 RPED worsens, interrupt trametinib, 
with monthly retinal exam until improved to ≤ 
Grade 1 and restart with reduction by one dose 
level. 
Grade 2 
Immediately interrupt trametinib therapy and 
refer patient for ophthalmic exam. 
Continue durvalumab at same dose 
level OR interrupt therapy until eye 
disorder is stable; then resume 
therapy at same dose level. 
If RPED or RVO excluded, restart trametinib at 
same dose level. 
If RVO diagnosed, permanently discontinue 
trametinib. 
Grade 3 
If RPED diagnosed and asymptomatic, continue 
trametinib with monthly retinal exam until 
resolution. If symptomatic or grade 1 RPED 
worsens, interrupt trametinib, with monthly 
retinal exam until improved to ≤ Grade 1 and 
restart at reduction by one dose level. 
Interrupt therapy until eye disorder 
is stable. If found to have 
inflammatory condition, treat with 
steroids and permanently 
discontinue durvalumab. 
Grade 4 
•   Immediately interrupt trametinib therapy and 
refer patient for ophthalmic exam. 
–     If RPED or RVO excluded, consider 
restarting trametinib at same or reduced dose 
level after discussion with AstraZeneca / 
MedImmune . 


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45
CTCAE v4.0 
Trametinib 
Durvalumab 
Adverse Event 
–     If RVO or RPED diagnosed, permanently 
discontinue trametinib. 
Skin and Subcutaneous Tissue Disorders 
Rash 
• Continue trametinib at current dose 
Continue durvalumab at current 
dose. 
Grade 1 (Mild) 
• If rash does not recover to baseline within 2 
weeks despite best supportive care, reduce 
trametinib by one dose level 
Grade 2 (Moderate) 
• Reduce trametinib by one dose level 
Continue durvalumab at current 
dose. 
 
Consider skin biopsy if persistent for 
>2 weeks or recurs 
      • 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, 
and then restart trametinib at  reduced dose level 
Grade 3 (Severe) 
• Interrupt trametinib until rash recovers to grade 
≤1 
• Hold durvalumab until rash 
recovers to grade ≤2.  If rash 
recovers to ≤grade 2, restart 
durvalumab. 
• Restart with trametinib reduced by one dose 
level 
• If grade 3 rash occurs a second 
time, withhold durvalumab until rash 
recovers to grade ≤2.  If rash 
recovers to ≤grade 2, restart 
durvalumab. 
• If no recovery to grade ≤2 within 4 weeks, 
permanently discontinue trametinib 
• If grade 3 rash occurs a third time, 
permanently discontinue 
durvalumab. 
 
• Consider consult dermatology  
• Consider promptly initiate empiric 
IV methylprednisolone 1 to 4 
mg/kg/day or equivalent if believed 
immune-related rash 
• Consider skin biopsy (preferably 
more than 1) as clinically feasible. 
- If felt to be immune related 
discuss with Principal investigator 
 
**IF THERE IS ANY BULLOUS 
FORMATION, THE PRINCIPAL 
INVESTIGATOR SHOULD BE 
CONTACTED AND STUDY DRUG 
DISCONTINUED** 


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46
CTCAE v4.0 
Trametinib 
Durvalumab 
Adverse Event 
Grade 4 
  
Permanently discontinue 
durvalumab. 
 
• Consult dermatology  
• Consider promptly initiate empiric 
IV methylprednisolone 1 to 4 
mg/kg/day or equivalent if believed 
immune-related rash 
• Consider skin biopsy (preferably 
more than 1) as clinically feasible. 
- If felt to be immune related 
discuss with Principal investigator 
 
 
**IF THERE IS ANY BULLOUS 
FORMATION, THE PRINCIPAL 
INVESTIGATOR SHOULD BE 
CONTACTED AND STUDY DRUG 
DISCONTINUED** 
 
 


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47
Table 6.4 
Dosing Modification and Toxicity Management Guidelines for Immune-mediated, Infusion Related, and Non 
Immune-mediated Reactions (MEDI4736 Monotherapy) 1 November 2017 Version 
Dose Modifications 
Toxicity Management 
Drug administration modifications of study drug/study regimen will be made to 
manage potential immune-related AEs based on severity of treatment-emergent 
toxicities graded per NCI CTCAE v4.03. 
In addition to the criteria for permanent discontinuation of study drug/study 
regimen based on CTC grade/severity (table below), permanently discontinue 
study drug/study regimen for the following conditions: 
• 
Inability to reduce corticosteroid to a dose of ≤10 mg of prednisone per 
day (or equivalent) within 12 weeks after last dose of study drug/study 
regimen 
• 
Recurrence of a previously experienced Grade 3 treatment-related AE 
following resumption of dosing 
Grade 1 
No dose modification 
Grade 2 
Hold study drug/study regimen dose until Grade 2 resolution to 
Grade ≤1. 
If toxicity worsens, then treat as Grade 3 or Grade 4. 
Study drug/study regimen can be resumed once event stabilizes to 
Grade ≤1 after completion of steroid taper. 
Patients with endocrinopathies who may require prolonged or 
continued steroid replacement can be retreated with study 
drug/study regimen on the following conditions: 
1. 
The event stabilizes and is controlled. 
2. 
The patient is clinically stable as per Investigator or treating 
physician’s clinical judgement. 
3. 
Doses of prednisone are at ≤10 mg/day or equivalent. 
Grade 3 
Depending on the individual toxicity, study drug/study regimen may 
be permanently discontinued. Please refer to guidelines below. 
Grade 4 
Permanently discontinue study drug/study regimen. 
It is recommended that management of immune-mediated adverse events (imAEs) 
follows the guidelines presented in this table: 
− 
It is possible that events with an inflammatory or immune mediated 
mechanism could occur in nearly all organs, some of them not noted 
specifically in these guidelines. 
− 
Whether specific immune-mediated events (and/or laboratory indicators of 
such events) are noted specifically in these guidelines or not, patients should 
be thoroughly evaluated to rule out any alternative etiology  
− 
(e.g., disease progression, concomitant medications, and infections).) to a 
possible immune-mediated event. In the absence of a clear alternative 
etiology, all such events should be managed as if they were immune related. 
General recommendations follow. 
− 
Symptomatic and topical therapy should be considered for low-grade (Grade 
1 or 2, unless otherwise specified) events. 
− 
For persistent (>3 to 5 days) low-grade (Grade 2) or severe (Grade ≥3) 
events, promptly start prednisone 1 to 2 mg/kg/day PO or IV equivalent. 
− 
Some events with high likelihood for morbidity and/or mortality – e.g., myo-
carditis, or other similar events even if they are not currently noted in the 
guidelines – should progress rapidly to high dose IV corticosteroids 
(methylprednisolone at 2 to 4 mg/kg/day) even if the event is Grade 2, and if 
clinical suspicion is high and/or there has been clinical confirmation. Discuss 
these eventsConsider, as necessary, discussing with the study physician, and 
promptly pursue subspecialisty consultation. 
− 
If symptoms recur or worsen during corticosteroid tapering (28 days of 
taper), increase the corticosteroid dose (prednisone dose [eg, up to 2 to 
4 mg/kg/day PO or IV equivalent]) until stabilization or improvement of 
symptoms, then resume corticosteroid tapering at a slower rate (>28 days of 
taper). 


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48
Table 6.4 
Dosing Modification and Toxicity Management Guidelines for Immune-mediated, Infusion Related, and Non 
Immune-mediated Reactions (MEDI4736 Monotherapy) 1 November 2017 Version 
Dose Modifications 
Toxicity Management 
Note: For Grade ≥3 asymptomatic amylase or lipase levels, hold study drug/study 
regimen, and if complete work up shows no evidence of pancreatitis, study 
drug/study regimen may be continued or resumed. 
 
Note: Study drug/study regimen should be permanently discontinued in Grade 3 
events with high likelihood for morbidity and/or mortality – e.g., myocarditis, or 
other similar events even if they are not currently noted in the guidelines. Similarly, 
consider whether study drug/study regimen should be permanently discontinued 
in Grade 2 events with high likelihood for morbidity and/or mortality – e.g., 
myocarditis, or other similar events even if they are not currently noted in the 
guidelines – when they do not rapidly improve to Grade <1 upon treatment with 
systemic steroids and following full taper 
Note: There are some exceptions to permanent discontinuation of study drug for 
Grade 4 events (i.e., hyperthyroidism, hypothyroidism, Type 1 diabetes mellitus).  
 
− 
More potent immunosuppressives such as TNF inhibitors (eg, infliximab) 
(also refer to the individual sections of the irAE for specific type of 
immunosuppressive) should be considered for events not responding to 
systemic steroids. 
− 
Discontinuation of study drug/study regimen is not mandated for Grade 
3/Grade 4 inflammatory reactions attributed to local tumor response 
(eg, inflammatory reaction at sites of metastatic disease and lymph nodes). 
Continuation of study drug/study regimen in this situation should be based 
upon a benefit/risk analysis for that patient. 
AE  Adverse event; CTC  Common Toxicity Criteria; CTCAE  Common Terminology Criteria for Adverse Events; imAE immune-mediated adverse event; IV  intravenous; NCI  National Cancer 
Institute; PO  By mouth. 
 
 
 


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49
Pediatric Considerations 
Dose Modifications 
Toxicity Management 
The criteria for permanent discontinuation of study drug/study regimen based on 
CTC grade/severity is the same for pediatric patients as it is for adult patients, as 
well as to permanently discontinue study drug/study regimen if unable to reduce 
corticosteroid ≤ a dose equivalent to that required for corticosteroid replacement 
therapy within 12 weeks after last dose of study drug/study regimen 
− 
All recommendations for specialist consultation should occur with a 
pediatric specialist in the specialty recommended. 
− 
The recommendations for dosing of steroids (i.e., mg/kg/day) and for IV IG 
and plasmapheresis that are provided for adult patients should also be used 
for pediatric patients. 
− 
The infliximab 5 mg/kg IV dose recommended for adults is the same as 
recommended for pediatric patients ≥ 6 years old.  For dosing in children 
younger than 6 years old, consult with a pediatric specialist. 
− 
For pediatric dosing of mycophenolate mofetil, consult with a pediatric 
specialist. 
− 
With long-term steroid and other immunosuppressive use, consider need for 
PJP prophylaxis, gastrointestinal protection, and glucose monitoring. 


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50
Specific Immune-mediated Reactions 
Adverse Events 
Severity Grade of the 
Event (NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
Pneumonitis/Interstitial 
Lung Disease (ILD) 
Any Grade 
General Guidance 
For Any Grade: 
− 
Monitor patients for signs and symptoms of pneumonitis or 
ILD (new onset or worsening shortness of breath or cough). 
Patients should be evaluated with imaging and pulmonary 
function tests, including other diagnostic procedures as 
described below. 
− 
Initial work-up may include clinical evaluation, monitoring of 
oxygenation via pulse oximetry (resting and exertion), 
laboratory work-up, and high- resolution CT scan. 
Grade 1 
(asymptomatic, clinical 
or diagnostic 
observations only; 
intervention not 
indicated) 
No dose modifications required. 
However, consider holding study 
drug/study regimen dose as clinically 
appropriate and during diagnostic work-
up for other etiologies. 
For Grade 1 (radiographic changes only): 
− 
Monitor and closely follow up in 2 to 4 days for clinical 
symptoms, pulse oximetry (resting and exertion), and 
laboratory work-up and then as clinically indicated. 
− 
Consider pulmonary and infectious disease consult. 
Grade 2 
(symptomatic; medical 
intervention indicated; 
limiting instrumental 
ADL) 
Hold study drug/study regimen dose until 
Grade 2 resolution to Grade ≤1. 
• 
If toxicity worsens, then treat as 
Grade 3 or Grade 4. 
• 
If toxicity improves to Grade ≤1, then 
the decision to reinitiate study 
drug/study regimen will be based 
upon treating physician’s clinical 
judgment and after completion of 
steroid taper. 
For Grade 2 (mild to moderate new symptoms): 
− 
Monitor symptoms daily and consider hospitalization. 
− 
Promptly start systemic steroids (eg, prednisone 1 to 
2 mg/kg/day PO or IV equivalent). 
− 
Reimage as clinically indicated. 
− 
If no improvement within 3 to 5 days, additional workup 
should be considered and prompt treatment with IV 
methylprednisolone 2 to 4 mg/kg/day started 
− 
If still no improvement within 3 to 5 days despite IV 
methylprednisone at 2 to 4 mg/kg/day, promptly start 
immunosuppressive therapy such as TNF inhibitors 
(eg, infliximab at 5 mg/kg every 2 weeks). Caution: It is 


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Specific Immune-mediated Reactions 
Adverse Events 
Severity Grade of the 
Event (NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
important to rule out sepsis and refer to infliximab label for 
general guidance before using infliximab. 
− 
Once the patient is improving, gradually taper steroids over 
≥28 days and consider prophylactic antibiotics, antifungals, or 
anti-PCP treatment (refer to current NCCN guidelines for 
treatment of cancer-related infections (Category 2B 
recommendation)a 
− 
Consider pulmonary and infectious disease consult. 
− 
Consider, as necessary, discussing with principal investigator. 
Grade 3 or 4 
(Grade 3: severe 
symptoms; limiting 
self-care ADL; oxygen 
indicated) 
 
(Grade 4: life-
threatening respiratory 
compromise; urgent 
intervention indicated 
[eg, tracheostomy or 
intubation]) 
Permanently discontinue study 
drug/study regimen. 
For Grade 3 or 4 (severe or new symptoms, new/worsening hypoxia, 
life-threatening): 
− 
Promptly initiate empiric IV methylprednisolone 1 to 
4 mg/kg/day or equivalent. 
− 
Obtain pulmonary and infectious disease consult. 
− 
Hospitalize the patient. 
− 
Supportive care (eg, oxygen). 
− 
If no improvement within 3 to 5 days, additional workup 
should be considered and prompt treatment with additional 
immunosuppressive therapy such as TNF inhibitors 
(eg, infliximab at 5 mg/kg every 2 weeks dose) started. 
Caution: rule out sepsis and refer to infliximab label for 
general guidance before using infliximab. 
− 
Once the patients is improving, gradually taper steroids over 
≥28 days and consider prophylactic antibiotics, antifungals, 
and, in particular, anti-PCP treatment (refer to current NCCN 
guidelines for treatment of cancer-related infections 
(Category 2B recommendation).a 
Diarrhea/Colitis 
Any Grade 
General Guidance 
For Any Grade: 


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52
Specific Immune-mediated Reactions 
Adverse Events 
Severity Grade of the 
Event (NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
− 
Monitor for symptoms that may be related to 
diarrhea/enterocolitis (abdominal pain, cramping, or changes 
in bowel habits such as increased frequency over baseline or 
blood in stool) or related to bowel perforation (such as sepsis, 
peritoneal signs, and ileus). 
− 
Patients should be thoroughly evaluated to rule out any 
alternative etiology (eg, disease progression, other 
medications, or infections), including testing for clostridium 
difficile toxin, etc. 
− 
Steroids should be considered in the absence of clear 
alternative etiology, even for low-grade events, in order to 
prevent potential progression to higher grade event. 
− 
Use analgesics carefully; they can mask symptoms of 
perforation and peritonitis. 
Grade 1 
(Diarrhea: stool 
frequency of 
<4 over baseline per 
day) (Colitis: 
asymptomatic; clinical 
or diagnostic 
observations only) 
No dose modifications. 
For Grade 1: 
− 
Monitor closely for worsening symptoms. 
− 
Consider symptomatic treatment, including hydration, 
electrolyte replacement, dietary changes (eg, American 
Dietetic Association colitis diet), and loperamide. Use 
probiotics as per treating physician’s clinical judgment. 
Grade 2 
(Diarrhea: stool 
frequency of 4 to 6 
over baseline per day) 
Hold study drug/study regimen until 
resolution to Grade ≤1 
• 
If toxicity worsens, then treat as 
Grade 3 or Grade 4. 
For Grade 2: 
− 
Consider symptomatic treatment, including hydration, 
electrolyte replacement, dietary changes (eg, American 
Dietetic Association colitis diet), and loperamide and/or 
budesonide. 


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53
Specific Immune-mediated Reactions 
Adverse Events 
Severity Grade of the 
Event (NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
(Colitis: abdominal 
pain; mucus or blood in 
stool) 
• 
If toxicity improves to Grade ≤1, then 
study drug/study regimen can be 
resumed after completion of steroid 
taper. 
− 
Promptly start prednisone 1 to 2 mg/kg/day PO or IV 
equivalent. 
− 
If event is not responsive within 3 to 5 days or worsens despite 
prednisone at 1 to 2 mg/kg/day PO or IV equivalent, GI consult 
should be obtained for consideration of further workup, such 
as imaging and/or colonoscopy, to confirm colitis and rule out 
perforation, and prompt treatment with IV 
methylprednisolone 2 to 4 mg/kg/day started. 
− 
If still no improvement within 3 to 5 days despite 2 to 4 mg/kg 
IV methylprednisolone, promptly start immunosuppressives 
such as infliximab at 5 mg/kg once every 2 weeksa. Caution: it 
is important to rule out bowel perforation and refer to 
infliximab label for general guidance before using infliximab. 
− 
Consult principal investigator if no resolution to Grade ≤1 in 3 
to 4 days. 
− 
Once the patient is improving, gradually taper steroids over 
≥28 days and consider prophylactic antibiotics, antifungals, 
and anti-PCP treatment (refer to current NCCN guidelines for 
treatment of cancer-related infections [Category 2B 
recommendation]).a 
Grade 3 or 4 
(Grade 3: stool 
frequency of ≥7 over 
baseline per day; 
 
 
 
Grade 3 
Permanently discontinue study 
drug/study regimen  for Grade 3 if 
toxicity does not improve to Grade ≤1 
within 14 days; study drug/study regimen 
can be resumed after completion of 
steroid taper 
 
For Grade 3 or 4: 
− 
Promptly initiate empiric IV methylprednisolone 2 to 
4 mg/kg/day or equivalent. 
− 
Monitor stool frequency and volume and maintain hydration. 
− 
Urgent GI consult and imaging and/or colonoscopy as 
appropriate. 
− 
If still no improvement within 3 to 5 days of IV 
methylprednisolone 2 to 4 mg/kg/day or equivalent, promptly 
start further immunosuppressives (eg infliximab at 5 mg/kg 


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version 4.03) 
Dose Modifications 
Toxicity Management 
Grade 4: diarrhea life 
threatening 
consequences)  
(Grade 3 colitis: severe 
abdominal pain, 
change in bowel habits, 
medi-cal intervention 
indi-cated, peritoneal 
signs; 
Grade 4 colitis: life-
threatening 
consequences, urgent 
intervention indicated) 
Grade 4 
Permanently discontinue  
study drug/study regimen. 
once every 2 weeks). Caution: Ensure GI consult to rule out 
bowel perforation and refer to infliximab label for general 
guidance before using infliximab. 
− 
Once the patient is improving, gradually taper steroids over 
≥28 days and consider prophylactic antibiotics, antifungals, 
and anti-PCP treatment (refer to current NCCN guidelines for 
treatment of cancer-related infections [Category 2B 
recommendation]).a 
Hepatitis (elevated LFTs) 
Infliximab should not be 
used for management of 
immune-related hepatitis. 
Any Grade 
General Guidance 
For Any Grade: 
− 
Monitor and evaluate liver function test: AST, ALT, ALP, and 
TB. 
− 
Evaluate for alternative etiologies (eg, viral hepatitis, disease 
progression, concomitant medications,). 
Grade 1 
AST or ALT > to 3 × ULN 
and/or TB > to 1.5 × 
ULN) 
No dose modifications. 
• 
If it worsens, then treat as 
Grade 2 event. 
For Grade 1: 
− 
Continue LFT monitoring per protocol. 
Grade 2 
(AST or ALT > 3 to 5 × 
• 
Hold study drug/study regimen 
dose until Grade 2 resolution to 
For Grade 2: 
− 
Regular and frequent checking of LFTs (eg, every 1 to 2 days) 


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Dose Modifications 
Toxicity Management 
ULN and/or TB >1.5 to 
3.0 × ULN) 
Grade ≤1. 
• 
If toxicity worsens, then treat as 
Grade 3 or Grade 4. 
• 
If toxicity improves to Grade ≤1 or 
baseline, resume study drug/study 
regimen after completion of steroid 
taper. 
until elevations of these are improving or resolved. 
− 
If no resolution to Grade ≤1 in 1 to 2 days, consider as 
necessary, discussing with principal investigator. 
− 
If event is persistent (>3 to 5 days) or worsens, promptly start 
prednisone 1 to 2 mg/kg/day PO or IV equivalent. 
− 
If still no improvement within 3 to 5 days despite 1 to 
2 mg/kg/day of prednisone PO or IV equivalent, consider 
additional work up and start prompt treatment with IV 
methylprednisolone 2 to 4 mg/kg/day. 
− 
If still no improvement within 3 to 5 days despite 2 to 
4 mg/kg/day of IV methylprednisolone, promptly start 
immunosuppressives (i.e. mycophenolate mofetil)a Discuss 
with principal investigator if mycophenolate mofetil is not 
available. Infliximab should NOT be used. 
− 
Once the patient is improving, gradually taper steroids over 
≥28 days and consider prophylactic antibiotics, antifungals, 
and anti-PCP treatment (refer to current NCCN guidelines for 
treatment of cancer-related infections [Category 2B 
recommendation]).a 
Grade 3 or 4 
(Grade 3: AST or ALT >5 
to 20 × ULN and/or TB 
>3.0 to 10 × ULN) 
 
(Grade 4: AST or ALT 
>20 × ULN and/or TB 
>10 × ULN) 
For Grade 3: 
For elevations in transaminases ≤8 × ULN, 
or elevations in bilirubin ≤5 × ULN: 
• Hold study drug/study regimen dose 
until resolution to Grade ≤1 or 
baseline 
• Resume study drug/study regimen if 
elevations downgrade to Grade ≤1 or 
baseline within 14 days and after 
For Grade 3 or 4: 
− 
Promptly initiate empiric IV methylprednisolone at 1 to 
4 mg/kg/day or equivalent. 
− 
If still no improvement within 3 to 5 days despite 1 to 
4 mg/kg/day methylprednisolone IV or equivalent, promptly 
start treatment with immunosuppressive therapy (i.e 
mycophenolate mofetil). Discuss with principal investigator if 
mycophenolate is not available. Infliximab should NOT be 
used. 
− 
Perform hepatology consult, abdominal workup, and imaging 


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Dose Modifications 
Toxicity Management 
completion of steroid taper. 
• Permanently discontinue study 
drug/study regimen if the elevations 
do not downgrade to Grade ≤1 or 
baseline within 14 days 
For elevations in transaminases >8 × ULN 
or elevations in bilirubin >5 × ULN, 
discontinue study drug/study regimen. 
Permanently discontinue study 
drug/study regimen for any case meeting 
Hy’s law criteria (AST and/or ALT >3 × 
ULN + bilirubin >2 × ULN without initial 
findings of cholestasis (ie, elevated 
alkaline P04) and in the absence of any 
alternative cause.b 
 
For Grade 4: 
Permanently discontinue study 
drug/study regimen. 
as appropriate. 
− 
Once the patient is improving, gradually taper steroids over 
≥28 days and consider prophylactic antibiotics, antifungals, 
and anti-PCP treatment (refer to current NCCN guidelines for 
treatment of cancer-related infections [Category 2B 
recommendation]).a 
 
 
 
 
Hepatitis  
(elevated LFTs) 
Infliximab should not be 
used for management of 
Any Grade 
 
General Guidance 
 
For Any Grade: 
− 
Monitor and evaluate liver function test: AST, ALT, ALP, and 
TB. 


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Dose Modifications 
Toxicity Management 
immune-related hepatitis.  
 
− 
Evaluate for alternative etiologies (e.g., viral hepatitis, disease 
progression, concomitant medications, worsening of liver 
cirrhosis [e.g., portal vein thrombosis]). 
− 
For HBV+ patients: evaluate quantitative HBV viral load, 
quantitative HBsAg, or HBeAg 
− 
For HCV+ patients: evaluate quantitative HCV viral load 
− 
Consider consulting hepatologist/Infectious disease specialist 
regarding change/implementation in/of antiviral medications 
for any patient with an elevated HBV viral load >2000 IU/ml 
− 
Consider consulting hepatologist/Infectious disease specialist 
regarding change/implementation in/of antiviral HCV 
medications if HCV viral load increased by ≥2-fold 
For HCV+ with HBcAB+: Evaluate for both HBV and HCV as above 
 
 
Grade 1 
(Isolated AST or ALT 
>ULN and ≤5.0×ULN, 
whether normal or 
elevated at baseline)  
• 
No dose modifications. 
• 
If ALT/AST elevations represents 
significant worsening based on 
investigator assessment, then treat 
as Grade 2 event. 
For all grades, see instructions at bottom 
of shaded area if transaminase rise is not 
isolated but (at any time) occurs in 
setting of either increasing bilirubin or 
signs of DILI/liver decompensation 
 
 


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version 4.03) 
Dose Modifications 
Toxicity Management 
 
Grade 2 
(Isolated AST or ALT 
>5.0×ULN and 
≤8.0×ULN, if normal at 
baseline) 
 
(Isolated AST or ALT 
>2.0×baseline and 
≤12.5×ULN, if elevated 
>ULN at baseline) 
• 
Hold study drug/study regimen dose 
until Grade 2 resolution to Grade ≤1 
or baseline. 
• 
If toxicity worsens, then treat as 
Grade 3 or Grade 4. 
If toxicity improves to Grade ≤1 or 
baseline, resume study drug/study 
regimen after completion of steroid 
taper. 
For Grade 2: 
− 
Regular and frequent checking of LFTs (e.g., every 1 to 3 days) 
until elevations of these are improving or resolved. 
− 
Recommend consult hepatologist; consider abdominal 
ultrasound, including Doppler assessment of liver perfusion. 
− 
Consider, as necessary, discussing with study physician. 
− 
If event is persistent (>3 to 5 days) or worsens, and 
investigator suspects toxicity to be immune-mediated AE, 
recommend to start prednisone 1 to 2 mg/kg/day PO or IV 
equivalent. 
− 
If still no improvement within 3 to 5 days despite 1 to 
2 mg/kg/day of prednisone PO or IV equivalent, consider 
additional workup and treatment with IV methylprednisolone 
2 to 4 mg/kg/day. 
If still no improvement within 3 to 5 days despite 2 to 4 mg/kg/day of IV 
methylprednisolone, consider additional abdominal workup (including 
liver biopsy) and imaging (i.e., liver ultrasound), and consider starting 
immunosuppressives (i.e., mycophenolate mofetil).a Discuss with study 
physician if mycophenolate mofetil is not available. Infliximab should 
NOT be used. 
 
 
Grade 3 
(Isolated AST or ALT 
>8.0×ULN and 
≤20.0×ULN, if normal 
at baseline) 
• Hold study drug/study regimen dose 
until resolution to Grade ≤1 or 
baseline 
• Resume study drug/study regimen if 
elevations downgrade to Grade ≤1 or 
For Grade 3: 
− 
Regular and frequent checking of LFTs (e.g., every 1-2 days) 
until elevations of these are improving or resolved. 
− 
Consult hepatologist (unless investigator is hepatologist); 
obtain abdominal ultrasound, including Doppler assessment of 
liver perfusion; and consider liver biopsy. 


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Dose Modifications 
Toxicity Management 
 
(Isolated AST or ALT 
>12.5×ULN and 
≤20.0×ULN, if  elevated 
>ULN at baseline) 
baseline within 14 days and after 
completion of steroid taper. 
• Permanently discontinue study 
drug/study regimen if the elevations 
do not downgrade to Grade ≤1 or 
baseline within 14 days 
Permanently discontinue study 
drug/study regimen for any case meeting 
Hy’s law criteria, in the absence of any 
alternative cause.b 
− 
Consider, as necessary, discussing with study physician. 
− 
If investigator suspects toxicity to be immune-mediated, 
promptly initiate empiric IV methylprednisolone at 1 to 
4 mg/kg/day or equivalent. 
− 
If no improvement within 3 to 5 days despite 1 to 4 mg/kg/day 
methylprednisolone IV or equivalent, obtain liver biopsy (if it 
has not been done already) and promptly start treatment with 
immunosuppressive therapy (mycophenolate mofetil). Discuss 
with study physician if mycophenolate is not available. 
Infliximab should NOT be used. 
− 
Once the patient is improving, gradually taper steroids over 
≥28 days and consider prophylactic antibiotics, antifungals, 
and anti-PCP treatment (refer to current NCCN guidelines for 
treatment of cancer-related infections [Category 2B 
recommendation]).a 
 
 
Grade 4 
(Isolated AST or ALT 
>20×ULN,  whether 
normal or elevated at 
baseline) 
Permanently discontinue study 
drug/study regimen. 
For Grade 4: 
Same as above  
(except would recommend obtaining liver biopsy early) 
 
Nephritis or renal 
dysfunction 
(elevated serum 
creatinine) 
Any Grade 
General Guidance 
For Any Grade: 
− 
Consult with nephrologist. 
− 
Monitor for signs and symptoms that may be related to 
changes in renal function (eg, routine urinalysis, elevated 
serum BUN and creatinine, decreased creatinine clearance, 
electrolyte imbalance, decrease in urine output, or 


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version 4.03) 
Dose Modifications 
Toxicity Management 
proteinuria). 
− 
Patients should be thoroughly evaluated to rule out any 
alternative etiology (eg, disease progression or infections). 
− 
Steroids should be considered in the absence of clear 
alternative etiology even for low-grade events (Grade 2), in 
order to prevent potential progression to higher grade event. 
Grade 1 
(Serum creatinine > 1 
to 1.5 × baseline; > ULN 
to 1.5 × ULN) 
No dose modifications. 
For Grade 1: 
− 
Monitor serum creatinine weekly and any accompanying 
symptoms. 
• 
If creatinine returns to baseline, resume its regular 
monitoring per study protocol. 
• 
If creatinine worsens, depending on the severity, 
treat as Grade 2, 3, or 4. 
− 
Consider symptomatic treatment, including hydration, 
electrolyte replacement, and diuretics. 
Grade 2 
(serum creatinine >1.5 
to 3.0 × baseline; >1.5 
to 3.0 × ULN) 
Hold study drug/study regimen until 
resolution to Grade ≤1 or baseline.  
• 
If toxicity worsens, then treat as 
Grade 3 or 4. 
• 
If toxicity improves to Grade ≤1 or 
baseline, then resume study 
drug/study regimen after completion 
of steroid taper. 
For Grade 2: 
− 
Consider symptomatic treatment, including hydration, 
electrolyte replacement, and diuretics. 
− 
Carefully monitor serum creatinine every 2 to 3 days and as 
clinically warranted. 
− 
Consult nephrologist and consider renal biopsy if clinically 
indicated. 
− 
If event is persistent (>3 to 5 days) or worsens, promptly start 
prednisone 1 to 2 mg/kg/day PO or IV equivalent. 
− 
If event is not responsive within 3 to 5 days or worsens despite 
prednisone at 1 to 2 mg/kg/day PO or IV equivalent, additional 
workup should be considered and prompt treatment with IV 


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Toxicity Management 
methylprednisolone at 2 to 4 mg/kg/day started. 
− 
Once the patient is improving, gradually taper steroids over 
≥28 days and consider prophylactic antibiotics, antifungals, 
and anti-PCP treatment (refer to current NCCN guidelines for 
treatment of cancer-related infections [Category 2B 
recommendation]).a 
− 
When event returns to baseline, resume study drug/study 
regimen and routine serum creatinine monitoring per study 
protocol. 
Grade 3 or 4 
(Grade 3: serum 
creatinine 
>3.0 × baseline; >3.0 to 
6.0 × ULN; 
 
Grade 4: serum 
creatinine >6.0 × ULN) 
Permanently discontinue study 
drug/study regimen. 
For Grade 3 or 4: 
− 
Carefully monitor serum creatinine on daily basis. 
− 
Consult nephrologist and consider renal biopsy if clinically 
indicated. 
− 
Promptly start prednisone 1 to 2 mg/kg/day PO or IV 
equivalent. 
− 
If event is not responsive within 3 to 5 days or worsens despite 
prednisone at 1 to 2 mg/kg/day PO or IV equivalent, additional 
workup should be considered and prompt treatment with IV 
methylprednisolone 2 to 4 mg/kg/day started. 
− 
Once the patient is improving, gradually taper steroids over 
≥28 days and consider prophylactic antibiotics, antifungals, 
and anti-PCP treatment (refer to current NCCN guidelines for 
treatment of cancer-related infections [Category 2B 
recommendation]).a 
Rash 
(excluding bullous skin 
formations) 
Any Grade 
(refer to NCI CTCAE 
v 4.03 for definition of 
severity/grade 
General Guidance 
For Any Grade: 
− 
Monitor for signs and symptoms of dermatitis (rash and 
pruritus). 
− 
IF THERE IS ANY BULLOUS FORMATION, THE PRINCIPAL 


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Severity Grade of the 
Event (NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
depending on type of 
skin rash) 
INVESTIGATOR SHOULD BE CONTACTED AND STUDY DRUG 
DISCONTINUED. 
Grade 1 
No dose modifications. 
For Grade 1: 
− 
Consider symptomatic treatment, including oral antipruritics 
(eg, diphenhydramine or hydroxyzine) and topical therapy 
(eg, urea cream). 
Grade 2 
For persistent (>1 to 2 weeks) Grade 2 
events, hold scheduled study drug/study 
regimen until resolution to Grade ≤1 or 
baseline. 
• 
If toxicity worsens, then treat as 
Grade 3. 
• 
If toxicity improves to Grade ≤1 or 
baseline, then resume drug/study 
regimen after completion of steroid 
taper. 
For Grade 2: 
− 
Obtain dermatology consult. 
− 
Consider symptomatic treatment, including oral antipruritics 
(eg, diphenhydramine or hydroxyzine) and topical therapy 
(eg, urea cream). 
− 
Consider moderate-strength topical steroid. 
− 
If no improvement of rash/skin lesions occurs within 3 to 
5 days or is worsening despite symptomatic treatment and/or 
use of moderate strength topical steroid, consider, as 
necessary, discussing with principal investigator and promptly 
start systemic steroids such as prednisone 1 to 2 mg/kg/day 
PO or IV equivalent. 
− 
Consider skin biopsy if the event is persistent for >1 to 2 weeks 
or recurs. 
 
 
Grade 3 or 4 
For Grade 3: 
Hold study drug/study regimen until 
resolution to Grade ≤1 or baseline. 
If temporarily holding the study 
For Grade 3 or 4: 
− 
Consult dermatology. 
− 
Promptly initiate empiric IV methylprednisolone 1 to 
4 mg/kg/day or equivalent. 


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Dose Modifications 
Toxicity Management 
drug/study regimen does not provide 
improvement of the Grade 3 skin rash to 
Grade ≤1 or baseline within 30 days, then 
permanently discontinue study 
drug/study regimen. 
 
For Grade 4: 
Permanently discontinue study 
drug/study regimen. 
− 
Consider hospitalization. 
− 
Monitor extent of rash [Rule of Nines]. 
− 
Consider skin biopsy (preferably more than 1) as clinically 
feasible. 
− 
Once the patient is improving, gradually taper steroids over 
≥28 days and consider prophylactic antibiotics, antifungals, 
and anti-PCP treatment (refer to current NCCN guidelines for 
treatment of cancer-related infections [Category 2B 
recommendation]).a 
− 
Consider, as necessary, discussing with principal investigator. 
Endocrinopathy 
(eg, hyperthyroidism, 
hypothyroidism, Type 1 
diabetes mellitus, 
hypophysitis 
hypopituitarism, and 
adrenal insufficiency; 
exocrine event of 
amylase/lipase increased 
also included in this 
section) 
Any Grade 
(depending on the type 
of endocrinopathy, 
refer to NCI CTCAE 
v4.03 for defining the 
CTC grade/severity) 
General Guidance 
For Any Grade: 
− 
Consider consulting an endocrinologist for endocrine events. 
− 
Consider, as necessary, discussing with principal investigator. 
− 
Monitor patients for signs and symptoms of endocrinopathies. 
Non-specific symptoms include headache, fatigue, behavior 
changes, changed mental status, vertigo, abdominal pain, 
unusual bowel habits, polydipsia, polyuria, hypotension, and 
weakness. 
− 
Patients should be thoroughly evaluated to rule out any 
alternative etiology (eg, disease progression including brain 
metastases, or infections). 
− 
Depending on the suspected endocrinopathy, monitor and 
evaluate thyroid function tests: TSH, free T3 and free T4 and 
other relevant endocrine and realted labs (e.g., blood glucose 
and ketone levels, HgA1c). 
− 
For modest asymptomatic elevations in serum amylase and 
lipase, corticosteroid treatment is not indicated as long as 


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Dose Modifications 
Toxicity Management 
there are no other signs or symptoms of pancreatic 
inflammation. 
− 
If a patient experiences an AE that is thought to be possibly of 
autoimmune nature (eg, thyroiditis, pancreatitis, hypophysitis, 
or diabetes insipidus), the investigator should send a blood 
sample for appropriate autoimmune antibody testing. 
 
Grade  1 
No dose modifications. 
For Grade 1 (including those with asymptomatic TSH elevation): 
− 
Monitor patient with appropriate endocrine function tests. 
− 
For suspected hypophysitis/hypopituitarism, consider 
consultation of an endocrinologist to guide assessment of 
early-morning ACTH, cortisol, TSH and free T4; also consider 
gonadotropins, sex hormones, and prolactin levels, as well as 
cosyntropin stimulation test (though it may not be useful in 
diagnosing early secondary adrenal insufficiency). 
− 
If TSH < 0.5 × LLN, or TSH >2 × ULN or consistently out of range 
in 2 subsequent measurements, include free T4 at subsequent 
cycles as clinically indicated and consider consultation of an 
endocrinologist. 
Grade 2 
For Grade 2 endocrinopathy other than 
hypothyroidism and Type 1 diabetes 
mellitus,, hold study drug/study regimen 
dose until patient is clinically stable. 
• 
If toxicity worsens, then treat as 
Grade 3 or Grade 4. 
Study drug/study regimen can be 
resumed once event stabilizes and after 
For Grade 2 (including those with symptomatic endocrinopathy): 
− 
. 
− 
Consult endocrinologist to guide evaluation of endocrine 
function and, as indicated by suspected endocrinopathy and as 
clinically indicated, consider pituitary scan. 
− 
For patients with abnormal endocrine work up, except for 
those with isolated hypothyroidism or Type 1 DM, and as 
guided by an  endocrinologist, consider short-term 
corticosteroids (eg, 1 to 2 mg/kg/day methylprednisolone or 
IV equivalent) and prompt initiation of treatment with 


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completion of steroid taper. 
Patients with endocrinopathies who may 
require prolonged or continued steroid 
replacement (e.g., adrenal insufficiency)  
can be retreated with study drug/study 
regimen on the following conditions: 
1. 
The event stabilizes and is 
controlled. 
2. 
The patient is clinically stable as per 
investigator or treating physician’s 
clinical judgement. 
3. 
Doses of prednisone are 
≤10 mg/day or equivalent. 
relevant hormone replacement (eg, levothyroxine, 
hydrocortisone, or sex hormones). – 
− 
Isolated hypothyroidism may be treated with replacement 
therapy, without study drug/study regimen interruption, and 
without corticosteroids. 
− 
Isolated Type 1 diabetes mellitus (DM) may be treated with 
appropriate diabetic therapy, without study drug/study 
regimen interruption, and without corticosteroids. 
− 
Once patients on steroids are improving, gradually taper 
immunosuppressive steroids (as appropriate and with 
guidance of endocrinologist) over ≥28 days and consider 
prophylactic antibiotics, antifungals, and anti-PCP treatment 
(refer to current NCCN guidelines for treatment of cancer-
related infections [Category 2B recommendation]).a 
− 
For patients with normal endocrine workup (laboratory 
assessment or MRI scans), repeat laboratory assessments/MRI 
as clinically indicated. 
Grade 3 or 4 
For Grade 3 or 4 endocrinopathy other 
than hypothyroidism and Type 1 diabetes 
mellitus,, hold study drug/study regimen 
dose until endocrinopathy symptom(s) 
are controlled.  
Study drug/study regimen can be 
resumed once event stabilizes and after 
completion of steroid taper. 
Patients with endocrinopathies who may 
require prolonged or continued steroid 
For Grade 3 or 4: 
− 
Consult endocrinologist to guide evaluation of endocrine 
function and, as indicated by suspected endocrinopathy and as 
clinically indicated, consider pituitary scan. Hospitalization 
recommended. 
− 
For all patients with abnormal endocrine work up, except 
those with isolated hypothyroidism or Type 1 DM, and as 
guided by an  endocrinologist, consider short-term 
corticosteroids (e.g., 1 to 2 mg/kg/day methylprednisolone or 
IV equivalent) and prompt initiation of treatment with 
relevant hormone replacement (e.g., hydrocortisone, sex 
hormones) 
− 
For adrenal crisis, severe dehydration, hypotension, or shock, 


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replacement (e.g., adrenal insufficiency) 
can be retreated with study drug/study 
regimen on the following conditions: 
1. 
The event stabilizes and is 
controlled. 
2. 
The patient is clinically stable as per 
investigator or treating physician’s 
clinical judgement. 
Doses of prednisone are ≤10 mg/day or 
equivalent. 
immediately initiate IV corticosteroids with mineralocorticoid 
activity. 
− 
Isolated hypothyroidism may be treated with replacement 
therapy without treatment interruption and without 
corticosteroids. 
− 
Isolated Type 1 diabetes mellitus (DM) may be treated with 
appropriate diabetic therapy, without study drug/study 
regimen interruption, and without corticosteroids. 
− 
Once the patients on steroids are improving, gradually taper 
immunosuppressive steroids over ≥28 days and consider 
prophylactic antibiotics, antifungals, and anti-PCP treatment 
(refer to current NCCN guidelines for treatment of cancer-
related infections [Category 2B recommendation]).a 
− 
For patients with normal endocrine workup (laboratory 
assessment or MRI scans), repeat laboratory assessments/MRI 
as clinically indicated. 
− 
Discuss with principal investigator. 
Neurotoxicity 
(to include but not be 
limited to limbic 
encephalitis and 
autonomic neuropathy, 
excluding Myasthenia 
Gravis and Guillain-Barre) 
Any Grade 
(depending on the type 
of neurotoxicity, refer 
to NCI CTCAE v4.03 for 
defining the CTC 
grade/severity) 
General Guidance 
For Any Grade: 
− 
Patients should be evaluated to rule out any alternative 
etiology (eg, disease progression, infections, metabolic 
syndromes, or medications). 
− 
Monitor patient for general symptoms (headache, nausea, 
vertigo, behavior change, or weakness). 
− 
Consider appropriate diagnostic testing (eg, electromyogram 
and nerve conduction investigations). 
− 
Perform symptomatic treatment with neurological consult as 
appropriate. 
Grade 1 
No dose modifications. 
For Grade 1: 


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Toxicity Management 
− 
See “Any Grade” recommendations above. 
Grade 2 
For acute motor neuropathies or 
neurotoxicity, hold study drug/study 
regimen dose until resolution to Grade 
≤1. 
For sensory neuropathy/neuropathic 
pain, consider holding study drug/study 
regimen dose until resolution to Grade 
≤1. 
If toxicity worsens, then treat as 
Grade 3 or 4. 
Study drug/study regimen can be 
resumed once event improves to Grade 
≤1 and after completion of steroid taper. 
For Grade 2: 
− 
Consider, as necessary, discussing with the principal 
investigator. 
− 
Obtain neurology consult. 
− 
Sensory neuropathy/neuropathic pain may be managed by 
appropriate medications (eg, gabapentin or duloxetine). 
− 
Promptly start systemic steroids prednisone 1 to 2 mg/kg/day 
PO or IV equivalent. 
− 
If no improvement within 3 to 5 days despite 1 to 2 mg/kg/day 
prednisone PO or IV equivalent, consider additional workup 
and promptly treat with additional immunosuppressive 
therapy (eg, IV IG). 
Grade 3 or 4 
For Grade 3: 
Hold study drug/study regimen dose until 
resolution to Grade ≤1. 
Permanently discontinue study 
drug/study regimen if Grade 3 irAE does 
not resolve to Grade ≤1 within 30 days. 
 
For Grade 4: 
Permanently discontinue study 
For Grade 3 or 4: 
− 
Consider, as necessary, discussing with principal investigator. 
− 
Obtain neurology consult. 
− 
Consider hospitalization. 
− 
Promptly initiate empiric IV methylprednisolone 1 to 
2 mg/kg/day or equivalent. 
− 
If no improvement within 3 to 5 days despite IV 
corticosteroids, consider additional workup and promptly 
treat with additional immunosuppressants (eg, IV IG). 
− 
Once stable, gradually taper steroids over ≥28 days. 


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68
Specific Immune-mediated Reactions 
Adverse Events 
Severity Grade of the 
Event (NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
drug/study regimen. 
Peripheral neuromotor 
syndromes 
(such as Guillain-Barre 
and myasthenia gravis) 
Any Grade 
General Guidance 
For Any Grade: 
− 
The prompt diagnosis of immune-mediated peripheral 
neuromotor syndromes is important, since certain patients 
may unpredictably experience acute decompensations that 
can result in substantial morbidity or in the worst case, death. 
Special care should be taken for certain sentinel symptoms 
that may predict a more severe outcome, such as prominent 
dysphagia, rapidly progressive weakness, and signs of 
respiratory insufficiency or autonomic instability. 
− 
Patients should be evaluated to rule out any alternative 
etiology (eg, disease progression, infections, metabolic 
syndromes or medications). It should be noted that the 
diagnosis of immune-mediated peripheral neuromotor 
syndromes can be particularly challenging in patients with 
underlying cancer, due to the multiple potential confounding 
effects of cancer (and its treatments) throughout the neuraxis. 
Given the importance of prompt and accurate diagnosis, it is 
essential to have a low threshold to obtain a neurological 
consult. 
− 
Neurophysiologic diagnostic testing (eg, electromyogram and 
nerve conduction investigations, and “repetitive stimulation” if 
myasthenia is suspected) are routinely indicated upon 
suspicion of such conditions and may be best facilitated by 
means of a neurology consultation. 
− 
It is important to consider that the use of steroids as the 
primary treatment of Guillain-Barre is not typically considered 
effective. Patients requiring treatment should be started with 
IV IG and followed by plasmapheresis if not responsive to IV 
IG. 


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69
Specific Immune-mediated Reactions 
Adverse Events 
Severity Grade of the 
Event (NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
Grade 1 
No dose modifications. 
For Grade 1: 
− 
Consider, as necessary, discussing with the principal 
investigator. 
− 
Care should be taken to monitor patients for sentinel 
symptoms of a potential decompensation as described above. 
− 
Obtain a neurology consult  
Grade 2 
Hold study drug/study regimen dose until 
resolution to Grade ≤1. 
Permanently discontinue study 
drug/study regimen if it does not resolve 
to Grade ≤1 within 30 days or if there are 
signs of respiratory insufficiency or 
autonomic instability. 
For Grade 2: 
− 
Consider, as necessary, discussing with the principal 
investigator. 
− 
Care should be taken to monitor patients for sentinel 
symptoms of a potential decompensation as described above. 
− 
Obtain a neurology consult 
− 
Sensory neuropathy/neuropathic pain may be managed by 
appropriate medications (eg, gabapentin or duloxetine). 
MYASTHENIA GRAVIS: 
o 
Steroids may be successfully used to treat 
myasthenia gravis. It is important to consider that 
steroid therapy (especially with high doses) may 
result in transient worsening of myasthenia and 
should typically be administered in a monitored 
setting under supervision of a consulting neurologist. 
o 
Patients unable to tolerate steroids may be 
candidates for treatment with plasmapheresis or IV 
IG. Such decisions are best made in consultation 
with a neurologist, taking into account the unique 
needs of each patient. 
o 
If myasthenia gravis-like neurotoxicity is present, 
consider starting AChE inhibitor therapy in addition 


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Specific Immune-mediated Reactions 
Adverse Events 
Severity Grade of the 
Event (NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
to steroids. Such therapy, if successful, can also 
serve to reinforce the diagnosis. 
GUILLAIN-BARRE: 
o 
It is important to consider here that the use of 
steroids as the primary treatment of Guillain-Barre is 
not typically considered effective. 
o 
Patients requiring treatment should be started with 
IV IG and followed by plasmapheresis if not 
responsive to IV IG. 
Grade 3 or 4 
For Grade 3: 
Hold study drug/study regimen dose until 
resolution to Grade ≤1. 
Permanently discontinue study 
drug/study regimen if Grade 3 irAE does 
not resolve to Grade ≤1 within 30 days or 
if there are signs of respiratory 
insufficiency or autonomic instability. 
 
For Grade 4: 
Permanently discontinue study 
drug/study regimen. 
For Grade 3 or 4 (severe or life-threatening events): 
− 
Consider, as necessary, discussing with principal investigator. 
− 
Recommend hospitalization. 
− 
Monitor symptoms and obtain neurological consult. 
MYASTHENIA GRAVIS: 
o 
Steroids may be successfully used to treat 
myasthenia gravis. They should typically be 
administered in a monitored setting under 
supervision of a consulting neurologist. 
o 
Patients unable to tolerate steroids may be 
candidates for treatment with plasmapheresis or IV 
IG. 
o 
If myasthenia gravis-like neurotoxicity present, 
consider starting AChE inhibitor therapy in addition 
to steroids. Such therapy, if successful, can also 
serve to reinforce the diagnosis. 
 
GUILLAIN-BARRE: 


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71
Specific Immune-mediated Reactions 
Adverse Events 
Severity Grade of the 
Event (NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
o 
It is important to consider here that the use of 
steroids as the primary treatment of Guillain-Barre is 
not typically considered effective. 
o 
Patients requiring treatment should be started with 
IV IG and followed by plasmapheresis if not 
responsive to IV IG. 
Myocarditis 
Any Grade 
General Guidance 
Discontinue drug permanently if biopsy-
proven immune-mediated myocarditis. 
For Any Grade: 
− 
The prompt diagnosis of immune-mediated myocarditis is 
important, particularly in patients with baseline 
cardiopulmonary disease and reduced cardiac function.  
− 
Consider, as necessary, discussing with the study physician. 
− 
Monitor patients for signs and symptoms of myocarditis (new 
onset or worsening chest pain, arrhythmia, shortness of breath, 
peripheral edema). As some symptoms can overlap with lung 
toxicities, simultaneously evaluate for and rule out pulmonary 
toxicity as well as other causes (e.g., pulmonary embolism, 
congestive heart failure, malignant pericardial effusion). A 
Cardiology consultation should be obtained early, with prompt 
assessment of whether and when to complete a cardiac biopsy, 
including any other diagnostic procedures. 
− 
Initial work-up should include clinical evaluation, BNP, 
cardiac enzymes, ECG, echocardiogram (ECHO), monitoring 
of oxygenation via pulse oximetry (resting and exertion), and 
additional laboratory work-up as indicated. Spiral CT or 
cardiac MRI can complement ECHO to assess wall motion 
abnormalities when needed. 
− 
Patients should be thoroughly evaluated to rule out any 
alternative etiology (e.g., disease progression, other 
medications, or infections) 


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72
 
Grade 1 
(asymptomatic with 
laboratory (e.g., BNP) 
or cardiac imaging 
abnormalities) 
No dose modifications required unless 
clinical suspicion is high, in which case 
hold study drug/study regimen dose 
during diagnostic work-up for other 
etiologies. If study drug/study regimen is 
held, resume after complete resolution to 
Grade 0. 
For Grade 1 (no definitive findings): 
- 
Monitor and closely follow up in 2 to 4 days for clinical 
symptoms,  BNP, cardiac enzymes, ECG, ECHO, pulse oximetry 
(resting and exertion), and laboratory work-up as clinically 
indicated. 
- 
Consider using steroids if clinical suspicion is high. 
 
Grade 2, 3 or 4 
(Grade 2: Symptoms 
with mild to moderate 
activity or exertion) 
 
 (Grade 3: Severe with 
symptoms at rest or 
with minimal activity 
or exertion; 
intervention indicated) 
 
(Grade 4: Life-
threatening 
consequences; urgent 
intervention indicated 
(e.g., continuous IV 
therapy or mechanical 
hemodynamic support)) 
 
- If Grade 2 -- Hold study drug/study 
regimen dose until resolution to 
Grade 0. If toxicity rapidly improves to 
Grade 0, then the decision to reinitiate 
study drug/study regimen will be based 
upon treating physician’s clinical 
judgment and after completion of 
steroid taper. If toxicity does not 
rapidly improve, permanently. 
discontinue study drug/study regimen. 
If Grade 3-4, permanently discontinue 
study drug/study regimen. 
For Grade 2-4: 
− 
Monitor symptoms daily, hospitalize. 
− 
Promptly start IV methylprednisolone 2 to 4 mg/kg/day or 
equivalent after Cardiology consultation has determined 
whether and when to complete diagnostic procedures including 
a cardiac biopsy. 
− 
Supportive care (e.g., oxygen). 
− 
If no improvement within 3 to 5 days despite IV 
methylprednisolone at 2 to 4 mg/kg/day, promptly start 
immunosuppressive therapy such as TNF inhibitors 
(e.g., infliximab at 5 mg/kg every 2 weeks). Caution: It is 
important to rule out sepsis and refer to infliximab label for 
general guidance before using infliximab. 
− 
Once the patient is improving, gradually taper steroids over 
≥28 days and consider prophylactic antibiotics, antifungals, or 
anti-PJP treatment (refer to current NCCN guidelines for 
treatment of cancer-related infections [Category 2B 
recommendation]).a 
Myositis/Polymyositis 
(“Poly/myositis”) 
Any Grade 
General Guidance 
For Any Grade: 
− 
Monitor patients for signs and symptoms of poly/myositis. 
Typically, muscle weakness/pain occurs in proximal muscles 


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73
including upper arms, thighs, shoulders, hips, neck and back, 
but rarely affects the extremities including hands and fingers; 
also difficulty breathing and/or trouble swallowing can occur 
and progress rapidly. Increased general feelings of tiredness 
and fatigue may occur, and there can be new-onset falling, 
difficulty getting up from a fall, and trouble climbing stairs, 
standing up from a seated position, and/or reaching up. 
− 
If poly/myositis is suspected, a Neurology consultation should 
be obtained early, with prompt guidance on diagnostic 
procedures. Myocarditis may co-occur with poly/myositis; 
refer to guidance under Myocarditis. Given breathing 
complications, refer to guidance under Pneumonitis/ILD.  
Given possibility of an existent (but previously unknown) 
autoimmune disorder, consider Rheumatology consultation. 
− 
Consider, as necessary, discussing with the study physician. 
− 
Initial work-up should include clinical evaluation, creatine 
kinase, aldolase, LDH, BUN/creatinine, erythrocyte 
sedimentation rate or C-reactive protein level, urine myoglobin, 
and additional laboratory work-up as indicated, including a 
number of possible rheumatological/antibody tests (i.e., 
consider whether a rheumatologist consultation is indicated and 
could guide need for rheumatoid factor, antinuclear antibody, 
anti-smooth muscle, antisynthetase [such as anti-Jo-1], and/or 
signal-recognition particle antibodies). Confirmatory testing 
may include electromyography, nerve conduction studies, MRI 
of the muscles, and/or a muscle biopsy. Consider Barium 
swallow for evaluation of dysphagia or dysphonia. 
Patients should be thoroughly evaluated to rule out any alternative 
etiology (e.g., disease progression, other medications, or infections). 
 
Grade 1 
(mild pain) 
- No dose modifications. 
For Grade 1: 
− 
Monitor and closely follow up in 2 to 4 days for clinical 
symptoms and initiate evaluation as clinically indicated. 
− 
Consider Neurology consult. 
− 
Consider, as necessary, discussing with the study physician. 


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74
 
Grade 2 
(moderate pain 
associated with 
weakness; pain limiting 
instrumental activities 
of daily living [ADLs]) 
Hold study drug/study regimen dose until 
resolution to Grade ≤1. 
- Permanently discontinue study 
drug/study regimen if it does not 
resolve to Grade ≤1 within 30 days or 
if there are signs of respiratory 
insufficiency. 
For Grade 2: 
− 
Monitor symptoms daily and consider hospitalization. 
− 
Obtain Neurology consult, and initiate evaluation. 
− 
Consider, as necessary, discussing with the study physician. 
− 
If clinical course is rapidly progressive (particularly if 
difficulty breathing and/or trouble swallowing), promptly start 
IV methylprednisolone 2 to 4 mg/kg/day systemic steroids 
along with receiving input from Neurology consultant  
− 
If clinical course is not rapidly progressive, start systemic 
steroids (e.g., prednisone 1 to 2 mg/kg/day PO or IV 
equivalent); if no improvement within 3 to 5 days, continue 
additional work up and start treatment with IV 
methylprednisolone 2 to 4 mg/kg/day 
− 
If after start of IV methylprednisolone at 2 to 4 mg/kg/day 
there is no improvement within 3 to 5 days, consider start of 
immunosuppressive therapy such as TNF inhibitors 
(e.g., infliximab at 5 mg/kg every 2 weeks). Caution: It is 
important to rule out sepsis and refer to infliximab label for 
general guidance before using infliximab. 
− 
Once the patient is improving, gradually taper steroids over 
≥28 days and consider prophylactic antibiotics, antifungals, or 
anti-PJP treatment (refer to current NCCN guidelines for 
treatment of cancer-related infections [Category 2B 
recommendation]).a 
 
Grade 3 or 4 
(pain associated with 
severe weakness; 
limiting self-care 
ADLs) 
For Grade 3: 
Hold study drug/study regimen dose until 
resolution to Grade ≤1. 
Permanently discontinue study drug/study 
regimen if Grade 3 imAE does not resolve 
to Grade ≤1 within 30 days or if there are 
signs of respiratory insufficiency. 
 
For Grade 3 or 4 (severe or life-threatening events): 
− 
Monitor symptoms closely; recommend hospitalization. 
− 
Obtain Neurology consult, and complete full evaluation. 
− 
Consider, as necessary, discussing with the study physician. 
− 
Promptly start IV methylprednisolone 2 to 4 mg/kg/day 
systemic steroids along with receiving input from Neurology 
consultant. 
− 
If after start of IV methylprednisolone at 2 to 4 mg/kg/day 
there is no improvement within 3 to 5 days, consider start of 
immunosuppressive therapy such as TNF inhibitors 
(e.g., infliximab at 5 mg/kg every 2 weeks). Caution: It is 


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75
 
 
 
 
a
 
ASCO Educational Book 2015 “Managing Immune Checkpoint Blocking Antibody Side Effects” by Michael Postow MD. 
b 
FDA Liver Guidance Document 2009 Guidance for Industry: Drug Induced Liver Injury – Premarketing Clinical Evaluation. 
AChE  Acetylcholine esterase; ADL  Activities of daily living; AE  Adverse event; ALP  Alkaline phosphatase test; ALT  Alanine aminotransferase; AST  Aspartate aminotransferase; 
BUN  Blood urea nitrogen; CT  Computed tomography; CTCAE  Common Terminology Criteria for Adverse Events; ILD  Interstitial lung disease; imAE immune-mediated adverse 
event; IG  Immunoglobulin; IV  Intravenous; GI  Gastrointestinal; LFT  Liver function tests; LLN  Lower limit of normal; MRI  Magnetic resonance imaging; NCI  National Cancer 
Institute; NCCN  National Comprehensive Cancer Network; PCP ; PO  By mouth; T3  Triiodothyronine; T4  Thyroxine; TB  Total bilirubin; TNF  Tumor necrosis factor; TSH  Thyroid-
stimulating hormone; ULN  Upper limit of normal. 
For Grade 4: 
- Permanently discontinue study 
drug/study regimen. 
important to rule out sepsis and refer to infliximab label for 
general guidance before using infliximab. 
− 
Consider whether patient may require IV IG, plasmapheresis. 
− 
Once the patient is improving, gradually taper steroids over 
≥28 days and consider prophylactic antibiotics, antifungals, or 
anti-PJP treatment (refer to current NCCN guidelines for 
treatment of cancer-related infections [Category 2B 
recommendation]).a 


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76
Infusion-related Reactions 
Severity Grade of the 
Event (NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
Any Grade 
General Guidance 
For Any Grade: 
− 
Manage per institutional standard at the discretion of 
investigator. 
− 
Monitor patients for signs and symptoms of infusion-related 
reactions (eg, fever and/or shaking chills, flushing and/or itching, 
alterations in heart rate and blood pressure, dyspnea or chest 
discomfort, or skin rashes) and anaphylaxis (eg, generalized 
urticaria, angioedema, wheezing, hypotension, or tachycardia). 
Grade 1 or 2 
For Grade 1: 
The infusion rate of study drug/study regimen may be 
decreased by 50% or temporarily interrupted until resolution 
of the event. 
 
For Grade 2: 
The infusion rate of study drug/study regimen may be 
decreased 50% or temporarily interrupted until resolution of 
the event. 
Subsequent infusions may be given at 50% of the initial 
infusion rate. 
For Grade 1 or 2: 
− 
Acetaminophen and/or antihistamines may be administered per 
institutional standard at the discretion of the investigator. 
− 
Consider premedication per institutional standard prior to 
subsequent doses. 
− 
Steroids should not be used for routine premedication of Grade 
≤2 infusion reactions. 
Grade 3 or 4 
For Grade 3 or 4: 
Permanently discontinue study drug/study regimen. 
For Grade 3 or 4: 
− 
Manage severe infusion-related reactions per institutional 
standards (eg, IM epinephrine, followed by IV diphenhydramine 
and ranitidine, and IV glucocorticoid). 
CTCAE  Common Terminology Criteria for Adverse Events; IM  Intramuscular; IV  Intravenous; NCI  National Cancer Institute. 


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77
Non-immune-mediated Reactions 
Severity Grade of the Event 
(NCI CTCAE version 4.03) 
Dose Modifications 
Toxicity Management 
Any Grade 
Note: Dose modifications are not required for AEs not deemed 
to be related to study treatment (ie, events due to underlying 
disease) or for laboratory abnormalities not deemed to be 
clinically significant. 
Treat accordingly, as per institutional standard. 
Grade 1 
No dose modifications. 
Treat accordingly, as per institutional standard. 
Grade 2 
Hold study drug/study regimen until resolution to ≤Grade 1 or 
baseline. 
Treat accordingly, as per institutional standard. 
Grade 3 
Hold study drug/study regimen until resolution to ≤Grade 1 or 
baseline. 
For AEs that downgrade to ≤Grade 2 within 7 days or resolve to 
≤Grade 1 or baseline within 14 days, resume study drug/study 
regimen administration.  Otherwise, discontinue study 
drug/study regimen. 
Treat accordingly, as per institutional standard. 
Grade 4 
 
Discontinue study drug/study regimen (Note: For Grade 4 labs, 
decision to discontinue should be based on accompanying 
clinical signs/symptoms, the Investigator’s clinical judgment, and 
consultation with the MedImmune (AstraZeneca). 
Treat accordingly, as per institutional standard. 
Note: As applicable, for early phase studies, the following sentence may be added: “Any event greater than or equal to Grade 2, please discuss with Principal investigator.” 
AE  Adverse event; CTCAE  Common Terminology Criteria for Adverse Events; NCI  National Cancer Institute. 
 
 
 


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Table 6.5 
Adverse events of special interest (AESI): durvalumab and trametinib dose 
adjustment schedule. 
 
Grade of 
the Event 
(NCI 
CTCAE 
version 
4.03) 
Dose Modifications 
Toxicity Management 
 
Pneumoniti
s/ILD 
Grade of 
Pneumonitis 
(CTCAE 
version 
4.03)  
Any Grade 
- 
Monitor patients for signs and symptoms of 
pneumonitis or ILD (new onset or worsening 
shortness of breath or cough).  Patients 
should be evaluated with imaging and 
pulmonary function tests including other 
diagnostic procedures as described below. 
- 
Initial work-up may include clinical 
evaluation, monitoring of oxygenation via 
pulse oximetry (resting and exertion), 
laboratory work-up and high-resolution CT 
scan.  
Grade 1  
(Asymptoma
tic, clinical 
or 
diagnostic 
observation
s only, 
intervention 
not 
indicated) 
No dose modification 
required. However, 
consider holding 
trametinib and 
durvalumab dosing 
as clinically 
appropriate and 
during diagnostic 
work-up for other 
etiologies 
For Grade 1 (Radiographic Changes Only) 
- 
Monitor and closely follow up in 2-4 days for 
clinical symptoms, pulse oximetry (resting 
and exertion) and laboratory work-up and 
then as clinically indicated. 
- 
Consider pulmonary and  infectious disease 
consult. 
Grade 2  
(Symptomati
c, medical 
intervention 
indicated, 
limiting 
instrumental 
ADL)  
 Hold trametinib and 
durvalumab dose 
until grade 2 
resolution to ≤ Grade 
1 
• If  toxicity worsens 
then treat as Grade 
3 or Grade 4  
• If toxicity improves 
to baseline then 
the decision to 
reinitiate study 
drug/regimen at 
next scheduled 
For Grade 2 (Mild to Moderate New Symptoms) 
- 
Monitor symptoms daily and consider 
hospitalization. 
- 
Promptly start systemic steroids (e.g., 
prednisone 1-2mg/kg/day or IV equivalent) 
Reimaging as clinically indicated 
- 
If no improvement within 3-5 days, additional 
workup should be considered and prompt 
treatment with IV methylprednisolone 2-
4mg/kg/day started  


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Grade of 
the Event 
(NCI 
CTCAE 
version 
4.03) 
Dose Modifications 
Toxicity Management 
treatment date will 
be based upon 
treating physician’s 
clinical judgment.  
durvalumab 
treatment can be 
resumed at the 
next scheduled 
dose once event 
stabilizes to grade 
≤1 and 5-7 days 
have passed after 
completion of 
steroid taper   
When recovered, 
restart trametinib 
by one dose level. 
May consider 
reescalation to 
previous dose level 
after 4 weeks after 
discussion with 
AstraZeneca / 
MedImmune . 
  
- 
If still no improvement within 3-5 days 
despite IV methylprednisone at 2-4/g/kg/day, 
promptly start immunosuppressive therapy 
such as TNF inhibitors (e.g. infliximab at 
5mg/kg every 2 weeks). Caution: Important 
to rule out sepsis and refer to infliximab label 
for general guidance before using infliximab  
- 
Once improving, gradually taper steroids 
over ≥4 weeks  and consider prophylactic 
antibiotics, antifungal or anti PCP treatment 
(refer to current  NCCN guidelines for 
treatment of  cancer-related infections 
(Category 2B recommendation)121 
- 
Consider pulmonary and infectious disease 
consult 
- 
Consider as necessary  discussing with 
principal investigator 
Grade 3 or 4  
(Grade 3: 
Severe 
symptoms; 
limiting self-
care ADL; 
oxygen 
indicated;  
 
Grade 4: life 
threatening 
respiratory 
compromise
, urgent 
intervention 
indicated 
[e.g. 
Permanently 
discontinue 
trametinib and 
durvalumab 
 
For Grade 3 or 4 (severe or new symptoms, 
new/worsening hypoxia, life threatening  
- 
Promptly initiate empiric IV 
methylprednisolone 1 to 4 mg/kg/day or 
equivalent  
- 
Obtain pulmonary and infectious disease  
consult 
- 
Hospitalize the patient 
- 
Supportive Care (oxygen, etc.) 
- 
If no improvement within 3-5 days, additional 
workup should be considered and prompt 
treatment with additional 
immunosuppressive therapy such as TNF 
inhibitors (e.g. infliximab at 5mg/kg every 2 
 
1 ASCO Educational Book 2015. Michael Postow MD. “Managing Immune Checkpoint Blocking Antibody Side 
Effects”  


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80
 
Grade of 
the Event 
(NCI 
CTCAE 
version 
4.03) 
Dose Modifications 
Toxicity Management 
tracheostom
y or 
intubation])  
weeks dose) started. Caution: rule out 
sepsis and refer to infliximab label for 
general guidance before using infliximab  
- 
Once improving, gradually taper steroids 
over ≥28 days  and consider prophylactic 
antibiotics, antifungals and in particular,  anti 
PCP treatment (please refer to current  
NCCN guidelines for treatment of  cancer-
related infections (Category 2B 
recommendation)3 
Diarrhea/ 
Enterocoliti
s 
Grade of 
Diarrhea 
(CTCAE 
version 
4.03) 
Any Grade 
- 
Monitor for symptoms that may be related to 
diarrhea/enterocolitis (abdominal pain, 
cramping, or changes in bowel habits such 
as increased frequency over baseline or 
blood in stool) or related to bowel perforation 
(such as sepsis, peritoneal signs and ileus) 
- 
Patients should be thoroughly evaluated to 
rule out any alternative etiology (e.g., 
disease progression, other medications, 
infections including testing for clostridium 
difficile toxin,  etc.) 
- 
Steroids should be considered  in the 
absence of clear alternative etiology, even 
for low grade events, in order to prevent 
potential progression to higher grade event 
- 
Use analgesics carefully; they can mask 
symptoms of perforation and peritonitis 
Grade 1 
diarrhea  
(stool 
frequency of 
<4 over 
baseline per 
day)  
No dose modification 
For Grade 1 diarrhea :  
-      Close monitoring for worsening symptoms 
-      Consider symptomatic treatment including 
hydration, electrolyte replacement, dietary 
changes (e.g., American Dietetic Association 
colitis diet), and loperamide. Use of 
probiotics as per treating physician’s clinical 
judgment. 
Grade 2 
diarrhea 
(stool 
Hold trametinib and 
durvalumab until 
resolution to ≤ Grade 
For Grade 2 diarrhea:  


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Grade of 
the Event 
(NCI 
CTCAE 
version 
4.03) 
Dose Modifications 
Toxicity Management 
frequency of 
4-6 over 
baseline per 
day)  
1 
• 
If  toxicity 
worsens then 
treat as Grade 3 
or Grade 4 
• 
If toxicity 
improves to 
baseline then 
treat at next 
scheduled 
treatment date 
Study trametinib and 
durvalumab can 
be resumed at the 
next scheduled 
dose once event 
stabilizes to grade 
≤1 and 5-7 days 
have passed after 
completion of 
steroid taper    
- 
Consider symptomatic treatment including 
hydration, electrolyte replacement, dietary 
changes (e.g., American Dietetic Association 
colitis diet), and loperamide and/or 
budesonide  
- 
Promptly start  prednisone 1 to 2  mg/kg/day 
or IV equivalent  
- 
If event is not responsive within 3-5 days or 
worsens despite prednisone at 1-2 
mg/kg/day or IV equivalent, GI consult 
should be obtained for consideration of 
further workup such as imaging and/or 
colonoscopy to confirm colitis and rule out 
perforation,   and prompt treatment with IV 
methylprednisolone 2-4mg/kg/day started.  
- 
If still no improvement within 3-5 days 
despite 2-4mg/kg IV methylprednisolone, 
promptly start  immunosuppressives such as  
(infliximab at 5mg/kg once every 2 weeks2). . 
Caution: Important to rule out bowel 
perforation and refer to infliximab label for 
general guidance before using infliximab   
- 
Consult principal investigator if no resolution 
to ≤ Grade 1 in 3-4 days 
- 
Once improving, gradually taper steroids 
over ≥28 days  and consider prophylactic 
antibiotics, antifungals and anti PCP 
treatment (please refer to current  NCCN 
guidelines for treatment of  cancer-related 
infections [Category 2B recommendation]) 
 
2 ASCO Educational Book 2015 Michael Postow MD “Managing Immune Checkpoint Blocking Antibody Side Effects   


2017-0514 
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82
 
Grade of 
the Event 
(NCI 
CTCAE 
version 
4.03) 
Dose Modifications 
Toxicity Management 
Grade 3 or 4 
diarrhea  
 
(Grade 3: 
stool 
frequency of 
≥7 over 
baseline per 
day;  
 
Grade 4: life 
threatening 
consequenc
es) 
Interrupt both 
therapies until 
symptoms resolve to 
≤ Grade 1 or baseline. 
 
Resume therapy with 
a ↓ of one dose level 
of trametinib. If 
immune related 
diarrhea, permanently 
discontinue 
durvalumab.   
For Grade 3 or 4 diarrhea: 
- 
Promptly initiate empiric IV 
methylprednisolone 2 to 4 mg/kg/day or 
equivalent  
- 
Monitor stool frequency and volume and 
maintain hydration   
- 
Urgent GI consult and imaging and/or 
colonoscopy as appropriate 
- 
If still no improvement within 3-5 days of IV 
methylprednisolone  2 to 4mg/kg/day or 
equivalent, promptly start further 
immunosuppressives (e.g. infliximab at 
5mg/kg once every 2 weeks).   
- 
Caution: Ensure GI consult to rule out bowel 
perforation and refer to infliximab label for 
general guidance before using infliximab.  
- 
Once improving, gradually taper steroids 
over ≥28 days and consider prophylactic 
antibiotics, antifungals and anti PCP 
treatment (please refer to current  NCCN 
guidelines for treatment of  cancer-related 
infections [Category 2B recommendation]) 
Hepatitis 
(Elevated 
LFTs) 
Infliximab 
should not 
be used 
for 
managem
ent of 
Immune 
Related 
Hepatitis 
Grade of 
Liver 
Function 
Test 
Elevation 
(CTCAE 
version 
4.03) 
Any Grade 
  
- 
Monitor and evaluate liver function test: AST, 
ALT, ALP and total bilirubin  
- 
Evaluate for alternative etiologies (e.g., viral 
hepatitis, disease progression, concomitant 
medications)  
Grade 1  
(AST or ALT 
> ULN to 3 
times ULN 
and/or TB > 
ULN to 1.5 
times ULN) 
No dose modification 
If  it worsens, treat as 
Grade 2 event 
For Grade 1 AST or ALT and/or TB elevation        
  -    Continue LFT monitoring per protocol   


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Grade of 
the Event 
(NCI 
CTCAE 
version 
4.03) 
Dose Modifications 
Toxicity Management 
Grade 2  
(AST or ALT 
> 3 to 5 
times ULN 
and/or TB 
>1.5-3.0 
times ULN) 
Hold Study 
trametinib and 
durvalumab dose 
until grade 2 
resolution to ≤ Grade 
1 
• If  toxicity worsens 
then treat as Grade 
3 or Grade 4 
• If improves to 
baseline then treat 
at next scheduled 
treatment date 
Study trametinib and 
durvalumab can 
be resumed at the 
next scheduled 
dose once event 
stabilizes to grade 
≤1 and 5-7 days 
have passed after 
completion of 
steroid taper    
For Grade 2 AST or ALT and or TB elevation :  
- 
Regular and frequent checking of LFTs (e.g. 
every 1-2 days) until elevations of these are 
improving or resolved.   
- 
If no resolution to ≤ Grade 1 in 1-2 days, 
discuss with principal investigator. 
- 
If event is persistent (> 3-5 days) or 
worsens, promptly start prednisone 1-
2mg/kg/day or IV equivalent.  
- 
If still no improvement within 3-5 days 
despite 1-2mg/kg/day of prednisone or IV 
equivalent, consider additional workup and 
prompt treatment with IV methylprednisolone 
2-4mg/kg/day started. 
- 
If still no improvement within 3-5 days 
despite 2-4mg/kg/day of IV 
methylprednisolone, promptly start 
immunosuppressives (mycophenolate 
mofetil)3 . Discuss with principal investigator 
if mycophenolate mofetil is not available.  
Infliximab should NOT be used. 
- 
Once improving, gradually taper steroids 
over ≥28 days  and consider prophylactic 
antibiotics, antifungals and anti PCP 
treatment (please refer to current  NCCN 
guidelines for treatment of  cancer-related 
infections [Category 2B recommendation]) 
Grade 3 
(AST or ALT 
>5-20 times 
ULN and/or 
TB > 3.0-10 
times ULN 
For elevations in 
transaminases ≤ 8 
× ULN, or 
elevations in 
bilirubin ≤ 5 × ULN  
-Hold trametinib 
and durvalumab 
dose until 
resolution to ≤ 
Grade 1 or 
For Grade 3 or 4 AST or ALT and/or TB 
elevation: 
- 
Promptly initiate empiric IV 
methylprednisolone at 1 to 4 mg/kg/day or 
equivalent  
- 
If still no improvement within 3-5 days 
despite 1 to 4 mg/kg/day methylprednisolone 
IV or equivalent , promptly start treatment 
 
3 ASCO Educational Book 2015 “Managing Immune Checkpoint Blocking Antibody Side Effects” , by Michael 
Postow MD 


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CTCAE 
version 
4.03) 
Dose Modifications 
Toxicity Management 
baseline   
-Resume 
trametinib and 
durvalumab 
administration at 
the next 
scheduled dose if 
elevations 
downgrade ≤ 
Grade 1 or 
baseline within 14 
days 
Permanently 
discontinue 
trametinib and 
durvalumab if the 
elevations do not 
downgrade to ≤ 
Grade 1 or baseline 
within 14 days  
For elevations in 
transaminases > 8 
× ULN or 
elevations in 
bilirubin > 5 × ULN, 
discontinue 
trametinib and 
durvalumab 
Permanently 
discontinue 
trametinib and 
durvalumab for 
any case meeting 
Hy’s law criteria 
(ALT > 3x ULN + 
bilirubin > 2x ULN 
without initial 
findings of 
cholestasis (i.e. 
elevated alkaline 
P04) and  in the 
absence of any 
alternative cause4 
with immunosuppressive therapy 
(mycophenolate mofetil)  Discuss with 
principal investigator if mycophenolate is not 
available. Infliximab should NOT be used. 
- 
Hepatology consult, abdominal workup, and 
imaging as appropriate. 
- 
Once improving, gradually taper steroids 
over ≥28 days  and consider prophylactic 
antibiotics, antifungals and anti PCP 
treatment (please refer to current  NCCN 
guidelines for treatment of  cancer-related 
infections [Category 2B recommendation]) 


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Grade of 
the Event 
(NCI 
CTCAE 
version 
4.03) 
Dose Modifications 
Toxicity Management 
Grade 4  
(AST or ALT 
> 20 times 
ULN and/or 
TB > 10 
times ULN)  
Permanently 
discontinue 
trametinib and 
durvalumab 
Nephritis or 
Renal 
Dysfunctio
n (Elevated 
Serum 
Creatinine)  
Grade of 
Elevated 
Serum 
Creatinine 
(CTCAE 
version 
4.03) 
 
Any Grade  
 
 
 
 
- 
Consult with Nephrologist 
- 
Monitor for signs and symptoms that may be 
related to changes in renal function (e.g. 
routine urinalysis, elevated serum BUN and 
creatinine, decreased creatinine clearance, 
electrolyte imbalance, decrease in urine 
output, proteinuria, etc.)  
- 
Patients should be thoroughly evaluated to 
rule out any alternative etiology (e.g., 
disease progression, infections etc.) 
- 
Steroids should be considered in the 
absence of clear alternative etiology even for 
low grade events (Grade 2) , in order to 
prevent potential progression to higher grade 
event 
Grade 1 
[Serum 
Creatinine > 
1-1.5X 
baseline;  > 
ULN to 1.5X 
ULN]  
No dose modification 
For Grade 1 elevated creatinine:  
- 
Monitor serum creatinine weekly and any 
accompanying symptom 
• 
If creatinine returns to baseline, resume 
its regular monitoring per study protocol. 
• 
If it worsens, depending on the severity , 
treat as Grade 2 or Grade 3 or 4  
-     Consider symptomatic treatment including 
hydration, electrolyte replacement, diuretics, 
etc. 


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Grade of 
the Event 
(NCI 
CTCAE 
version 
4.03) 
Dose Modifications 
Toxicity Management 
Grade 2 
[Serum 
Creatinine>
1.5-3.0X 
baseline; 
>1.5X-
3.0XULN] 
 
Hold trametinib and 
durvalumab until 
resolution to ≤ Grade 
1 
• 
If  toxicity 
worsens then 
treat as Grade 3 
or Grade 4 
• 
If toxicity 
improves to 
baseline then 
treat at next 
scheduled 
treatment date 
trametinib and 
durvalumab can 
be resumed at the 
next scheduled 
dose once event 
stabilizes to grade 
≤1 for 5-7 days 
have passed after 
completion of 
steroid taper    
For Grade 2 elevated creatinine:  
- 
Consider symptomatic treatment including 
hydration, electrolyte replacement, diuretics, 
etc.  
- 
Carefully monitor serum creatinine  every 2-
3 days and as clinically warranted 
- 
Consult Nephrologist and consider renal 
biopsy if clinically indicated 
- 
If event is persistent (> 3-5 days) or 
worsens,  promptly start  prednisone 1 to 2 
mg/kg/day or IV equivalent  
- 
If event is not responsive within 3-5 days or 
worsens despite prednisone at 1-2 
mg/kg/day or IV equivalent, additional 
workup should be considered and prompt 
treatment with IV methylprednisolone at 2-
4mg/kg/day started.  
- 
Once improving gradually taper steroids over 
≥28 days and   consider prophylactic 
antibiotics, antifungals and anti PCP 
treatment (please refer to current NCCN 
guidelines for treatment of cancer-related 
infections [Category 2B recommendation]).  
- 
When event returns to baseline, resume 
study drug/study regimen and routine serum 
creatinine monitoring per study protocol. 
Grade 3 or 4  
(Grade 3:  
Serum 
Creatinine > 
3.0 X 
baseline; 
>3.0-6.0 X 
ULN 
 
Grade 4: 
Serum 
Creatinine > 
Permanently 
discontinue 
trametinib and 
durvalumab 
- 
Carefully monitor serum creatinine  on  daily 
basis 
- 
Consult Nephrologist and consider renal 
biopsy if clinically indicated 
- 
Promptly  start  prednisone 1 to 2  mg/kg/day 
or IV equivalent  
- 
If event is not responsive within 3-5 days or 
worsens despite prednisone at 1-2 
mg/kg/day or IV equivalent, additional 
workup should be considered and prompt 


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the Event 
(NCI 
CTCAE 
version 
4.03) 
Dose Modifications 
Toxicity Management 
6.0 X ULN)  
treatment with IV methylprednisolone 2-
4mg/kg/day started.  
- 
Once improving,  gradually taper steroids 
over ≥28 days  and consider prophylactic 
antibiotics, antifungals and anti PCP 
treatment (please refer to current  NCCN 
guidelines for treatment of  cancer-related 
infections [Category 2B recommendation]  
Grade 4 
Permanently 
discontinue 
trametinib and 
durvalumab 
 
Endocrinop
athy (e.g., 
hyperthyroi
dism, 
hypothyroi
dism, 
hypopituita
rism, 
adrenal 
insufficienc
y, etc.) 
Any Grade  
(Depending 
on the type 
of 
endocrinopa
thy, refer to 
NCI CTCAE 
version 4.03 
for defining 
the CTC 
grade/severi
ty)  
 
- 
Consult Endocrinologist 
- 
Monitor patients for signs and symptoms of 
endocrinopathies.  Non-specific symptoms 
include headache, fatigue, behavior 
changes, changed mental status, vertigo, 
abdominal pain, unusual bowel habits, 
hypotension and weakness. 
- 
Patients should be thoroughly evaluated to 
rule out any alternative etiology (e.g., 
disease progression including brain 
metastases, infections, etc.) 
- 
Monitor and evaluate thyroid function tests: 
TSH, free T3 and free T4 and other relevant 
endocrine labs depending on suspected 
endocrinopathy.  
- 
If a patient experiences an AE that is thought 
to be possibly of autoimmune nature (e.g., 
thyroiditis, pancreatitis, hypophysitis, 
diabetes insipidus), the investigator should 
send a blood sample for appropriate 
autoimmune antibody testing  


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Grade of 
the Event 
(NCI 
CTCAE 
version 
4.03) 
Dose Modifications 
Toxicity Management 
Grade 1 
(Depending 
on the type 
of 
endocrinopa
thy, refer to 
NCI CTCAE 
version 4.03 
for defining 
the CTC 
grade 1) 
No dose modification 
For Grade 1: (including those with asymptomatic 
TSH elevation) 
- 
Monitor patient with appropriate endocrine 
function tests 
- 
If TSH < 0.5X LLN, or TSH >2X ULN or 
consistently out of range in 2 subsequent 
measurements, include FT4 at subsequent 
cycles as clinically indicated and consider 
endocrinology consult. 
Grade 2  
(Depending 
on the type 
of 
endocrinopa
thy, refer to 
NCI CTCAE 
version 4.03 
for defining 
the CTC 
grade/severi
ty 2) 
 
 
For Grade 2 
endocrinopathy 
other than 
hypothyroidism, 
hold durvalumab 
dose until  subject 
is clinically stable 
• If  toxicity worsens 
then treat as Grade 
3 or Grade 4  
• If toxicity improves 
to baseline then 
treat at next 
scheduled 
treatment date 
Study durvalumab 
can be resumed at 
the next scheduled 
dose once event 
stabilizes to grade 
≤1 and 5-7 days 
have passed after 
completion of 
steroid taper 
   Patients with 
endocrinopathies 
who may require 
prolonged or 
continued steroid 
replacement can 
be retreated with 
durvalumab on 
the following 
conditions: 1) the 
For Grade 2: (including those with symptomatic 
endocrinopathy) 
- 
Isolated hypothyroidism may be treated with 
replacement therapy without treatment 
interruption and without corticosteroids 
- 
Initiate hormone replacement as needed for 
management 
- 
Evaluate endocrine function, and as clinically 
indicated,  consider pituitary scan 
- 
For patients with abnormal endocrine work 
up, except for those  with isolated 
hypothyroidism,  consider short-term, 
corticosteroids (e.g., 1-2mg/kg/day 
methylprednisolone or IV equivalent) and 
prompt initiation of treatment with relevant 
hormone replacement (e.g. Levothyroxine, 
hydrocortisone, or sex hormones). -  
- 
Once improving, gradually taper steroids 
over ≥28 days and consider prophylactic 
antibiotics, antifungals and anti PCP 
treatment (please refer to current NCCN 
guidelines for treatment of  cancer-related 
infections [Category 2B recommendation]) 
- 
For patients with normal endocrine work up 
(lab or MRI scans), repeat labs/MRI as 
clinically indicated. 


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Grade of 
the Event 
(NCI 
CTCAE 
version 
4.03) 
Dose Modifications 
Toxicity Management 
event stabilizes 
and is controlled 
,2) the patient is 
clinically stable as 
per Investigator or 
treating physician’s 
clinical judgement, 
and 3) doses of 
prednisone are at 
less than or equal 
to 10mg/day or 
equivalent. 
Grade 3 or 4 
(Depending 
on the type 
of 
endocrinopa
thy, refer to 
NCI CTCAE 
version 4.03 
for defining 
the CTC 
grade/severi
ty 3 or 4)  
For Grade 3 or 4 
endocrinopathy other 
than hypothyroidism, 
hold trametinib and 
durvalumab until 
endocrinopathy 
symptom(s) are 
controlled 
Resume trametinib 
and durvalumab n if 
controlled at the next 
scheduled dose 
Study trametinib and 
durvalumab can be 
resumed at the next 
scheduled dose once 
event stabilizes to 
grade ≤1 and 5-7 
days have passed 
after completion of 
steroid taper    
 
For Grade 3 or 4: 
- 
Consult endocrinologist 
- 
Isolated hypothyroidism may be treated with 
replacement therapy without treatment 
interruption and without corticosteroids 
- 
Promptly initiate empiric IV 
methylprednisolone 1 to 2 mg/kg/day or 
equivalent 
- 
Administer hormone replacement therapy as 
necessary. 
- 
For adrenal crisis, severe dehydration, 
hypotension, or shock: immediately initiate 
intravenous corticosteroids with 
mineralocorticoid activity 
- 
Once improving, gradually taper 
immunosuppressive steroids over ≥4 weeks 
and consider prophylactic antibiotics, 
antifungals and anti PCP treatment (please 
refer to current NCCN guidelines for 
treatment of  cancer-related infections 
[Category 2B recommendation]) 
- 
Discuss with principal investigator 


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Grade of 
the Event 
(NCI 
CTCAE 
version 
4.03) 
Dose Modifications 
Toxicity Management 
Immune 
mediated  
Neurotoxici
ty (to 
include but 
not limited 
to limbic 
encephaliti
s . 
autonomic 
neuropathy
, excluding 
Myasthenia 
Gravis and 
Guillain-
Barre)   
 
Any Grade  
 
 
 
 
 
 
 
- 
Patients should be evaluated to rule out any 
alternative 
etiology 
(e.g., 
disease 
progression, infections, metabolic syndromes 
and medications, etc.)  
- 
Monitor patient  for general symptoms 
(headache, nausea, vertigo, behavior 
change, or weakness) 
- 
Consider appropriate diagnostic testing (e.g. 
electromyogram and nerve conduction 
investigations) 
- 
Symptomatic treatment with neurological 
consult as appropriate 
Grade 1 
 No dose 
modifications 
See “Any Grade” recommendations above. 
Grade 2 
• 
For acute motor 
neuropathies or  
neurotoxicity, hold 
durvalumab until 
resolution to ≤ 
Grade 1 
• 
For sensory 
neuropathy/neuro
pathic pain, 
consider holding 
durvalumab dose 
until resolution to 
≤ Grade 1. 
• 
If toxicity worsens 
then treat as 
Grade 3 or Grade 
4  
• 
If  toxicity 
improves to 
baseline then 
treat at next 
- 
Discuss with the principal investigator  
- 
Obtain  Neurology Consult  
- 
Sensory neuropathy/neuropathic pain may 
be managed by appropriate medications 
(e.g., gabapentin, duloxetine, etc.) 
- 
Promptly start systemic steroids prednisone 
1-2mg/kg/day or IV equivalent  
- 
If no improvement within 3-5 days despite 1-
2mg/kg/day prednisone or IV equivalent 
consider additional workup and promptly 
treat with additional immunosuppressive 
therapy (e.g. IVIG)  
 


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(NCI 
CTCAE 
version 
4.03) 
Dose Modifications 
Toxicity Management 
scheduled 
treatment date 
durvalumab can be 
resumed at the next 
scheduled dose once 
event stabilizes to 
grade ≤1 and 5-7 
days have passed 
after completion of 
steroid taper    
Grade 3 
• 
Hold trametinib 
and durvalumab 
until resolution to 
≤ Grade 1 
• 
Permanently 
discontinue 
trametinib and 
durvalumab if 
Grade 3 irAE 
does not resolve 
to ≤ Grade 1 
within 30 days. 
For Grade 3 or 4: 
- 
Discuss with principal investigator 
- 
Obtain Neurology Consult 
- 
Consider hospitalization 
- 
Promptly initiate empiric IV 
methylprednisolone 1 to 2 mg/kg/day or 
equivalent  
- 
If no improvement within 3-5 days despite IV 
corticosteroids, consider additional workup 
and promptly treat with additional 
immunosuppressants (e.g. IVIG)  
Once stable, gradually taper steroids over ≥4 
weeks 
 
Grade 4 
 
• 
Permanently 
discontinue 
trametinib and 
durvalumab 
For Grade 3 or 4: 
- 
Discuss with principal investigator 
- 
Obtain Neurology Consult 
- 
Consider hospitalization 
- 
Promptly initiate empiric IV 
methylprednisolone 1 to 2 mg/kg/day or 
equivalent  
- 
If no improvement within 3-5 days despite IV 
corticosteroids, consider additional workup 
and promptly treat with additional 
immunosuppressants (e.g. IVIG)  
- 
Once stable, gradually taper steroids over ≥4 
weeks 
 
• 
Any Grade 


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Grade of 
the Event 
(NCI 
CTCAE 
version 
4.03) 
Dose Modifications 
Toxicity Management 
- 
The prompt diagnosis of immune-mediated 
peripheral neuromotor syndromes is 
important, since certain patients may 
unpredictably experience acute 
decompensations which can result in 
substantial morbidity or in the worst case, 
death. Special care should be taken for 
certain sentinel symptoms which may predict 
a more severe outcome, such as prominent 
dysphagia, rapidly progressive weakness, 
and signs of respiratory insufficiency or 
autonomic instability 
- 
Patients should be evaluated to rule out any 
alternative etiology (e.g., disease 
progression, infections, metabolic 
syndromes and medications, etc.). It should 
be noted that the diagnosis of immune-
mediated peripheral neuromotor syndromes 
can be particularly challenging in patients 
with underlying cancer, due to the multiple 
potential confounding effects of cancer (and 
its treatments) throughout the neuraxis. 
Given the importance of prompt and 
accurate diagnosis, it is essential to have a 
low threshold to obtain a neurological 
consult 
- 
Neurophysiologic diagnostic testing (e.g., 
electromyogram and nerve conduction 
investigations, and  “repetitive stimulation” if 
myasthenia is suspected) are routinely 
indicated upon suspicion of such conditions 
and may be best facilitated by means of a 
neurology consultation  
- 
Important to consider that the use of steroids 
as the primary treatment of Guillain-Barre is 
not typically considered effective. Patients 
requiring treatment should be started  with 


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the Event 
(NCI 
CTCAE 
version 
4.03) 
Dose Modifications 
Toxicity Management 
IVIG and followed by plasmapheresis if not 
responsive to IVIG  
Immune-
mediated 
peripheral 
neuromotor 
syndromes
, such as 
Guillain-
Barre and 
Myasthenia 
Gravis 
Grade 1 
No dose modification 
- 
Discuss with the principal investigator 
- 
Care should be taken to monitor patients for 
sentinel symptoms of a potential 
decompensation as described above 
Obtain a neurology consult unless the 
symptoms are very minor and stable 
Grade 2 
Hold study trametinib 
and durvalumab 
dose until 
resolution to ≤ 
Grade 1 
Permanently 
discontinue 
trametinib and 
durvalumab if it 
does not resolve to 
≤ Grade 1 within 30 
days or if there are 
signs of respiratory 
insufficiency or 
autonomic 
instability 
 
Grade 2  
- 
Discuss with the principal investigator  
- 
Care should be taken to monitor patients for 
sentinel symptoms of a potential 
decompensation as described above 
- 
Obtain a Neurology Consult  
- 
Sensory neuropathy/neuropathic pain may 
be managed by appropriate medications 
(e.g., gabapentin, duloxetine, etc.) 
MYASTHENIA GRAVIS 
- 
Steroids may be successfully used to treat 
Myasthenia Gravis. Important to consider that 
steroid therapy (especially with high doses) 
may 
result 
in 
transient 
worsening 
of 
myasthenia 
and 
should 
typically 
be 
administered in a monitored setting under 
supervision of a consulting neurologist. 
- 
Patients unable to tolerate steroids may be 
candidates for treatment with plasmapheresis 
or IVIG. Such decisions are best made in 
consultation with a neurologist, taking into 
account the unique needs of each patient. 
- 
If Myasthenia Gravis-like neurotoxicity 
present, consider starting acetylcholine 
esterase (AChE) inhibitor therapy in addition 
to steroids. Such therapy, if successful, can 
also serve to reinforce the diagnosis. 
GUILLAIN-BARRE:  


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Grade of 
the Event 
(NCI 
CTCAE 
version 
4.03) 
Dose Modifications 
Toxicity Management 
- 
Important to consider here that the use of 
steroids as the primary treatment of Guillain-
Barre is not typically considered effective. 
Patients requiring treatment should be 
started with IVIG and followed by 
plasmapheresis if not responsive to IVIG. 
Grade 3 
Hold trametinib and 
durvalumab dose 
until resolution to ≤ 
Grade 1 
Permanently 
discontinue 
trametinib and 
durvalumab if 
Grade 3 irAE does 
not resolve to ≤ 
Grade 1 within 30 
days or if there are 
signs of respiratory 
insufficiency or 
autonomic 
instability 
For severe or life threatening (Grade 3 or 4) 
events:  
- 
Discuss with principal investigator 
- 
Recommend hospitalization 
- 
Monitor symptoms and obtain neurological 
consult 
MYASTHENIA GRAVIS 
- 
Steroids may be successfully used to treat 
Myasthenia Gravis.  It should typically be 
administered in a monitored setting under 
supervision of a consulting neurologist. 
- 
Patients unable to tolerate steroids may be 
candidates for treatment with 
plasmapheresis or IVIG. 
- 
If Myasthenia Gravis-like neurotoxicity 
present, consider starting acetylcholine 
esterase (AChE) inhibitor therapy in addition 
to steroids. Such therapy, if successful, can 
also serve to reinforce the diagnosis. 
GUILLAIN-BARRE:  
- 
Important to consider here that the use of 
steroids as the primary treatment of Guillain-
Barre is not typically considered effective. 
Patients requiring treatment should be 
started with IVIG and followed by 
plasmapheresis if not responsive to IVIG 
Grade 4 
Permanently 
discontinue 
trametinib and 
durvalumab 
For severe or life threatening (Grade 3 or 4) 
events:  
- 
Discuss with principal investigator 


2017-0514 
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95
 
Grade of 
the Event 
(NCI 
CTCAE 
version 
4.03) 
Dose Modifications 
Toxicity Management 
 
 
- 
Recommend hospitalization 
- 
Monitor symptoms and obtain neurological 
consult 
MYASTHENIA GRAVIS 
- 
Steroids may be successfully used to treat 
Myasthenia Gravis.  It should typically be 
administered in a monitored setting under 
supervision of a consulting neurologist. 
- 
Patients unable to tolerate steroids may be 
candidates for treatment with 
plasmapheresis or IVIG. 
- 
If Myasthenia Gravis-like neurotoxicity 
present, consider starting acetylcholine 
esterase (AChE) inhibitor therapy in addition 
to steroids. Such therapy, if successful, can 
also serve to reinforce the diagnosis. 
GUILLAIN-BARRE:  
- 
Important to consider here that the use of 
steroids as the primary treatment of Guillain-
Barre is not typically considered effective. 
Patients requiring treatment should be 
started with IVIG and followed by 
plasmapheresis if not responsive to IVIG 
 
 


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DURVALUMAB Infusion-Related Reactions 
Severity 
Grade 
Dose Modifications 
Toxicity Management 
Any Grade 
 
- 
Management per institutional standard at 
the discretion of investigator 
- 
Monitor patients for signs and symptoms of 
infusion-related reactions (e.g., fever 
and/or shaking chills, flushing and/or 
itching, alterations in heart rate and blood 
pressure, dyspnea or chest discomfort, 
skin rashes etc.) and anaphylaxis (e.g., 
generalized urticaria, angioedema, 
wheezing, hypotension, tachycardia, etc.) 
Grade 1 
The infusion rate of study 
drug/study regimen may be 
decreased by 50% or temporarily 
interrupted until resolution of the 
event 
For Grade 1 or Grade 2: 
- 
Acetaminophen and/or antihistamines may 
be administered per institutional standard 
at the discretion of the investigator  
- 
Consider premedication per institutional 
standard prior to subsequent doses 
Grade 2 
 
The infusion rate of study 
drug/study regimen may be 
decreased 50% or temporarily 
interrupted until resolution of the 
event  
Subsequent infusions may be 
given at 50% of the initial infusion 
rate 
Grade 3/4 
 
 
Permanently discontinue study 
drug/study regimen 
For Grade 3 or 4: 
Manage severe infusion-related reactions 
per institutional standards (e.g., IM 
epinephrine, followed by IV 
diphenhydramine and ranitidine, and IV 
glucocorticoid) 
 
 
6.6  
Permanent discontinuation of Durvalumab therapy  
 
An individual subject will not receive any further investigational product if any of the 
following occur in the subject in question: 
1.     
An individual patient will not receive any further durvalumab monotherapy if 
their weight falls to 30kg or less 


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2.     
Withdrawal of consent or lost to follow-up 
3.     
Adverse event that, in the opinion of the investigator or the  MedImmune 
(AstraZeneca), contraindicates further dosing 
4.     
Subject is determined to have met one or more of the exclusion criteria for study 
participation at study entry and continuing investigational therapy might constitute a 
safety risk 
5.     
Pregnancy or intent to become pregnant 
6.     
Any AE that meets criteria for discontinuation as defined in Section 6.6 
7.     
Dose-limiting toxicity (See Section 6.5 for definition of DLT) if applicable 
8.     
Grade ≥ 3 infusion reaction 
9.     
Subject noncompliance that, in the opinion of the investigator, warrants 
withdrawal; eg, refusal to adhere to scheduled visits 
10.     Initiation of alternative anticancer therapy including another investigational 
agent 
11.     Confirmation of PD and investigator determination that the subject is no longer 
benefiting from treatment with durvalumab  
12.     Subjects who are permanently discontinued from receiving investigational 
product will be followed for safety, including the collection of any protocol-specified 
blood specimens, unless consent is withdrawn or the subject is lost to follow-up or 
enrolled I another clinical study. All subjects will be followed for survival. Subjects who 
decline to return to the site for evaluations will be offered follow-up by phone every 3 
months as an alternative 
 
Withdrawal of consent 
 
Subjects are free to withdraw from the study at any time (IP and assessments) without 
prejudice to further treatment. 
 
Subjects who withdraw consent for further participation in the study will not receive any 
further IP or further study observation, with the exception of follow-up for survival, 
which will continue until the end of the study unless the patient has expressly 
withdrawn their consent to survival follow-up. Note that the patient may be offered 
additional tests or tapering of treatment to withdraw safely. 
 
A patient who withdraws consent will always be asked about the reason(s) for 
withdrawal and the presence of any AE. The Investigator will follow up AEs outside of 
the clinical study.  
 
If a patient withdraws consent, they will be specifically asked if they are withdrawing 
consent to: 
• 
all further participation in the study including any further follow up (eg, survival 
contact telephone calls) 


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• 
withdrawal of consent to the use of their study generated data 
• 
withdrawal to the use of any samples 
 
 
7. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS  
 
 
7.1 Definition of Adverse Events 
 
The International Conference on Harmonisation (ICH) Guideline for Good Clinical Practice 
 
(GCP) E6(R1) defines an AE as:  
 
Any untoward medical occurrence in a patient or clinical investigation subject administered a 
pharmaceutical product and which does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product. 
 
An AE includes but is not limited to any clinically significant worsening of a subject’s pre-
existing condition. An abnormal laboratory finding (including ECG finding) that requires 
medical intervention by the investigator, or a finding judged by the investigator as medically 
significant should be reported as an AE. If clinical sequelae are associated with a laboratory 
abnormality, the diagnosis or medical condition should be reported (eg, renal failure, 
hematuria) not the laboratory abnormality (eg, elevated creatinine, urine red blood cells 
increased). Abnormal laboratory values that are not, in the investigator’s opinion, medically 
significant and do not require intervention should not be reported as AEs. 
 
Adverse events may be treatment emergent (ie, occurring after initial receipt of 
investigational product) or nontreatment emergent. A nontreatment-emergent AE is any 
new sign or symptom, disease, or other untoward medical event that begins after written 
informed consent has been obtained but before the subject has received investigational 
product. Elective treatment or surgery or preplanned treatment or surgery (that was 
scheduled prior to the subject being enrolled into the study) for a documented pre-existing 
condition that did not worsen from baseline is not considered an AE (serious or nonserious). 
An untoward medical event occurring during the prescheduled elective procedure or 
routinely scheduled treatment (i.e. a research tumor biopsy) should be recorded as an AE or 
SAE. 
 
Not every laboratory abnormality qualifies as an adverse event.  A laboratory test result 
must be reported as an adverse event if it meets any of the following criteria: 
·           Is accompanied by clinical symptoms 
·           Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation) 
·           Results in a medical intervention (e.g., potassium supplementation for hypokalemia) 


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or a change in concomitant therapy 
·           Is clinically significant in the investigator’s judgment 
Certain abnormal values may not qualify as adverse events. It is the investigator’s 
responsibility to review all laboratory findings.  Medical and scientific judgment should be 
exercised in deciding whether an isolated laboratory abnormality should be classified as an 
adverse event. 
 
 
7.2 Definition of Adverse Events of Special Interest 
An adverse event of special interest (AESI) is one of scientific and medical interest specific to 
understanding of the Investigational Product and may require close monitoring and rapid 
communication by the investigator.. An AESI may be serious or non-serious. The rapid 
reporting of AESIs allows ongoing surveillance of these events in order to characterize and 
understand them in association with the use of this investigational product. 
 
 
If the Investigator has any questions in regards to an event being an imAE, the Investigator 
should promptly contact the Principal investigator. 
 
AESIs observed with durvalumab ± tremelimumab include: 
• 
Pneumonitis / ILD 
• 
hepatitis / transaminase increases 
• 
Neuropathy / neuromuscular toxicity (e.g. Guillain-Barré, and myasthenia gravis) 
• 
Endocrinopathies 
(i.e. 
events 
of 
hypophysitis, 
hypopituitarism 
adrenal 
insufficiency, diabetes insipidus, hyper- and hypothyroidism and type I diabetes 
mellitus) 
• 
Rash / Dermatitis 
• 
Nephritis / Blood creatinine increases 
• 
Pancreatitis/serum lipase and amylases increases 
• 
Other inflammatory responses that are rare with a potential immune-mediated 
aetiology include, but are not limited to, myocarditis, pericarditis, and uveitis and 
other events involving the eye, skin, haematological and rheumatological events. 
 
In addition, infusion-related reactions and hypersensitivity/anaphylactic reactions with a 
different underlying pharmacological aetiology are also considered AESIs. 
 
Further information on these risks (e.g. presenting symptoms) can be found in the current 
version of the durvalumab and tremelimumab Investigator’s Brochures. More specific 
guidelines for their evaluation and treatment are described in detail in the Dosing 
Modification and Toxicity Management Guidelines (see Section 6). These guidelines have 
been prepared by the MedImmune (AstraZeneca) and Novartis to assist the Investigator in 
the exercise of his/her clinical judgment in treating these types of toxicities.  These guidelines 


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apply to AEs considered causally related to the study drug/study regimen by the reporting 
investigator. 
 
Further information on these risks (eg. presenting symptoms) can be found in the current 
version of the durvalumab Investigator Brochure.  
 
If new or worsening pulmonary symptoms (e.g. dyspnoea) or radiological abnormality 
suggestive of pneumonitis/interstitial lung disease is observed, toxicity management as 
described in detail in the Dosing Modification and Toxicity Management Guidelines will be 
applied. It is strongly recommended to perform a full diagnostic workup, to exclude 
alternative causes such as lymphangitic carcinomatosis, infection, allergy, cardiogenic edema, 
or pulmonary hemorrhage.  
 
 In the presence of confirmatory HRCT scans where other causes of respiratory symptoms 
have been excluded, a diagnosis of pneumonitis (ILD) should be considered and the Dosing 
Modification and Toxicity Management Guidelines should be followed.  
 
Pneumonitis (ILD) investigation 
The following assessments, and additional assessments if required, will be performed to 
enhance the investigation and diagnosis of potential cases of pneumonitis. The results of the 
assessment will be collected. 
• 
Physical examination 
− 
Signs and symptoms (cough, shortness of breath and pyrexia, etc.) including 
auscultation for lung field will be assessed. 
• 
SpO2 
− 
Saturation of peripheral oxygen (SpO2) 
• 
Other items 
− 
When pneumonitis (ILD) is suspected during study treatment, the following 
markers should be measured where possible: 
(i) 
ILD Markers (KL-6, SP-D) and β-D-glucan 
(ii) 
Tumour markers: Particular tumour markers which are related to 
disease progression.   
Additional Clinical chemistry: CRP, LDH 
 
 
 
7.2.1 Hepatic Function Abnormality 
Hepatic function abnormality meeting the definition of Hy’s law (ie, any increase in ALT or 
AST to greater than 3 × ULN and concurrent increase in total bilirubin to be greater than 
2 × ULN) is considered an AESI. Concurrent findings are those that derive from a single 
blood draw or from separate blood draws taken within 8 days of each other. Follow-up 


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investigations and inquiries will be initiated promptly by the investigational site to 
determine whether the findings are reproducible and/or whether there is objective 
evidence that clearly supports causation by a disease (eg, cholelithiasis and bile duct 
obstruction with distended gallbladder) or an agent other than the investigational product. 
Guidelines for management of subjects with hepatic function abnormality are outlined in 
table 6.5. 
 
7.2.2 Pneumonitis 
Adverse events of pneumonitis are also of interest, as pneumonitis has been observed with 
anti-PD-1 mAbs (but not with anti-PD-L1 mAbs). Initial work-up should 
include high-resolution CT scan, ruling out infection, and pulse oximetry. Pulmonary 
consultation is highly recommended. Guidelines for management of subjects with 
pneumonitis are outlined in Section 7.7. 
 
7.2.3 Infusion Reactions 
Adverse events of infusion reactions (also termed infusion-related reactions) are of special 
interest and are defined, for the purpose of this protocol, as all AEs occurring from the start 
of the study treatment infusion up to 48 hours after the infusion start time. For all infusion 
reactions, the eCRF should be completed as instructed in Section, 7.4 and all SAEs should be 
reported to MedImmune Patient Safety as described in Section 7.5. 
 
7.2.4 Hypersensitivity Reactions 
Hypersensitivity reactions as well as infusion-related reactions have been reported with 
anti-PD-L1 and anti-PD-1 therapy [33]. As with the administration of any foreign protein 
and/or other biologic agents, reactions following the infusion of mAbs can be caused by 
various mechanisms, including acute anaphylactic (immunoglobulin E-mediated) and 
anaphylactoid reactions against the mAb, and serum sickness. Acute allergic reactions 
may occur, may be severe, and may result in death. Acute allergic reactions may include 
hypotension, dyspnea, cyanosis, respiratory failure, urticaria, pruritus, angioedema, 
hypotonia, urticaria, arthralgia, bronchospasm, wheeze, cough, dizziness, fatigue, headache, 
hypertension, myalgia, vomiting and unresponsiveness. Guidelines for management of 
subjects with hypersensitivity (including anaphylactic reaction) and infusion-related 
reactions are outlined in Section 7.7. 
 
7.2.5 Gastrointestinal Disorders 
Diarrhea/colitis is the most commonly observed treatment emergent SAE. In rare cases 
colon perforation may occur that requires surgery (colectomy) or can lead to a fatal 
outcome if not properly managed. Diarrhea/colitis in subjects receiving durvalumab should 
be managed as outlined in Section 7.7. 
 
7.3 Recording of Adverse Events 


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AEs and SAEs will be collected from the time of the patient signing the informed consent 
form until the follow-up period is completed (90 days after the last dose of durvalumab 
±tremelimumab).  If an event that starts post the defined safety follow up period noted 
above is considered to be due to a late onset toxicity to study drug then it should be 
reported as an AE or SAE as applicable. 
 
During the course of the study, all AEs and SAEs should be proactively followed up for each 
patient for as long as the event is ongoing.  Every effort should be made to obtain a 
resolution for all events, even if the events continue after the patient has discontinued 
study drug or the study has completed. 
 
Any AEs that are unresolved at the patient’s last visit in the study are followed up by the 
Investigator for as long as medically indicated, but without further recording in the eCRF 
(Protocol Data Management System/Clinical Oncology Research System - PDMS/CORe).  
AstraZeneca retains the right to request additional information for any patient with ongoing 
AE(s)/SAE(s) at the end of the study, if judged necessary. 
 
See Section 7.2 for the definition of SAEs. If an AE evolves into a condition that meets the 
regulatory definition of “serious,” it will be reported on the SAE Report Form. Infusion of 
biological products is commonly associated with infusion-related reactions. 
 
The following variables will be collected for each AE: 
• AE (verbatim) 
• The date when the AE started and stopped 
• The maximum CTCAE grade reported 
• Changes in CTCAE grade 
• Whether the AE is serious or not 
• Investigator causality rating against the IPs (yes or no) 
• Action taken with regard to IPs 
• Administration of treatment for the AE 
• Outcome 
 
In addition, the following variables will be collected for SAEs: 
• Date the AE met criteria for SAE 
• Date the Investigator became aware of the SAE 
• Seriousness criteria fulfilled 
• Date of hospitalization 
• Date of discharge 
• Probable cause of death 
• Date of death 
• Whether an autopsy was performed 
• Causality assessment in relation to study procedure(s) 


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• Causality assessment in relation to other medication 
• Description of the SAE 
The grading scales found in the revised NCI CTCAE version 4.03 will be utilized for all events 
with an assigned CTCAE grading. For those events without assigned CTCAE grades, the 
recommendation in the CTCAE criteria that converts mild, moderate, and severe events into 
CTCAE grades should be used. A copy of the CTCAE version 4.03 can be downloaded from 
the Cancer Therapy Evaluation Program website (http://ctep.cancer.gov). 
 
Anaphylaxis and infusion-related reactions have some common manifestations and may be 
difficult to distinguish from each other. Infusion-related reactions are commonly observed 
during or shortly after the first time exposure to therapeutic mAbs delivered through 
intravenous infusion. These reactions are less common following subsequent exposures. 
Unlike infusion-related reactions, anaphylaxis is a rare event, usually occurring after 
subsequent exposure to an antigen, and it is most commonly accompanied by severe 
systemic skin and/or mucosal reactions. The investigator is advised to carefully examine 
symptoms of adverse reactions observed during or shortly after exposure to Durvalumab 
and Trametinib, and consider the above mentioned facts prior to making a final diagnosis. 
Reactions occurring at the time of or shortly after subsequent infusions of investigational 
product are to be judged by the investigator at his/her own discretion. For the Investigator’s 
convenience and in order to facilitate consistency in judgments a copy of the National 
Institute of Allergy and Infectious Diseases (NIAID) and Food Allergy and Anaphylaxis 
Network (FAAN) guidance for anaphylaxis diagnosis is provided in Appendix 2. 
 
7.3.1 Time Period for Collection of Adverse Events 
Adverse events will be collected from time of signature of informed consent, enrollment, 
throughout the treatment period and including the follow-up period of 
30 days after the last dose of study medication. Serious adverse events will be recorded 
from the time of informed consent signature through 30 days after the last dose of study 
medication. 
 
7.3.2  Follow-up of Unresolved Adverse Events 
Any AEs that are unresolved at the subject’s last AE assessment or other assessment/visit as 
appropriate in the study are followed up by the investigator for as long as medically 
indicated, but without further recording in the eCRF. MedImmune retains the right to 
request additional information for any subject with ongoing AE(s)/SAE(s) at the end of the 
study, if judged necessary. After 90 days, only subjects with investigational product-related 
SAEs will continue to be followed for safety. 
 
 
7.4 Investigator Communications with AstraZeneca/Medimmune 
All SAEs will be reported, whether or not considered causally related to the investigational 
product, or to the study procedure(s). The reporting period for SAEs is the period 


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immediately following the time that written informed consent is obtained through 90 days 
after the last dose of durvalumab or until the initiation of alternative anticancer therapy. 
The investigator is responsible for informing the Ethics Committee and/or the Regulatory 
Authority of the SAE as per local requirements. 
 
The investigator will forward all SAE reports to Medimmune/AstraZeneca. A copy of the SAE 
report must be emailed to Medimmune/AstraZeneca at the time the event is reported.  
* A cover page should accompany the SAE report form indicating the following: 
“Notification from an Investigator Inititated Study” 
The investigator’s name and address 
The trial name/title and AstraZeneca ISS reference number (ESR-16-12416) 
* MD Anderson must also indicate, either in the SAE report or the cover page, the causality 
of events in relation to all study medications and if the SAE is related to disease 
progression, as determined by the principal investigator. 
* Send SAE report and accompanying cover page by way of email to AstraZeneca’s 
designated mailbox:  AEMailboxClinicalTrialTCS@astrazeneca.com 
 
If a non-serious AE becomes serious, this and other relevant follow-up information must 
also be provided to Medimmune/AstraZeneca. 
 
Serious adverse events that do not require expedited reporting to the FDA still need to be 
reported to Medimmine/AstraZeneca using the MD Anderson SAE report form. This 
information should be reported on a monthly basis and under no circumstance less 
frequently than quarterly.  
 
AstraZeneca / MedImmune or designee contact information: 
 
Externally Sponsored Research / Patient Safety 
MedImmune 
One MedImmune Way 
Gaithersburg, MD 20878, USA 
 
Fax: +1-301-398-4205 
 
Investigators should not wait to collect additional information to full document the event 
before notifying MedImmune Patient Safety of an SAE. When additional information 
becomes available, investigators should submit a follow-up SAE Report Form (separate from 
the initial report form) with the new information. Any follow-up information to an SAE also 
needs to be provided to MedImmune Patient Safety within 24 hours of learning of the new 
information. 


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Reporting of deaths to AstraZeneca 
All deaths that occur during the study or within the protocol-defined 90-day post-last dose of 
durvalumab safety follow-up period must be reported to AstraZeneca as follows: 
Death that is clearly the result of disease progression should be documented but 
should not be reported as an SAE. 
Where death is not due (or not clearly due) to progression of the disease under 
study, the AE causing the death must be reported to AstraZeneca as a SAE within 
24 hours (see Section 10.3.2 for further details). The report should contain a 
comment regarding the co-involvement of progression of disease, if appropriate, 
and should assign main and contributory causes of death.  
Deaths with an unknown cause should always be reported as a SAE.  
 
Deaths that occur following the protocol-defined 90-day post-last-dose of durvalumab safety 
follow-up period will be documented as events for survival analysis, but will not be reported 
as an SAE. However, if an investigator learns of any SAEs, including death, at any time after 
the subject has been permanently withdrawn from study, and he/she considers there is a 
reasonable possibility that the event is related to study treatment, the investigator should 
notify the study AstraZeneca/MedImmune Drug Safety. 
Reporting to Novartis 
To ensure patient safety, every SAE, regardless of suspected causality, occurring after the 
patient has provided the main informed consent and until at least 30 days after the patient 
has stopped study treatment must be reported to Novartis within 24 hours of learning of its 
occurrence. 
Any SAEs experienced after this 30 days period should only be reported to Novartis if the 
investigator suspects a causal relationship to the study treatment. Recurrent episodes, 
complications, or progression of the initial SAE must be reported as follow-up to the original 
episode within 24 hours of the investigator receiving the follow-up information. An SAE 
occurring at a different time interval or otherwise considered completely unrelated to a 
previously reported one should be reported separately as a new event. 
Information about all SAEs is collected and recorded on the Serious Adverse Event Report 
Form; all applicable sections of the form must be completed in order to provide a clinically 
thorough report. The investigator must assess and record the relationship of each SAE to each 
specific study treatment (if there is more than one study treatment), complete the SAE Report 
Form in English, and send the completed, signed form by fax within 24 hours to the oncology 
Novartis Drug Safety and Epidemiology (DS&E) department - Fax: (877-778-9739). The 
original copy of the SAE Report Form and the fax confirmation sheet must be kept with the 
case report form documentation at the study site. 


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Follow-up information is sent to the same contact(s) to whom the original SAE Report Form 
was sent, using a new SAE Report Form stating that this is a follow-up to the previously 
reported SAE and giving the date of the original report. Each re-occurrence, complication, or 
progression of the original event should be reported as a follow-up to that event regardless 
of when it occurs. The follow-up information should describe whether the event has resolved 
or continues, if and how it was treated, whether the blind was broken or not, and whether 
the patient continued or withdrew from study participation. 
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert (new 
occurrence) and is thought to be related to the Novartis study treatment, an oncology 
Novartis Drug Safety and Epidemiology (DS&E) department associate may urgently require 
further information from the investigator for Health Authority reporting. Novartis may need 
to issue an Investigator Notification (IN), to inform all investigators involved in any study with 
the same drug that this SAE has been reported. Suspected Unexpected Serious Adverse 
Reactions (SUSARs) will be collected and reported to the competent authorities and relevant 
ethics committees in accordance with Directive 2001/20/EC or as per national regulatory 
requirements in participating countries. 
Pregnancies 
To ensure patient safety, each pregnancy occurring while the patient is on study treatment 
must be reported to Novartis within 24 hours of learning of its occurrence. The pregnancy 
should be followed up to determine outcome, including spontaneous or voluntary 
termination, details of the birth, and the presence or absence of any birth defects, congenital 
abnormalities, or maternal and/or newborn complications. 
Pregnancy should be recorded on a Clinical Trial Pregnancy Form and reported by the 
investigator to the oncology Novartis Drug Safety and Epidemiology Department (DS&E). 
Pregnancy follow-up should be recorded on the same form and should include an assessment 
of the possible relationship to the study treatment any pregnancy outcome. Any SAE 
experienced during pregnancy must be reported on the SAE Report Form. 
Warnings and precautions 
Additional safety information collected between IB updates will be communicated in the form 
of Investigator Notifications. This information will be included in the patient informed 
consent and should be discussed with the patient during the study as needed 
 
7.5 Definitions and Other Events Requiring Immediate Reporting 
 
7.5.1 Overdose 
An overdose is defined as a subject receiving a dose of investigational product in excess of 


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that specified in the Investigator’s Brochure, unless otherwise specified in this protocol. 
Any overdose of a study subject with the investigational product, with or without associated 
AEs/SAEs, is required to be reported within 24 hours of knowledge of the event to 
MedImmune Patient Safety using the Safety Fax Notification Form (see Section 7.5 for 
contact information). If the overdose results in an AE, the AE must also be recorded on the 
AE eCRF. Overdose does not automatically make an AE serious, but if the consequences of 
the overdose are serious, for example death or hospitalization, the event is serious and 
must be reported as an SAE (see Section 7.4 and Section 7.5). MedImmune does not 
recommend specific treatment for an overdose. The investigator will use clinical judgment 
to treat any overdose. 
 
7.5.2 Hepatic Function Abnormality 
Adverse events of hepatic function abnormality of special interest to the  MedImmune 
(AstraZeneca) and Novartis are defined as any increase in ALT or AST to greater than 3 × 
ULN and concurrent increase in bilirubin to greater than 2 × ULN (ie, Hy’s law cases). 
Concurrent findings are those that derive from a single blood draw or from separate blood 
draws taken within 8 days of each other. In the event of hepatic function abnormality where 
the etiology is unknown, timely follow-up investigations and inquiries should be initiated by 
the investigational site, based on medical judgment, to make an informed decision 
regarding the etiology of the event. 
 
If the underlying diagnosis for the hepatic function abnormality is known (including 
progression of pre-existing disease such as primary or metastatic malignancy), the diagnosis 
should be recorded as an AE/SAE. If the underlying diagnosis for the hepatic function 
abnormality remains unknown, the term “hepatic function abnormal” should be used to 
report the AE/SAE. Hepatic function abnormality of unknown etiology, or which is 
considered attributable to investigational product, is required to be reported as “hepatic 
function abnormal” within 24 hours of knowledge of the event to MedImmune Patient 
Safety using the SAE Report Form, even if the event is considered to be non-serious (see 
Section 7.5 for contact information). The investigator will review the data with the 
AstraZeneca / MedImmune . The investigator should then use clinical judgment to establish 
the cause based on local standard of care and follow the subject by conducting testing as 
clinically indicated. 
 
If, after appropriate workup, in the opinion of the investigator, the underlying diagnosis 
for the abnormality remains unexplained, or is considered attributable to investigational 
product, permanent discontinuation of dosing for the study subject should be considered. 
Each reported event of hepatic function abnormality will be followed by the investigator. If 
the etiology of the event remains unconfirmed and/or is considered related to 
investigational product, a prompt cumulative review of safety data and the circumstances 
of the event in question will be conducted and assessed by the AstraZeneca / MedImmune 
safety review committee (or equivalent) to determine whether continued dosing of current 


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study subjects and/or study entry should be interrupted, whether the protocol will be 
modified, or whether the study will be discontinued permanently. Review and approval by 
the MedImmune safety review committee (or equivalent) is required for resumption of 
subject dosing or study entry in the event that the study is interrupted. Where applicable, 
regulatory authorities IRBs/IECs will be notified of any actions taken with the study. 
 
7.5.3 Pregnancy 
Pregnancy in a female subject who has received investigational product is required to be 
reported within 24 hours of knowledge of the event to AstraZeneca / MedImmune Patient 
Safety using the MD Anderson SAE form (see Section 7.5 for contact information). Subjects 
who become pregnant during the study period must not receive additional doses of 
investigational product but will not be withdrawn from the study. The pregnancy will be 
followed for outcome of the mother and child (including any premature terminations) and 
should be reported to MedImmune Patient Safety after outcome. Should the investigator 
become aware of a pregnancy in the partner of a male study subject who has received 
investigational product this should be reported within 24 hours of knowledge of the event 
to MedImmune Patient Safety using the Safety Fax Notification Form (see Section 7.5 for 
contact information). The investigator will endeavor to collect follow-up information on 
such pregnancies provided the partner of the study subject provides consent. 
 
Maternal exposure 
If a patient becomes pregnant during the course of the study, the IPs should be 
discontinued immediately.  
 
Pregnancy itself is not regarded as an AE unless there is a suspicion that the IP under study 
may have interfered with the effectiveness of a contraceptive medication. Congenital 
abnormalities or birth defects and spontaneous miscarriages should be reported and 
handled as SAEs. Elective abortions without complications should not be handled as AEs.  
The outcome of all pregnancies (spontaneous miscarriage, elective termination, ectopic 
pregnancy, normal birth, or congenital abnormality) should be followed up and 
documented even if the patient was discontinued from the study.  
 
If any pregnancy occurs in the course of the study, then the Investigator or other site 
personnel should inform the appropriate AstraZeneca representatives within 1 day, ie, 
immediately, but no later than 24 hours of when he or she becomes aware of it.  
 
The designated AstraZeneca representative will work with the Investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site within 1 
to 5 calendar days for SAEs and within 30 days for all other pregnancies. The same timelines 
apply when outcome information is available.  
 
Paternal exposure  


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Male subjects should refrain from fathering a child or donating sperm during the study and 
for 180 days after the last dose of durvalumab + any drug combination therapy or 90 days 
after the last dose of durvalumab monotherapy, whichever is the longer time period.  
 
Pregnancy of the patient’s partner is not considered to be an AE. However, the outcome of 
all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal 
birth, or congenital abnormality) occurring from the date of the first dose until 180 days 
after the last dose of durvalumab + any drug combination therapy or 90 days after the last 
dose of durvalumab monotherapy, whichever is the longer time period should, if possible, 
be followed up and documented.  
 
Where a report of pregnancy is received, prior to obtaining information about the 
pregnancy, the Investigator must obtain the consent of the patient’s partner. Therefore, the 
local study team should adopt the generic ICF template in line with local procedures and 
submit it to the relevant Ethics Committees (ECs)/Institutional Review Boards (IRBs) prior to 
use. 
 
7.5.4 Pneumonitis 
Adverse events of pneumonitis are required to be reported within 24 hours of knowledge 
of the event to MedImmune Patient Safety using the MD Anderson SAE form (see Section 
7.5 for contact information). 
 
 
8. PHARMACEUTICAL INFORMATION 
 
A list of the adverse events and potential risks associated with the investigational or 
commercial agents administered in this study is presented in Section 7.1. 
 
 
8.1 Identity of Investigational Products 
MedImmune and Novartis will provide the investigators with investigational product using 
designated distribution centers (Table 8.1). 
 
Table 8.1 Identification of Investigational Products 
Investigational 
Product 
Manufacturer 
Concentration and Formulation as Supplied 
Durvalumab 
MedImmune 
Supplied as a vialed liquid solution containing 500 mg 
(nominal) Durvalumab per vial. The solution contains 
50 mg/mL Durvalumab, 26 mM histidine/histidine HCl, 
275 mM trehalose dihydrate, 0.02% (w/v) polysorbate 
80, at pH 6.0 
Trametinib 
Novartis 
Trametinib tablets are supplied as 0.5-mg, 1-mg, and 2-
mg tablets for oral administration. Each 0.5-mg tablet 
contains 0.5635 mg trametinib dimethyl sulfoxide 
equivalent to 0.5 mg of trametinib non-solvated parent. 


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Each 1-mg tablet contains 1.127 mg trametinib 
dimethyl sulfoxide equivalent to 1 mg of trametinib 
non-solvated parent. Each 2-mg tablet contains 2.254 
mg trametinib dimethyl sulfoxide equivalent to 2 mg of 
trametinib non-solvated parent 
 
The investigator’s or site’s designated investigational product manager is required to 
maintain accurate investigational product accountability records. Commercially available 
IV bags with 0.9% (weight per volume [w/v]) saline or 5% (w/v) dextrose will be supplied by 
each site. Upon completion of the study, copies of investigational product accountability 
records will be returned to MedImmune. All unused Durvalumab will be returned to a 
MedImmune-authorized depot or disposed of upon authorization by MedImmune 
according to the investigational site policy. Both investigational products should be kept in a 
secure and dry place. Durvalumab vials are stored at 2°C to 8°C (36°F to 46°F) and must not 
be frozen.  All unused Trametinib will be disposed of according to investigational site policy. 
 
 
8.1.1 Dose Calculation 
The dose of Durvalumab will be fixed 1500mg IV q4 weeks. The dose of Trametinib will be 
between 1-2mg PO daily. 
 
Durvalumab 
Durvalumab will be given intravenously at a dose of 1500mg every 4 weeks. 
 
Trametinib 
Trametinib will be taken orally at a dose between 1-2mg. Patients will self-administer at 
home  
 
 
8.1.2 Investigational Product Inspection 
 
 Durvalumab 
Durvalumab will be supplied as a 500 mg/vial concentrate for solution for infusion. The 
solution contains 50 mg/mL Durvalumab, 26 mM histidine/histidine hydrochloride, 275 mM 
trehalose dihydrate, and 0.02% (w/v) polysorbate 80; it has a pH of 6.0. If there are any 
defects noted with the investigational product, the investigator  should be notified 
immediately. Refer to the Product Complaint section for further instructions. 
 
Durvalumab will be supplied to the site in vials in coded kits. Each kit has a unique number 
that is printed on all labels within the kit (ie, the outer carton label and the label of each vial 
within the carton). Each vial selected for dose preparation should be inspected. If there are 
any defects noted with the investigational product(s), the investigator  should be notified 
immediately. Refer to the Product Complaint section (Section 8.1.6) for further instructions. 
 
Trametinib 


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The drug substance is blended with inert ingredients (mannitol, sodium lauryl sulfate, 
colloidal silicon dioxide, microcrystalline cellulose, hypromellose, croscarmellose sodium, 
and magnesium stearate) and compressed into tablets.  The tablets are then coated with a 
white or pink opaque film (Opadry White or Pink, a titanium dioxide-based formulation with 
iron oxide as colorant, as applicable). 
 
Trametinib will be dosage in tablets with unit dose strengths of 0.5 mg. The route of 
administration will be oral, continuous through the study, unless toxicity is presented, once 
daily. Trametinib should be administered under fasting conditions, either one hour before 
or 2 hours after a meal. Trametinib should be administered with approximately eight 
ounces of water.  If a subject vomits after taking study medication, the subject should be 
instructed not to retake the dose and should take the next scheduled dose.  
 
If a subject misses a dose, subject may take the dose if the next scheduled dose is at least 
12 hours later.  If the next scheduled dose is due in less than 12 hours, subject should skip 
the dose and resume dosing the next day at the regular time.   
 
Trametinib tablets are packaged into a high density polyethylene (HDPE) bottle that 
contains desiccant with a child-resistant closure that includes an induction seal liner.  The 
HDPE bottle is enclosed in a paperboard carton. 
 
8.1.3 Dose Preparation Steps 
 
Durvalumab 
Total time from needle puncture of the durvalumab vial to the start of administration 
should not exceed:  
• 24 hours at 2°C to 8°C (36°F to 46°F) 
• 4 hours at room temperature 
 
If in-use storage time exceeds these limits, a new dose must be prepared from new vials. 
Infusion solutions must be allowed to equilibrate to room temperature prior to 
commencement of administration.  
 
The IV line will be flushed with a volume of IV diluent equal to the priming volume of the 
infusion set used after the contents of the IV bag are fully administered, or complete the 
infusion according to institutional policy to ensure the full dose is administered and 
document if the line was not flushed. 
 
In the event that there are interruptions during infusion, the total allowed time should not 
exceed 8 hours at room temperature. 
  


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A dose of 1500mg will be administered using an IV bag containing 0.9% (w/v) saline or 5% 
(w/v) dextrose, with a final durvalumab (MEDI4736) concentration ranging from 1 to 20 
mg/mL, and delivered through an IV administration set with a 0.2- or 0.22-μm in-line filter.  
Add 30.0 mL of durvalumab (MEDI4736) (ie, 1500mg of durvalumab [MEDI4736]) to the IV 
bag. The IV bag size should be selected such that the final concentration is within 1 to 20 
mg/mL. Mix the bag by gently inverting to ensure homogeneity of the dose in the bag.  
 
Durvalumab will be administered at room temperature (approximately 25°C) by controlled 
infusion into a peripheral or central vein. Following preparation of durvalumab, the entire 
contents of the IV bag should be administered as an IV infusion over approximately 60 
minutes (±5 minutes). Less than 55 minutes is considered a deviation, the total allowed time 
should not exceed 8 hours at room temperature. 
 
If either preparation time or infusion time exceeds the time limits a new dose must be 
prepared from new vials.  Durvalumab (MEDI4736) does not contain preservatives, and any 
unused portion must be discarded.  
 
 
 
 
8.1.4 Treatment Administration 
The first day of durvalumab dosing is considered Day 1.  
 
Durvalumab should be administered using the following guidelines: 
 
1. Investigational product must be administered at room temperature by controlled infusion 
into a peripheral vein or central line. Prior to the start of the infusion, ensure that the bag 
contents are at room temperature to avoid an infusion reaction due to the administration 
of the solution at low temperatures. 
 
2. A physician must be present at the site or immediately available to respond to 
emergencies during all administrations of investigational product(s). Fully functional 
resuscitation facilities should be available. Investigational product(s) must not be 
administered via IV push or bolus but as an IV infusion. The entire content of each IV bag 
will be infused using an infusion pump. 
 
3. The infusion lines should be attached only at time of use. Lines used for infusion during 
dose administration will need to be equipped with 0.22- or 0.2-μm in-line filters. 
Durvalumab solution should not be infused with other solutions or medications. 
 
4. The entire contents of the IV bag should be administered as an IV infusion for 
approximately 1 hour. Some investigational product may remain in the IV line after the 
infusion has completed. Fifteen to 30 mL of IV solution should be added to the infusion bag 
after the investigational product has been administered to flush the line. The infusion rate 


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should not be changed unless necessary to manage acute reactions. Document if the line 
was not flushed. 
 
 
8.1.5 Monitoring of Dose Administration 
Subjects will be monitored prior to, during, and after infusion of Durvalumab. Vital signs 
(temperature, BP, pulse rate, and respiratory rate) will be measured on treatment days 
within 30 minutes prior to the start of Durvalumab administration, every 30 minutes (± 5 
minutes) during Durvalumab administration, at the end of Durvalumab infusion (+ 5 
minutes), and at 30 and 60 minutes (± 5 minutes) post end of infusion of Durvalumab. For 
Dose 1, an additional 2-hour (± 15 minutes) observation period will be required after the 60 
minutes (± 5 minutes) post end of infusion of Durvalumab vital sign assessment. The 
additional 2-hour observation period will not be required for subsequent doses unless the 
subject experiences an infusion reaction. 
 
In the event of Grade ≤ 2 infusion-related reaction, the infusion rate of Durvalumab may be 
decreased by 50% or interrupted until resolution of the event (up to 4 hours) and re-
initiated at 50% of the initial rate until completion of the infusion. In subjects experiencing 
Grade ≤ 2 infusion-related reaction, subsequent infusions may be administered at 50% of 
the initial rate. 
 
Primary prophylaxis against infusion-related reactions is not permitted during this study in 
order to avoid obscuring a potential safety signal and enable a future assessment regarding 
whether premedications should be required for all subjects in future studies. However, at 
the discretion of the investigator, secondary prophylaxis (ie, prevention of infusion-related 
reaction following initial episode) is appropriate and will be permitted. Acetaminophen 
and/or an antihistamine (eg, diphenhydramine) or equivalent medications per institutional 
standard may be administered at the discretion of the investigator. If the infusion-related 
reaction is Grade 3 or higher in severity, treatment with Durvalumab will be discontinued. 
 
As with any mAb, allergic reactions to dose administration are possible. Therefore, 
appropriate drugs and medical equipment to treat acute anaphylactic reactions must be 
immediately available, and study personnel must be trained to recognize and treat 
anaphylaxis. 
 
 
8.1.6 Reporting Product Complaints 
Any defects with Durvalumab must be reported immediately to MedImmune. Any defects 
with Trametinib must be reported immediately to Novartis. 
 
8.1.7  Additional Study Medications 
 
No other study medications are specified for use in this clinical protocol. 
 


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8.1.8  Labeling 
 
Labels for the investigational product will be prepared in accordance with Good 
Manufacturing Practice (GMP) and local regulatory guidelines. Label text will be translated 
into local languages, as required. 
 
8.1.9  Storage 
 
Store Durvalumab at 2°C to 8°C (36°F to 46°F). Do not freeze. 
 
Store Trametinib refrigerated at 2° to 8°C (36° to 46°F). Do not freeze. Dispense in original 
bottle. Do not remove desiccant. Protect from moisture and light. Do not place medication 
in pill boxes. 
 
8.1.10 Treatment Compliance 
Investigational product is administered by study site personnel, who will monitor 
compliance. 
 
8.1.11 Accountability 
 
The investigator’s or site’s designated investigational product manager is required to 
maintain accurate investigational product accountability records. Upon completion of the 
study, copies of investigational product accountability records will be returned along with 
all unused investigational product. 
 
 
9. CORRELATIVE/SPECIAL STUDIES 
9.1 
Laboratory Correlative Studies 
 
All correlative studies will be performed by the Immune Platform at MD.  Samples include 
tumor biopsy samples prior to checkpoint inhibitor therapy and at the start of cycles 2 and 4.  
Biopsies are optional, though at MTD paried biopsies are mandatory in 15 patients.  Peripheral 
blood samples will be collected in tubes at the time points outlined in section 5 and in the study 
calendar in section 10.  The exact collection methodology and standard operative procedures 
will be listed in a laboratory manual. We will be attempting to uncover biomarkers associated 
with safety and relapse-free survival by quantifying: 
1. Pre- and post-immune checkpoint inhibitor therapy effect on T-effector cell populations; 
CD4 subsets; T-regulatory populations; B cell populations; dendritic and macrophage 
populations. 
2. Pre- and post-immune checkpoint inhibitor therapy on functional assays related to Teff 
cells. 


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3. Analysis of PD-L1 expression in tumor cells and infiltrating immune cells pre- and post-
treatment. 
4. Immunologic markers obtained in peripheral blood versus those obtained at the tissue 
level.     
5. Immunologic biomarkers obtained in the tissue and peripheral blood correlated with 
safety, feasibility, and progression free survival. 
 
These will be reported via: 
1. Graphical displays will be used to display all biomarker data a baseline and follow-up.  
Transformation will be used as needed prior to hypothesis testing and estimating 
summary statistics. We will use a paired t test to determine if there is a difference in 
pre- and post-immune checkpoint inhibitor therapy in T-effector cell populations; T-
regulatory populations; CD4 subsets; B cell populations; dendritic and macrophage 
populations. 
2. We will use scatterplots to demonstrate correlation between immunologic markers 
obtained in peripheral blood versus those obtained at the tissue level.  A Pearson 
correlation will be estimated to describe the level of association.     
 


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10. STUDY CALENDAR 
 
 
 
Wk 
-1  
+/-3d 
 
Wk 
0 
+/-3d 
 
Wk 
2 
+/-3d 
 
Wk 
4 
+/-3d 
 
Wk  
6 
+/-3d 
 
Wk 8 
 
Wk 
12 
(every 
4 wks) 
 
Wk 
16 
(every 
8 wk) 
 
 
 
 
 
 
Comment 
Durvalumab 
 
X 
 
X 
 
X 
X 
 
 
Trametinib 
X 
X 
X 
X 
X 
X 
X 
 
 
Clinic Visit 
X 
X 
X 
X 
X 
X 
X 
 
 
Targeted Physical 
Examination 
X 
X 
X 
X 
X 
X 
X 
 
Targeted examination must include 
HEENT, CHEST, CV, ABD, SKIN, and 
NEURO 
Vital Signs and 
Oxygen Saturation 
X 
X 
X 
X 
X 
X 
X 
 
Including BP, HR, temperature and 
oxygen saturation by pulse oximetry (at 
rest). Obtain vital signs within 72 hours 
prior to first dose. 
Physical 
Measurements 
(including 
performance 
status) 
X 
X 
X 
X 
X 
X 
X 
 
Weight and ECOG performance status.  
See Appendix 1 for ECOG Performance 
Status scale. 
Review of 
Concomitant 
Medication 
X 
X 
X 
X 
X 
X 
X 
 
 
Laboratory Tests 
X 
X 
X 
X 
X 
X 
X 
 
On-study local laboratory assessments 
should be done within 72 hours prior to 
each dose: 
CBC w/differential and platelet count, 
LFTs (ALT, AST, total bilirubin, alkaline 
phosphatase), comprehensive metabolic 
panel, Mg)* 
Pregnancy test 
(WOCBP only) 
X 
 
 
 
 
 
 
 
Serum or urine pregnancy test to be 
done within 24 hours prior to first dose. 
ECOG PS 
X 
X 
 
X 
 
X 
X 
 
 
Adverse Events 
Assessment 
X 
X 
X 
X 
X 
X 
X 
 
Per CTCAE v4.03 
End of treatment 
visit 
 
 
 
 
 
 
 
 
Approximately 28 days (+/-7days after 
last treatment, Preferred in clinic visit 
though maybe via phone call** 
CT C/A/P with IV 
contrast with 
tumor 
measurements 
 
 
 
 
 
X 
 
X 
 
Biopsy (tumor) 
optional 
(mandatory for 15 
at MTD) 
X 
 
 
X 
 
 
 
 
 
Immunogenicity 
Assessments, 
Peripheral Blood 
• 
Week -1, week0, week 4, week 8, week 12, and progression, up to 8 tubes of blood with 10ml each will be collected for 
immunological assessment. See section 5.1.3 (up to 2 missed blood draws are allowed) 


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• 
Comprehensive metabolic panel: BUN or serum urea level, creatinine, Ca, Na, K, Cl, glucose, and bicarbonate 
• 
*CEA, TSH and FT4 at week 4 and 8 and then every 8weeks 
• 
*amylase and lipase with week 8 
 
** Subjects who decline to return to the site for evaluations will be offered follow-up by phone every 
3 months as an alternative 
 
 
 
 
 
 
 
11. MEASUREMENT OF EFFECT 
 
Immune related response criteria (irRC) described by Wolchok et al. will be used to identify 
measurable disease on baseline CT scans.  Further imaging will be performed according to 
the study outline in section 5 and study calendar in section 10.  
 
11.1.1. Definitions 
 
Evaluable for toxicity.  All patients will be evaluable for toxicity from the time of 
enrollment. 
 
Evaluable for 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.  
 
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 >10 mm with CT scan.  All tumor 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. 
 


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Non-measurable disease.  All other lesions (or sites of disease), including small 
lesions (<10 mm using CT scan), are considered non-measurable disease.  Bone 
lesions, leptomeningeal disease, ascites, pleural/pericardial effusions, 
lymphangitis cutis/pulmonis, inflammatory breast disease, abdominal masses 
(not followed by CT or MRI), and cystic lesions are all non-measurable. 
 
Target lesions.  All measurable lesions up to a maximum of 5 lesions per organ 
and 10 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) and 
their suitability for accurate repeated measurements (either by imaging 
techniques or clinically).  A sum of the longest diameter (LD) for all target lesions 
will be calculated and reported as the baseline sum LD.  The baseline sum LD will 
be used as reference by which to characterize the objective tumor response. 
 
Non-target lesions.  All other lesions (or sites of disease) including any 
measurable lesions over and above the 10 target lesions should be identified as 
non-target lesions and should also be recorded at baseline.  Measurements of 
these lesions are not required, but the presence or absence of each should be 
noted throughout follow-up.  
 
11.1.3 Methods for Evaluation of Measurable Disease 
 
Response and progression will be evaluated in this study using guidelines proposed by 
the Immune Related Response Criteria (irRC). 
 
 
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 2 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 preferred to evaluation by clinical examination when both 
methods have been used to assess the antitumor effect of a treatment. 
 
 
11.1.3.1 irRC: Measurable Disease 
 
 
 
Index lesions: Must be accurately measured in two dimensions, with a minimum size 
of ≥5 x 5mm (two largest perpendicular diameters) by CT scan (CT scan slice 
thickness no greater than 5 mm) or 10mm caliper measurement by clinical exam 
(lesions which cannot be accurately measured with calipers should be recorded as 
non-measurable). 
 


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11.1.3.2 irRC: Index and non-Index Lesions: 
 
 
For the irRC, only index and measurable new lesions are taken into account (in 
contrast to conventional WHO criteria, which do not require the measurement of 
new lesions, nor do they include new lesion measurements in the characterization 
of evolving tumor burden). At the baseline tumor assessment, the sum of the 
products of the two largest perpendicular diameters (SPD) of all index lesions (five 
lesions per organ, up to 10 visceral lesions and five cutaneous index lesions) is 
calculated. At each subsequent tumor assessment, the SPD of the index lesions and 
of new, measurable lesions (≥5 x 5 mm; up to 5 new lesions per organ: 5 new 
cutaneous lesions and 10 visceral lesions) are added together to provide the total 
tumor burden. 
 
11.1.4 Response Criteria 
 
11.1.4.1 Immune Related Response Criteria (irRC) 
Evaluation of Target Lesions 
Response in new patients will be conducted using the Immune Related Response 
Criteria (irRC), as described by Wolchok, et al 60. “For irRC, only index and 
measurable new lesions are taken into account. At the baseline tumor assessment, 
the sum of the products of the two largest perpendicular diameters (SPD) of all 
index lesions (five lesions per organ, up to 10 visceral lesions and five cutaneous 
index lesions) is calculated. At each subsequent tumor assessment, the SPD of the 
index lesions and of new, measurable lesions (≥5 x 5mm; up to 5 new lesions per 
organ: 5 new cutaneous lesions and 10 visceral lesions) are added together to 
provide the total tumor burden:” 
Tumor Burden=SPDindex lesions + SPDnew, measurable lesions 
Complete Response (irCR): irCR, complete disappearance of all lesions (whether 
measurable or not, and no new lesions) confirmation by a repeat, consecutive 
assessment no less than 4 wk from the date first documented. 
Partial Response (irPR): irPR, decrease in tumor burden ≥50% relative to baseline 
confirmed by a consecutive assessment at least 4 wk after first documentation. 
Progressive Disease (irPD): irPD, increase in tumor burden ≥25% relative to nadir 
(minimum recorded tumor burden) confirmation by a repeat, consecutive 
assessment no less than 4 wk from the date first documented. 
 
If a patient is classified as having irPD at a post-baseline tumor assessment, then 
confirmation of irPD by a second scan in the absence of rapid clinical deterioration is 
required. The definition of confirmation of progression represents an increase in 
tumor burden ≥25% compared with the nadir at two consecutive time points at least 


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4 wk apart. It is recommended that this be done at the discretion of the investigator 
because follow-up with observation alone may not be appropriate for patients with 
a rapid decline in performance status. 
 
Stable Disease (irSD): irSD, not meeting criteria for irCR or irPR, in absence of irPD. 
 
 
 
 
12. 
DATA REPORTING REQUIREMENTS / STUDY AND DATA MANAGEMENT 
 
12.1 
Monitoring of the Study 
 
 
During the study, a MedImmune representative will be available if the investigator(s) or 
other staff at the center needs information and advice about the study conduct. 
 
12.2.1 Source Data 
Data source will be at MD Anderson Cancer Center. 
 


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12.2.2 Study Agreements 
The principal investigator should comply with all the terms, conditions, and obligations of 
the Clinical Study Agreement, or equivalent, for this study. In the event of any inconsistency 
between this Clinical Study Protocol and the Clinical Study Agreement, the terms of Clinical 
Study Protocol shall prevail with respect to the conduct of the study and the treatment of 
subjects and in all other respects, not relating to study conduct or treatment of subjects, 
the terms of the Clinical Study Agreement shall prevail. 
 
12.2.3 Archiving of Study Documents 
The investigator follows the principles outlined in the Clinical Study Agreement. 
 
12.3 Study Timetable and End of Study 
The end of the study (“study completion”) is 1.5 years after the final subject is enrolled or 
the date the study is closed by MedImmune (AstraZeneca) and Novartis, whichever occurs 
first. 
 
12.4 Data Management 
The investigator ensures the accuracy, completeness, and timeliness of the data recorded.  
 
 
13. STATISTICAL CONSIDERATIONS 
This is a phase II open-label study to assess the efficacy and safety of the combination 
therapy with Durvalumab and Trametinib in MSS metastatic colon cancer patients. The 
primary endpoint is the best overall response (CR+PR) by immune response criteria. Up 
to 44 patients will be enrolled and treated at the MTD of the combination therapy. We 
conservatively expect to enroll between 4-6 patients per month on this protocol, 
requiring a total of approximately 10-12 months to complete enrollment. The Simon’s 
two-stage minimax design will be implemented based on a null hypothesis of 5% 
response rate and an alternative hypothesis of 15% response rate. In the first stage, we 
will enroll 29 patients; if 1 or fewer achieves response, patient enrollment will be 
stopped. Otherwise, we will continue to enroll all 44 patients and the combination 
therapy is deemed as promising if there are 5 or more responders. For efficacy 
monitoring purposes if inadequate responses are seen to proceed to the second stage, 
then the final assessment for response will occur 6months following the enrollment of 
the last patient. The design has a one-sided type I error rate of 0.10 and 80% power.  
The probability of early termination is 57% under the null hypothesis. Patient 
enrollment will be temporarily suspended when the enrollment for the first stage is 
completed yet not enough responders have been observed to trigger the start of the 
second stage.    
Additionally, toxicities (defined as any treatment related Grade 3 or higher toxicities) 
will be monitored using the Bayesian method of Thall, Simon and Estey. The toxicity 


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stopping rule to be applied is to stopped the trial early if Prob(p>0.35 |data ) > .92, 
where p denotes the probability of toxicity. This decision criterion will be applied after 
the first 8 patients have been evaluated, and then in cohort size of 6. Assuming a beta    
(1,1) priori for p, the stopping boundaries corresponding are shown in Table 1 below. 
For example, we will stop the trial if 8 or more patients experienced treatment related 
Grade 3 or higher toxicities among the first 14 evaluable patients.   
 
Toxicity monitoring will occur during the first cycle of therapy. 
 
The Investigator is responsible for completing efficacy/toxicity summary reports.  
A copy of the cohort summary should be placed in the Investigator’s Regulatory Binder 
under “sponsor correspondence”.  
 
Table 1. Toxicity stopping boundaries 
Number 
of 
evaluable 
patients  
Number 
of 
patients 
with 
toxicities is at least 
8 
5 
14 
8 
20 
10 
26 
13 
32 
15 
38 
18 
44 
20 
 
The operating characteristics of this study design based on 10,000 simulations are 
illustrated in Table 2.  
 
Table 2. Operating Characteristics for Toxicity Monitoring Rule.  
True toxicity rate 
Prob (stop early) 
Median (25th, 75th percentile) 
0.10 
0.001 
44 (44, 44) 
0.20 
0.016 
44 (44, 44) 
0.30 
0.114 
44 (44, 44) 
0.35 
0.237 
44 (44, 44) 
0.40 
0.410 
44 (20, 44) 
0.50 
0.824 
20 (8, 32) 
0.60 
0.981 
8 (8, 14) 


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Statistical software used Multc Lean Desktop V2.1. 
 
The best response (CR/PR) rate will be estimated along with the exact 95% confidence 
interval. Patients who drop out of the study prior to the assessment of response will be counted 
as non-responders for the primary analysis. Safety data will be summarized using descriptive 
statistics. Time-to-event outcomes, including time to treatment failure (i.e., death, progression 
or treatment related toxicities are counted as events), or progression-free survival (i.e., death 
or progression are counted as events) will be estimated using the Kaplan-Meier method.  
The immunological and molecular biomarker changes (such as CD4 and CD8 T-cell) will 
be summarized over time using descriptive statistics and graphical display. A paired t-test will 
be used to determine if there is a statistically significant change between pre- and post-
treatment. The correlation between change in CD8+ T-cell density from pre-treatment to on-
treatment biopsy tumor tissue will be conducted based on Pearson’s correlation coefficient and 
Spearman’s rank correlation coefficient.  With 15 paired biopsy samples, assuming normally 
distributed data and two-sided 0.05% alpha, we will have 80% power to detect a 0.723*s 
(where “s” is the within group standard deviation) or greater effect size, represented by change 
in immune cell markers with treatment. 
 


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Adam, R. and E. Vinet, Regional treatment of metastasis: surgery of colorectal liver 
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Parkin, D.M., et al., Global cancer statistics, 2002. CA Cancer J Clin, 2005. 55(2): p. 74-
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Gustavsson, B., et al., A Review of the Evolution of Systemic Chemotherapy in the 
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APPENDIX 1 
 
Performance Status Criteria 
 
 
 
ECOG Performance Status Scale 
 
 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor 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). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
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. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
50 
Requires considerable assistance 
and frequent medical care. 
3 
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 
 
 
 
 
 
 
 
 


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Appendix 2 
National Institute of Allergy and Infectious Diseases and Food Allergy and Anaphylaxis Network 
guidance for Anaphylaxis Diagnosis 
 
The NIAID and FAAN define anaphylaxis as a serious allergic reaction that is rapid in onset 
and may cause death [64]. They recognize 3 categories of anaphylaxis, with 
criteria designated to capture from 80% of cases (category 1) to > 95% of all cases of 
anaphylaxis (for all 3 categories). 
1. Acute onset of an illness (minutes to several hours) with involvement of the skin, 
mucosal tissue, or both (eg, generalized hives, pruritus or flushing, swollen lips, tongue, 
uvula) 
AND AT LEAST ONE OF THE FOLLOWING: 
a. Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced peak 
expiratory flow [PEF], hypoxemia) 
b. Reduced BP or associated symptoms of end-organ dysfunction (eg, hypotonia 
[collapse], syncope, incontinence) 
 
2. Two or more of the following that occur rapidly after exposure to a likely allergen for 
that patient (minutes to several hours): 
a. Involvement of the skin-mucosal tissue (eg, generalized hives, itch-flush, swollen 
lips-tongue-uvula) 
b. Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced PEF, 
hypoxemia) 
c. Reduced BP or associated symptoms (eg, hypotonia [collapse], syncope, 
incontinence) 
d. Persistent gastrointestinal symptoms (eg, crampy abdominal pain, vomiting) 
 
3. Reduced BP after exposure to known allergen for that patient (minutes to several 
hours): 
a. Infants and children: low systolic BP (age specific) or greater than 30% decrease in 
systolic BP 
b. Adults: systolic BP of less than 90 mm Hg or greater than 30% decrease from that 
person’s baseline. 
 
1 ASCO Educational Book 2015 “Managing Immune Checkpoint Blocking Antibody Side Effects” by Michael Postow 
MD  
2 NCI CTCAE version 4.03 
3 ASCO Educational Book 2015 “Managing Immune Checkpoint Blocking Antibody Side Effects” by Michael Postow 
MD 
4 FDA Liver Guidance Document 2009 Guidance for Industry: Drug Induced Liver Injury – Premarketing Clinical 
Evaluation