Pilot Study Assessing the Safety and Tolerability of the Neoadjuvant Use of Tremelimumab (Anti-CTLA-4) Plus Durvalumab (MEDI4736) (Anti-PD-L1) in the Treatment of Resectable Colorectal Cancer Liver Metastases
Phase: PHASE1
Conditions: Metastatic Carcinoma in the Liver, Resectable Mass, Stage IV Colorectal Cancer AJCC v7, Stage IVA Colorectal Cancer AJCC v7, Stage IVB Colorectal Cancer AJCC v7
Sponsor: M.D. Anderson Cancer Center

MD Anderson IND Sponsor Cover Sheet 
Protocol ID 
2015-0828 
Protocol Title 
Pilot Study Assessing the Safety and Tolerability of the Neoadjuvant 
Use of Durvalumab (anti-PD-L1)  combined with either Tremelimumab 
(anti-CTLA-4) or Monalizumab (anti-NKG2A) or Oleclumab (anti-CD73) 
in the Treatment of Resectable Colorectal Cancer Liver or Lung 
Metastases 
Phase 
Pilot 
Protocol Version 
9 
Version Date 
1/25/2019 
Protocol PI 
Michael Overman 
Department 
GI Medical Oncology 
IND Sponsor 
MD Anderson Cancer Center 
IND # 
130,357 

 
i 
TITLE: Pilot Study Assessing the Safety and Tolerability of the Neoadjuvant Use of Durvalumab 
(anti-PD-L1)  combined with either Tremelimumab (anti-CTLA-4) or Monalizumab (anti-NKG2A) 
or Oleclumab (anti-CD73) in the Treatment of Resectable Colorectal Cancer Liver or Lung 
Metastases. 
 
Coordinating Center: 
University of Texas MD Anderson Cancer Center 
 
Principal Investigator: 
Michael Overman, MD 
 
moverman@mdanderson.org 
 
 
Version: 9  dated January 25, 2019 
 

 
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TABLE OF CONTENTS 
 
Page 
 
 
1. OBJECTIVES ............................................................................................................................... 1 
1.1 
Primary Objectives ....................................................................................................... 1 
1.2 
Secondary Objectives................................................................................................... 1 
 
2. BACKGROUND .......................................................................................................................... 1 
2.1 
Study Disease ................................................................................................................ 1 
2.2 
Investigational Agent(s) ............................................................................................... 3 
2.6 
Rationale ..................................................................................................................... 21 
 
3. PATIENT SELECTION 
3.1 
Eligibility Criteria  ....................................................................................................... 23 
3.2 
Exclusion Criteria ........................................................................................................ 25 
 
4. REGISTRATION PROCEDURES ................................................................................................. 27 
 
5. TREATMENT PLAN .................................................................................................................. 27 
5.1  
Study Design………………………………………………………………………………………………………….27 
5.2  
General Concomitant Medication and Supportive Care Guidelines ........................ 32 
5.3 
Duration of Therapy ................................................................................................... 36 
5.4 
Duration of Follow Up ................................................................................................ 37 
 
6. DOSING DELAYS/DOSE MODIFICATIONS ............................................................................... 37 
 
7. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ................................................. 37 
7.1  
Definition of Adverse Event ....................................................................................... 37 
7.2  
Definition of Serious Adverse Event .......................................................................... 38 
7.3  
Definition of Adverse Event of Special Interest ........................................................ 38 
7.4  
Recording of Adverse Events ..................................................................................... 41 
7.5  
Reporting of Serious Adverse Events…………………………………………………………………….44 
7.6 
Other Events Requiring Immediate Reporting ..................................................... 45 
7.7 
Management of Study Medication Related Toxicities.............................................. 47 
 
8. PHARMACEUTICAL INFORMATION ........................................................................................ 72 
8.1  
Identity of Investigational Products  ......................................................................... 72 
 
9. CORRELATIVE/SPECIAL STUDIES ............................................................................................ 80 
9.1 
Laboratory Correlative Studies .................................................................................. 80 
10. STUDY CALENDAR ................................................................................................................... 82 

 
iii 
 
11. MEASUREMENT OF EFFECT……………………………………………………………………………………………….86  
 
12. DATA REPORTING REQUIREMENTS / STUDY AND DATA MANAGEMENT…………………………88 
12.1 
Training of Study Site Personnel ................................................................................ 88 
12.2 
Monitoring of the Study ............................................................................................. 88 
12.3 
Study Timetable and End of Study………………………………………………………………………...89 
12.4 
Data Management…………………………………………………………………………………………………89  
 
13. STATISTICAL CONSIDERATIONS ............................................................................................. 89 
 
13.1 
Endpoints .................................................................................................................... 89 
 
13.2 
Sample Size Justification ............................................................................................ 90 
 
13.3 
Interim Monitoring ..................................................................................................... 90 
 
13.4 
Analysis Plan ............................................................................................................... 94 
 
 
 
REFERENCES .................................................................................................................................. 96 
 
APPENDICES 
 
APPENDIX 1 
Performance Status Criteria ............................................................................................ 100 
 
APPENDIX 2 
Tremelimumab guidelines for the management of diarrhea and colitis ........................ 101 
 
 
APPENDIX 3 
 
 
NIAID and Food Allergy & Anaphylaxis Network guidance for Anaphylaxis Diagnosis .. 102 
 
 
 

 
1 
1. OBJECTIVES 
 
1.1. 
Primary Objective 
Assess the safety and feasibility of adding Immune-therapy with durvalumab (MEDI4736) (anti-
PD-L1) combined with either Tremelimumab (anti-CTLA-4) or Monalizumab (anti-NKG2A) or 
Oleclumab (MEDI9447) administered once pre-operatively and post-operatively in patients who 
are candidates for resection for colorectal cancer with liver or lung metastases (CRCLM). 
1.2. 
Secondary Objectives 
1. Explore the changes in various immune parameters, including PD-L1 and PD-1 
expression in the tumor, over treatment and correlate with response and survival 
with goal of biomarker discovery. 
2. Estimate the relapse-free survival (RFS) in all enrolled subjects. 
 
2. BACKGROUND 
 
2.1  
Study Disease 
 
 
2.1.1 
Colon Cancer Background and Treatment Options 
Colorectal cancer is the third most common cancer in the United States with an estimated 
136,830 new cases and 50,310 deaths in 2014 [1].  Of new cases, 20-25% will have clinically 
detectable liver metastases at the time of diagnosis, and a further 40-50% of patients will 
eventually develop CRCLM [2].  Therefore, approximately one-third of patients will develop 
liver metastases within 3 years of initial diagnosis [3].  Surgery is potentially curative in the 
15-20% of patients who meet criteria for resection [3-5]. As such, approximately 5,000-
10,000 patients will have resectable CRCLM per year in the U.S.  The definition of 
resectability varies, but in general resectability implies an achievable R0 surgical resection 
with adequate post-operative liver function [6]. 
For surgical candidates, complete surgical resection is associated with a 20-50% overall 
survival rate at 5 years [7-9].  For solitary CRCLM, the 5-year survival rate with surgery alone 
has been reported to be as high as 50%-71% [10].  Risk factors for survival after CRCLM 
identified in a meta-analysis of 60 studies include: node positive primary, CEA level, extra-
hepatic disease, poor tumor grade, positive surgical margin, >1 liver metastasis, and >3cm 
diameter of the liver metastasis [11].   
Unfortunately, 75% of resected patients ultimately recur, and there is an opportunity to 
improve this outcome with adjuvant therapy [12].  Aside from careful patient selection, 
many adjuvant and neo-adjuvant treatment strategies have been studied in an effort to 
improve outcomes.  In a meta-analysis of 2 large clinical trials, adjuvant 5-FU plus leucovorin 
demonstrated a trend toward improved progression free survival (PFS) (p=0.059) and 
improved OS (p=0.046) [13].  In EORTC Intergroup trial 40983, FOLFOX4 was given for 6 
cycles before and 6 cycles after hepatic resection.  There was an absolute 8.1% 

 
2 
improvement in 3-year PFS from 28.1% to 36.2% (p=0.041) in the intention-to-treat 
population [14].  Eighty-three percent of randomized patients in both surgical and neo-
adjuvant arms advanced to surgery, achieving an R0 resection.  Despite the high number of 
patients being able to undergo R0 surgical resection, this approach does not confer a 
survival benefit.  Post-operative hepatic arterial infusion (HAI) is performed in some high-
volume, specialized academic centers, and survival when combined with 5-FU is superior to 
5-FU alone (10 year survival 41% vs. 28%) [15].  However, HAI use is not a widely used 
strategy, especially in the community setting, and in general, there remains an urgent need 
to improve upon existing therapies. 
FOLFOX chemotherapy is used in both an adjuvant setting for resected stage III and selected 
high-risk stage II colorectal cancer (CRC) patients.  It was shown in a large, prospective, 
randomized phase III trial to be superior to infusional 5-FU in the adjuvant setting (MOSAIC 
[16]).  FOLFOX is also a standard first line treatment option for patients with metastatic CRC 
with median PFS of 8 months [17]. Bevacizumab, a monoclonal antibody targeting VEGFR, is 
often added to FOLFOX in the up-front metastatic setting as it confers a progression free 
survival benefit [18]. Irinotecan has also been studied in the adjuvant setting with 5-FU.  
However, when added to the historical standard, 5-FU, in the adjuvant setting, irinotecan-
based chemotherapy offered no benefit [19-21].   
As there is wide practice pattern variation in the number of cycles varying from 2 to 10 
cycles and exact type of chemotherapy (FOLFOX/Bev, FOFLOX, FOLFIRI, FOLFOXIRI, or 
FOLFIRI/cetuximab) that is given prior to CRC liver resection this study will not require a 
certain type or duration of therapy prior to liver resection.  In part this variation exists as 
patients may have multiple liver relapses and thus treatments utilized may be adjusted 
based upon prior chemotherapy exposure of the patient.  As oxaliplatin based therapies are 
the most common type, in order to maintain homogeneity in patient population at least 
75% of patients will be required to have had prior oxaliplatin-based neoadjuvant therapy.  
This approach is in line with this study design as a window study prior to liver resection 
where a distinct treatment modality, immune-checkpoint therapy is being explored. 
Following surgical resection, treating physicians may either give Durvalumab or continue 
the prior systemic chemotherapy that was given in the preoperative setting.  
Lung metastectomy for CRC mirrors data for liver resection as no large scale prospective 
clinical trials have been conducted for CRC lung metastectomy.  Based on retrospective 
clinical trials, outcomes for lung metastectomies are similar to what is seen for liver 
metastectomies.  Recently, studies have found the integration of checkpoint blockage into 
the treatment of early-stage and locally advanced NSCLC is safe, tolerable, and has the 
potential to improve outcomes without adding substantial toxicity [22] . As an example, 
Forde et al performed a pilot study to examine the safety and feasibility of the use of 
neoadjuvant nivolumab in 21 Stage I-IIIA resectable NSCLC. The study was designed such 
that treatment would not be considered feasible if the probability that surgery would be 
delayed was 90% or more for more than 25% of the patient. Of 21 planned resections, 20 

 
3 
were completed and there were no surgical delays thus feasibility endpoint was met. 
Similarly safety end point was satisfied with minor grade 3-4 events [23].  
 
 
2.1.2 
Cancer and Immune function 
 
The importance of the immune system in cancer development and progression has been 
recognized during the past decade [24]. Failure of immune surveillance of pre-neoplastic 
lesions and micro-metastases is a key step in cancer development. Chronically 
immunosuppressed individuals show higher rates of cancer. This observation led to the 
hypothesis that sporadic cancers among immunocompetent individuals are likely to be 
minimally immunogenic, allowing for passive escape from immune surveillance. Recent data 
suggests that this may be an oversimplification. Some sporadic tumors are highly 
immunogenic, but actively suppress the local immune environment through production of 
immunosuppressive cytokines [25]. As such, the local tumor environment is likely a highly 
dynamic environment where most tumors grow and metastasize through adaptive 
responses that modulate antitumor immunity. The complexity and redundancy of the 
immune system offers multiple targets that may be manipulated to maximize the body’s 
inherent immune response to a tumor. Immune response may be augmented by directly 
stimulating effector cells, indirectly stimulating effectors by augmenting antigen 
presentation activity or co-stimulation, or by suppressing immunosuppressive factors, cells, 
or messages [26]. 
 
 
2.1.3 
Immune Checkpoint Inhibition 
Tumor-infiltrating lymphocytes (TILs) have the capacity to control the growth of many types 
of cancers [27]. Most tumors show infiltration by TILs, but tumors modulate the local 
microenvironment through expression of inhibitory molecules. Engagement of TIL cell-
surface receptors with these inhibitory ligands leads to a dysfunctional immune response, 
causes T-cell exhaustion, and facilitates tumor progression [28, 29]. Novel monoclonal 
antibodies (mAbs) that block these inhibitory receptors have shown significant clinical 
activity across a number of tumor types [30-34]. Specifically, blockade of immune-
checkpoint inhibitors such as cytotoxic T-lymphocyte associated antigen 4 (CTLA-4), 
programmed cell death 1 (PD-1), and programmed cell death ligand 1 (PD-L1) have shown 
clinical activity not only in conventionally immune-responsive tumors such as melanoma 
and renal cell carcinoma but also in non-small-cell lung cancer (NSCLC) [33-35], prostate 
cancer [36, 37], pancreatic cancer [38], mesothelioma [39], and other solid tumors [33, 35]. 
 
2.2  
Investigational Agents-Durvalumab 
 
2.2.1 Durvalumab (MEDI4736) Background 
Durvalumab also called MEDI 4736 is a human immunoglobulin G (IgG)1 kappa mAb 
directed against human PD-L1. Durvalumab is expressed in Chinese hamster ovary cells and 

 
4 
has an overall molecular weight of approximately 149 kDa. Durvalumab6 selectively binds 
human PD-L1 with high affinity and blocks its ability to bind to PD-1 and CD80. 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) [40]. 
 
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 [41-47]. 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 [45, 48]. 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 
[49-54]. 
 
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. 
• 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 

 
5 
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 and tremelimumab, either 
alone or in combination, did not induce cytokine release in blood from any donor. 
 
2.2.3 Durvalumab Clinical Experience 
Study CD-ON-MEDI4736-1108 is a Phase 1, first-time-in-human, multicenter, open-label, 
dose-escalation, and dose-expansion study to determine the maximum tolerated dose 
(MTD) or optimal biologic dose, safety, PK, immunogenicity, and antitumor activity of 
Durvalumab in adult subjects with advanced solid tumors refractory to standard therapy or 
for which no standard therapy exists. As of 18Feb2014, a total of 198 subjects have been 
treated with at least 1 dose of Durvalumab (ranging from 1 to 27 doses). Of these subjects, 
177 have received Durvalumab 10 mg/kg every 2 weeks (Q2W) in either the dose-escalation 
or dose-expansion phase. In addition, 21 subjects have been enrolled in the following dose-
escalation cohorts: 4 subjects in each of the 0.1, 0.3, and 1.0 mg/kg Q2W cohorts, 3 subjects 
in the 3.0 mg/kg Q2W cohort, and 6 subjects in the 15 mg/kg every 3 weeks (Q3W) cohort. 
 

 
6 
In the 177 subjects who received Durvalumab 10 mg/kg Q2W, the most frequently reported 
treatment-emergent adverse events (TEAEs) in subjects treated with 10 mg/kg Durvalumab 
Q2W regardless of grade or causality (≥ 10% incidence) were fatigue (24.3%), dyspnea 
(17.5%), nausea (13.6%), constipation (10.7%), and decreased appetite (10.2%). The 
majority of TEAEs were Grades 1 or 2 in severity and manageable by the general treatment 
guidelines as described in the current Durvalumab study protocols. Treatment-related 
TEAEs (all grades) occurring in 5 or more subjects were fatigue (11.3%), nausea (5.6%), 
dyspnea (4.0%), diarrhea (3.4%), vomiting (3.4%), pyrexia (3.4%), and myalgia (2.8%). 
Serious adverse events (SAEs) reported for 3 or more subjects were dyspnea, dehydration, 
abdominal pain, and sepsis.  For the entire study population, none of the deaths in this 
study were considered related to Durvalumab. As of the data cutoff date of 18Feb2014, 
TEAEs resulting in discontinuation of Durvalumab have been reported for 13 subjects 
treated with Durvalumab 10 mg/kg Q2W (subjects could have more than one TEAE resulting 
in discontinuation). The TEAEs seen in 2 or more subjects resulting in discontinuation of 
subjects were: dyspnea (4 subjects), respiratory failure (2 subjects), “progression of disease” 
(verbatim term, 2 subjects). In addition, 1 subject in the 0.3 mg/kg Q2W cohort 
discontinued Durvalumab treatment due to a TEAE of pneumonia. All were Grade 3 or 
higher with the exception of the event of pneumonia. None of the TEAEs resulting in 
discontinuation of Durvalumab were considered related to Durvalumab by the investigator. 
No dose-limiting toxicities (DLTs) have been reported. Partial efficacy data are available as 
of 18Feb2014. Of the 177 subjects treated with Durvalumab 10 mg/kg Q2W, 77 subjects 
had at least 1 post-baseline disease assessment. Four subjects (5.2%) had a best response of 
partial response (PR; unconfirmed) assessed by Response Evaluation Criteria in Solid Tumors 
(RECIST) guidelines v1.1 with modifications. In addition, 36 subjects (46.8%) had stable 
disease (SD). Twelve of the 15 subjects in the 0.1, 0.3, 1.0, and 3.0 mg/kg Q2W dose-
escalation cohorts had at least 1 post-baseline disease assessment as of 18Feb2014. Four 
subjects had a best response of PR (3 confirmed and 1 unconfirmed) as assessed by 
immune-related response criteria (irRC) [30] with 2 subjects each in the 0.3- and 1.0-mg/kg 
cohorts. 
 
As of 18 Feb 2014, PK and pharmacodynamic data were available for the first 32 subjects 
following IV dosing of Durvalumab. Durvalumab exhibited nonlinear PK likely due to 
saturable target-mediated clearance. Significant target engagement, as measured by sPD-L1 
suppression, was observed following dosing in all subjects tested. Screening for ADA has 
detected positive samples from 3 of the 31 subjects tested, with evidence for an impact on 
PK and target suppression in 1 subject. 
 
Study D4190C00002 is a Phase 1 study of Durvalumab in Japanese subjects with advanced 
solid tumors. At present, durvalumab has been administered as mono- or combination 

 
7 
therapy with other anti-cancer agents to more than 6000 patients as part of ongoing 
studies. Section 6.5 contains details on the safety profile of durvalumab monotherapy. 
 
Further information on durvalumab safety, efficacy, and pharmacokinetics is provided in the 
latest Investigator Brochure (v12). 
 
2.3  
Investigational Agents-Tremelimumab 
 
 
2.3.1 Tremelimumab Background 
Tremelimumab (formerly CP-675,206) is a human IgG2 mAb being investigated as a cancer 
immunotherapeutic agent. Tremelimumab is expressed in NS0 (murine myeloma) cells and 
has an overall molecular weight of approximately 149 kDa. Tremelimumab is specific for 
human CTLA-4, with no cross-reactivity to related human proteins. Tremelimumab blocks 
the inhibitory effect of CTLA-4, and therefore enhances T-cell activation. Tremelimumab 
shows minimal specific binding to Fc receptors, does not induce natural killer (NK) ADCC 
activity, and does not deliver inhibitory signals following plate-bound aggregation. 
 
2.3.2 Tremelimumab Pre-Clinical Experience 
Cytotoxic T-lymphocyte-associated antigen 4 (CD152) is a cell-surface receptor expressed 
primarily on activated T cells. Cytotoxic T-lymphocyte-associated antigen 4 engagement on 
activated T cells inhibits cytokine synthesis and restricts cell proliferation [55-58]. Upon T-
cell activation, CTLA-4 expression is upregulated and acts to dampen immune responses, 
modulating and eventually switching off T-cell activation. The natural ligands for CTLA-4 are 
CD80 and CD86, which are present on antigen-presenting cells (APCs). Binding of these 
ligands to CTLA-4 delivers a negative regulatory signal to T cells. 
 
Tremelimumab selectively binds to human CTLA-4 and blocks binding of CD80 and CD86 
and has been shown to enhance human T-cell cytokine release in response to stimulation. 
Both in vitro and in vivo preclinical data suggest that a range of anti-CTLA-4 mAb 
exposures has the potential to be efficacious, the lower end of the potentially efficacious 
range being a plasma concentration of approximately 10 μg/mL and the target plasma 
concentration being 30 μg/mL. The toxicology program conducted for tremelimumab 
consisted of in vivo general toxicology studies in cynomolgus monkeys for up to 6 months 
duration, an embryo-fetal development study in monkeys, tissue cross-reactivity studies in 
both monkey and human tissues, and blood compatibility studies. Overall, tremelimumab 
toxicities were consistent with inhibition of CTLA-4 and with clinical safety findings, and 
indicated that chronic clinical use of tremelimumab may lead to adverse effects on the 
gastrointestinal tract, skin, lymphoid organs, thyroid tissues, and hematologic systems. 
Clinical dose-limiting toxicity (DLT; eg, gastrointestinal effects) and non-DLT (eg, skin 

 
8 
rash) were appropriately identified in a chronic toxicity study in monkeys. Most toxicities 
were reversible or showed a trend towards reversibility. 
 
An embryo-fetal development study was conducted in pregnant cynomolgus monkeys 
during the period of organogenesis. Tremelimumab administered intravenously (IV) once 
weekly from Days 20 to 50 of gestation at doses of 0, 5, 15, or 30 mg/kg did not elicit 
maternal toxicity, developmental toxicity, or teratogenicity. 
 
2.3.3 Tremelimumab Clinical Experience 
As of the data cutoff date of 30 Aug 2013, 15 sponsored clinical studies have been 
conducted as part of the tremelimumab clinical development program. Of these studies, 13 
have been completed and 2 are ongoing. Tremelimumab has been administered as 
monotherapy to subjects participating in 10 of the 15 clinical studies, 2 of which are 
ongoing. In total, 973 subjects with a variety of tumor types have been treated with 
tremelimumab monotherapy in the completed studies. Most of these subjects had 
melanoma and received the tremelimumab 15 mg/kg every 90 days dosing regimen. An 
additional 204 subjects (as of 07 Apr 2014) have been treated in the ongoing Phase 2b 
mesothelioma study, D4880C00003. In addition, 116 subjects with a variety of tumor types 
have received tremelimumab in combination with other anticancer agents in 5 of the 15 
clinical studies. 
 
Across the clinical development program for tremelimumab a pattern of efficacy has 
emerged, also observed for the related anti-CTLA-4 antibody, ipilimumab, which appears to 
be consistent across tumor types for this class of agents. Response rates to anti-CTLA-4 
antibodies are generally low, approximately 10%. However, in subjects who respond, the 
responses are generally durable, lasting months to years even in subjects with aggressive 
tumors, such as, refractory metastatic melanoma. Some subjects may have had progression 
of their disease early during treatment, with delayed tumor response or disease 
stabilization. Tremelimumab has been tested in a Phase 3 study for advanced melanoma. 
Although the study failed to demonstrate improved overall survival (OS; primary endpoint) 
following a prespecified interim futility analysis, the final analysis showed a median OS of 
12.6 months in the tremelimumab arm and 10.7 months in the dacarbazine/temozolomide 
arm. The ongoing Phase 2b study in recurrent pleural or peritoneal malignant mesothelioma 
is testing an alternative dosing schedule of tremelimumab with a dose of 10 mg/kg Q4W to 
maximize exposure to tremelimumab while managing safety according to the established 
anti-CTLA-4 AE management guidelines. The 10 mg/kg Q4W regimen is also being tested in 
an ongoing Phase 2 investigator-sponsored study in malignant mesothelioma 
(NCT01655888). In clinical subjects, tremelimumab exhibits linear (dose-proportional) PK 
following IV infusion. The estimate of clearance, volume of distribution at steady state, and 

 
9 
terminal-phase half-life is 0.132 mL/h/kg, 81.2 mL/kg, and 22.1 days, respectively. These 
values are consistent with those of natural IgG2. 
 
The profile of AEs and the spectrum of event severity have remained stable across the 
tremelimumab clinical program and are consistent with the pharmacology of the target. To 
date, no tumor type or stage appears to be associated with unique AEs (except for vitiligo 
that seems to be confined to subjects with melanoma). As of the data cutoff date of 
30Aug2013, events reported in the tremelimumab monotherapy studies at a frequency > 
5% and assessed by the investigator as treatment related were diarrhea (41.2%), rash 
(27.2%), pruritus (25.1%), fatigue (23.8%), nausea (21.9%), vomiting (13.5%), decreased 
appetite (11.3%), headache (7.2%), pyrexia (7.0%), abdominal pain (6.7%), and colitis (5.5%). 
The events of diarrhea, rash, and pruritus are considered as identified risks. Infusion-related 
side effects are rare. Acute renal failure was reported in subjects who received the 
combination of tremelimumab and sunitinib in a Phase 1 study; however, acute renal failure 
has not been an expected AE for single-agent tremelimumab. The incidence and/or severity 
of many of the AEs observed following administration of tremelimumab can be reduced by 
adherence to current immune-related toxicity management guidelines. 
 
At present, tremelimumab has been administered as mono- or combination therapy with 
other anti-cancer agents to more than 1500 patients as part of ongoing studies. 
Section_contains details on the safety profile of tremelimumab monotherapy. Further 
information on tremelimumab safety, efficacy and pharmacokinetics is provided in the 
Investigator Brochure. 
 
 
 
2.3.4 Combination Therapy Clinical Experience 
Study D4190C00006 is a dose-escalation and dose-expansion study of Durvalumab in 
combination with tremelimumab in subjects with advanced NSCLC. This study explored 
multiple dosing schedules and established Cohort 1 Q4W as the optimal dosing schedule of 
the Durvalumab and tremelimumab combination.  This schedule, 20 mg/kg Durvalumab + 1 
mg/kg tremelimumab, will be used in this study.  Subjects enrolled in the D4190000006 
study at the 20 mg/kg Durvalumab + 1 mg/kg tremelimumab dose administered Q4W have 
cleared the dose-limiting toxicity (DLT) evaluation period without identification of an MTD.  
At present, the combination has been administered to more than 3000 patients using 
various doses and dosing schedules. 
 
Subjects with histologically or cytologically confirmed locally advanced or metastatic NSCLC, 
with at least one measurable lesion, with adequate organ and marrow function, and with 
Eastern 

 
10 
Cooperative Oncology Group (ECOG) performance status of 0-1 are eligible. Subjects cannot 
have had more than 3 prior lines of therapy in the metastatic setting including standard of 
care. 
 
 
2.3.5 Potential Risks of Durvalumab + Tremelimumab in the Relevant Indication 
 
Overall risks 
 
Monoclonal antibodies may target several immune checkpoint proteins. These include 
programmed cell death ligand 1 (PD-L1), programmed cell death-1 (PD-1) or cytotoxic T-
lymphocyte antigen-4 (CTLA-4). The anticipated result is an enhanced endogenous immune 
responses directed against tumor cells. However, there is the likelihood for adverse effects on 
other tissues as a consequence of stimulating the immune system. 
Adverse drug reactions most seen with the immune checkpoint inhibitor class of agents are 
likely an outcome of the effects of inflammatory cells on specific tissues. These are generally 
events with a potential inflammatory or immune mediated mechanism and which may require 
more frequent monitoring and/or unique interventions such as immunosuppressants and/or 
endocrine therapy. Almost any organ system is susceptible to these immune mediated effects, 
and are most commonly seen as gastrointestinal AEs such as colitis and diarrhoea, 
pneumonitis/interstitial lung disease (ILD), hepatic AEs such as hepatitis and liver enzyme 
elevations, skin events such as rash and dermatitis and endocrinopathies including hypo- and 
hyper-thyroidism. 
 
Durvalumab 
 
The following are some risks associated with durvalumab: diarrhea/colitis and intestinal 
perforation, pneumonitis/ILD, endocrinopathies (hypo- and hyper-thyroidism, type I diabetes 
mellitus, hypophysitis and adrenal insufficiency) hepatitis/increases in transaminases, 
nephritis/increases 
in 
creatinine, 
pancreatitis/increases 
in 
amylase 
and 
lipase, 
rash/pruritus/dermatitis, myocarditis, myositis/polymyositis, other rare or less frequent 
inflammatory events including neurotoxicities, infusion-related reactions, hypersensitivity 
reactions and infections/serious infections.  
 
Please refer to the current version of the durvalumab IB for information on all identified and 
potential risks with the drug. 
 
In monotherapy clinical studies AEs (all grades) reported very commonly (≥ 10% of patients) 
are fatigue, nausea, decreased appetite, dyspnea, cough, constipation, diarrhea, vomiting, back 
pain, pyrexia, asthenia, anemia, arthralgia, peripheral edema, headache, rash, and pruritus. 
Approximately 9% of patients experienced an AE that resulted in permanent discontinuation 
of durvalumab and approximately 6% of patients experienced an SAE that was considered to 
be related to durvalumab by the study investigator. 
 
The majority of treatment-related AEs were manageable with dose delays, symptomatic 
treatment, and in the case of events suspected to have an immune basis, the use of established 
treatment guidelines for immune-mediated toxicity (please see Section 7.7). 
 

 
11 
A detailed summary of durvalumab monotherapy AE data can be found in the current version 
of the durvalumab IB. 
 
Tremelimumab 
 
The following are some risks associated with tremelimumab monotherapy: GI effects (colitis, 
diarrhoea, enterocolitis and intestinal perforation), endocrine disorders (hypo and 
hyperthyroidism, hypophysitis and adrenal insufficiency), skin effects (rash, and pruritus), 
elevations in lipase and amylase and clinical manifestations of pancreatitis, other 
gastrointestinal events e.g. ulcerative colitis, dehydration, nausea and vomiting; hepatic events 
including hepatitis, and liver enzyme elevations; pneumonitis and ILD; nervous system events 
including encephalitis, peripheral motor and sensory neuropathies, Guillain-Barre and 
proximal muscle weakness; cytopenias including thrombocytopenia, anemia and neutropenia; 
infusion-related reactions, anaphylaxis, and allergic reactions; renal events including renal 
failure, acute kidney injury, nephritis, nephrotic syndrome, autoimmune nephritis and 
electrolyte abnormalities such as hypokalemia; autoimmune diseases including autoimmune 
arthritis, Sjogren's syndrome and giant cell temporal arteritis; hyperglycemia and diabetes 
mellitus; and pyrexia.  
 
Please refer to the current version of the tremelimumab IB for information on all identified and 
potential risks with the drug.  
 
Using pooled data from monotherapy clinical studies AEs (all grades) reported very commonly 
(≥ 10% of patients)  were diarrhea, nausea, fatigue, pruritus, decreased appetite, rash,  
vomiting, dyspnea, constipation, cough, pyrexia, abdominal pain, decreased weight, headache, 
asthenia, and anemia. Approximately 16% of patients experienced an AE that resulted in 
permanent discontinuation of tremelimumab and approximately 45% of patients experienced 
an SAE. 
 
Further information on these risks can be found in the current version of the tremelimumab 
IB. 
 
A detailed summary of tremelimumab monotherapy AE data can be found in the current 
version of the tremelimumab IB.  
 
Durvalumab + tremelimumab  
The safety of durvalumab + tremelimumab combination therapy was initially evaluated in the 
ongoing dose escalation and dose expansion Study 006, in patients with NSCLC, and is being 
studied in a number of other ongoing clinical trials, in a number of different indications, and 
has to date shown a manageable safety and tolerability profile.   
 
The types of risks with the combination of durvalumab + tremelimumab (based on an 
equivalent durvalumab dose of 20m/kg and a tremelimumab dose of 1mg/kg) are similar to 
those for durvalumab and tremelimumab monotherapy. Emerging data from study 006, other 
studies evaluating the combination, and from combinations of other agents in the same class 
indicate an increased frequency and/or severity of some of these immune-mediated toxicities. 

 
12 
For information on all identified and potential risks with the durvalumab+tremelimumab 
combination please always refer to the current version of the durvalumab IB. 
 
In durvalumab+tremelimumab combination studies at the dose of durvalumab 20mg/kg and 
tremelimumab 1mg/kg AEs (all grades) reported very commonly (≥ 10% of patients) are 
fatigue, diarrhea, nausea, dyspnea, decreased appetite, pruritus, vomiting, anemia, 
constipation, cough, abdominal pain, pyrexia, back pain, arthralgia, hypothyroidism, asthenia, 
oedema peripheral, weight, decreased hyponatraemia and rash.  
Approximately 15% of patients experienced an AE that resulted in permanent discontinuation 
of study drug and approximately 15% of patients experienced an SAE that was considered to 
be related to durvalumab and tremelimumab by the study investigator. 
 
A detailed summary of durvalumab + tremelimumab combination AE data can be found in the 
current version of the durvalumab IB. 
 
 
2.4  
Investigational Agents-Monolizumab 
 
2.4.1 
Monolizumab Background 
 
Monalizumab is a humanized monoclonal antibody (mAb) of the immunoglobulin G4 (IgG4) 
subtype, that specifically binds and blocks the inhibitory receptor CD94/NKG2A (a 
heterodimer complex between CD94 and natural killer (NK) group 2 member A), which is 
mainly expressed on subsets of NK cells and CD8+ T cells.  
 
The CD94/NKG2A receptor is found on peripheral NK cells and subsets T cells in healthy 
volunteers as well as in patients with hematologic and solid malignancies. It is also present 
in tumor infiltrating NK and cytotoxic T cells in a number of solid tumors (including renal cell 
carcinoma, non-small cell lung cancer, cancer of the tongue, breast cancer, malignant 
melanoma, and endometrial, ovarian and cervical cancers).  
 
CD94/NKG2A is a receptor for human leukocyte antigen E (HLA-E), a non-classic, major 
histocompatibility complex (MHC), class I molecule expressed on the cell surface of most 
leukocytes and large variety of transformed cells (viruses infected cells, inflammatory cells 
and malignant cells). HLA-E is expressed or over-expressed on human leukemic blasts in 
acute myeloblastic leukemia (AML), acute lymphoblastic leukemia (ALL) and chronic 
lymphocytic leukemia (CLL) patients, as well as in human solid cancers such as colon 
adenocarcinoma, ovarian adenocarcinoma, malignant melanoma and esophagus squamous 
cell carcinoma. When engaging with the ligand HLA-E, the CD94/NKG2A receptor on NK cells 
and CD8+ T cells transduces inhibitory signals that suppress effector functions, such as 
cytotoxicity. This mechanism is relevant to HLA-E expressing hematological malignancies 
and solid tumors.  
 
Blockade of the inhibitory signaling mediated by CD94/NKG2A receptor has the potential of 
restoring the ability of peripheral and tumor-infiltrating NK cells or cytotoxic CD8+ T cells to 
kill HLA-E expressing tumor cells. 

 
13 
 
 
 
2.4.2 
Monolizumab Pre-Clinical Experience 
 
The pharmacological, pharmacokinetic (PK) and toxicological properties of monalizumab 
have been investigated in the nonclinical development program, which consisted of both in 
vitro and in vivo studies. The initial studies included selection, cloning and characterization 
of the drug substance, as well as examinations of the pharmacological effect of 
monalizumab. Species-selection studies identified the cynomolgus monkey to be the most 
relevant species for nonclinical assessment of monalizumab, which exhibited binding to 
lymphocytes only in humans and monkeys.  
 
Monalizumab is also being developed in combination with ibrutinib in CLL, with cetuximab 
in Squamous Cell Carcinoma of the Head and Neck (SCCHN), and with durvalumab in various 
solid tumors.  
 
Data from nonclinical studies show that B-CLL cells express HLA-E in all patients tested by 
immunohistochemistry (n=7) and by flow cytometry (n=12); functional data indicate that 
monalizumab stimulates NK cell-mediated killing of transformed B cells and of CLL 
malignant cells obtained from CLL patients in vitro and in vivo.  
 
In vitro efficacy data of the combination of monalizumab and cetuximab show that: (1) 
monalizumab induces increased CD107 mobilization and CD137 expression on NKG2A+ NK 
cells suggesting the NK cell-mediated lysis of HLA-E expressing cell lines by blocking the 
interaction of the inhibitory receptor CD94/NKG2A with HLA-E; (2) monalizumab enhances 
cetuximab–mediated Antibody Dependent Cell Cytoxicity (ADCC) in concentration-
dependent manner.  
 
A nonclinical study combining NKG2A and PD-1 checkpoint inhibitors in in vivo model of PD-
L1 expressing solid tumors demonstrated enhanced anti-tumor activity, supporting the 
rationale for the clinical trial testing the combination with monalizumab and durvalumab 
(anti-PD-L1). 
The nonclinical safety profiling of monalizumab has not identified any safety issues. To 
address specific theoretical, acute safety pharmacological effects, monalizumab was tested 
in various human in vitro biological assays. These assays identified no non target-related or 
potentially target-related safety issues. No toxicities were observed in cynomolgus monkeys 
after 13 weeks of dosing of up to 150 mg/kg weekly. The highest dose (150 mg/kg) resulted 
in approximately 18 weeks of full CD94/NKG2A receptor saturation. In humans, 
monalizumab binds selectively to CD94/NKG2A receptors. In monkeys, monalizumab binds 
with equal affinity to the activating CD94/NKG2C receptor in addition to the inhibitory 
CD94/NKG2A receptor. This is most likely the reason why it has been impossible to observe 
effects comparable to those seen in human in functional in vitro assays with cynomolgus vs 
human cells. Further risk assessment of long-term blocking of the CD94/NKG2A receptor 
was therefore performed with a surrogate anti-mouse NKG2A antibody that has been used 

 
14 
to demonstrate in vitro anti-tumor efficacy with mouse cells. In toxicology studies, mice 
were dosed s.c. every second day for up to 26 weeks at doses up to 50 mg/kg. As with the 
cynomolgus monkey studies, the toxicity studies in mice did not identify any safety issues. 
 
In summary, monalizumab specifically binds and blocks the CD94/NKG2A receptor 
expressed on subsets of NK cells and CD8+ T cells leading to increased anti-tumor activities 
including cytotoxicity against HLA-E expressing tumor cells without impairing normal and 
resting cells. Monalizumab holds promises for a future treatment of HLA-E expressing 
hematologic malignancies and solid tumors by activating immune-responses in different 
subsets of cytotoxic lymphocytes. Safety pharmacology studies have not raised any safety 
concerns that would preclude further progression of the clinical investigation of 
monalizumab in patients suffering from cancer. 
 
2.4.3 Monolizumab Clinical Experience 
 
The safety and tolerability as well as single-dose and multiple-dose pharmacokinetic (PK) 
and pharmacodynamic (PD) properties of monalizumab were initially investigated in 
patients with active rheumatoid arthritis (RA) (NN8765-3658 trial). In this first trial 
(completed), the maximum tested levels were 10 mg/kg during intravenous (i.v.) infusion 
and 4.0 mg/kg following subcutaneous (s.c.) administrations (in single and multiples doses 
(MD)), with a good safety profile.  
 
Monalizumab is now being developed in patients with various hematologic malignancies 
and solid tumors in monotherapy or in combination with some other drugs. A total of 190 
patients have been treated with monalizumab: 68 out of 92 patients in the phase 1 in RA 
and 122 patients in 6 hematology/oncology trials.  
 
One study was terminated (IPH2201-201) and 5 other studies are ongoing.  
• _IPH2201-201 is a monotherapy, open label single arm phase 1b/2 study, assessing the 
pre-operative administration of monalizumab in patients with locally advanced 
resectable squamous cell carcinoma of the oral cavity. This study was terminated on 26-
Nov-2016 due to slow recruitment and strategic reasons and not due to any safety 
concerns.  
• _IPH2201-202 is an open label phase 1b/2a trial of a combination of monalizumab and 
ibrutinib in patients with relapsed, refractory or previously untreated CLL.  
• _IPH2201-203 is a phase 1b/2 trial of a combination of monalizumab and cetuximab in 
patients with HPV (+) and HPV (-) recurrent or metastatic SCCHN.  
• _IND.221 is an Investigator Sponsored Study (ISS) conducted by the Canadian Cancer 
Trials Group (CCTG). This is a dose-ranging study of monalizumab in patients with 
gynecologic malignancies (ovarian, endometrial and cervical cancer).  

 
15 
• _D419NC0001 is conducted by AstraZeneca/MedImmune. This is a phase 1 in solid 
tumors testing the combination of durvalumab (anti-PD-L1) and monalizumab.  
• _PIRAT-IPC 2015-018 is an Investigator Sponsored Study (ISS) conducted by a French 
anticancer institute “Paoli Calmettes Institute” in France. This is an open label phase 1 
dose ranging study testing single dose of monalizumab in patients following HLA 
matched allogeneic hematopoietic stem cell transplantation (allo-HSCT).  
 
 
 
2.4.3.1 Clinical pharmacokinetics  
Final PK data of the first phase 1 study conducted with monalizumab in RA and 
preliminary PK data from the IND.221 trial (part 1) in gynecological malignancies are 
presented in the Investigator Brochure.  
The pharmacokinetics of monalizumab was originally evaluated in a first phase 1 study 
conducted in RA. The PK of monalizumab was as expected for a monoclonal antibody 
that binds to a membrane-bound target, which expression is restricted to a small subset 
of immune cells, and which Ab does not demonstrate intracellular internalization.  
 
The PK of monalizumab was similar in RA patients and gynecologic cancer patients 
(IND.221 part 1 study). In patients with gynecologic malignancies (ovarian, endometrial 
and cervical cancer), the PK of monalizumab was dose proportional across the entire 
dose range (1-10 mg/kg). There was a 1.4-2 fold accumulation of monalizumab after the 
administration of four intravenous doses, which was consistent with administration 
frequency and the half-life of 2-3 weeks seen with single dose i.v. dosing in RA patients 
at similar doses.  
 
2.4.3.2 Clinical pharmacodynamics  
Final PD data of the first phase 1 study conducted with monalizumab in RA and 
preliminary PD data from the IND.221 trial (part 1) in gynecological malignancies are 
presented in the Investigator Brochure.  
In the first study conducted in RA, levels of CD94/NKG2A receptor occupancy were 
detectable for all patients treated with single i.v. or s.c. or multiple s.c. doses of 
monalizumab. Rapid (within 0.5−1 hour and 4-8 hours post i.v. and s.c. administration 
respectively) and high level of receptor occupancy was reached at monalizumab single 
i.v. dose of 0.005 mg/kg and above and at single s.c. dose of 0.1 mg/kg and above. A 
clear dose–response relationship was observed as increasing doses of monalizumab 
resulted in both increasing CD94/NKG2A receptor occupancy and increasing duration of 
receptor occupancy.  
 
A high CD94/NKG2A receptor occupancy was sustained on average for 2 weeks for 
doses above 0.4 mg/kg after single i.v. administration and 1.1 mg/kg after single s.c. 
administration and for less than 10 weeks after multiple s.c. administrations at dose 4 
mg/kg.  
The CD94/NKG2A receptor occupancy profiles for the first 14 days after single and 
multiple administrations of doses of 0.005 mg/kg, 0.025 mg/kg, 0.1 mg/kg and 0.4 
mg/kg of monalizumab appeared similar considering the inter-individual variability in 
the receptor saturation assay. In the part 1 of the IND.221 trial in gynecological 

 
16 
malignancies, full NKG2A saturation was achieved from the first administration (Cycle 
1, D1, H2) in all the patients at all dose levels (1, 4 and 10 mg/kg, 6 patients per dose 
level). 
 
2.4.3.3 Clinical safety  
Safety data from the phase 1 trial in patients with RA were based on total of 92 patients 
treated with monalizumab single dose i.v. up to 10 mg/kg or single dose or multiple 
doses, s.c. up to 4 mg/kg or placebo (monalizumab: 68; placebo: 24). No death, no Dose-
Limiting Toxicity (DLT), no Suspected Unexpected Serious Adverse Reaction (SUSAR), no 
grade 4 Adverse Event (AE) and no adverse event leading to treatment withdrawal were 
reported. No infusion related reaction or immune related disorder was observed. No 
Serious Adverse Event (SAE) related to study treatment was reported. Only 4 Grade 3 
AEs, all considered as unrelated to the study treatment, occurred in the monalizumab 
treated patients. Most of the AEs were mild (142 AEs) or moderate (61 AEs) in intensity, 
self-limiting and manageable. The two2two most frequent AEs were nasopharyngitis 
and headache. Three subjects developed treatment-related Anti-Drug Antibodies (ADA) 
at a low titer; one was in vitro neutralizing (patient in the dose level 1.1 mg/kg single 
dose, i.v.), whereas the other two showed no neutralizing capacity (one patient in the 
dose level 0.4 mg/kg single dose and one patient in the dose level 0.4 mg/kg MD, s.c.).  
 
In hematology/oncology trials, 122 patients have been treated up to 10 mg/kg multiple 
doses i.v. Most of the reported AEs were of grade 1-2. Only 9% of events are of grade 3 
or higher. Sixteen (16)% of all events were considered as related to study treatment, 
with less than 1% related event of grade 3-4. There was no obvious dose relationship for 
adverse events.  
The most frequent (> 5%) adverse events considered related to monalizumab were 
headache, asthenia/fatigue, nausea, vomiting, diarrhea, anorexia/decreased appetite, 
rash/erythema and myalgia.  There were 4 SAEs related to study treatment: asthenia 
(grade 2), nausea (grade 3) combined with vomiting (grade 3), infusion related reaction 
(grade 2).  There was no death related to treatment. In the IND.221 study in 
gynecological indications, six subjects developed treatment-related low ADA response at 
least at one time point. No impact was detected on exposure in all these patients.  
 
The safety data obtained up to date do not change the overall safety or risk/benefit 
profile of monalizumab; the data support the continuation of the clinical development 
of monalizumab for the treatment of various malignancies as monotherapy and 
combination therapy. 
 
2.4.4 Combination Therapy Clinical Experience and Rationale 
 
 
On ongoing phase clinical trial (NT02671435, D419NC0001) is a phase 1 in solid tumors that 
has determined the recommended phase II dosing for the combination of durvalumab (anti-
PD-L1) and monalizumab.  This combination was shown to be safe and was expanded in 
cohort of CRC patients and demonstrated anti-tumor responses.  As of 28-Apr-2017, 12 

 
17 
patients had been treated in the trial in escalation part and had received 22.5 mg,75 mg, 
225 mg, or 750 mg of monalizumab q2w in combination with 1500 mg of durvalumab q4w. 
Another cohort of 3 patients received 750 mg of monalizumab q4w with durvalumab 1500 
mg q4w. Fourteen (14) patients received 750 mg of monalizumab q2w with durvalumab 
1500 mg q4w in extension part.  
One hundred thirty (130) AEs were reported in 26 patients. Most of AEs were Grade 1 or 2, 
only 10 were Grade 3 and 2 were Grade 4 (dehydration, hyponatremia). Twenty-three (23) 
AEs were considered as related to monalizumab and were all Grade 1-2.  
 
- Seven SAEs were reported in 4 patients: one grade 4 dehydration and 6 grade 3 SAEs 
(abdominal pain, ascites, hematochezia, pleural effusion, sepsis, hydronephrosis). None of 
them were related to study drug. There were no AE leading to treatment withdrawal.  
- No death occurred at time of this report.  
 
 
HLA-E is expressed in 81% to 82% of patients with colorectal carcinoma (internal data in file) 
(9). Over-expression of HLA-E correlates with a poor outcome in colorectal carcinoma (9).  
Binding of HLA-E to CD94/NKG2A induces inhibitory signals which suppress the cytokine 
secretion and direct cytotoxicity of lymphocytes against malignant cells. This mechanism 
may play a significant role in the immune escape of tumor cells (10), (11). NK cells 
overexpressing CD94/NKG2A in the peripheral blood of patients with hematological 
malignancies transplanted with hematopoietic cells from allogeneic donors, or infiltrating 
solid tumors are usually dysfunctional (12), (13), (14), (15).  
 
By suppressing the inhibitory signal transduced by CD94/NKG2A, monalizumab enhances 
the anti-tumor functions, including cytolytic activity of these immune effector cells, as 
shown ex vivo and in vivo in several experimental models described in Section 4. 
Furthermore, it has to be emphasized that ADCC mediating at least partly the anti-tumor 
effect of cytotoxic mAbs widely used in oncology is mainly supported in human by NK cells. 
Interestingly cetuximab-induced ADCC on NK cells is inhibited by HLA-E expression and this 
inhibition can be circumvented with CD94/NKG2A blockade (16). 
 
 
2.5  Investigational Agents- Oleclumab 
 
2.5.1 Oleclumab Background 
 
Oleclumab, also known as MEDI9447, is a human immunoglobulin G1 lambda (IgG1λ) mAb 
that is expressed in Chinese Hamster Ovary cells. It specifically binds and inhibits CD73 
ectonucleotidase activity, an enzyme catalyzing adenosine and organic phosphate 
production from adenosine monophosphate (AMP), which leads to inhibition of T-cell 
receptor activation through increased extracellular adenosine. Oleclumab decreases 
expression of CD73 by internalizing the receptor and causing shedding of the extracellular 
domain. It has a triple mutation within the heavy chain constant region that decreases 

 
18 
immunoglobulin G (IgG) effector function, thereby resulting in an increase in anti-tumor 
immunity. 
 
 
2.5.2 Oleclumab Pre-Clinical Experience 
CD73 is a receptor located on tumor cells, endothelial cells and some leukocytes. Its 
ectonucleotidase activity allows increased extracellular adenosine which inhibits T-cell 
receptor activation by binding receptors and triggering cyclic AMP signaling. It thus serves a 
regulatory role in B and T lymphocyte function. Additionally, this activity within the tumor 
microenvironment creates an “immunosuppressive halo” that limits antitumor immunity, 
downregulates phagocytosis, and increases pro-angiogenic factors, among other effects . 
Binding of oleclumab to the N-terminal domain of CD73 causes non-competitive inhibition 
by preventing structural conversion to the active, closed state.  
 
Oleclumab has shown the following activity in non-clinical studies (see Investigator’s 
Brochure): 
• After incubation of human mammary carcinoma (MDA-MB-231) with Oleclumab, 
assessment by flow cytometry demonstrated 73% reduction in cell surface expression of 
CD73, suggesting shedding or internalization of the molecule after drug binding (Report 
ONC94470002). 
• In human in vitro studies, Oleclumab impedes dephosphorylation of AMP and 
conversion to adenosine by CD73 was decreased in a dose dependent manner. 
• In vitro models exhibit anti-CD73 antibody binding to CD73 can limit production of 
adenosine and the regulatory effect on T-cell function. 
• Balb/C, syngeneic, CT26 colon carcinoma tumor model mice demonstrated >= 50% 
inhibition of tumor growth from day 7 – day 16 with intraperitoneal treatment of 
Oleclumab.  
• In the same study, tumors harvested after day 16 showed Oleclumab inhibits myeloid-
derived suppressor cells (MDSCs), which have demonstrated suppression of anti-tumor 
immunity. 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 murine model, the combination of 
Oleclumab and anti-PD-1 treated animals produced 60% tumor-free mice, compared to 
10% tumor-free animals in receiving monotherapy. 
• In another study using MC38-OVA and 4T1.2 pre-clinical mouse models, Oleclumab 
showed syngergistic effect with anti-CTLA4, demonstrated by increased antigen-specific 
CD8+ T cell infiltration within tumors of mice receiving combination therapy.  
 
In general, there were no Oleclumab-related adverse effects in toxicology studies 
conducted in CD-1 [ICR] mice that were of relevance to humans. Adverse findings in the 
Good Laboratory Practice (GLP)-compliant repeat dose toxicity study on cynomolgus 
monkeys (Oleclumab once weekly via a 30-minute IV infusion for 5 weeks), showed no 
adverse changes on clinical or anatomic pathology parameters during the dosing or 
recovery phases. Therefore, the no-observed-adverse-effect level (NOAEL) of Oleclumab in 

 
19 
all the general toxicity studies was considered to be 300.7 mg/kg, the highest dose tested in 
these studies. GLP tissue cross-reactivity study conducted on human tissue cryosections 
showed predicted diffuse immunoreactivity of Oleclumab as CD73 is present in most 
tissues. In the monotherapy dose-escalation phase study, NOAEL in cynomolgus monkeys 
was noted at 300 mg/kg. 
 
 
 
2.5.3 Oleclumab Clinical Experience 
 
The ongoing multicenter, open-label, dose-escalation, dose-expansion study with 
oleclumab (D6070C00001) is a first-time-in-human, phase 1 study, used to model the 
agent’s pharmacokinetics, pharmacodynamics, and clinical safety profile. It was 
administered as a single agent or in combination with durvalumab in adults with selected 
advanced solid tumors. There were 42 and 24 subjects enrolled in the monotherapy and 
combination therapy dose escalation phases, respectively, which were completed by the 
data cut-off on 09 January 2018.  The dose-expansion phase of the study, with combination 
therapy, is ongoing. There are 50 subjects enrolled with diagnoses of CRC (n=21), 
pancreatic adenocarcinoma (n=25), and epidermal growth factor receptor mutant (EGFRm) 
non-small cell lung cancer (NSCLC) (n=4).  
 
2.5.3.1 Clinical Pharmacokinetics 
As of the 09 Nov 2017 data cut-off, preliminary population PK was modelled by means of the 
nonlinear mixed-effects modelling approach (NONMEM). Data was used from 97 subjects after 
receiving 5, 10, 20, and 40 mg/kg Q2W IV doses of Oleclumab as monotherapy (N=40) or 
combination therapy with durvalumab at 10 mg/kg (N=57). Outcomes demonstrated PK that 
was dose-dependent (non-linear) and congruent with target-mediated clearance of the 
antibody, thus rates of Oleclumab elimination was faster at lower doses than higher doses. In 
the same study, there was similar steady-state PK concentrations and general between-patient 
variability during simulations for body weight-based and fixed dosing regimens. Fixed dose of 
1500 mg or 3000 mg Q2W of Oleclumab for an average body weight of 75 mg/kg is comparable 
to 20 mg/kg or 40 mg/kg Q2W, respectively. Simulations to predict Oleclumab concentration 
profiles recommend 3000 mg Q2W or first four doses at 3000mg Q2W followed by 3000 mg 
Q4W for maintenance dose.  
 
2.5.3.2 Clinical Pharmacodynamics 
No new pharmacodynamics data is available as of 09 Nov 2017 since the last IB update. 
Assessment of target engagement demonstrates IV administration of Oleclumab 
monotherapy or combination therapy serves to completely suppress free soluble CD73 
in serum. 
 
Summary of Clinical Safety: Oleclumab Monotherapy 

 
20 
There were 39 (92.9%) and 23 (54.8%) subjects reporting >= 1 TEAE and treatment-
related TEAE, respectively with no significant trends among dosing groups. Fatigue 
(38.1%), anemia, abdominal pain, and dyspnea (21.4%) were the most frequently 
reported TEAEs while fatigue (16.7%), nausea (9.5%), and anemia (9.5%) were the most 
frequently reported treatment-related TEAE.  
 
Grade 3 or 4 TEAEs were experienced by 19 subjects (45.2%). The most common (>1 
subject) were ascites (11.9%), acute kidney injury (4.8%), hyperglycemia (4.8%), and 
hyponatremia (4.8%).  
 
The only treatment-emergent SAE effect reported by more than one subject was ascites 
(7.1%); no treatment-related SAE were reported.  
 
Three subjects required discontinuation due to AEs during the dose-escalation phase, 
none were treatment related. Two subjects were in the 10 mg/kg treatment group and 
experienced a Grade 3 event ascites and Grade 4 event metastasis to the central 
nervous system. One subject in the 20mg/kg group developed Grade 4 pulmonary 
embolism.  
 
Three deaths were reported during the study which were not related to treatment. One 
subject in the 20 mg/kg dose group experienced a Grade 5 treatment-emergent SAE of 
small intestinal obstruction. Two subjects had deaths due to disease under study 
treatment (one subject in each of the 20 mg/kg and 40 mg/kg dose group) 
 
2.5.4 Combination clinical therapy experience and rationale: Oleclumab and Durvalumab 
 
The dose expansion phase of the study D6070C00001 with combination therapy of 
Oleclumab and durvalumab is ongoing. The overall objective response rates (ORR) 
(confirmed and unconfirmed) for Oleclumab 40 mg/kg +  durvalumab 10 mg/kg dose-
expansion was 7.1% (95% CI; 1.5%, 19.5%). The CRC and PANC cohorts had ORR (confirmed 
and unconfirmed) of 4.8% (95% CI: 0.1%, 23.8%) and 10.0% (95% CI: 1.2%, 31.7%), 
respectively. The overall disease control rate (DCR) was 16.7% (95% CI: 7.0%, 31.4%) in the 
Oleclumab 40 mg/kg + durvalumab 10 mg/kg dose-expansion group. This included 3 
subjects in the CRC cohort; 2 stable disease (SD) and 1 partial response (PR). The DCR in the 
CRC and PANC cohorts was 14.3% (95% CI; 3.0%, 36.3%) and 20.0% (95% CI; 5.7%, 43.7%), 
respectively. 
 
Among the subjects treated with combination therapy, 91.9% experienced >= 1 TEAE 
without clinically significant patterns emerging across all combination therapy dose groups. 
The most frequent ones (reported in >=15% of total subjects) were fatigue (25.7%), 
abdominal pain, constipation, and vomiting (16.2%). Treatment-related TEAE was 

 
21 
experienced by 47.3%. The most frequent (reported in >=5% total subjects) were fatigue 
(13.5%); increased AST, diarrhea, and pyrexia (8.1%); increased blood ALP (6.8%); and 
increased ALT, decreased appetite and vomiting (5.4%).  
 
Grade 3 or 4 severity TEAE were found in 52.7% of total subjects. The most common (in >2 
subjects) were increased ALP (8.1%); anemia, increased ALT, AST and GGT (5.4%); 
pulmonary embolism, increased bilirubin, abdominal pain and ascites (4.1%). Treatment-
related TEAE of Grade 3 or 4 severity were the following: anemia, thrombocytopenia, 
increased lipase, hyponatremia, headache and dyspnea reported in one subject each; 
hepatitis, increased ALT and ALP in two subjects each; and AST increase in three subjects.  
 
Treatment-emergent SAE were reported in 44.6% of total subjects. The most common (>2 
subjects) were abdominal pain and ascites (4.1%). Treatment-related SAE occurred in 5.4% 
of total subjects: anemia, thrombocytopenia and abdominal pain reported in one subject; 
hepatitis reported by two subjects.  
 
TEAEs resulting in permanent discontinuation of treatment occurred in 10.8% of the 
subjects receiving combination therapy. Treatment-related TEAEs resulting in permanent 
discontinuation occurred in 4.1% of this population. 
 
During the study, six deaths were reported in subjects receiving combination therapy, none 
related to the study treatment. The following is a brief summary:  
• 
One subject in the Oleclumab 20 mg/kg + durvalumab 10 mg/kg dose group experienced 
Grade 5 SAE of renal failure.  
• 
One subject in the Oleclumab 40 mg/kg + durvalumab 10 mg/kg dose group developed a 
new extrahepatic biliary obstruction due to a new mass with ensuing clinical deterioration.  
• 
One subject with CRC in the expansion cohort experienced fatal SAE of pneumonia 
• 
One subject in the PANC cohort developed Grade 5 SAE of vomiting.  
• 
One subject in the CRC cohort experienced Grade 5 SAE of respiratory failure.  
• 
One subject in the CRC cohort experienced fatal pneumonitis. 
 
 
 
 
 
 
2.6     Rationale 
 
Colorectal cancer is potentially curable at a metastatic stage, provided the metastases can 
be resected surgically.  A meaningful subset of patients is able to undergo resection with 
expected long term survival of ~20%.  Efforts to improve survival, including chemotherapy, have 

 
22 
only had a modest benefit on relapse-free but not overall survival.  New approaches are needed 
to improve the outcomes in this patient population.  Harnessing the immune system via immune 
checkpoint blockade has already increased survival in many solid malignancies and is the 
standard of care in advanced melanoma.  Checkpoint blockade has the potential of increasing 
survival when given pre-operatively in the case of resectable CRCLM.   
Single agent blockade, with anti-CTLA-4, anti-PD-1, or anti-PD-L1, has not demonstrated robust 
responses in metastatic colorectal cancer in phase I studies with the exception of PD-1 blockade 
in patients with tumors that demonstrate microsatellite instability (MSI-high).  However, the 
combination of anti-CTLA-4 with anti-PD-1, which operate to enhance the immune response at 
different levels and, in general, have non-overlapping effects on the immune system, has led to 
a nearly 50% response rate in metastatic melanoma.  In a CT26 BALB/c mouse CRC pre-clinical 
model, the combination of tremelimumab and Durvalumab led to disease regression and long 
term disease control, whereas each individual agent did not.  As single agents, both 
tremelimumab and Durvalumab  have been shown to be safe in humans with metastatic solid 
tumors [61, 62].  The combination has demonstrated encouraging safety and efficacy profiles in 
a Phase 1b study of patients with advanced NSCLC [63]Based on the pre-clinical efficacy and the 
established safety profile, the combination of tremelimumab and Durvalumab may offer 
enhanced survival when used pre-operatively prior to CRCLM resection.  The addition of 
Durvalumab as a single agent post-operatively may counteract immune surveillance inhibition 
and prevent CRC recurrence. 
One of the major research questions in immunotherapy—and checkpoint inhibitor therapy in 
particular—is establishing why only a subset of patients responds.  Early data point to overall 
mutation burden as a key factor.  More research is needed in this area to help delineate 
biomarkers of response and, ultimately, to choose the best candidates for what can be toxic 
therapy.  A pre-operative approach will allow biomarker discovery and validation as tissue will be 
available before and after the therapy is given.  MD Anderson—through the Immune Platform—
has the capability and expertise to optimize such discovery.  
 
As of 6-1-2018 this clinical trial (2015-0828) has enrolled 18 patients of which 2 screen failed, 2 
have been treated but not yet reached the point of surgical resection, and 14 patients have 
undergone therapy and reached the point of surgical liver resection.  Eleven of these 14 patients, 
79%, have undergone liver resection, which is similar to the historical rate of 80%, and 
demonstrates this neoadjuvant approach to be safe.   Treatment toxicity did not preclude any 
patient from undergoing surgery, with the reasons for non-surgery being progression in two 
patients and underlying prior chemotherapy induced liver toxicity in one patient. Grade 3/4 
reported toxicities were fatigue (n=1), thromboembolic event (n=1), lipase elevation (n=1) and 
AST/ALT increase (n=3).  Given the demonstrated safety of this approach we have amendment 
the protocol to evaluate the safety of other novel immune therapy combinations and thus, this 
study will explore the safety of three immunotherapy based approaches all utilizing durvalumab 

 
23 
as the consistent agent.  In part, the rationale for exploring additional combinations rests upon 
the early clinical signals of activity with these other immune therapy agents in solid cancer and 
especially colorectal cancer.  In addition, at this time after 15 patients enrolled, the safety of such 
a preoperative immune therapy approach has been determined.  The translational knowledge 
gained from the combination of durvalumab and tremilimumab has clearly demonstrated T-cell 
activity with this combination occurs and, at present, greater knowledge gained from the 
translational aspects of this clinical trial will be best optimized by exploring  additional immune 
therapy combinations prior to liver resection. 
 
The rationale for the addition of cohorts B and C,patients with resectable CRC with liver or lung 
metastasis receiving durvalumab+oleclumab or durvalumab+monalizumab, respectively (refer to 
Section 5 for detailed definition of all cohorts), are discussed above in detail. In brief, we 
hypothesize that targeting CD73 and NKG2A will be safe in the neoadjuvant setting and will 
have the ability to generate anti-tumor immune responses that can provide successful eradication 
of minimal residual disease following surgical resection of metastatic disease.  In particular for 
cohort B, the CD73 antibody, oleclumab  can mitigate the inhibition of T-cell activation by 
extracellular adenosine in conjuncture with durvalumab.  By curtailing the effector function of 
CD73 on the immune system, there will be enhanced anti-tumor activity.  We anticipate that 
oleclumab will enhance the immunological response and  enable T-cell functioning within the 
tumor environment to help to control minimal residual disease following surgical resection.  For 
cohort C, binding of HLA-E to CD94/NKG2A induces inhibitory signals which suppress the 
cytokine secretion and direct cytotoxicity of lymphocytes against malignant cells. HLA-E is 
expressed in 81% to 82% of patients with colorectal carcinoma representing a common target and 
active mechanism of immune escape.  We hypothesize that monalizumab in conjuncture with 
durvalumab will be safe and generate an immunological response to CRC and that this activation of 
T-cells will help to control minimal residual disease following surgical resection. 
 
 
 
 
3. PATIENT SELECTION 
 
3.1  
Eligibility Criteria 
 
3.1.1 Patients must have histologically or cytologically confirmed colorectal cancer 
with liver or lung metastases deemed resectable by a liver or thoracic 
surgeon, respectively (resectability may involve the use of ablative 
techniques to some but not all liver or lung metastases).  Patients with a 
primary colorectal tumor that is planned for surgical resection are eligible. In 
addition patients with nonspecific lung lesions (lesions that are uncertain to 
be metastases given their small size, defined here as <1cm) are eligible.   
3.1.2 Patients must have measurable disease, defined as at least one lesion that 
can be accurately measured in at least one dimension (longest diameter to 
be recorded) as >10 mm with spiral CT scan.  See Section 11 for the 
evaluation of measurable disease.  

 
24 
 
3.1.3 All lines of prior therapy accepted. Subjects with prior hepatic or extra-
hepatic resections of metastatic disease will be included. 
 
3.1.4 Age >18 years.  Because no dosing or adverse event data are currently 
available on the use of tremelimumab, oleclumab, or monalizumab in 
combination with durvalumab in patients <18 years of age, children are 
excluded from this study. 
 
3.1.5 Life expectancy of greater than 6 months. 
 
3.1.6 ECOG performance status <1 (Karnofsky >70%; see Appendix1). 
 
3.1.7 Patients must have normal organ and marrow function as defined below: 
 
- 
leukocytes  
 
 
 
 
>3,000/mcL 
- 
absolute neutrophil count 
>1,500/mcL 
- 
platelets  
 
 
 
 
>100,000/mcL 
- 
total bilirubin  
 
 
 
< 1.5 X institutional normal limits (subjects 
with known Gilbert syndrome are eligible 
with total bilirubin < 3.0 mg/dL) 
- 
Hemoglobin 
 
 
 
 
>9g/dL 
-     AST(SGOT)/ALT(SGPT)  
 
< 3 X institutional upper limit of normal 
- 
creatinine  
 
 
 
 
within normal institutional limits 
OR 
- 
creatinine clearance  
 
>60 mL/min/1.73 m2 for patients with 
creatinine levels above institutional normal 
 
 
3.1.8 Known or ordered molecular testing for MSI, BRAF, and KRAS status. 
 
 3.1.9 Evidence of post-menopausal status or negative urinary or serum pregnancy 
test for female pre-menopausal patients. 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). 

 
25 
 
 
3.1.10 Ability to understand and the willingness to sign a written informed consent 
document. 
 
3.1.11 Weight ≥35kg (required for flat dose-based administration of study agents) 
 
3.2  
Exclusion Criteria 
 
3.2.1 Prior chemotherapy < 2 weeks prior to study drug treatment and treatment 
related adverse events that have not recovered to baseline or grade 1 
(alopecia excluded).  Prior radiation therapy <4weeks prior to study drug 
treatment (excluding short course radiation for rectal primaries).   
 
3.2.2 Patients may not be receiving any other investigational agents. 
 
 
3.2.3 Active or prior documented autoimmune or inflammatory disorders 
(including inflammatory bowel disease [e.g., colitis or Crohn's disease], 
diverticulitis [with the exception of diverticulosis], systemic lupus 
erythematosus, Sarcoidosis syndrome, or Wegener syndrome 
[granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, 
hypophysitis, uveitis, etc]). The following are exceptions to this criterion: 
--Patients with vitiligo or alopecia 
--Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable 
on hormone replacement  
--Any chronic skin condition that does not require systemic therapy 
--Patients without active disease in the last 5 years may be included but only 
after consultation with the study physician 
--Patients with celiac disease controlled by diet alone 
 
3.2.4 Current or prior use of immunosuppressive medication within 14 days before 
the first dose of durvalumab or tremelimumab. The following are exceptions 
to this criterion: 
• 
Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra 
articular injection) 
• 
Systemic corticosteroids at physiologic doses not to exceed <<10 mg/day>> of 
prednisone or its equivalent 
• 
Steroids as premedication for hypersensitivity reactions (e.g., CT scan 
premedication) 
  
 
3.2.5 Prior exposure to T cell checkpoint inhibitor therapies for colorectal cancer, 
including durvalumab and tremelimumab, monalizumab, oleclumab. 
 

 
26 
 
3.2.6 Uncontrolled intercurrent illness including, but not limited to, ongoing or 
active infection, interstitial lung disease, symptomatic congestive heart 
failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric 
illness/social situations that would limit compliance with study requirements.  
 
 
 
 
 
3.2.7 Known allergy or hypersensitivity to any of the study drugs or any of the study 
drug excipients. 
 
 
 
 
3.2.8 History of active primary immunodeficiency  
 
 
3.2.9 Women who are pregnant, which includes women with a positive pregnancy 
test at enrollment or prior to the administration of study medication, or 
breastfeeding are not allowed on study.   
 
3.2.10  Receipt of a live vaccine within 30 days of study entry 
 
3.2.11   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  
---Patients with Grade ≥2 neuropathy will be evaluated on a case-by-case 
basis after consultation with the Study Physician. 
---Patients with irreversible toxicity not reasonably expected to be 
exacerbated by treatment with durvalumab or tremelimumab may be 
included only after consultation with the Study Physician. 
 
3.2.12 Any concurrent chemotherapy, biologic, or hormonal therapy for cancer treatment. 
Concurrent use of hormonal therapy for non–cancer-related conditions (e.g., 
hormone replacement therapy) is acceptable.  
 
3.2.13 Major surgical procedure within 28 days prior to the first dose of IP. Note: Local 
surgery of isolated lesions for palliative intent is acceptable. 
 
3.2.14 History of allogenic organ transplantation. 
 
3.2.15 Known active infection including tuberculosis (clinical evaluation that includes clinical 
history, physical examination and radiographic findings, and TB testing in line with 
local practice), hepatitis B (known positive HBV surface antigen (HBsAg) result), 
hepatitis C, or human immunodeficiency virus (positive HIV 1/2 antibodies). Patients 
with a past or resolved HBV infection (defined as the presence of hepatitis B core 
antibody [anti-HBc] and absence of HBsAg) are eligible. Patients positive for hepatitis 
C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV 
RNA. 

 
27 
 
3.2.16 Female patients who are pregnant or breastfeeding or male or female patients of 
reproductive potential who are not willing to employ effective birth control from 
screening to 90 days after the last dose of durvalumab monotherapy or 180 days 
after the last dose of durvalumab and tremelimumab or durvalumab and oleclumab 
or durvalumab and monalizumab combination therapy. 
 
3.2.17 For cohort B only (durvalumab and oleclumab), patients with a recent (within three 
months) myocardial infarction, stroke, transient ischemic attack or 
thromboembolism are not eligible. 
 
 
4. REGISTRATION PROCEDURES 
 
This is a single institution study. 
 
5. TREATMENT PLAN 
 
5.1  
Study Design and Duration 
 
This study is an open-label, single center trial assessing the safety and feasibility of using 
perioperative neoadjuvant and adjuvant immune-therapy for resectable liver or lung 
metastases.  
 
Cohort A will consist of neoadjuvant tremelimumab 75 mg IV flat dose and durvalumab 
1500 mg IV flat dose.   Adjuvant therapy will consist of 4 monthly doses of durvalumab 
1500mg IV. 
 
Cohort B will consist of neoadjuvant oleclumab 3000 mg IV flat dose followed by 
durvalumab 1500 mg IV flat dose.   Adjuvant therapy will consist of 4 months of oleclumab 
every two weeks at 3000 mg IV flat dose and durvalumab every 4 weeks at 1500 mg IV flat 
dose. On days oleclumab and durvalumab are both administered, oleclumab will be given 
first (see Section 8.1.4). 
 
Cohort C will consist of neoadjuvant durvalumab 1500 mg IV flat dose then Monalizumab 
750mg IV flat dose. Adjuvant therapy will consist of 4 months of durvalumab   1500 mg IV 
flat dose and monolizumab 750 mg, both administered every four weeks.  
 
Cohort A has been enrolling since the study initiation and will enroll up to 25 patients.  At 
the time of amendment activation initially opening, cohort B may enroll 5 patients followed 
by 5 patient enrollment for cohort C. Enrollment will continue in this alternating manner 
with approximately 5 patient blocks at a time for these cohorts. Enrollment may be 
adjusted based on Medimmune/MD Anderson determined priorities and drug availability.  
Cohort B and C will each be 15 patients.   
 

 
28 
Lung or liver resection will be scheduled approximately 3-weeks after the infusion of the 
immunotherapeutic agents.  Completing up to 4 months of chemotherapy after surgical 
resection instead of immunotherapy (durvalumab for cohort A, durvalumab/oleclumab for 
cohort B, or durvalumab/monalizumab for cohort C) continuation is an option depending on 
the preferences of the treating physician/patient (i.e., subjects can opt out of the planned 
post-operatively immuntherapy). Post-operative therapy will be either chemotherapy per 
physician/patient choice or 4months of immunotherapy. As synchronous primary lesions 
are allowed in this study, the appropriate clinical care as determined by the treating 
multidisciplinary team for addressing the primary lesion will be allowed.  Though primary 
resection on clinical trial prior to liver resection will not be allowed, primary resection may 
be simultaneous with liver resection or occur after liver resection.  In addition as short 
course radiation therapy (5 days) is often employed for rectal primaries this will be allowed 
in this clinical trial as long as radiation therapy is ≥1 week from first dose of study 
treatment.  Factoring the occurrence of potential immune mediated AEs prior to resection, 
an allowance of a 3-10 weeks from neoadjuvant therapy administration will be permitted to 
complete metastatic and/or primary resection 
 
As the mechanism of action of immunotherapy should not impact wound healing, patients 
may start adjuvant therapy as early as 4 weeks after resection, per treating physician 
discretion, provided they have achieved adequate status after surgery (ex. Resolution of 
post-operative concerns).  Post-operative therapy thus can begin between 4weeks to 12 
weeks post-operatively.  However, if patients require >12weeks for postoperative recovery 
they will not be allowed to initiate adjuvant immunotherapy. 
 
The study design schematic is below. 
 
Study Schematic 
 
Cohort A:  
 
 
 
 
 
 
 
 
 
 
 
 
Cohort B:  
 
 
Cohort C:  
Metastatic 
CRC with 
Resectable 
Liver or lung disease 
(N = 25) 
Surgical 
Resection 
durvalumab 1500 mg+ 
tremelimumab 75mg 
IV x 1 
  
Approximately week 4 
CTscan 
CTscan and Mandatory 
Liver or lung Biopsy 
Approximately 4wks 
Durvalumab  
1500 mg IV  
Q4 weeks x 4  
Metastatic 
CRC with 
Resectable 
Liver/Lung disease 
(N = 15) 
  
Surgical 
Resection 
Durvalumab 1500 mg+ 
Oleclumab 3000mg 
IV x 1 
  
CTscan 
Regimen for 4 
months: 
Durvalumab  
1500 mg IV  
Q4 weeks;  
Oleclumab 3000 
mg Q2W 
CTscan and Mandatory 
Liver or lung Biopsy 
Approximately 4wks 
Approximately week 4 
Cohort B:  

 
29 
 
 
 
 
 
 
 
 
 
  
 
 
 
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-14 to D-1.  Previously conducted HIV, PT/PTT, and hepatitis testing within 30 
days does not need to be repeated and will be acceptable for screening purposes (tests 
performed at outside laboratories as standard of care testing will be accepted).  
 
Table 5.1-1: 
Screening Procedural Outline 
Procedure 
Screening 
Visit 
From D-
14 to D-1 
Notes 
 
Eligibility 
Assessments 
 
 
Informed Consent (IC) 
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. 
Surgical Evaluation to 
determine resectability 
X 
 
Medical History 
X 
 
Tumor Tissue Sample  
X 
Confirm diagnosis of colorectal adenocarcinoma 
MSI Status 
X 
If not done or not available, then MSI status may be 
obtained either from archived tissue or at hepatic 
resection.  
Determine KRAS 
Mutation Status 
X 
If not done or not available, then KRAS mutation status 
may be obtained either from archived tissue or at 
hepatic resection. 
Metastatic 
CRC with 
Resectable 
Liver or lung disease 
(N = 15) 
  
Surgical 
Resection 
Durvalumab 1500 mg+ 
monalizumab 750mg 
IV x 1 
  
Approximately week 4  
CTscan 
CTscan and Mandatory 
Liver or lungBiopsy 
Approximately 4wks 
Regimen for 4 
months: 
Durvalumab  
1500 mg IV  
Q4 weeks;  
Monalizumab 
750 mg Q2 weeks  
Metastatic 
CRC with 
Resectable 
Liver/Lung disease 
(N = 15) 
  
Surgical 
Resection 
Durvalumab 1500 mg+ 
monalizumab 750mg 
IV x 1 
  
CTscan 
Approximately 4wks 
Regimen for 4 
months: 
Durvalumab  
1500 mg IV  
 and  
Monalizumab 
750 mg  
Q4 weeks  

 
30 
Table 5.1-1: 
Screening Procedural Outline 
Procedure 
Screening 
Visit 
From D-
14 to D-1 
Notes 
 
Determine BRAF 
Mutation Status 
X 
If not done or not available, then BRAF mutation status 
may be obtained either from archived tissue or at 
hepatic resection. 
Prior Medications 
X 
Prior exposure to checkpoint inhibitor therapy excluded 
ECOG Performance 
Status 
X 
Within 14 days prior to first dose 
Safety Assessments 
 
 
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, ALP, T.Bili, 
BUN or serum urea level, creatinine, Ca, Mg, Na, K, Cl, 
Glucose, CEA, amylase, lipase, TSH, Free T4, Free T3, 
within 14 days prior to first dose 
HIV, hepatitis, PT/PTT 
laboratory tests 
X 
HIV Ab, Hepatitis B surface antigen (HBV sAg), and 
hepatitis C antibody (HCV Ab) or Hepatitis C RNA (HCV 
RNA)  or PT/PTT within 30 days prior to first dose 
Pregnancy Test 
(WOCBP only) 
X 
Serum or urine to be done at screening visit and 
repeated within 72hours of first dose of study therapy 
Efficacy Assessment 
 
 
Baseline Tumor 
Imaging Assessment 
X 
CT of the C/A/P or MRI of the liver within 28 days of 
signing of informed consent.  
 
 
5.1.2 Treatments 

 
31 
Management of and dose modifications in response to adverse events related to study 
medications are outlined in section 7.7, below. 
 
 
5.1.2.1  Cohort A: 
Tremelimumab 
Tremelimumab is a human IgG2 anti-CTLA-4 mAb. It will be given at a dose of 75 mg IV 
over 1 hour in an outpatient setting beginning week 1 of the trial.  No premedications 
are needed. This drug will only be used as neo-adjuvant therapy. In the post-resection 
portion of the study, Cohort A will only receive Durvalumab according to its schedule 
(see tables 10.1, 10.2, 10.3). Pharmaceutical details and preparation are given in section 
8. 
 
Durvalumab 
Durvalumab, a human IgG1κ mAb directed against PD-L1, and with reduced binding to 
C1q and the Fcγ receptors.  It will be given immediately following tremelimumab 
beginning week 1 at a dose of 1500 mg IV over 1 hour.  No premedications are needed.  
Pharmaceutical details and preparation are given in section 8.   
 
5.1.2.2 Cohort B 
 
Oleclumab 
Oleclumab, a human IgG1λ mAb that selectively binds to and inhibits CD 73, will be 
administered following Durvalumab.  Please note duvalumab will always be given first. 
Oleclumab will be given in an outpatient setting at a dose of 3000 mg IV fixed dose over 
one hour. Pharmaceutical details and preparation are given in section 8.  
 
Durvalumab 
Durvalumab, a human IgG1κ mAb directed against PD-L1, and with reduced binding to 
C1q and the Fcγ receptors.  It will be given immediately before Oleclumab beginning 
week 1 at a dose of 1500 mg IV over 1 hour.  No premedications are needed.  
Pharmaceutical details and preparation are given in section 8.   
 
 
5.1.2.3 Cohort C 
 
Monalizumab is a mAb of the IgG4 subtype that specifically binds and blocks the 
inhibitory receptor CD94/NKG2A for HLA-E, potentially restoring the ability of 
peripheral and tumor infiltrating NK cells or cytotoxic CD8+ T-cells to kill HLA-E 
expressing tumor cells. It will be administered following Durvalumab infusion at a dose 
of 750mg. Pharmaceutical details and preparation are given in section 8 
 
 
Durvalumab 
Durvalumab will be given immediately following monalizumab beginning week 1 at a 
dose of 1500 mg IV over 1 hour.  No premedications are needed.  Pharmaceutical details 

 
32 
and preparation are given in section 8.   
 
 
 
5.1.3 Treatment and Follow Up visits 
Once enrolled on trial, he/she will have the following visits/events.  The study calendar 
is in section 10 outlines schedule of treatments and assessments.  Treatment will not 
commence until at least 2 weeks from prior systemic chemotherapy.  Patients may 
undergo screening during this time or after two weeks.  There is no maximum time from 
prior chemotherapy till immune-therapy treatment. 
 
 
PREOPERATIVE SCHEDULE 
 
 
Refer to Table 10.1 for the preoperative schedule of visits, assessments and treatments 
for all cohorts.   
 
Note, due to the variation in recovery from surgical resection, weeks will restart 
following surgical resection when Durvalumab is administered.  
 
POST-OPERATIVE SCHEDULE 
  
Refer to Table 10.2 for cohort A post-operative schedule and Table 10.3 for cohort B and C 
post-operative schedule.    
 
 
5.2  
General Concomitant Medication and Supportive Care Guidelines 
 
No formal drug interaction studies have been performed with either experimental 
agent.  However, as an antibody, it is not expected to cause significant interaction 
with medications metabolized by the cytochrome P450 system. 
 
Permitted concomitant medications 

 
33 
Table 5.2.1. Supportive medications 
Supportive medication/class of drug: 
Usage: 
Concomitant medications or treatments 
(e.g., 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 patients 
Inactivated viruses, such as those in the 
influenza vaccine 
     Permitted 
 
Excluded concomitant medications 
Table 5.2.2. 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 
[e.g., insulin 
for 
diabetes and hormone replacement therapy] is 
acceptable. Local treatment of isolated lesions, 
excluding target lesions, for palliative intent is 
acceptable [e.g., by local surgery or radiotherapy]) 

 
34 
Prohibited medication/class of drug: 
Usage: 
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 (e.g., 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 tremelimumab 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) 
EGFR TKIs  
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 investigational agents (including SoC) 
Herbal and natural remedies which may have 
immune-modulating effects 
Should not be given concomitantly unless agreed by 
the sponsor 
 
Blood donation 
Patients should not donate blood while participating in this study, or for at least 180 
days following the last infusion of durvalumab or tremelimumab. 
 
Reproductive Guidelines 
The following restrictions apply while the patient is receiving study treatment and 
for the specified times before and after: 
Female patient of child-bearing potential 

 
35 
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 
5.2.3) from the time of screening and must agree to continue using such 
precautions for 180 days after the last dose of durvalumab + oleclumab or 
durvalumab + monalizumab 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 patients should also refrain from breastfeeding 
throughout this period. 
 
Male patients 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 + oleclumab or 
durvalumab + monalizumab  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 
patients should refrain from sperm donation throughout this period. 
Female partners (of childbearing potential) of male patients must also use a 
highly effective method of contraception throughout this period (Table 5.2.3). 
 
Females of childbearing potential are defined as those who are not surgically sterile 
(i.e., 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 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 (i.e., less than 1% per year) when used consistently and correctly are 

 
36 
described in (Table 5.2.3).  Note that some contraception methods are not 
considered highly effective (e.g., 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 5.2.3. Highly effective methods of contraception (<1% failure rate) 
Barrier/Intrauterine methods 
Hormonal Methods 
• 
Copper T intrauterine device 
• 
Levonorgestrel-releasing intrauterine system 
(e.g., Mirena®)a 
 
• 
Implants: Etonogestrel-releasing implants: 
e.g. Implanon® or Norplant®  
• 
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 pill 
a 
This is also considered a hormonal method 
 
 
5.4  
Duration of Therapy 
 
In the absence of treatment delays due to adverse events, treatment may continue 
until one of the following criteria applies: 
 
Χ 
Disease recurrence 
 
Χ 
Intercurrent illness that prevents further administration of treatment, 
 
Χ 
Unacceptable adverse events(s), 
 
Χ 
Patient decides to withdraw from the study, or 
 
Χ 
General or specific changes in the patient's condition render the patient 
unacceptable for further treatment in the judgment of the investigator. 
 

 
37 
5.4 
Duration of Follow Up 
 
Patients may be followed for up to 2 years from liver surgery 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. 
 
Note after one year of follow-up without recurrence schedule of follow-ups can be 
adjusted according to standard of care. This will take precedence over the study 
calendar.  
 
 
6. DOSING DELAYS/DOSE MODIFICATIONS 
 
Dose modifications for adverse events are per section 7.7.   
 
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 
preexisting 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 should be recorded as an AE or SAE. 

 
38 
 
The investigator (or physician designee) is responsible for verifying and providing source 
documentation for all adverse events and assigning the attribution for all adverse events for 
subjects enrolled. 
 
 
7.2 Definition of Serious Adverse Events 
 
An SAE is any AE that: 
• Results in death 
• Is immediately life-threatening 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability/incapacity 
• Is a congenital anomaly/birth defect in offspring of the subject 
• Is an important medical event that may jeopardize the subject or may require medical 
intervention to prevent one of the outcomes listed above 
 
Medical or scientific judgment should be exercised in deciding whether expedited reporting 
is appropriate in this situation. Examples of medically important events are intensive 
treatment in an emergency room or at home for allergic bronchospasm, blood dyscrasias, or 
convulsions that do not result in hospitalizations; or development of drug dependency or 
drug abuse. 
 
7.3 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 to the supporting company. 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. 
 
AESIs for durvalumab ±tremelimumab include but are not limited to events with a potential 
inflammatory or immune-mediated mechanism and which may require more frequent 
monitoring and/or interventions such as steroids, immunosuppressants and/or hormone 
replacement therapy. These AESIs are being closely monitored in clinical studies with 
durvalumab monotherapy and combination therapy. An immune-mediated adverse event 
(imAE) is defined as an AESI that is associated with drug exposure and is consistent with an 
immune-mediated mechanism of action and where there is no clear alternate etiology. 
Serologic, immunologic, and histologic (biopsy) data, as appropriate, should be used to support 
an imAE diagnosis. Appropriate efforts should be made to rule out neoplastic, infectious, 
metabolic, toxin, or other etiologic causes of the imAE.  
If the Investigator has any questions in regards to an event being an imAE, the Investigator 
should promptly contact the Study Physician. 
AESIs observed include: 
• 
Fatigue / asthenia  
• 
Pyrexia  
• 
Diarrhea / Colitis 

 
39 
• 
Pneumonitis / Interstitial lung disease (ILD) 
• 
ALT/AST increases / hepatitis / hepatotoxicity 
• 
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 (or labs suggestive of pancreatitis - increased serum lipase , increased 
serum amylase)  
• 
Other inflammatory responses that are rare with a potential immune-mediated 
aetiology include, but are not limited to, myocarditis, pericarditis, and uveitis. 
• 
AESI specifically related to Oleclumab (cohort B) include):: 
• 
Cardiac chest pain, transient ischemic attack, and thromboembolism 
These are of interest due to the drug’s risk of arterial calcifications, arterial ischemic 
disorder and thrombosis.  
 
• 
Edema 
Oleclumab has potential risk of increased microvascular permeability, thus edema 
(pulmonary, peripheral, etc.) is considered an AESI. In the case of >= Grade 3 edema, 
doses should be omitted and therapy may be discontinued at the discretion of the 
investigator. 
 
• 
Immune complex disease 
This may occur when human-anti-human antibodies are produced as a response to 
humanized mAb, resulting in formation and deposition of immune complexes in blood 
vessels, joints and glomeruli leading to symptomatic diseases (vasculitis, 
glomerulonephritis, arthritis, serum sickness, etc.). Subjects will be monitored 
clinically and with labs. If subjects experience a suspected immune-complex related 
AE, with confirmed presence of ADAs treatment will be discontinued and the condition 
will be managed based on standard of care.  
 
In addition, infusion-related reactions and hypersensitivity/anaphylactic reactions with a 
different underlying pharmacological etiology 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. Additional 
information on the anticipated AE’s for duvalumab + monalizumab combination therapy is 
noted in the current version of the monalizumab Investigator’s Brochure (v.6). More specific 
guidelines for their evaluation and treatment are described in detail in the Dosing Modification 

 
40 
and Toxicity Management Guidelines (see Section 7.7). These guidelines have been prepared 
by the supporting company to assist the Investigator in the exercise of his/her clinical judgment 
in treating these types of toxicities. These guidelines apply to AEs considered causally related 
to the study drug/study regimen by the reporting investigator. 
 
If new or worsening pulmonary symptoms (e.g. dyspnea) 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 (see 
Table 7.7.1) will be applied. The results of the full diagnostic workup (including high-
resolution computed tomography (HRCT), blood and sputum culture, hematological 
parameters etc) will be captured in the eCRF. 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.  
 
 
7.3.1 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 
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 
section 7.7. 
 
7.3.2 Pneumonitis 
Adverse events of pneumonitis are also of interest for the supporting company, 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. 
 
 
7.3.3 Infusion Reactions 
Adverse events of infusion reactions (also termed infusion-related reactions) are of special 
interest to the supporting company 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. 
 
7.3.4 Hypersensitivity Reactions 

 
41 
Hypersensitivity reactions as well as infusion-related reactions have been reported with 
anti-PD-L1 and anti-PD-1 therapy[35]. 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. 
 
7.3.5 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 tremelimumab 
should be managed as per Tremelimumab Guidelines for the Management of Diarrhea and 
Colitis (Appendix 2). 
 
7.4 Recording of Adverse Events 
Adverse events will be recorded on the eCRF (Protocol Data Management System/Clinical 
Oncology Research System - PDMS/CORe) using a recognized medical term or diagnosis that 
accurately reflects the event. Adverse events will be assessed by the investigator for 
severity, relationship to the investigational product, possible etiologies, and whether the 
event meets criteria of an SAE and therefore requires immediate notification to 
MedImmune Patient Safety. 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. 
 
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 tremelimumab, 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 

 
42 
Institute of Allergy and Infectious Diseases (NIAID) and Food Allergy and Anaphylaxis 
Network (FAAN) guidance for anaphylaxis diagnosis is provided in Appendix 3. 
 
7.4.1 Time Period for Collection of Adverse Events 
Adverse events will be collected from time of signature of informed consent, enrollment, 
randomization, throughout the treatment period and including the follow-up period of 
90 days after the last dose of Durvalumab post-operatively. Serious adverse events will be 
recorded from the time of informed consent signature through 90 days after the last dose 
of Durvalumab. 
 
7.4.2  Follow-up of Unresolved Adverse Events 
Any possible/probably/definite treatment-related SAEs 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.  
 
7.5        Serious Adverse Event Reporting (SAE) for M.D. Anderson-sponsored IND 
Protocols  
 
An adverse event or suspected adverse reaction is considered “serious” if, in the view of 
either the investigator, it results in any of the following outcomes: 
 
• Death 
• A life-threatening adverse drug experience – any adverse experience that places the 
patient, in the view of the initial reporter, at immediate risk of death from the adverse 
experience as it occurred. It does not include an adverse experience that, had it 
occurred in a more severe form, might have caused death. 
• Inpatient hospitalization or prolongation of existing hospitalization 
• A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions. 
• A congenital anomaly/birth defect. 
 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based upon 
appropriate medical judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition. 
Examples of such medical events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, blood dyscrasias or convulsions that do not 
result in inpatient hospitalization, or the development of drug dependency or drug abuse 
(21 CFR 312.32). 
• 
Important medical events as defined above may also be considered serious adverse events. Any 
important medical event can and should be reported as an SAE if deemed appropriate by the 
Principal Investigator or the IND Sponsor, IND Office. 
 

 
43 
• All events occurring during the conduct of a protocol and meeting the definition of a SAE 
must be reported to the IRB in accordance with the timeframes and procedures outlined 
in “The University of Texas M. D. Anderson Cancer Center Institutional Review Board 
Policy for Investigators on Reporting Unanticipated Adverse Events for Drugs and 
Devices”.  Unless stated otherwise in the protocol, all SAEs, expected or unexpected, 
must be reported to the IND Office, regardless of attribution (within 5 working days of 
knowledge of the event). 
 
• All life-threatening or fatal events, that are unexpected, and related to the study drug, 
must have a written report submitted within 24 hours (next working day) of knowledge 
of the event to the Safety Project Manager in the IND Office.   
 
• Unless otherwise noted, the electronic SAE application (eSAE) will be utilized for safety 
reporting to the IND Office and MDACC IRB.  
 
• Serious adverse events will be captured from the time of the first protocol-specific 
intervention, until 90 days after the last dose of drug, unless the participant withdraws 
consent. Serious adverse events must be followed until clinical recovery is complete and 
laboratory tests have returned to baseline, progression of the event has stabilized, or 
there has been acceptable resolution of the event. 
 
• Additionally, any serious adverse events that occur after the 90 day time period that are 
related to the study treatment must be reported to the IND Office. This may include the 
development of a secondary malignancy. 
 
Reporting to FDA: 
 
• 
Serious adverse events will be forwarded to FDA by the IND Sponsor (Safety Project Manager 
IND Office) according to 21 CFR 312.32. 
 
It is the responsibility of the PI to ensure serious adverse events are reported according to 
the Code of Federal Regulations, Good Clinical Practices, the protocol guidelines, the IND 
Office guidelines, and Institutional Review Board policy. 
 
 
 
 
Attribution 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
 
  
  
  
  
Unrelated 
Phase I 
  Phase I 
  Phase I        
Phase II   
  
Phase I        
Phase II  
Phase III 
  
Phase I         
Phase II  
Phase III 
Unlikely 
Phase I 
  Phase I 
  Phase I        
Phase II   
  
Phase I        
Phase II  
Phase III 
  
Phase I         
Phase II  
Phase III 

 
44 
Possible 
Phase I       
Phase II 
  
Phase I        
Phase II  
Phase III 
  
Phase I        
Phase II  
Phase III 
  
Phase I        
Phase II  
Phase III 
  
Phase I         
Phase II  
Phase III 
Probable 
Phase I       
Phase II 
  
Phase I        
Phase II  
Phase III 
  
Phase I        
Phase II  
Phase III 
  
Phase I        
Phase II  
Phase III 
  
Phase I         
Phase II  
Phase III 
Definitive 
Phase I       
Phase II 
  
Phase I        
Phase II  
Phase III 
  
Phase I        
Phase II  
Phase III 
  
Phase I        
Phase II  
Phase III 
  
Phase I         
Phase II  
Phase III 
 
 
7.5.1 Reporting of Serious Adverse Events 
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 immediately following the first protocol intervention 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 and/or sponsor must inform the FDA, via a eSAE form, of any serious or 
unexpected adverse events that occur in accordance with the reporting obligations of 21 
CFR 312.32, and will concurrently forward all such reports to AstraZeneca. A copy of 
the eSAE report must be emailed to AstraZeneca at the time the event is reported to the 
FDA. It is the responsibility of the sponsor to compile all necessary information and 
ensure that the FDA receives a report according to the FDA reporting requirement 
timelines and to ensure that these reports are also submitted to AstraZeneca at the same 
time. 
* A cover page should accompany the eSAE form indicating the following: 
• “Notification from an Investigator Sponsored Study” 
• The investigator IND number assigned by the FDA 
• The investigator’s name and address 
• The trial name/title and AstraZeneca ISS reference number (ESR-16-11821) 
* Sponsor 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 AstraZeneca and the FDA. 
 
Serious adverse events that do not require expedited reporting to the FDA still need to be 
reported to AstraZeneca. This information should be reported on a monthly basis and 
under no circumstance less frequently than quarterly.  

 
45 
 
7.6 Other Events Requiring Immediate Reporting 
 
 
 
7.6.1 Overdose and Death 
7.6.1.1 Overdose 
An overdose is defined as a subject receiving a dose of investigational product in excess of 
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 If the 
overdose results in an AE, the AE must also be recorded on the AE eCRF. Even when an 
overdose does not automatically make an AE serious, it will be reported to the IND Office 
through the eSAE application within the supporting company required reporting period. 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). The 
investigator will use clinical judgment to treat any overdose. 
 
7.6.1.2 Death 
All deaths that occur during the study, or within the protocol-defined 90-day post-last dose of 
durvalumab + tremelimumab 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. 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.  
 
7.6.2 Hepatic Function Abnormality 
Adverse events of hepatic function abnormality of special interest to the supporting 
company 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 

 
46 
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 AstraZeneca Patient 
Safety, 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 medical monitor. 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 
and evaluated by the supporting company. 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 safety review committee (or equivalent) to determine whether 
continued dosing of current 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 AstraZeneca 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. 
 
7.6.3 Pregnancy 
All pregnancies and outcomes of pregnancy should be reported to AstraZeneca except 
for: 
• 
Pregnancy discovered before the study patient has received any study drugs. 
• 
Pregnancy of a female partner of male patient, providing there is no restriction of 
male patient fathering a child. 
 
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 

 
47 
personnel should inform the appropriate AstraZeneca representatives within 1 day, i.e., 
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  
Male patients should refrain from fathering a child or donating sperm during the study and 
for 180 days after the last dose of durvalumab + tremelimumab 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 + tremelimumab 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.  
7.6.4 Pneumonitis 
Adverse events of pneumonitis are required to be reported within 24 hours of knowledge 
of the event to AstraZeneca Patient Safety  
 
7.7 Management of Study Medication Related Toxicities 
Adjustments for the trial drugs will follow the guidelines and recommendations noted 
below. Based on the mechanism of action of Durvalumab,  tremelimumab, oleclumab, and 
monalizumab 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. Potential irAEs may be similar to those seen with the use of ipilimumab, 
nivolumab, or the combination thereof and may include [31, 34, 35, 64]: 
 
• 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 

 
48 
Elevation (reported in Tremelimumab).  
• 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 7.7.1 it is 
recommended that management of irAEs follow the guidelines outlined for ipilimumab [65]. 
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). 
 
If the investigator has any question in regards to an AE being an irAE, the investigator 
should immediately contact the medical monitor. Treatment modifications will not be 
required for AEs that are clearly not attributed to Durvalumab, tremelimumab, oleclumab  
or Monalizumab (such as an accident) or for laboratory abnormalities that are not deemed 
to be clinically significant. 
 
Dose reductions of Durvalumab, tremelimumab, oleclumab or Monalizumab are not 
permitted. 
 
Treatment modifications may be required for Durvalumab, tremelimumab, monalizumab, 
and oleclumab in the event of treatment-related toxicity. General guidelines regarding 
treatment modification are provided in Table 7.7.1 for all cohorts.  In addition, management 
guidelines for adverse events of special interest (AESI) are detailed in Section 7.3. All 
toxicities will be graded according to NCI CTCAE v4.03 for cohort A and CTCAE v5.0 for 
cohorts B and C (CTCAE v5.0 is referenced in Table 7.7.1). In case of doubt, the investigator 
should consult with the medical monitor. 
 
 
Table 7.7.1 
Dosing Modification and Toxicity Management Guidelines 

 
49 
 
 

 
50 
Dosing Modification and Toxicity Management Guidelines for Immune-Mediated, 
Infusion-Related, and  
Non-Immune–Mediated Reactions (Use for all Cohorts)  
1 November 2017 (CTCAE Version 5.0) 
General Considerations 
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 v5.0 . 
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 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. Consider, as necessary, 
discussing with the study physician, and promptly 
pursue specialist consultation. 
− 
If symptoms recur or worsen during corticosteroid 
tapering (28 days of taper), increase the 
corticosteroid dose (prednisone dose [e.g., 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). 
− 
More potent immunosuppressives such as TNF 
inhibitors (e.g., infliximab) (also refer to the 
individual sections of the imAEs for specific type of 
immunosuppressive) should be considered for 
events not responding to systemic steroids. 
Progression to use of more potent 
immunosuppressives should proceed more rapidly 
in 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 

 
51 
Dosing Modification and Toxicity Management Guidelines for Immune-Mediated, 
Infusion-Related, and  
Non-Immune–Mediated Reactions (Use for all Cohorts)  
1 November 2017 (CTCAE Version 5.0) 
General Considerations 
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).  
 
– when these events are not responding to systemic 
steroids. 
− 
With long-term steroid and other 
immunosuppressive use, consider need for 
Pneumocystis jirovecii pneumonia (PJP, formerly 
known as Pneumocystis carinii pneumonia) 
prophylaxis, gastrointestinal protection, and glucose 
monitoring. 
− 
Discontinuation of study drug/study regimen is not 
mandated for Grade 3/Grade 4 inflammatory 
reactions attributed to local tumor response 
(e.g., 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. 
 
 

 
52 
Specific Immune-Mediated Reactions 
Adverse Events 
Severity Grade 
of the Event 
(NCI CTCAE 
version5.0 ) 
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 
(e.g., 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 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 

 
53 
Specific Immune-Mediated Reactions 
Adverse Events 
Severity Grade 
of the Event 
(NCI CTCAE 
version5.0 ) 
Dose Modifications 
Toxicity Management 
antibiotics, antifungals, or anti-PJP 
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 study physician. 
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., 
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; consider, as 
necessary, discussing with study 
physician. 
− 
Hospitalize the patient. 
− 
Supportive care (e.g., 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 
(e.g., 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 patient is improving, 
gradually taper steroids over ≥28 
days and consider prophylactic 
antibiotics, antifungals, and, in 
particular, anti-PJP 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: 
− 
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, 

 
54 
Specific Immune-Mediated Reactions 
Adverse Events 
Severity Grade 
of the Event 
(NCI CTCAE 
version5.0 ) 
Dose Modifications 
Toxicity Management 
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; mild 
increase in 
ostomy output 
compared to 
baseline) 
(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 (e.g., 
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; 
moderate 
increase in 
ostomy output 
compared to 
baseline; limiting 
instrumental 
ADL) (Colitis: 
abdominal pain; 
mucus or blood 
in stool) 
Hold study drug/study 
regimen until resolution to 
Grade ≤1 
• 
If toxicity worsens, 
then treat as Grade 3 
or Grade 4. 
• 
If toxicity improves to 
Grade ≤1, then study 
drug/study regimen 
can be resumed after 
completion of steroid 
taper. 
For Grade 2: 
− 
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 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. 

 
55 
Specific Immune-Mediated Reactions 
Adverse Events 
Severity Grade 
of the Event 
(NCI CTCAE 
version5.0 ) 
Dose Modifications 
Toxicity Management 
− 
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. 
− 
Consider, as necessary, discussing 
with study physician 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-PJP 
treatment (refer to current NCCN 
guidelines for treatment of cancer-
related infections [Category 2B 
recommendation]).a 
Grade 3 or 4 
(Grade 3 
diarrhea: stool 
frequency of ≥7 
over baseline per 
day; 
hospitalization 
indicated; severe 
increase in 
ostomy 
compared to 
baseline; limiting 
self care ADL 
Grade 4 diarrhea: 
life threatening 
consequences; 
urgent 
intervention 
indicated) 
(Grade 3 colitis: 
severe abdominal 
pain, peritoneal 
signs; 
Grade 4 colitis: 
life-threatening 
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. 
 
Grade 4 
Permanently discontinue  
study drug/study regimen.  
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 (e.g., 
infliximab at 5 mg/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 the patient is improving, 
gradually taper steroids over ≥28 
days and consider prophylactic 
antibiotics, antifungals, and anti-PJP 
treatment (refer to current NCCN 
guidelines for treatment of cancer-
related infections [Category 2B 
recommendation]).a 

 
56 
Specific Immune-Mediated Reactions 
Adverse Events 
Severity Grade 
of the Event 
(NCI CTCAE 
version5.0 ) 
Dose Modifications 
Toxicity Management 
consequences, 
urgent 
intervention 
indicated) 
 
Hepatitis  
(elevated LFTs) 
Infliximab should not be 
used for management of 
immune-related hepatitis. 
Refer to CTCAEv5 for 
criteria of each grade 
Any Grade 
General Guidance 
For Any Grade: 
− 
Monitor and evaluate liver function 
test: AST, ALT, ALP, and TB. 
− 
Evaluate for alternative etiologies 
(e.g., viral hepatitis, disease 
progression, concomitant 
medications). 
Grade 1 
()) 
• 
No dose modifications. 
• 
If it worsens, then treat 
as Grade 2 event. 
For Grade 1: 
− 
Continue LFT monitoring per 
protocol. 
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. 
• 
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 2 days) until 
elevations of these are improving or 
resolved. 
− 
If no resolution to Grade ≤1 in 1 to 
2 days, consider, as necessary, 
discussing with study physician. 
− 
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 study physician 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-PJP 
treatment (refer to current NCCN 

 
57 
Specific Immune-Mediated Reactions 
Adverse Events 
Severity Grade 
of the Event 
(NCI CTCAE 
version5.0 ) 
Dose Modifications 
Toxicity Management 
guidelines for treatment of cancer-
related infections [Category 2B 
recommendation]).a 
Grade 3 or 4 
(Grade 3: ) 
 
(Grade 4:  ) 
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 
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 (i.e., 
elevated alkaline P04) and 
in the absence of any 
alternative cause.b 
 
For Grade 4: 
Permanently discontinue 
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 study physician if 
mycophenolate is not available. 
Infliximab should NOT be used. 
− 
Perform hepatology consult, 
abdominal workup, and imaging as 
appropriate. 
− 
Once the patient is improving, 
gradually taper steroids over ≥28 
days and consider prophylactic 
antibiotics, antifungals, and anti-PJP 
treatment (refer to current NCCN 
guidelines for treatment of cancer-
related infections [Category 2B 
recommendation]).a 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
58 
Specific Immune-Mediated Reactions 
Adverse Events 
Severity Grade 
of the Event 
(NCI CTCAE 
version5.0 ) 
Dose Modifications 
Toxicity Management 
study drug/study regimen. 
 
Nephritis or renal 
dysfunction 
(elevated serum 
creatinine) 
Refer to CTCAEv5 – 
Renal and urinary 
disorders 
Any Grade 
General Guidance 
For 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, or 
proteinuria). 
− 
Patients should be thoroughly 
evaluated to rule out any alternative 
etiology (e.g., 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 
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 

 
59 
Specific Immune-Mediated Reactions 
Adverse Events 
Severity Grade 
of the Event 
(NCI CTCAE 
version5.0 ) 
Dose Modifications 
Toxicity Management 
after completion of 
steroid taper. 
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 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-PJP 
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-PJP 
treatment (refer to current NCCN 
guidelines for treatment of cancer-
related infections [Category 2B 
recommendation]).a 
 
 
Rash 
(excluding bullous skin 
Any Grade 
(refer to NCI 
CTCAE 
General Guidance 
For Any Grade: 
− 
Monitor for signs and symptoms of 
dermatitis (rash and pruritus). 

 
60 
Specific Immune-Mediated Reactions 
Adverse Events 
Severity Grade 
of the Event 
(NCI CTCAE 
version5.0 ) 
Dose Modifications 
Toxicity Management 
formations) 
v5.0   for 
definition of 
severity/grade 
depending on 
type of skin rash) 
− 
IF THERE IS ANY BULLOUS 
FORMATION, THE STUDY 
PHYSICIAN SHOULD BE 
CONTACTED AND STUDY 
DRUG DISCONTINUED. 
Grade 1 
No dose modifications. 
For Grade 1: 
− 
Consider symptomatic treatment, 
including oral antipruritics (e.g., 
diphenhydramine or hydroxyzine) 
and topical therapy (e.g., 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 (e.g., 
diphenhydramine or hydroxyzine) 
and topical therapy (e.g., 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 study 
physician 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 drug/study regimen 
does not provide 
improvement of the Grade 
3 skin rash to Grade ≤1 or 
baseline within 30 days, 
For Grade 3 or 4: 
− 
Consult dermatology. 
− 
Promptly initiate empiric IV 
methylprednisolone 1 to 
4 mg/kg/day or equivalent. 
− 
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 

 
61 
Specific Immune-Mediated Reactions 
Adverse Events 
Severity Grade 
of the Event 
(NCI CTCAE 
version5.0 ) 
Dose Modifications 
Toxicity Management 
then permanently 
discontinue study 
drug/study regimen. 
 
For Grade 4: 
Permanently discontinue 
study drug/study regimen. 
 
antibiotics, antifungals, and anti-PJP 
treatment (refer to current NCCN 
guidelines for treatment of cancer-
related infections [Category 2B 
recommendation]).a 
− 
Consider, as necessary, discussing 
with study physician. 
Endocrinopathy 
(e.g., 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 v5.0  for 
defining the CTC 
grade/severity) 
General Guidance 
For Any Grade: 
− 
Consider consulting an 
endocrinologist for endocrine 
events. 
− 
Consider, as necessary, discussing 
with study physician. 
− 
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 (e.g., 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 related 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 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 (e.g., thyroiditis, 
pancreatitis, hypophysitis, or 
diabetes insipidus), the investigator 
should send a blood sample for 
appropriate autoimmune antibody 
testing. 
 

 
62 
Specific Immune-Mediated Reactions 
Adverse Events 
Severity Grade 
of the Event 
(NCI CTCAE 
version5.0 ) 
Dose Modifications 
Toxicity Management 
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 
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 
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 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). 
− 
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. 

 
63 
Specific Immune-Mediated Reactions 
Adverse Events 
Severity Grade 
of the Event 
(NCI CTCAE 
version5.0 ) 
Dose Modifications 
Toxicity Management 
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. 
− 
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-PJP 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 
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. 
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, promptly initiate 
empiric IV methylprednisolone 1 to 
2 mg/kg/day or equivalent, as well 
as relevant hormone replacement 
(e.g., hydrocortisone, sex 
hormones). 
− 
For adrenal crisis, severe 
dehydration, hypotension, or shock, 
immediately initiate IV 
corticosteroids with 
mineralocorticoid activity. 
− 
Isolated hypothyroidism may be 
treated with replacement therapy, 
without study drug/study regimen 
interruption, and without 
corticosteroids. 
− 
Isolated Type 1 diabetes mellitus 
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 

 
64 
Specific Immune-Mediated Reactions 
Adverse Events 
Severity Grade 
of the Event 
(NCI CTCAE 
version5.0 ) 
Dose Modifications 
Toxicity Management 
3. 
Doses of prednisone 
are ≤10 mg/day or 
equivalent. 
consider prophylactic antibiotics, 
antifungals, and anti-PJP treatment 
(refer to current NCCN guidelines 
for treatment of cancer-related 
infections [Category 2B 
recommendation]).a 
 
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 v5.0  for 
defining the CTC 
grade/severity) 
General Guidance 
For Any Grade: 
− 
Patients should be evaluated to rule 
out any alternative etiology (e.g., 
disease progression, infections, 
metabolic syndromes, or 
medications). 
− 
Monitor patient for general 
symptoms (headache, nausea, 
vertigo, behavior change, or 
weakness). 
− 
Consider appropriate diagnostic 
testing (e.g., electromyogram and 
nerve conduction investigations). 
− 
Perform symptomatic treatment 
with neurological consult as 
appropriate. 
− 
 
Grade 1 
No dose modifications. 
For Grade 1: 
− 
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 
For Grade 2: 
− 
Consider, as necessary, discussing 
with the study physician. 
− 
Obtain neurology consult. 
− 
Sensory neuropathy/neuropathic 
pain may be managed by 
appropriate medications (e.g., 
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 (e.g., 
IV IG). 

 
65 
Specific Immune-Mediated Reactions 
Adverse Events 
Severity Grade 
of the Event 
(NCI CTCAE 
version5.0 ) 
Dose Modifications 
Toxicity Management 
improves to Grade ≤1 and 
after completion of steroid 
taper. 
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 imAE does not 
resolve to Grade ≤1 within 
30 days. 
 
For Grade 4: 
Permanently discontinue 
study drug/study regimen. 
For Grade 3 or 4: 
− 
Consider, as necessary, discussing 
with study physician. 
− 
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 (e.g., IV IG). 
− 
Once stable, gradually taper steroids 
over ≥28 days. 
Peripheral neuromotor 
syndromes 
(such as Guillain-Barre 
and myasthenia gravis) 
Refer to CTCAEv5 for 
grade criteria 
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 (e.g., 
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 

 
66 
Specific Immune-Mediated Reactions 
Adverse Events 
Severity Grade 
of the Event 
(NCI CTCAE 
version5.0 ) 
Dose Modifications 
Toxicity Management 
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. 
− 
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. 
 
Grade 1 
No dose modifications. 
For Grade 1: 
− 
Consider, as necessary, discussing 
with the study physician. 
− 
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 study physician. 
− 
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 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 

 
67 
Specific Immune-Mediated Reactions 
Adverse Events 
Severity Grade 
of the Event 
(NCI CTCAE 
version5.0 ) 
Dose Modifications 
Toxicity Management 
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 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 imAE does not 
resolve to Grade ≤1 within 
30 days or if there are 
signs of respiratory 
insufficiency or autonomic 
instability. 
 
For Grade 3 or 4 (severe or life-threatening 
events): 
− 
Consider, as necessary, discussing 
with study physician. 
− 
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. 

 
68 
Specific Immune-Mediated Reactions 
Adverse Events 
Severity Grade 
of the Event 
(NCI CTCAE 
version5.0 ) 
Dose Modifications 
Toxicity Management 
For Grade 4: 
Permanently discontinue 
study drug/study regimen. 
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: 
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. 

 
69 
Specific Immune-Mediated Reactions 
Adverse Events 
Severity Grade 
of the Event 
(NCI CTCAE 
version5.0 ) 
Dose Modifications 
Toxicity Management 
− 
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) 
 
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; new 
onset of 
symptoms) 
 
(Grade 4: Life-
threatening 
consequences; 
urgent 
intervention 
indicated (e.g., 
continuous IV 
therapy or 
mechanical 
- 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 
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 

 
70 
Specific Immune-Mediated Reactions 
Adverse Events 
Severity Grade 
of the Event 
(NCI CTCAE 
version5.0 ) 
Dose Modifications 
Toxicity Management 
hemodynamic 
support)) 
 
drug/study regimen. 
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 
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 

 
71 
Specific Immune-Mediated Reactions 
Adverse Events 
Severity Grade 
of the Event 
(NCI CTCAE 
version5.0 ) 
Dose Modifications 
Toxicity Management 
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. 
 
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 

 
72 
 
 
 
 
Specific Immune-Mediated Reactions 
Adverse Events 
Severity Grade 
of the Event 
(NCI CTCAE 
version5.0 ) 
Dose Modifications 
Toxicity Management 
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 
( severe pain; 
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 4: 
- Permanently 
discontinue study 
drug/study regimen. 
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 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 

 
73 
 
 
PCP ; PO  By mouth; T3  Triiodothyronine; T4  Thyroxine; TB  Total bilirubin; TNF  Tumor necrosis factor; TSH  Thyroid-
stimulating hormone; ULN  Upper limit of normal. 
CTCAE  Common Terminology Criteria for Adverse Events; IM  Intramuscular; IV  Intravenous; NCI  National Cancer Institute. 
Table 7.7.1 (cont.) Infusion-related Reactions 
Severity Grade of 
the Event (NCI 
CTCAE 
version 5.0 ) 
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). 

 
74 
Table 7.7.1 Non-immune-mediated Reactions 
Severity Grade of the 
Event (NCI CTCAE 
version 5.0 ) 
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 IND 
Medical Monitor.). 
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 Study Physician.” 
AE  Adverse event; CTCAE  Common Terminology Criteria for Adverse Events; NCI  National Cancer Institute. 
 
 
 
8. PHARMACEUTICAL INFORMATION 
 
A list of the adverse events and potential risks associated with the investigational or 
commercial agents administered in this study can be found in Section 7.1. 
 
 
8.1 Identity of Investigational Products 
MedImmune 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, 

 
75 
275 mM trehalose dihydrate, 0.02% (w/v) polysorbate 
80, at pH 6.0 
Tremelimumab 
MedImmune 
Formulated at a nominal concentration of 20 mg/mL in 
20 mM histidine/histidine HCl, 222 mM trehalose 
dihydrate, 0.02% (w/v) polysorbate 80, and 0.27 mM 
EDTA, pH 5.5. 
 
 
 
 
 
OLECLUMAB (liquid) 
MedImmune 
Oleclumab is supplied as a sterile liquid product. It is 
formulated at 50 mg/mL in 25 mM histidine/histidine 
hydrochloride, 240 mM sucrose, 0.03% (w/v) 
polysorbate 80, pH 6.0.  
 
 
Monalizumab 
Merck (Drug 
substance), 
Rentschler (Drug 
Product) 
Monalizumab is supplied as 100mg/vial as a 
lyophilized powder in a 10 mL vial. 
Additional ingredients are L-Histidine buffer, sucrose 
for tonicity/stability, polysorbate 80 for surfactant, 
hydrogen chloride for pH adjustment, and sodium 
hydroxide for pH adjustment. 
 
 
The investigator’s or site’s designated investigational product manager is required to 
maintain accurate investigational product accountability records. Commercially available 
IV bags containing 0.9% (weight per volume [w/v]) saline or 5% (w/v) dextrose will be 
supplied by the site. Upon completion of the study, copies of investigational product 
accountability records will be returned to MedImmune. All unused investigational product 
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 place at 2°C to 8°C (36°F to 46°F) and must not be frozen. 
 
 
8.1.1 Investigational Product Inspection 
 
Investigational products 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 and site monitor should be notified immediately. Refer to the Product 
Complaint section (8.1.6) for further instructions. 
 
8.1.2 Investigational Agents 
 
Durvalumab  
The doses of durvalumab will be a flat dose.  This prescription is based on an expectation of 
similar pharmacokinetic exposure and variability to weight-based dosing.  If a patients’ 
weight drops below 30 kg, then therapy must be held until the weight returns to 30 kg or 
more. 
 
  
Durvalumab will be given at a dose of 1500 mg IV flat dose per 4 week cycle. 
 

 
76 
Durvalumab will be supplied as a 500 mg/vial concentrate solution for infusion after 
dilution. 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. The nominal fill volume is 10.0 mL. If there are any defects noted with the 
investigational product, the investigator and site monitor should be notified immediately. 
Refer to the Product Complaint section (section 8.1.6) for further instructions. 
 
Tremelimumab 
 
The dose of tremelimumab will be a flat doses.  This prescription is based on an expectation 
of similar pharmacokinetic exposure and variability to weight-based dosing.   If a patients’ 
weight drops below 30 kg than therapy must be held until the weight returns to 30 kg or 
more. 
 
Tremelimumab will be given at a flat dose of 75 mg IV once pre-operatively along with 
Durvalumab. 
 
Tremelimumab is supplied as a sterile IV solution for infusion after dilution, filled in 20 mL 
clear glass vials with a rubber stopper and aluminum seal. Each vial contains 20 mg/mL 
(with a nominal fill of 20.0 mL accounting to 400 mg/vial) of tremelimumab, in an isotonic 
solution at pH 5.5. During the inspection if the solution is not clear or any turbidity, 
discoloration, or particulates are observed, notify your site monitor and store the vial(s) in 
QUARANTINE at refrigerated (2ºC to 8ºC) temperature for drug accountability and potential 
future inspection. 
 
Oleclumab 
 
 
Liquid product:  
The product is supplied as a sterile liquid product in a 10R glass vial at nominal fill volume 
of 10.0 mL, with each vial containing 500 mg (nominal) of active investigational product. 
This is formulated at 50 mg/mL in 25 mM histidine/histidine hydrochloride, 240 mM 
sucrose, 0.03% (w/v) polysorbate 80, pH 6.0. The drug is intended for IV administration 
following dilution into commercially available 0.9% (w/v) saline.  
 
Oleclumab will be given at a flat dose of 3000 mg IV with durvalumab.  
 
If there are any defects noted with the investigational product, the investigator and site 
monitor should be notified immediately. Refer to the Product Complaint section (section 
8.1.6) for further instructions. 
 
Monalizumab 
 
Monalizumab is supplied as a 100 mg/vial lyophilized powder in a 10 mL vial.  Vials of the 
drug product should be reconstituted in 1.1 mL of sterile water for injection. After 
reconstitution, the concentration of the active ingredient monalizumab in the solution is 

 
77 
100 mg/mL, and 1 mL can be drawn from the vial.  The reconstituted drug product is a clear 
to slightly opalescent and colorless to slightly yellow liquid, essentially free of visible 
particles and with a pH of 6.0.  
 
Monalizumab will be given at a flat dose of 750 mg IV with durvalumab.  
 
If there are any defects noted with the investigational product, the investigator and site 
monitor should be notified immediately. Refer to the Product Complaint section (section 
8.1.6) for further instructions. 
 
 
8.1.3 Dose Preparation Steps 
 
 
Durvalumab (MEDI4736) 
No incompatibilities between Durvalumab and polyvinylchloride or polyolefin IV bags have 
been observed. Total in use storage time from needle puncture of Durvalumab vial to the 
start of administration should not exceed 4 hours at room temperature or 24 hours at 2°C 
to 8°C (36°F to 46°F). If the in-use storage time exceeds these limits, a new dose must be 
prepared from new vials. Durvalumab does not contain preservatives, and any unused 
portion must be discarded. The infusion solution in the prepared final IV bag should be 
equilibrated to room temperature prior to administration. 
 
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  concentration ranging from 1 to 15 mg/mL, and 
delivered through an IV administration set with a 0.2- or 0.22-μm in-line filter. 
 
Preparation of Durvalumab and preparation of the IV bag are to be performed aseptically by 
the investigational product manager or qualified personnel using the following steps: 
 
1. Select 3 vials of investigational product required to prepare the subject’s dose. 
2. Add 30 mL of durvalumab (ie, 1500mg of durvalumab  to the IV bag. The IV bag size 
should be selected such that the final concentration is within 1 to 15 mg/mL. The bag is 
mixed by gentle inversion to ensure homogeneity of the dose in the bag. 
 
Tremelimumab 
 
Tremelimumab does not contain preservatives and any unused portion must be discarded. 
Preparation of tremelimumab and preparation of the IV bag are to be performed 
aseptically. Total in-use storage time from needle puncture of the product vial to start of 
administration should not exceed 4 hours at room temperature or 24 hours at 2ºC to 8°C 
(36ºF to 46°F). If storage time exceeds these limits, a new dose must be prepared from new 
vials. The infusion solution in the prepared final IV bag should be equilibrated to room 
temperature  prior to administration. 
 

 
78 
For dose preparation steps, the following ancillary items are required: 
 
• IV bags of 0.9% (w/v) saline or 5% (w/v) dextrose. IV bags can be made of 
polyvinylchloride (PVC) or polyolefin. 
• IV infusion lines should contain a 0.22 or 0.2-μm in-line filter.  
•  Syringes and needles. 
 
The investigational product manager or qualified personnel will be responsible for preparing 
the IV doses using the following steps: 
 
1. Select one vial of investigational product required to prepare the subject’s dose. 
2. Add 3.8 mL (ie,75 mg of tremelimumab, with the dose volume rounded to the nearest 
tenth mL) to the IV bag. The IV bag size should be selected such that the final concentration 
is within 0.10 to 10 mg/mL. Gently mix the solution in the bag by inverting up and down to 
ensure homogeneity of the dose in the bag. 
 
 
Oleclumab (based on protocol D6010C00005) 
 
The Oleclumab (MEDI9447) doses must be prepared by the investigator’s or site’s 
designated investigational product manager using aseptic technique. 
Total time from needle puncture of the Oleclumab (MEDI9447) 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 preparation time exceeds the time limits a new dose must be prepared from new vials. 
Oleclumab (MEDI9447) does not contain preservatives, and any unused portion must be 
discarded. 
 
No incompatibilities between Oleclumab (MEDI9447) and polyvinylchloride or polyolefin 
bags have been observed. 
 
Dose of 3000 mg will be administered using an IV bag containing 0.9% (w/v) saline, with a 
final Oleclumab  (MEDI9447) concentration ranging from 1.5 to 30 mg/ml, and delivered 
through an IV administration set with a 0.2- or 0.22-μm in-line filter. Add 60.0 mL (ie, 3000 
mg dose) of Oleclumab (MEDI9447) to the IV bag. The IV bag size should be selected such 
that the final concentration is within 1.5 to 30 mg/mL. Mix the bag gently to ensure 
homogeneity of the bag. 
 
 
 
 
Monalizumab 
 

 
79 
   
The dose of monalizumab for administration must be prepared by the investigators or site’s 
designated investigational product manager using aseptic technique.  
Slowly add 1.1 mL of sterile Water for Injection by tilting the vial to one side such that the liquid 
stream is directed along the vial wall and not directly onto the lyophilized cake. Gently swirl the 
solution until all solids are dissolved. DO NOT SHAKE OR VIGOROUSLY AGITATE THE 
VIAL. Visually inspect the solution to ensure that the entire content of the lyophilized cake is 
completely reconstituted. The reconstituted solution should appear clear to opalescent. A thin 
layer of bubbles on the surface of the liquid is normal.  
Monalizumab should be protected from direct sunlight during preparation and handling. Total 
time from start of reconstitution to the start of monalizumab administration must be no longer 
than 4 hours and the temperature must be kept lower than 25°C. No freezing is allowed.  
No incompatibilities between monalizumab and polyethylene, polypropylene, and polyvinyl 
chloride have been observed.  
Add 7.5 mL (750 mg) of monalizumab to the IV bag containing 100 to 500 mL of 0.9% saline. A 
total of 750 mg will be delivered through a 0.2- or 0.22-μm polyether sulfone in-line filter 
(ethylhexyl-phthalate free). Mix the bag by gently inverting to ensure homogeneity of the dose in 
the bag. 
 
8.1.4 Treatment Administration 
The first day of dosing is considered Day 1.  
 
For cohort A tremelimumab will be administered first; the durvalumab infusion will start 
approximately 1 hour (maximum 2 hours) after the end of the tremelimumab infusion. 
Standard infusion time for each is approximately 60 minutes In the event that there are 
interruptions during infusion, the total allowed time should not exceed 8 hours at room 
temperature.  
 
For cohort B, oleclumab will be infused with standard infusion time of approximately 60 
minutes. The drug will be administered at room temperature (approximately 20 to 25°C) by 
controlled infusion into a peripheral or central vein. Standard infusion time for Oleclumab 
(MEDI9447) is 1 hour; however, if there are interruptions during infusion, the total allowed 
time should not exceed 4 hours at room temperature. If this duration is met, then the 
remainder of the dose should be abandoned and should not be completed with a second 
prepared dose.  On days where both oleclumab and durvalumab are administered, 
durvalumab infusion will start no less than 15 minutes after the end of Oleclumab infusion. 
Standard infusion time for durvalumab is 1 hour; however, if there are interruptions during 
the infusion, the total allowed time should not exceed 8 hours at room temperature.  
 
Do not co-administer other drugs through the same infusion line. 

 
80 
 
Flush the IV line 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. 
 
 
 
 
 
For cohort C durvalumab will be infused first with standard infusion time of approximately 
60 minutes. In the event that there are interruptions during infusion, the total allowed time 
should not exceed 8 hours at room temperature.   
 
 
Each dose of intravenous investigational product should be administered using the 
following guidelines: 
 
1. Investigational product(s) 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.  
Tremelimumab, Durvalumab, Oleclumab, or Monalizumab solution should not be infused 
with each other or with other solutions or medications in the same infusion line. 
 
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 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, 
Tremelimumab, Oleclumab and Monalizumab.  

 
81 
 
Refer to Table 10.4 for monitoring schedule for vitals during dose administration for all 
cohorts. 
 
  
 
 
In the event of Grade ≤ 2 infusion-related reaction, the infusion rate of Durvalumab, 
Tremelimumab, Oleclumab or monalizumab 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, tremelimumab, 
Oleclumab and monalizumab 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 the investigational product must be reported immediately to the 
MedImmune Product Complaint Department by the site with further notification to the site 
monitor. All defects will be communicated to MedImmune and investigated further with the 
Product Complaint Department. During the investigation of the product complaint, all 
investigational product must be stored at labeled conditions unless otherwise instructed. 
MedImmune contact information for reporting product complaints: 
 
Email: productcomplaints@medimmune.com 
Phone: +1-301-398-2105 
+1-877-MEDI-411 (+1-877-633-4411) 
Fax: +1-301-398-8800 
Mail: MedImmune, LLC 
Attn: Product Complaint Department 
One MedImmune Way 

 
82 
Gaithersburg, MD 20878, USA 
 
8.1.7  Additional Study Medications 
 
No other study medications are specified for use in this clinical protocol. 
 
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, tremelimumab, Oleclumab and monalizumab  at 2°C to 8°C (36°F to 
46°F). Do not freeze. 
 
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 to 
MedImmune. All unused investigational product will be returned to MedImmune- 
authorized depot or disposed of upon authorization by MedImmune. 
 
 
9. CORRELATIVE/SPECIAL STUDIES 
9.1 
Laboratory Correlative Studies 
 
All correlative studies will be performed by the Immune Platform at MD Anderson except 
for PD-L1 staining/status. Studies in the study cohorts may include, but are not limited to, 
identification of relevant immunologic biomarkers and CMS typing. Samples include tumor 
biopsy samples prior to checkpoint inhibitor therapy and resection specimens after surgery.  
Peripheral blood samples will be collected in red top tubes at the time points outlined in 
section 5 and in the study calendar in section 10.  We will be attempting to uncover 
biomarkers associated with safety and relapse-free survival.  These will be uncovered 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. 

 
83 
2. Pre- and post-immune checkpoint inhibitor therapy on functional assays related to Teff 
cells. 
3. Immunologic markers obtained in peripheral blood versus those obtained at the tissue 
level.     
4. 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.     
 

 
84 
10. STUDY CALENDAR AND SCHEDULES 
 
 
 
 
 
Table 10.1 Study Calendar from Enrollment until Surgical Resection 
TIME PERIOD 
Screening 
Wk 
Wk 
  
  
1 
4** 
Comment 
within 14 days 
+/-3d 
3 - 10 
weeks** 
  
PROCEDURE 
  
Cohort A: Tremelimumab + 
Durvalumab 
  
X 
  
  
Cohort B: Durvalumab + 
Oleclumab 
  
X 
  
  
Cohort C: Durvalumab + 
Monalizumab 
  
X 
  
  
Liver/lung  resection 
  
  
X 
  
Clinic Visit 
X 
X 
X 
  
Physical Examination 
X 
X 
X 
  
Vital Signs 
X 
X 
X 
Including BP,HR, temperature. 
Obtain vital signs 
Review of Concomitant 
Medication 
X 
X 
X 
  
Laboratory 
X 
X 
X 
CBC w/differential and platelet 
count,LFTs (ALT, AST, total 
bilirubin, alkaline phosphatase), 
BUN or serum urea level, 
creatinine, Ca, Mg, Na, K, Cl, 
glucose)  
CEA lab  
  
X 
X 
  
HIV and hepatitis and 
PT/PTT 
X (within 30 
days allowed) 
  
  
HIV, hepatits B and C testing 
and PT/PTT 
Specialized laboratory tests 
X 
  
X 
Lipase, amylase, TSH, FT4 
Pregnancy test (WOCBP 
only) 
X 
X 
  
Serum or urine pregnancy test to 
be done within 72 hours prior to 
first dose. 
ECOG PS 
X 
X 
X 
see appendix 1 
Adverse Events Assessment 
X 
  
X 
Per CTCAE v4.03 for Cohort A 
and v5.0 for Cohorts B and C 
CT C/A/P with IV contrast 
with tumor measurements 
X (within 30 
days) 
  
X 
  
Immunogenicity Assessment 
(special lab) 
  
X 
X 
  
Liver biopsy (tumor) 
X 
  
  
  
Immuno- genicity 
Assessments, Peripheral 
Blood 
12 red top tubes of blood with 5ml each will be collected for immunological 
assessment. See section 5.1.3 (up to 4 missed blood draws are allowed) 
**Factoring the occurrence of potential immune mediated adverse eventsprior to resection, an allowance of 3 
-10 weeks after the administration of neoadjuvant therapy will be permitted to complete metastatic and/or 
primary resection. 

 
85 
CEA: Carcioembryonic Antigen; ECOG PS: Eastern Cooperative Oncology Group Performance Status; TSH: 
Thyroid stimulating hormone; FT4: Free T4; WOCBP: Women of child bearing potential; CT C/A/P: CT scan 
chest, abdomen and pelvis 
 
 
 
 
 
 
Table 10.2 Post-Resection Study Calender for Cohort A (Durvalumab + 
Tremlimumab)  
(Week 1 begins the day Durvalumab treatment is given) 
TIME 
PERIO
D 
Post-
operative 
evaluatio
n 
Wk 
Wk 
Wk 
Wk 
Wk 
Comment 
  
1 
5 
9 
13 
every 4months 
  
(0.5-
2wks 
post 
surgery) 
+/-
3d 
+/-
7d 
+/-7d 
+/-7d 
+/-6 weeks 
  
PROCE
DURE 
  
Durvalu
mab 
  
X 
X 
X 
X 
  
 If patient requires >12 
weeks for postop recovery, 
they will not be initiated on 
adjuvant immunotherapy 
Clinic 
Visit 
X 
X 
X 
X 
X 
X 
  
Physical 
Examinat
ion 
X 
X 
X 
X 
X 
X 
  
Vital 
Signs 
X 
X 
X 
X 
X 
X 
Including BP, HR, 
temperature 
Review 
of 
Concomi
tant 
Medicati
on 
X 
X 
X 
X 
X 
 
  
Laborato
ry 
X 
X 
X 
X 
X 
X 
CBC w/differential and 
platelet count,LFTs (ALT, 
AST, total bilirubin, alkaline 
phosphatase), BUN or 
serum urea level, creatinine, 
Ca, Mg, Na, K, Cl, glucose)  
CEA 
X 
  
  
X 
  
X 
  
TSH/FT4 
X 
  
  
X 
  
 
  
Lipase/a
mylase 
X 
  
  
  
  
  
  
Immuno
genicity 
Assessm
ents, 
Periphera
l Blood 
X 
  
  
  
X 
X (at first visit 
only) 
  

 
86 
Pregnanc
y test 
(WOCB
P only) 
  
X 
As indicated clinically 
Serum or urine 
pregnancy test 
to be done 
within 72 hours 
of dose 
ECOG 
PS 
X 
X 
X 
X 
X 
 
see appendix 1 
Adverse 
Events 
Assessm
ent 
X 
X 
X 
X 
X 
 
Per CTCAE v4.03 for 
Cohort A and v5.0 for 
Cohorts B and C 
CT 
C/A/P 
with IV 
contrast 
with 
tumor 
measure
ments 
  
  
  
  
X 
X 
  
Immuno
genicity 
Assessm
ents, 
Periphera
l Blood 
Up to 12 tubes of blood with 5ml each will be collected for immunological assessment. For specific 
details see laboratory manual (up to 4 missed blood draws are allowed) 
 
CEA: Carcioembryonic Antigen; ECOG PS: Eastern Cooperative Oncology Group Performance Status; 
TSH: Thyroid stimulating hormone; FT4: Free T4; WOCBP: Women of child bearing potential; CT 
C/A/P: CT scan chest, abdomen and pelvis 
 
Toxicity 30 day f/u can happen 30 days (+/-2 weeks) after last treatment dose and this can be done by 
phone call. 
 
Note after one year of follow-up without recurrence schedule of follow-ups can be adjusted according to 
standard of care. This will take precedence over the study calendar.  
 
Table 10.3 Post-Resection Study Calender for Cohorts (B and C) 
TIME 
PERIOD 
Post-
operative 
evaluation 
Wk 
Wk 
Wk 
Wk 
Wk 
Wk 
Wk 
Wk 
Wk 
Commen
t 
  
1             
(same day as 
Durvalumab) 
3 
5 
7 
9 
11 
13 
15 
every 
4mont
hs 
 
(0.5-2wks 
post 
surgery) 
+/-3d 
+/-3d 
+/-3d 
+/-3d 
+/-3d 
+/-3d 
+/-
3d 
+/-
3d 
+/-6 
weeks 
 
PROCED
URE 
  
Durvalum
ab 
  
X 
 
X 
 
X 
 
X 
 
 
 If 
patient 
requires 
>12 
weeks 
for 
postop 
recovery
, they 
will not 
be 
initiated 
on 
adjuvant 
immunot
herapy 
Olecluma
b ( cohort 
B)  
  
X 
X 
X 
X 
X 
X 
X 
X 
 
Monalizu
mab 
(cohort C) 
 
X 
 
X 
 
X 
 
X 
 
 
Clinic Visit 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
Physical 
Examinatio
n 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
Vital Signs 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
Includin
g BP, 
HR, 

 
87 
temperat
ure 
Review of 
Concomita
nt 
Medication 
  
X 
X 
X 
X 
X 
X 
X 
X 
 
  
Laboratory 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
CBC 
w/differe
ntial and 
platelet 
count,LF
Ts 
(ALT, 
AST, 
total 
bilirubin, 
alkaline 
phosphat
ase), 
BUN or 
serum 
urea 
level, 
creatinin
e, Ca, 
Mg, Na, 
K, Cl, 
glucose)  
CEA 
X 
  
  
  
  
  
  
  
X 
X 
  
TSH/FT4 
X 
  
  
X 
  
X 
  
X 
  
 
  
Lipase/am
ylase 
X 
  
  
  
  
  
  
  
  
 
  
Immunoge
nicity 
Assessmen
ts, 
Peripheral 
Blood 
X 
  
 
X 
 
 
 
X 
  
X (at 
first 
visit 
only) 
  
Pregnancy 
test 
(WOCBP 
only) 
 
X 
As indicated clinically 
 
Serum or 
urine 
pregnanc
y test to 
be done 
within 
72 hours 
of dose 
CT C/A/P 
with IV 
contrast 
with tumor 
measureme
nts 
 
 
 
 
 
 
 
X 
 
X 
 
ECOG PS 
  
X 
 
X 
 
X 
 
X 
 
 
see 
appendix 
1 
Adverse 
Events 
Assessmen
t 
  
X 
X 
X 
X 
X 
X 
X 
X 
 
Per 
CTCAE 
v4.03 for 
Cohort 
A and 
v5.0 for 
Cohorts 
B and C 
Immunoge
nicity 
Assessmen
ts, 
Peripheral 
Blood 
 
Up to 12 tubes of blood with 5ml each will be collected for immunological assessment. 
For specific details see laboratory manual (up to 4 missed blood draws are allowed) 

 
88 
 
CEA: Carcioembryonic Antigen; ECOG PS: Eastern Cooperative Oncology Group Performance Status; TSH: Thyroid 
stimulating hormone; FT4: Free T4; WOCBP: Women of child bearing potential; CT C/A/P: CT scan chest, abdomen and 
pelvis 
 
Toxicity 30 day f/u can happen 30 days (+/-2 weeks) after last treatment dose and this can be done by phone call. 
 
Note after one year of follow-up without recurrence schedule of follow-ups can be adjusted according to standard of care. 
This will take precedence over the study calendar. 
 
 
 
 
 
 
 
 
11. MEASUREMENT OF EFFECT 
 
RECIST 1.1 will be used to identify measurable disease on baseline CT scans.  Tumor 
measurements will be made upon restaging CT scans prior to surgery.  Further imaging will 
be performed according to the study outline in section 5 and study calendar in section 10.  
No tumor measurements will take place post-operatively as the goal of therapy is no 
evidence of disease.  Suspected first site of recurrence should be biopsied to confirm CRC 
recurrence unless interval imaging demonstrates clear growth / progression.   
 
11.1.1. Definitions 
 
 
Evaluable for toxicity.  All patients will be evaluable for toxicity from the time of 
enrollment. 
 
Table 10.4 Collection Times for Vitals During Treatment Period 
Treatmen
t Arm 
Durvalumab 
Tremelimumab 
Oleclumab 
Monolizumab 
Pre-
dose 
During 
EOI 
Pre-
dose 
During 
EOI 
Pre-
dose 
During 
EOI 
Pre-
dose 
During 
EOI 
Cohort A 
Within 
30 
mins 
N/A 
Within 
15 mins 
Within 
30 mins 
Q15 
mins 
Within 
5, 30 
and 60 
mins 
N/A 
N/A 
N/A 
N/A 
N/A 
N/A 
Cohort B 
Within 
30 
mins 
N/A 
Within 
15 mins 
N/A 
N/A 
N/A 
Within 
30 
mins 
None 
Within 
15 
mins 
N/A 
N/A 
N/A 
Cohort C 
Within 
30 
mins 
N/A 
Within 
15 mins 
N/A 
N/A 
N/A 
N/A 
N/A 
N/A 
Within 
30 
mins 
N/A 
Within 5, 
and 30  
All Cohorts will require an additional 2-hour observation period for Dose-1 of each drug. This will not be 
required for subsequent doses unless the subject experiences an infusion reaction.  Note: exact times for vital 
signs are approximate. 

 
89 
Evaluable for recurrence.  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 recurrence.  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 >20 mm with conventional techniques (CT, MRI, x-ray) or as >10 mm with 
spiral 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. 
 
Non-measurable disease.  All other lesions (or sites of disease), including small 
lesions (longest diameter <20 mm with conventional techniques or <10 mm 
using spiral 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 
 
CT will be used for all evaluations.  
 
11.1.4 Response Criteria 
 

 
90 
Subjects will be monitored for recurrence, not response, and thus no formal response 
criteria will be employed. 
 
11.1.5 Relapse-Free Survival 
 
Relapse-Free Survival is defined as the time from surgical excision of CRCLM to 
evidence of definite recurrence, as determined by the treating physician. 
 
12. 
DATA REPORTING REQUIREMENTS / STUDY AND DATA MANAGEMENT 
 
12.1 
Training of Study Site Personnel 
Before the first subject is entered into the study, a MedImmune representative will review 
and discuss the requirements of the Clinical Study Protocol and related documents with the 
investigational staff and also train them in any study-specific procedures and system(s) 
utilized. 
 
The principal investigator will ensure that appropriate training relevant to the study is given 
to all of these staff, and that any new information relevant to the performance of this study is 
forwarded to the staff involved. The principal investigator will maintain a record of all 
individuals involved in the study (medical, nursing and other staff). 
 
12.2 
Monitoring of the Study 
During the study, a MedImmune representative will have regular contacts with the study 
site, including visits to: 
 
• Provide information and support to the investigator(s). 
 
• Confirm that facilities remain acceptable. 
 
• Confirm that the investigational team is adhering to the protocol, that data are being 
 
accurately and timely recorded in the eCRFs, that biological samples are handled in 
 
accordance with the Laboratory Manual and that study drug accountability checks are 
 
being performed. 
 
• Perform source data verification (a comparison of the data in the eCRFs with the 
 
subject’s medical records at the hospital or practice, and other records relevant to the 
 
study) including verification of informed consent of participating subjects. This will 
 
require direct access to all original records for each subject (eg, clinic charts). 
• Ensure withdrawal of informed consent to the use of the subject’s biological samples 
isreported and biological samples are identified and disposed of/destroyed accordingly, 
and the action is documented, and reported to the subject. 
 
The MedImmune representative will be available between visits if the investigator(s) or 
other staff at the center needs information and advice about the study conduct. 
 
12.2.1 Source Data 
Refer to the Clinical Study Agreement for location of the source data. 
 
12.2.2 Study Agreements 

 
91 
The principal investigator at each/the center 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. 
 
Agreements between MedImmune and the principal investigator must be in place before 
any study-related procedures can take place, or subjects are enrolled. 
 
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 
An individual subject will be considered to have completed the study if the subject was 
followed through the DLT-evaluation period or experienced a DLT during the DLT-evaluation 
period (for subjects in the dose-exploration phase) or the subject completed at least 1 on-
treatment disease evaluation (for subjects in dose-expansion phase) regardless of the 
number of doses of investigational product that was received. The end of the study (“study 
completion”) is 5 years after the final subject is enrolled or the date the study is closed by 
the sponsor, whichever occurs first. 
 
12.4 Data Management 
Data management will be performed according to the Data Management Plan. 
A Web Based Data Capture system will be used for data collection and query handling. The 
investigator will ensure that data are recorded on the eCRFs as specified in the study 
protocol and in accordance with the instructions provided. 
 
The investigator ensures the accuracy, completeness, and timeliness of the data recorded 
and of the provision of answers to data queries according to the Clinical Study Agreement. 
The investigator will sign the completed eCRFs. A copy of the completed eCRFs will be 
archived at the study site. 
 
 
13. STATISTICAL CONSIDERATIONS 
13.1 
Endpoints 
1. Primary Endpoints 
• Feasibility will be assessed by whether or not the patient successfully goes to surgery 
following the planned treatments, scans, and biopsy.   
• Safety will be assessed by CTCAE version 4.03 for cohort A and 5.0 for cohorts B and C. 
2.  Secondary Endpoints 
• Various immune parameters 
• Response - irRECIST 
• Overall survival (OS) measured from the date of study entry until death from any cause 
• Relapse-free survival (RFS) from the date of study entry until relapse or death from any cause 

 
92 
13.2 
Sample Size Justification 
 
Sample sizes of 15 and 25 patients, are driven by safety and feasibility endpoints.  
The selection of 25 patients in cohort A ensures that if the trial continues to full size, 
a posterior 95% credible interval (ci) of surgery received will be (0.62, 0.92), 
assuming that the proportion of patients successfully getting to surgery is 80%, with 
a prior of beta(1.2, 0.8) and 20 patients getting to surgery. Cohorts B and C will 
enroll 15 patients, which will ensure that a posterior 95% credible interval (ci) of 
surgery received will be (0.57, 0.94), assuming that the proportion of patients 
successfully getting to surgery is 80%, with a prior of beta(1.2, 0.8) and 12 patients 
getting to surgery. The smaller number in cohorts B and C are due to feasibility 
constraints of accrual rate and overall trial budget.  We expect to enroll 
approximately 25 patients in Cohort A by the time this protocol revision is approved.   
 
In order to ensure a homogenous population clinical trial will require that at least 
66% of patients have pre-treatment with either no chemotherapy or oxaliplatin-
based chemotherapy.  The use and type of per-operative therapy prior to 
enrollment in this clinical trial will be monitored. 
 
13.3      Interim Monitoring 
A Bayesian sequential monitoring design[66, 67] will be used to monitor the trial for 
surgery and toxicity rates.  Generally, interim analyses will begin after 3 patients 
become evaluable, and will then be performed continuously to ensure that patients 
are exhibiting reasonable toxicity and surgery rates to continue the trial.  Specific 
rules are in each subsection below.  Since 1-2 patients are expected to be enrolled 
each month, monitoring data will be kept up-to-date and the tables below checked 
prior to consenting each patient once the 3rd patient in each cohort has been on 
study 4 weeks after the first dose of Durvalumab. Enrollment will not need to wait 
for the previous patient to become evaluable, but the rules will be checked for all 
evaluable patients before consenting each patient.  This includes a risk of 1-2 
patients entering on the study beyond the designed stopping rules, which is 
considered a reasonable risk.  If accrual occurs faster than 1-2 patients per month, 
this practice will be reconsidered.  All calculations for stopping boundaries and 
operating characteristics were performed in Multc Lean Desktop v2.1. 
 
Patients will be evaluable once they have received the first dose of 
Durvalumab/tremilimumab, durvalumab/oleclumab or durvalumab/monalizumab 
and have then had 8 weeks time to go to surgery.  If surgery has not occurred by 8 
weeks then for monitoring these patients will have been considered not to have 
gone to surgery even if they do after 8 weeks.  Patients will be allowed up to 12 
weeks to complete surgical resection. If surgical resection is not done within 12 
weeks from then patient will be removed from clinical trial  
 
13.3.1  Interim Analyses for Futility per cohort 

 
93 
 For futility, the trial will be stopped early if Pr[θS < 0.60 | data] > 0.90 , where θS 
denotes the proportion of patients who successfully receive surgery. That is, 
given the outcomes from the patients who have already been evaluated, if it is 
determined that there is a more than 90% chance that the surgery rate is 60% or 
less, the trial will be stopped for futility. Assuming a prior distribution of θS of 
~beta(1.2, 0.8) for this experimental treatment  against a constant 60%, pre-
defined stopping boundaries corresponding to this probability criterion are 
provided in the following table.  Once 3 patients have been enrolled in a cohort, 
follow the instructions in this table according to the schedule described above. 
 
If there are this 
many (or more) 
patients whose 
surgery status is 
determined 
Stop if there are 
this many or 
fewer patients 
who received 
surgery 
If there are this 
many (or more) 
patients whose 
surgery status is 
determined 
Stop if there are 
this many or 
fewer patients 
who received 
surgery 
3 
0 
15* 
6 
5 
1 
17 
7 
7 
2 
19 
8 
9 
3 
20 
9 
11 
4 
22 
10 
13 
5 
24 
11 
* Cohorts B and C will stop at 15 patients regardless of the number of patients who 
received surgery 
 
Three patients will be accrued first. If 0 of the 3 patients receive surgery in a 
given cohort as scheduled, the cohort should be stopped and the treatment will 
be declared as not feasible for this population. If there is at least 1 patient with 
surgery, the next patient will be entered in the study, unless the trial needs to 
stop according to the toxicity boundaries below.  Check continuously as 
described above for sufficient surgery rate assuming the trial does not stop for 
toxicity first.  The operating characteristics for futility and toxicity are 
summarized below the toxicity rules. 
 
13.3.2 Interim Analyses for Toxicity 
Under the same model described for futility, toxicities will be monitored 
assuming a prior probability of toxicity following Beta(0.6,1.4) in the current 
treatment arm against a constant rate of 0.30.   Based on a previous study, we 
assume that a 15% rate of toxicity events would be acceptable and a 30% rate of 
toxicity would be unacceptable. [68]  For trial monitoring and decisions about 
future trials, extreme toxicities (TOX) will be defined as any grade 3 or higher 
adverse event that is possibly, probably, or definitely related to any therapy 
received on this protocol and occur between the first dose of Durvalumab  and 
surgery (or 4 weeks after that dose if the patient does not receive surgery as 
scheduled) with the following exception.  Any grade 3 adverse event that is 

 
94 
potentially treatable with steroids will only count as an extreme toxicity if it does 
not improve to grade 2 or better within 2 weeks.  Grade 3 nausea or vomiting 
that responds to anti-emetics within 72 hours and asymptomatic grade 3 or 4 
lipase or amylase elevations will not count as TOX.  The trial will be terminated if 
Prob(ΘTOX > 0.30 | data) > 0.9, where ΘTOX is the proportion of patients 
experiencing a TOX event. Following this rule, the trial will be terminated 
according to the following table once the first 3 patients are evaluable. 
 
 
If there are this many patients (or more) 
with TOX 
3 
4 
5 
6 
7 
8 
9 
10 11 
Stop the cohort if there are this many  (or 
fewer) patients who are evaluable (have 
TOX or completed 4 weeks after first 
Durvalumab dose without TOX) 
3 
7 
9 
12 14 17* 20 22 25* 
* Always stop with 25 patients in Cohort A, but if 11 or more patients have TOX, then this 
treatment regimen is too toxic for further use.  Always stop at 15 patients in Cohorts B 
and C, but if 8 or more patients have TOX, then this regimen is too toxic for further use. 
 
Three patients in each cohort will be accrued first. If 3 of the 3 patients have 
TOX, stop that cohort and the treatment will be declared as too toxic for that 
cohort. If there is at least 1 patient with surgery without TOX, the next patient 
will be entered in the study, unless the trial needs to stop according to futility 
boundaries above.  Check continuously as described above for toxicity assuming 
the trial does not stop for futility first.  The operating characteristics for the 
combined futility and toxicity are summarized in the following table 
 
The operating characteristics for the combined futility and toxicity based on Multc Lean are 
shown in the following table, assuming that toxicity and surgery rates are independent.   
 
 
 
 
 
Stop if Prob(ΘTOX > 0.30 | data) > 0.90  
or Prob (θS < 0.60 | data) > 0.90 
 
 
Cohort A (N=25) 
Cohorts B and C ( N=15) 
True  
Toxicity 
 Rate 
True  
Surgery  
Rate 
Pr(stop early) 
Mean Number of 
Patients 
Median 
(25th %ile, 
75th %ile) Pr(stop early) 
Mean 
Number of 
Patients 
Median 
(25th %ile, 
75th %ile) 
0.10 
0.50 
0.59 
16.2 
19 (7, 25) 
0.43 
11.4 
15 (7, 15) 
0.20 
0.50 
0.62 
15.6 
17 (7, 25) 
0.46 
11.1 
15 (7, 15) 
0.30 
0.50 
0.69 
13.9 
12 (5, 25) 
0.55 
10.3 
12 (5, 15) 
0.40 
0.50 
0.83 
11.2 
7 (4, 19) 
0.69 
8.9 
7 (4, 15) 
0.50 
0.50 
0.94 
8.3 
6 (4, 11) 
0.84 
7.3 
6 (4, 11) 
0.10 
0.60 
0.27 
20.8 
25 (20, 25) 
0.21 
13.2 
15 (15, 15) 

 
95 
0.20 
0.60 
0.32 
20.0 
25 (15, 25) 
0.25 
12.8 
15 (15, 15) 
0.30 
0.60 
0.46 
17.6 
25 (7, 25) 
0.37 
11.8 
15 (7, 15) 
0.40 
0.60 
0.69 
13.7 
11 (5, 25) 
0.57 
10.1 
11 (5, 15) 
0.50 
0.60 
0.90 
9.6 
7 (4, 12)  
0.78 
8.1 
7 (4, 12)  
0.10 
0.70 
0.09 
23.5 
25 (25, 25) 
0.08 
14.3 
15 (15, 15) 
0.20 
0.70 
0.14 
22.5 
25 (25, 25) 
0.12 
13.9 
15 (15, 15) 
0.30 
0.70 
0.31 
19.8 
25 (12, 25) 
0.27 
12.7 
15 (12, 15) 
0.40 
0.70 
0.61 
15.2 
15 (6, 25) 
0.50 
10.8 
15 (6, 15) 
0.50 
0.70 
0.87 
10.4 
7 (4, 16) 
0.74 
8.6 
7 (4, 15) 
0.10 
0.80 
0.02 
24.6 
25 (25, 25) 
0.02 
14.8 
15 (15, 15) 
0.20 
0.80 
0.08 
23.6 
25 (25, 25) 
0.07 
14.3 
15 (15, 15) 
0.30 
0.80 
0.27 
20.6 
25 (20, 25) 
0.22 
13.1 
15 (15, 15) 
0.40 
0.80 
0.59 
15.8 
17 (7, 25) 
0.47 
11.1 
15 (7, 15) 
0.50 
0.80 
0.86 
10.7 
7 (4, 16) 
0.73 
8.8 
7 (4, 15) 
 
 
13.3.3 Interim Analyses for Toxicity Post Surgery Immune-therapy  
Under the same model described for futility and toxicity above, toxicities on 
immune-therapy after surgery will be monitored assuming an a priori probability 
of toxicity following Beta(0.4,1.6) in the current treatment against a constant 
rate of 0.20.   For trial monitoring and decisions about future trials, extreme 
toxicities (TOXpost) will be defined as any grade 3 or higher adverse event  that 
is possibly, probably, or definitely related to any therapy received on this 
protocol and occur after surgery between the first dose of adjuvant immune-
therapy  and the final dose received (up to 12 weeks) with the following 
exception.  Any grade 3 adverse event that is potentially treatable with steroids 
will only count as an extreme toxicity if it does not improve to grade 2 or better 
within 2 weeks.  Grade 3 nausea or vomiting that responds to anti-emetics 
within 72 hours and asymptomatic grade 3 or 4 lipase or amylase elevations will 
not count as TOXpost.  The trial will be terminated if Prob(TOXpost > 0.20 | data) 
> 0.9. Following this rule, the trial will be terminated according to the following 
table once the first 3 patients are evaluable. 
 
 
If there are this many patients (or more) with TOXpost 2 
3 
4 
5 
6 
7 
8 
Stop the cohort if there are this many  (or fewer) 
patients who are evaluable (have TOXpost or 
completed 4 weeks after first adjuvant immune-
therapy dose without TOXpost) 
3 
6 
9 
13 17 21 25* 
* Only patients who successfully have surgery and begin treatment with immune-therapy 
will be included. The table goes to 25 patients as the maximum of possible patients. 

 
96 
 
Three patients in each cohort will be accrued first. If 2 of the 3 patients have 
TOXpost, stop this portion of the trial and the adjuvant treatment will be 
declared as too toxic for this population. Check continuously as described above 
for toxicity.  The operating characteristics (OCs) for this stopping rule for are 
summarized in the following table assuming all 25 or 15 patients in each cohort 
receive surgery and start adjuvant immune-therapy.  Since we do not expect all 
25 or 15 patients to enter this portion of the study, the OCs are slightly over-
estimated. 
 
 
 
Stop if Prob(TOXpost > 0.20 | data) > 0.90  
 
Cohort A (N=25) 
Cohorts B and C ( N=15) 
True  
Toxicity 
 Rate 
Pr(stop early) 
Mean Number 
of 
Patients 
Median 
(25th %ile, 75th 
%ile) 
Pr(stop early) 
Mean Number 
of 
Patients 
Median 
(25th %ile, 75th 
%ile) 
0.05 
0.01 
24.8 
25 (25, 25) 
0.01 
14.9 
15 (15, 15) 
0.10 
0.04 
24.2 
25 (25, 25) 
0.04 
14.6 
15 (15, 15) 
0.20 
0.25 
20.8 
25 (24, 25) 
0.20 
13.1 
15 (15, 15) 
0.30 
0.62 
15.2 
16 (5, 25) 
0.47 
10.8 
15 (5, 15) 
0.40 
0.89 
9.9 
6 (3, 15) 
0.73 
8.3 
6 (3, 15) 
 
13.4 Analysis Plan  
Primary endpoint: Each combination regimen will be considered feasible if at least 80% 
of patients successfully undergo surgery.  It will be infeasible if fewer than 60% of 
patients can undergo surgery.  If the successful surgery rate is between 60% and 80%, 
then consideration will be given to toxicity, clinical outcome measures, and immune 
changes to determine whether this regimen warrants further investigation.  The 95% 
posterior credible interval will be calculated for proportion of patients undergoing 
surgery.  Adverse events will be tabulated. 
Additional analyses: Demographic and patient baseline disease characteristics will be 
summarized for all patients. Descriptive tables and figures will be presented for immune 
markers.  Overall (OS) and relapse-free survival (RFS) will be calculated and plotted by 
Kaplan-Meier methods[69].  Relationships between baseline characteristics, immune 
markers, and outcomes (response, OS, or RFS) will be explored with logistic or Cox[70] 
models as patient numbers allow.  No formal hypotheses will be tested, but results will 
be used to design the next formal trial if toxicity and feasibility are reasonable for 
further investigation. 
 
The Investigator is responsible for completing a futility/toxicity summary report, and 
submitting it to the IND Office Medical Affairs and Safety Group, for review and 
approval. This should be submitted after the first 3 evaluable patients per cohort, have 
surgery or 4 weeks after the first dose of immune-therapy, whichever comes first, and 

 
97 
every 2 to 4 evaluable patients thereafter, according to the schedule described in the 
toxicity/futility monitoring tables.  
 
On every summary submission, futility information about previous reported patients will 
need to be updated to week eight.  
 
A copy of the cohort summary should be placed in the Investigator’s Regulatory Binder 
under “sponsor correspondence”.  

 
98 
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102 
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. 
 
 
 
 
 
 
 
 
 
 

 
103 
APPENDIX 2 
 
 

 
104 
Appendix 3 
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 [71]. 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.