Clinical trial NCT02898116
Conditions: Non-small Cell Lung Cancer Carcinoma NSCLC
Keywords: ALK-rearranged ALK-positive ALK Inhibitor Ensartinib X-396 anti-PD-L1 Durvalumab MEDI4736 ALK
Sponsor: Ludwig Institute for Cancer Research
Start date: 2017-05-10; Completion date: 2017-08-04
Enrollment: 2 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This was a Phase 1/2, open-label, multicenter, single-arm study of combination therapy with ensartinib, an anaplastic lymphoma kinase (ALK) inhibitor, and durvalumab, an anti-programmed cell death ligand 1 (PD-L1) antibody, in subjects with ALK-rearranged (ALK-positive) non-small cell lung cancer (NSCLC). Primary study objectives were to determine the recommended combination dose (RCD) and safety and tolerability of the combination. Further objectives were to evaluate the clinical efficacy and biologic activity of the combination.

Detailed description:
Prior to initiation of combination therapy with ensartinib plus durvalumab, subjects were enrolled sequentially to receive ensartinib monotherapy (orally once daily) during a pre-immunotherapy Run-in Period for one to two 28-day cycles. The purpose of the Run-in Period was to determine whether any safety signals might compromise combination therapy and to determine the effect of ALK inhibitor therapy on the immune tumor microenvironment. For subjects with no dose-limiting toxicity (DLT) during the Run-in Period, combination therapy was then initiated during a dose-finding phase using a standard 3 + 3 design until determination of the RCD, which was defined as the highest dose level at which ≤ 1 of 6 subjects (i.e., \< 33%) experienced DLTs during the first 2 cycles of combination treatment.

A fixed dose of durvalumab (1500 mg by intravenous \[IV\] infusion every 4 weeks) was administered in all cohorts. Ensartinib dosing started at 200 mg, with subsequent cohorts receiving a reduced (150 mg) or escalated (225 mg) ensartinib dose depending upon observed toxicity. The study was then designed to include an expansion phase, in which the RCD cohort would be expanded to a total of 20 subjects.

Subjects were monitored for safety (including immune-related adverse events), disease status (using the Response Evaluation Criteria in Solid Tumors \[RECIST\] version 1.1 and immune-related RECIST), and biologic activity (peripheral blood assays and immunological changes in the tumor microenvironment) for the duration of study participation.

Arms: arm 1: Subjects were to receive ensartinib monotherapy during a pre-immunotherapy Run-in Period for one to two 28-day cycles, followed by combination therapy with ensartinib plus durvalumab for subjects with no DLTs during the Run-in Period.
Interventions: intervention 1: Ensartinib intervention 2: Durvalumab
Intervention descriptions: intervention 1: Ensartinib was administered orally once daily at a dose of 200 mg during the Run-in Period. During combination therapy, the ensartinib starting dose was to be 200 mg. Based on observed toxicity at the starting dose level, the ensartinib dose may have been escalated to the recommended single-agent dose (225 mg) or de-escalated to the minimum effective dose (150 mg). intervention 2: During combination therapy, durvalumab was to be administered as an IV infusion over 60 (± 5) minutes every 4 weeks at a dose of 1500 mg.

Protocol documents:
Prot_SAP_000.pdf: 
 
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Study Protocol 
LUD2014-012-ALK 
US-IND# 131960 
NCT02898116 
Amendment 2 
Final  
14-AUG-2017 
 
Protocol Title 
A Phase 1/2 Study of ALK Inhibitor, ensartinib (X-396), and anti-PD-L1, durvalumab 
(MEDI4736), in Subjects with ALK-rearranged (ALK-positive) Non-small Cell Lung Cancer 
(NSCLC) 
 
Objectives and Synopsis 
This is an open-label, multicenter, single-arm study to evaluate the safety and preliminary 
efficacy of a targeted therapy for NSCLC in combination with a checkpoint inhibitor: 
• 
Ensartinib (X-396), an anaplastic lymphoma kinase (ALK) Inhibitor and  
• 
Durvalumab (MEDI4736), an anti-programmed cell death ligand 1 (PD-L1) antibody.  
Prior to starting the combination drug therapy, there will be a pre-immunotherapy Run-in 
Period (one 28-day cycle), where ensartinib will be given as monotherapy. The Run-in Period 
will be followed by the combination drug therapy, starting with Cycle 1. 
The dose escalation phase (see table below) will utilize a standard 3 + 3 design to determine 
the Recommended Combination Dose (RCD), followed by an expansion phase, in which the 
dose escalation cohort at the RCD will be expanded to 20 subjects.   
Dose 
Level 
Doses 
Ensartinib 
Durvalumab 
-1 
150 mg 
1500 mg 
Starting 
200 mg 
1500 mg 
+1 
225 mg 
1500 mg 
NOTE: if a subject’s body weight drops to ≤ 30 kg while on the study, the durvalumab dose 
will be weight based as long as the body weight remains ≤ 30 kg (see Section 6.1.3). 
Primary 
Objective 
[Endpoints] 
Phase 1 Dose Escalation Phase:  
Recommended Combination Dose (RCD) 
Safety and Tolerability [CTCAE 4.03, including DLTs and RCD] 
Expansion Phase:  
Safety and Tolerability [CTCAE 4.03] 
Secondary 
Objectives 
[Endpoints] 
Dose Escalation and Expansion Phases (all subjects): 
Clinical Efficacy by irRECIST and RECIST 1.1 [PFS rate and ORR at 8 and 24 
weeks, overall best response, DCR, DoR, OS] 
Exploratory 
Objectives 
[Endpoints] 
Dose Escalation and Expansion Phases (all subjects): 
Biologic Activity [Effects on Tumor Microenvironment, Immune Response] 
DLT=Dose-limiting Toxicity; RCD=Recommended Combination Dose; ORR=Objective Response Rate; 
DCR=Disease Control Rate; DoR=Duration of Response; PFS=Progression-free Survival; OS=Overall Survival; 
CTCAE=National Cancer Institute Common Terminology Criteria for Adverse Events; RECIST = Response 
Evaluation Criteria in Solid Tumors; irRECIST=immune-related RECIST. 
 


 
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Sponsor: Ludwig Institute for Cancer Research 
 
 
 
 
 
 
 
 
 
 
Sponsor Representative Signature and Date 
Study Chair: Leena Gandhi, MD, PhD, NYU Perlmutter 
Cancer Center, NYU Langone Medical Center 
 
 
 
 
 
 
 
 
 
Study Chair Signature and Date 
 
Confidentiality Statement 
The confidential and proprietary information in this document is owned by the Ludwig Institute for Cancer Research and 
provided to you as an Investigator, potential Investigator, or consultant, for review by you, your staff, and applicable institutional 
review board(s). The information cannot be used, or divulged to any third party or published without the written consent of the 
Ludwig Institute for Cancer Research, except to the extent necessary to obtain informed consent from those persons to whom 
study medication may be administered. Any misappropriation of this information is prohibited by law. 
 


 
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Table of Contents 
1 
Background ............................................................................................................................. 7 
1.1 
Checkpoint Inhibitors and ALK Inhibitors in the Treatment of Non-Small Cell Lung 
Cancer ......................................................................................................................................... 7 
1.2 
Study Drugs ...................................................................................................................... 8 
1.2.1 
Durvalumab (MEDI4736) - PD-L1 Antibody ............................................................. 8 
1.2.2 
Ensartinib (X-396) .................................................................................................. 10 
2 
Study Rationale ..................................................................................................................... 13 
2.1 
Ensartinib Dose .............................................................................................................. 13 
2.2 
Durvalumab Dose .......................................................................................................... 14 
2.2.1 
Pharmacokinetics (PK)/Pharmacodynamics (PD) Data ......................................... 14 
2.2.2 
Clinical Data ........................................................................................................... 15 
2.2.3 
Fixed Dosing for Durvalumab ................................................................................ 15 
2.3 
Rationale for Amendment 2 .......................................................................................... 15 
3 
Experimental Plan ................................................................................................................. 16 
3.1 
Study Design .................................................................................................................. 16 
3.1.1 
Study Phase ........................................................................................................... 16 
3.1.2 
Enrollment/Randomization ................................................................................... 16 
3.1.3 
Blinding/Unblinding ............................................................................................... 16 
3.1.4 
Subject Population................................................................................................. 16 
3.1.5 
Number of Sites/Subjects ...................................................................................... 16 
3.1.6 
Sample Size Considerations ................................................................................... 16 
3.1.7 
Treatment Schema ................................................................................................ 17 
 
Run-in Period ................................................................................................. 18 
 
Dose Escalation Phase ................................................................................... 18 
 
Dose Expansion Phase ................................................................................... 19 
3.1.8 
Dosing Adjustments, Delays, and Discontinuations .............................................. 19 
 
Monitoring for Hepatic Toxicity During Combination Therapy ..................... 20 
3.1.9 
DLT and MTD/RCD for the Combination Therapy ................................................. 20 
3.1.10 
Subject Withdrawal from Treatment or from Study ............................................. 22 
 
Treatment beyond Progression ..................................................................... 22 
3.1.11 
Subject Evaluability and Subject Replacements .................................................... 23 
3.1.12 
Optional Study Treatment Extension .................................................................... 23 
3.1.13 
Interim Analysis ..................................................................................................... 23 
3.1.14 
Safety Monitoring and Study Stopping Rules ........................................................ 23 
3.1.15 
Duration of Study .................................................................................................. 24 
3.1.16 
On Study and Post-Study Follow-up ...................................................................... 24 
 
End of Study Visit ........................................................................................... 25 
3.2 
Study Flowcharts ........................................................................................................... 26 
3.2.1 
Flowchart for Subjects Who Proceed with Combination Therapy after Run-in .... 26 
3.2.2 
Flowchart for Subjects who Continue Treatment with Ensartinib (X-396) 
Monotherapy after Run-in .................................................................................................... 29 


 
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4 
Study Objectives and Endpoints ........................................................................................... 30 
4.1 
Safety and Tolerability ................................................................................................... 30 
4.1.1 
Endpoints and Assessment Methods .................................................................... 30 
4.1.2 
Subject Evaluation and Statistics ........................................................................... 30 
4.2 
Clinical Efficacy .............................................................................................................. 31 
4.2.1 
Endpoints and Assessment Methods .................................................................... 31 
 
Objective Response Rate (ORR) ..................................................................... 31 
 
Disease Control Rate (DCR) ........................................................................... 32 
 
Duration of Response (DoR) .......................................................................... 32 
 
Progression-free Survival (PFS) ...................................................................... 32 
 
Overall Survival (OS) ...................................................................................... 32 
4.2.2 
Subject Evaluation and Statistics ........................................................................... 32 
4.3 
Biological Activity........................................................................................................... 33 
4.3.1 
Endpoints and Assessment Methods .................................................................... 33 
 
Tumor Microenvironment ............................................................................. 33 
 
Biological Activity in Blood Samples .............................................................. 34 
4.3.2 
Subject Evaluation and Statistics ........................................................................... 34 
5 
Subject Eligibility ................................................................................................................... 36 
5.1 
Inclusion Criteria ............................................................................................................ 36 
5.2 
Exclusion Criteria ........................................................................................................... 37 
5.3 
Restrictions on Concomitant Therapies ........................................................................ 40 
5.3.1 
Non-Permitted Concomitant Therapies ................................................................ 40 
5.3.2 
Permitted Concomitant Therapies ........................................................................ 40 
6 
Study Drug Preparation and Administration ........................................................................ 42 
6.1 
Durvalumab (MEDI4736) ............................................................................................... 42 
6.1.1 
Study Drug Information ......................................................................................... 42 
6.1.2 
Durvalumab Investigational Product Inspection ................................................... 42 
6.1.3 
Durvalumab Preparation ....................................................................................... 42 
6.1.4 
Durvalumab Administration .................................................................................. 43 
6.2 
Ensartinib (X-396) .......................................................................................................... 44 
6.2.1 
Study Drug Information ......................................................................................... 44 
6.2.2 
Preparation ............................................................................................................ 44 
6.2.3 
Administration ....................................................................................................... 44 
6.3 
Estimated Study Requirements ..................................................................................... 45 
6.4 
Monitoring of Durvalumab Dose Administration .......................................................... 45 
6.5 
Drug Overdose Management ........................................................................................ 45 
7 
Administrative, Legal and Ethical Requirements .................................................................. 46 
7.1 
Documentation and Reporting of Adverse Events ........................................................ 46 
7.1.1 
Definitions ............................................................................................................. 46 
7.1.2 
Additional Expedited Reporting Requirements for this Study .............................. 47 
 
Pregnancy ...................................................................................................... 47 
 
Overdose ....................................................................................................... 48 
 
Hepatic Function Abnormality ....................................................................... 48 
7.1.3 
Severity of an Adverse Event ................................................................................. 48 


 
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7.1.4 
Relationship of Adverse Events to Study Drug ...................................................... 48 
7.1.5 
General Reporting Requirements .......................................................................... 49 
7.1.6 
Expedited Serious Adverse Event (SAE) Reporting Requirements ........................ 49 
7.1.7 
Serious Adverse Event (SAE) Follow-up Requirements ......................................... 50 
7.1.8 
Adverse Events of Special Interest (AESIs) ............................................................ 50 
7.2 
Administrative Sponsor Requirements ......................................................................... 53 
7.2.1 
Study Master Files ................................................................................................. 53 
7.2.2 
Case Report Form Data Collection ........................................................................ 53 
7.2.3 
Language ................................................................................................................ 53 
7.2.4 
Monitoring ............................................................................................................. 53 
7.2.5 
Protocol Amendments ........................................................................................... 54 
7.2.6 
Premature Subject Withdrawal from Treatment or from Study ........................... 54 
7.2.7 
Early Trial Termination .......................................................................................... 54 
7.2.8 
Study Drug Shipments and Accountability ............................................................ 54 
7.3 
Regulatory, Legal and Ethical Requirements ................................................................. 55 
7.3.1 
Good Clinical Practice (GCP), Laws and Regulations ............................................. 55 
7.3.2 
Informed Consent .................................................................................................. 55 
7.3.3 
Institutional Review Board .................................................................................... 55 
7.3.4 
Subject Confidentiality .......................................................................................... 56 
8 
Appendices ........................................................................................................................... 57 
8.1 
Protocol Version History ................................................................................................ 57 
8.2 
Participating Study Sites, Investigators and Staff, Laboratories, and Sponsor 
Information ............................................................................................................................... 61 
8.3 
Dose Adjustments and Delays for Durvalumab ............................................................. 62 
8.3.1 
Durvalumab Dose Modification Due to Toxicity ................................................... 62 
8.3.2 
Durvalumab Dose Modification Not Due to Treatment-related Toxicities ........... 64 
8.4 
Ensartinib (X-396) Toxicity Management and Dose Modification................................. 66 
8.5 
RECIST 1.1 and irRECIST Guidelines ............................................................................... 69 
8.6 
Exploratory Assessment of Correlative Immunologic Research .................................... 77 
8.7 
Drugs with Known Risk of Torsades de Pointes ............................................................ 78 
8.8 
ECOG Performance Status ............................................................................................. 79 
8.9 
List of Abbreviations ...................................................................................................... 80 
9 
References ............................................................................................................................ 83 
 
 


 
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Figures 
Figure 1. Dose Escalation and De-Escalation Schema ................................................................... 19 
 


 
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1 Background 
1.1 Checkpoint Inhibitors and ALK Inhibitors in the Treatment of Non-
Small Cell Lung Cancer 
Lung cancer is responsible for nearly 1 in 5 cancer-related deaths, or an estimated 1.6 million 
people, worldwide. In the U.S., lung cancer is the leading cause of cancer-related death among 
both men and women.(1)  For patients who are diagnosed with advanced disease, conventional 
treatment options including surgery, chemotherapy, and radiation are unlikely to result in cure.  
Lung cancer has also emerged as an exciting target of immune-based therapies, specifically 
checkpoint inhibitors.(2)  In non-small cell lung cancer (NSCLC), marked single-agent activity has 
been observed with inhibition of programmed death receptor 1 (PD-1) on immune cells or 
inhibition of programmed death receptor ligand 1 (PD-L1).(3-5)  Notably, PD-L1 appears to be 
expressed in 25% to 50% of NSCLC tumors, with expression both on tumor cells and within the 
tumor microenvironment (TME) on tumor-associated macrophages.(6)  While the relationship of 
expression to therapeutic response is still being defined, early studies indicate there may be 
some activity of such inhibitors in NSCLC.(7-9) 
PD-1/PD-L1 inhibitors in NSCLC 
Checkpoint inhibitors, particularly PD-1/PD-L1 antibodies, have been shown to be effective in 
the treatment of NSCLC (10-12), and in 2015, nivolumab and pembrolizumab were approved by 
FDA for the treatment of lung cancer after progression on or after platinum-based 
chemotherapy.  
In March 2015, FDA approved the PD-1 checkpoint inhibitor nivolumab for the treatment of 
advanced squamous NSCLC that has stopped responding to chemotherapy. This approval was 
based on results of a Phase 3 trial in which subjects receiving nivolumab had median overall 
survival was 9.2 months versus 6.0 months with docetaxel.(11)  In October 2015, FDA expanded 
its approval of nivolumab to include non-squamous NSCLC that has stopped responding to 
chemotherapy. This approval was based on the results of a Phase 3 trial that showed that 
subjects who received nivolumab had a median overall survival of 12.2 months compared to 9.4 
months for those receiving docetaxel. (10)  
Also in October 2015, pembrolizumab, a PD-1 checkpoint inhibitor was approved for patients 
with NSCLC (both squamous and non-squamous) with tumors that test positive for PD-L1. In a 
Phase 1 clinical trial, PD-L1 expression level of 50% was associated with the likelihood of clinical 
benefit. Among subjects with a proportion score of at least 50%, the response rate was 45.2%. 
(12)  
For both of these immunotherapies, it is recommended that patients with epidermal growth 
factor receptor (EGFR) or ALK genomic tumor aberrations should have disease progression on 
FDA-approved therapy prior to receiving nivolumab or pembrolizumab. 
Both nivolumab and pembrolizumab are being studied in multiple indications in randomized 
Phase 3 trials compared to standard of care chemotherapy as first-line treatment, and several 
other PD-1/PD-L1 checkpoint inhibitors are also in late stage clinical testing.  


 
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ALK Inhibitors 
Anaplastic lymphoma kinase (ALK) was first identified as a chromosomal rearrangement in 
anaplastic large cell lymphoma (ALCL). Genetic studies indicate that abnormal expression of ALK 
is a key driver of certain types of NSCLC and neuroblastomas. Since ALK is generally not 
expressed in normal adult tissues, it represents a highly promising target for molecularly 
targeted cancer therapy.   
Crizotinib was the first ALK inhibitor approved in 2011 for the treatment of patients with 
metastatic ALK positive NSCLC. More recently, ceritinib and alectinib, second generation ALK 
inhibitors, have also been approved for the treatment of patients with ALK positive metastatic 
NSCLC who have progressed on or are intolerant to crizotinib. Ensartinib (X-396) is also a next 
generation ALK inhibitor that has shown greater potency than crizotinib in vitro and in vivo.   
Rationale for combination therapy 
PD-L1 expression may be modulated by anti-cancer therapies and may be more important in the 
setting of oncogene-driven cancers.  For instance, oncogenic EGFR signaling induces PD-L1 
upregulation in EGFR-mutant NSCLC cell lines, and mouse models of EGFR-driven lung 
adenocarcinoma show tumor shrinkage and prolonged survival with PD-1 inhibition.(13)  
Therefore, in oncogene-driven NSCLC in particular, combining targeted therapy with PD-1/PD-L1 
checkpoint inhibitor therapy may be particularly important, as the effective tumor shrinkage 
seen with targeted agents combined with the durable responses seen with PD-1/PD-L1 
checkpoint inhibitor agents may result in lasting tumor control.   
The EML4-ALK fusion oncogene is molecular target in NSCLC.  EML4-ALK positive NSCLC patients 
also have higher PD-L1 expression levels, compared to those negative for the fusion gene,(14) 
suggesting that their tumors are not only driven by EML4-ALK activity but also repress T-cell 
function. Thus, the simultaneous inhibition of EML4-ALK by ensartinib and de-repression of 
T-cell function by checkpoint inhibitors might be necessary, leading to additive or synergistic 
outcomes.  
Tumor lysis due to ALK inhibition may enhance immune priming and thus also contribute to the 
synergy. In addition, ensartinib has some Axl (IC50: 24nM) and CSF1R (IC50:13nM) inhibitory 
activities. Inhibition of Axl activates T-cells,(15) while inhibition of CSF1R modulates the tumor 
microenvironment including tumor-associated macrophages and myeloid-derived suppressor 
cells.(16)  Both might further potentiate response to T-cell checkpoint immunotherapy.  
This study will evaluate a checkpoint inhibitor, durvalumab, which targets PD-L1, in combination 
with ensartinib. 
1.2 Study Drugs 
1.2.1 Durvalumab (MEDI4736) - PD-L1 Antibody 
Durvalumab is briefly described in the section below using excerpts that have been extracted 
from the Investigator’s Brochure (IB). Please refer to the current IB for complete and current 
information. 


 
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Durvalumab is a human immunoglobulin G1 kappa monoclonal antibody (mAb) directed against 
human PD-L1.  Durvalumab is selective for recombinant PD-L1 and blocks the binding of 
recombinant PD-L1 to the PD-1 and cluster of differentiation (CD) 80 receptors.  
As of the data cutoff dates in the IB (15Apr2015 to 18Sep2015), a total of 1,910 subjects have 
been enrolled and treated in 30 ongoing durvalumab clinical studies, including 20 sponsored and 
10 collaborative studies. Of the 1,910 subjects, 1,279 received durvalumab monotherapy, 454 
received durvalumab in combination with tremelimumab or other anticancer agents, 14 
received other agents (1 gefitinib, 13 MEDI6383), and 163 have been treated with blinded 
investigational product. No studies have been completed or terminated prematurely due to 
toxicity. 
The safety profile of durvalumab as monotherapy and combined with other anticancer agents 
was consistent with the pharmacology of the target and other agents in the immune checkpoint 
inhibitor class. No tumor types appeared to be associated with unique AEs. Immune-related AEs 
(irAEs), which are important risks of immune checkpoint inhibitors, have been observed with 
durvalumab and include colitis, pneumonitis, hepatitis / hepatotoxicity, neuropathy / 
neuromuscular toxicity, endocrinopathy, dermatitis, and nephritis. In addition, pancreatitis is an 
important potential risk particularly with durvalumab and tremelimumab combination therapy. 
These events are manageable by available/established treatment guidelines as described in 
Section 8.3. 
Partial efficacy data are available for 2 monotherapy studies (CD-ON-MEDI4736-1108 and 
D4190C00007) and 2 combination therapy studies (CD-ON-MEDI4736-1161 and D4190C00006). 
Clinical activity has been observed across the 4 studies, and two of the studies have data for 
NSCLC as detailed below. 
Study CD-ON-MEDI4736-1108: Overall, 456 of 694 subjects treated with durvalumab 10 mg/kg 
Q2W were evaluable for response (defined as having ≥ 24 weeks follow-up, measurable disease 
at baseline, and ≥ 1 follow-up scan, or discontinued due to disease progression or death without 
any follow-up scan). In PD-L1 unselected subjects, the objective response rate (ORR), based on 
investigator assessment per RECIST v1.1, ranged from 0% in uveal melanoma (n = 23) to 20.0% 
in bladder cancer (n = 15), and disease control rate at 24 weeks ranged from 4.2% in triple-
negative breast cancer (n = 24) to 39.1% in advanced cutaneous melanoma (n = 23). PD-L1 
status was known for 383 of the 456 response evaluable subjects. Across the PD-L1 positive 
tumors, ORR was highest for bladder cancer, advanced cutaneous melanoma, hepatocellular 
carcinoma (HCC) (n = 3 each, 33.3% each), NSCLC (n = 86; 26.7%), and squamous cell carcinoma 
of the head and neck (SCCHN; n = 22; 18.2%). In the PD-L1 positive subset, disease control rate 
at 24 weeks was highest in advanced cutaneous melanoma (n = 3; 66.7%), NSCLC (n = 86; 
36.0%), HCC and bladder cancer (n = 3 each; 33.3% each), and SCCHN (n = 22; 18.2%). 
Study D4190C00006: Of the 102 subjects with advanced NSCLC treated with durvalumab in 
combination with tremelimumab, 63 subjects with at least 16 weeks of follow-up were 
evaluable for response (defined as measurable disease at baseline and at least 1 follow-up scan; 
this included discontinuations due to disease progression or death without follow-up scan). Of 
the 63 evaluable subjects, 17 (27%) had a best overall response of partial response (PR), 14 
(22%) had stable disease (SD), 22 (35%) had progressive disease (PD), and 10 (16%) were not 
evaluable. The ORR (confirmed and unconfirmed complete response (CR) or PR) was 27% and 
the DCR (CR, PR, or SD) was 49% as assessed by RECIST v1.1. 


 
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Durvalumab, like other drugs in the anti PD-L1 class, has shown early evidence of activity against 
solid tumors as a single agent and is currently being evaluated in combination with 
tremelimumab and other therapies in NSCLC.(17, 18) 
1.2.2 Ensartinib (X-396) 
Ensartinib is briefly described in this section below.  Refer to the current IB for complete and 
current information.  
ALK is a highly conserved receptor tyrosine kinase (RTK) first discovered as a fusion with 
nucleophosmin (NPM) in ALCL.(19)  ALK has three structural domains: an extracellular ligand-
binding domain, a trans-membrane region, and an intracellular tyrosine kinase domain.  It is 
structurally most similar to leukocyte tyrosine kinase (LTK), and both belong to the insulin-
receptor super family.  Homo dimerization of ALK leads to trans-phosphorylation and kinase 
activation.  In ALK translocations, the 5’ fusion partners provide dimerization domains, 
permitting ligand-independent activation of the kinase.  In addition to NPM in lymphoma, other 
fusion partners for ALK have been described in NSCLC and in inflammatory myofibroblastic 
tumors (IMT).  Activating mutations in wild-type ALK have also been identified in both familial 
and sporadic neuroblastoma.  Most of these activating mutations occur within the tyrosine 
kinase domain and are transforming in vitro and in vivo. 
The EML4-ALK fusion oncogene is a relatively new molecular target in NSCLC.   The ALK fusion 
arises from an inversion on the short arm of chromosome 2 [Inv (2) (p21p23)] that joins exons 1 
to 13 of echinoderm microtubule associated protein-like 4(EML4) to exons 20 to 29 of ALK.  The 
resulting chimeric protein, EML4-ALK, contains an N terminus derived from EML4 and a C 
terminus containing the entire intracellular tyrosine kinase domain of ALK.  The fusion protein is 
constitutively active and a driver of cell transformation in cells expressing the fusion protein. 
The ALK inhibitor, crizotinib, was the first ALK inhibitor approved (2011) for the treatment of 
patients with metastatic ALK positive NSCLC. More recently, ceritinib and alectinib, second 
generation ALK inhibitors, have also been approved for the treatment of patients with ALK 
positive metastatic NSCLC who have progressed on or are intolerant to crizotinib.  
Ensartinib is a second generation ALK inhibitor with activity against certain, but not all, 
crizotinib-resistant mutations.  Ensartinib is a potent and selective ALK inhibitor for the 
treatment of NSCLC in patients with ALK fusion proteins, neuroblastoma in patients with ALK 
mutation, activation, or amplification, other tumor types with ALK fusion, activating mutation, 
or amplification, and tumor types with alterations of or dependence on MNNG HOS 
transforming gene or c-Met (MET).  Ensartinib is currently undergoing Phase 1/2 evaluation 
(20) in subjects with ALK rearranged NSCLC who are either crizotinib naïve or crizotinib resistant 
as described below. A randomized Phase 3 trial comparing ensartinib to crizotinib in tyrosine 
kinase inhibitor (TKI) naïve subjects is planned to be initiated in April 2016. 
In animal studies, ensartinib induced tumor stasis at well-tolerated doses in xenografts of 
human EML4-ALK positive NSCLC in nude mice. Human tumor xenografts of the neuroblastoma 
SH-SY5Y that carry a crizotinib-resistant mutation (F1174L) were growth inhibited by ensartinib. 
In an intracranial tumor model using SH-SY5Y tumors treated with ensartinib and crizotinib at 
equivalent doses, a significant increase in life span was observed in mice treated with ensartinib 
but not in mice treated with crizotinib. Taken together, these non-clinical data supported the 
potential utility of ensartinib in crizotinib-resistant tumors and the potential use of ensartinib for 


 
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the treatment of NSCLC tumors that have metastasized to the brain. The first-in-human (FIH) 
study of ensartinib has demonstrated that ensartinib does, in fact, have good activity in ALK 
positive NSCLC patients who progressed after prior crizotinib and that it has activity against CNS 
metastases. 
The dose escalation phase of the FIH Phase 1/2 study of ensartinib has been completed, and 
enrollment in the expansion cohort phase is ongoing. In this study, ensartinib is administered 
once daily, and cycles are approximately 28 days. Subjects have been treated with doses ranging 
from 25-250 mg once daily (qd). Initially, the study drug was taken without food, although 
subjects in the last cohort in the dose escalation phase took the drug with food (200 mg with 
food cohort). Subjects in the expansion cohorts are assigned to take the drug with or without 
food in Cycle 1; after that, they may take the drug either way.  
Based on data in the database as of March 2016, the total number of subjects enrolled to date is 
63. Of the 63 subjects in the study, 35 have received a dose of ≥ 200 mg. There are 16 subjects 
continuing on treatment, the longest being for 41+ cycles. For the study as a whole, as well as 
those receiving ≥ 225 mg, the drug has generally been well tolerated.  
Two subjects (100 mg and 250 mg) died during the study, related to disease progression; there 
were no drug-related deaths. Eight subjects discontinued for an adverse event (AE), two of 
which were considered by the Investigator to be related to study drug. One was 
hyperbilirubinemia and abdominal pain (200 mg) and the other was thrombotic 
microangiopathy (TMA; 25mg). The latter was considered by the Investigator to be an 
idiosyncratic reaction possibly related to the study drug, but the Sponsor considered it unlikely 
related to study drug and more likely related to other factors.  
Five serious AEs (SAEs) considered drug-related by the Investigator have been reported to date 
from 4 subjects: the TMA described above, peripheral edema and fluid overload (200 mg), and 
erythematous rash (2 subjects; 225 mg and 250 mg). 
The most frequent drug-related adverse events (AEs) are rash, nausea, fatigue, vomiting, and 
pruritis. The most prominent toxicity is skin toxicity, which is easily managed with topical 
treatment and, for the more severe events, holding study drug until improvement and then 
resuming treatment at a reduced dose of study drug. The frequency of gastrointestinal AEs, 
particularly diarrhea, appears to be relatively low for ensartinib, as is the frequency of 
transaminase elevations. Minimal QTc (corrected QT interval) prolongation has been observed 
to date; this has been reported as a related AE (Grade 2) in one subject.  
With respect to preliminary efficacy in ALK positive NSCLC, an overall response rate of 57% 
(20/35 subjects) has been observed to date in all evaluable subjects treated at doses ≥ 200 mg, 
with a median duration of response of approximately 9.5+ months.  
Looking at subpopulations of these subjects, 8 evaluable ALK TKI naïve subjects have been 
enrolled to date at doses ≥200 mg, resulting in a response rate of 88% (7/8 subjects) in the ALK 
TKI naïve subjects. The only one having progressive disease as the best response to ensartinib 
was borderline ALK positive. Although there have been few ALK TKI naïve subjects treated to 
date, good responses have also been observed in subjects who have failed prior crizotinib but 
have not received another ALK TKI (overall response rate of 58%; 11/19 subjects), with a median 
duration of response of approximately 5.5 months. Eight subjects have received a prior second 


 
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generation ALK TKI, with or without prior crizotinib. Two of these subjects have had responses, 
and one had stable disease on ensartinib.  Responses have also been reported in subjects with 
CNS metastases: of the 8 subjects, 4 (50%) had objective responses and 3 had stable disease.   
In summary, ensartinib is a potent second generation ALK inhibitor that is demonstrating activity 
in subjects with ALK positive NSCLC who are either crizotinib-naïve or who have progressed after 
prior crizotinib; and responses have been observed in subjects with CNS metastases and in 
subjects who received another second generation ALK inhibitor. To date, the drug has been 
generally well tolerated, with skin toxicity as the most prominent adverse event. The clinical 
data support the further evaluation of ensartinib in the clinic.  
 
 


 
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2 Study Rationale 
As described in Section 1.1, checkpoint inhibitors, particularly PD-1/PD-L1 antibodies, have been 
shown to be effective in the treatment of NSCLC.  Checkpoint inhibitors are also associated with 
minimal toxicities compared with chemotherapy or targeted therapies and function quite 
distinctly from other therapies. Therefore, the potential for effective and safe combination with 
existing therapies is significant.   
Effective therapies, such as targeted therapies in oncogene-driven NSCLC, generate visible 
tumor shrinkage within days to weeks, suggesting rapid tumor lysis that should generate large 
amounts of tumor antigen for antigen presentation and subsequent priming of tumor-specific 
T-cells.(21)  The addition of checkpoint inhibitor therapy could capitalize on this immunologic 
priming effect of targeted therapies for a potentially marked synergistic efficacy.(22)  
As with EGFR-mutant NSCLC, no subject with an ALK rearrangement is cured with crizotinib, and 
the median PFS is less than 1 year.  Second generation ALK inhibitors, including ensartinib, have 
substantially increased potency compared with crizotinib and have demonstrated activity in 
both crizotinib-naïve and crizotinib-resistant subjects.(20, 23)  Therefore, this study, which will 
combine durvalumab with ensartinib, represents an opportunity to test the synergy of 
immunotherapy with a potentially more effective ALK tyrosine kinase inhibitor (TKI) than 
crizotinib. 
PD-L1 expression may be modulated by anti-cancer therapies and may be more important in the 
setting of oncogene-driven cancers.  Therefore, in oncogene-driven NSCLC in particular, 
combining targeted therapy with PD-1/PD-L1 checkpoint inhibitor therapy may be particularly 
important, as the effective tumor shrinkage seen with targeted agents combined with the 
durable responses seen with PD-1/PD-L1 checkpoint inhibitor agents may result in lasting tumor 
control.   
EML4-ALK positive NSCLC patients have higher PD-L1 expression levels, compared to those 
negative for the fusion gene, (14), suggesting that their tumors are not only driven by EML4-ALK 
activity but also repress T-cell function. Thus, the simultaneous inhibition of EML4-ALK by 
ensartinib and de-repression of T-cell function by checkpoint inhibitors might be necessary, 
leading to additive or synergistic outcomes.  
Tumor lysis due to ALK inhibition may enhance immune priming and thus also contribute to the 
synergy. In addition, ensartinib has some Axl (IC50: 24nM) and CSF1R (IC50:13nM) inhibitory 
activities. Inhibition of Axl activates T-cells,(15) while inhibition of CSF1R modulates the tumor 
microenvironment including tumor-associated macrophages and myeloid-derived suppressor 
cells.(16)  Both might further potentiate response to T-cell checkpoint immunotherapy such as 
durvalumab. 
2.1 Ensartinib Dose 
In this study, the starting dose for ensartinib will be 200 mg, which is considered an efficacious 
dose. Based on the results of the dose escalation phase, this dose may be escalated to the 
recommended ensartinib single agent dose of 225 mg or de-escalated to the minimum effective 
dose of 150 mg in the case of overlapping toxicities. 


 
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2.2 Durvalumab Dose 
A durvalumab dose of 20 mg/kg every 4 weeks (Q4W) is supported by in-vitro data, non-clinical 
activity, clinical PK/pharmacodynamics, biomarkers, and activity data from Study 1108 in 
patients with advanced solid tumors and from a Phase 1 trial performed in Japanese patients 
with advanced solid tumor (D4190C00002). See durvalumab IB for details. 
2.2.1 Pharmacokinetics (PK)/Pharmacodynamics (PD) Data 
Based on available PK/PD data from ongoing Study 1108 with doses ranging from 0.1 to 
10 mg/kg Q2W or 15 mg/kg Q3W, durvalumab exhibited non-linear (dose-dependent) PK 
consistent with target-mediated drug disposition.  The PK approached linearity at ≥3 mg/kg 
Q2W, suggesting near complete target saturation (membrane-bound and sPD-L1), and further 
shows that the durvalumab dosing frequency can be adapted to a particular regimen given the 
linearity seen at doses higher than 3 mg/kg. The expected half-life with doses ≥3 mg/kg Q2W is 
approximately 21 days.  A dose-dependent suppression in peripheral sPD-L1 was observed over 
the dose range studied, consistent with engagement of durvalumab with PD-L1.  A low level of 
immunogenicity has been observed.  No patients have experienced immune-complex disease 
following exposure to durvalumab. For further information on immunogenicity, please see the 
current IB.   
Data from Study D4190C00006 (Phase 1 trial in NSCLC patients using the combination of 
durvalumab and tremelimumab) also show an approximately dose-proportional increase in PK 
exposure for durvalumab over the dose range of 3 to 20 mg/kg durvalumab Q4W or Q2W.  For 
further information on PK observations in Study 006, please see the current IB.   
The observed durvalumab PK data from the combination study were well in line with the 
predicted monotherapy PK data (5th median and 95th percentiles) for a Q4W regimen.   
A population PK model was developed using the data from Study 1108 (doses=0.1 to 10 mg/kg 
Q2W or 15 mg/kg Q3W.(24)  Multiple simulations indicate that a similar overall exposure is 
expected following both 10 mg/kg Q2W and 20 mg/kg Q4W regimens, as represented by the 
area under the concentration-time curve (AUC) at 4 weeks.  Median maximum concentration 
(Cmax) is expected to be higher with 20 mg/kg Q4W (~1.5 fold) and median Cmin is expected to 
be higher with 10 mg/kg Q2W (~1.25 fold).  Clinical activity with the 20 mg/kg Q4W dosing 
regimen is anticipated to be consistent with 10 mg/kg Q2W with the proposed similar dose of 
20 mg/kg Q4W expected to (a) achieve complete target saturation in majority of patients; 
(b) account for anticipated variability in PK, pharmacodynamics, and clinical activity in diverse 
cancer populations; (c) maintain sufficient PK exposure in case of ADA impact; and (d) achieve 
PK exposure that yielded maximal antitumor activity in animal models. 
Given the similar AUC and modest differences in median peak and trough levels at steady state, 
the observation that both regimens maintain complete sPD-L1 suppression at trough, and the 
available clinical data, the 20 mg/kg Q4W and 10 mg/kg Q2W regimens are expected to have 
similar efficacy and safety profiles, supporting further development with a dose of 20 mg/kg 
Q4W.   


 
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2.2.2 Clinical Data 
Refer to the current durvalumab IB for a complete summary of clinical information including 
safety, efficacy and PK for the 20mg/kg Q4W regimen.  
2.2.3 Fixed Dosing for Durvalumab  
A population PK model was developed for durvalumab using monotherapy data from a Phase 1 
study (study 1108; N=292; doses= 0.1 to 10 mg/kg Q2W or 15 mg/kg Q3W; solid tumors). 
Population PK analysis indicated only minor impact of body weight on PK of durvalumab 
(coefficient of ≤ 0.5). The impact of body weight-based (10 mg/kg Q2W) and fixed dosing (750 
mg Q2W) of durvalumab was evaluated by comparing predicted steady state PK concentrations 
(5th, median and 95th percentiles) using the population PK model. A fixed dose of 750 mg was 
selected to approximate 10 mg/kg (based on median body weight of ~75 kg). A total of 1000 
patients were simulated using body weight distribution of 40–120 kg. Simulation results 
demonstrate that body weight-based and fixed dosing regimens yield similar median steady 
state PK concentrations with slightly less overall between-subject variability with fixed dosing 
regimen.   
Similar findings have been reported by others.(25-28) Wang and colleagues investigated 12 
monoclonal antibodies and found that fixed and body size-based dosing perform similarly, with 
fixed dosing being better for 7 of 12 antibodies. In addition, Zhang et al. investigated 18 
therapeutic proteins and peptides and showed that fixed dosing performed better for 12 of 18 
in terms of reducing the between-subject variability in PK/PD parameters. (27)  
A fixed dosing approach is preferred by the prescribing community due to ease of use and 
reduced dosing errors. Given expectation of similar PK exposure and variability, it was 
considered feasible to switch to fixed dosing regimens. Based on average body weight of 75 kg, 
a fixed dose of 750 mg Q2W durvalumab (equivalent to 10 mg/kg Q2W) or 1500 mg Q4W 
durvalumab (equivalent to 20 mg/kg Q4W) is recommended. 
This dosing of durvalumab is recommended only for subjects with > 30 kg body weight due to 
endotoxin exposure.  Subjects with a body weight ≤ 30 kg are not eligible for enrollment in the 
current study. If a subject’s body weight drops to ≤ 30 kg while on the study, the durvalumab 
dose will be weight based as long as the body weight remains ≤30 kg (see Section 6.1.3). 
2.3 Rationale for Amendment 2 
Xcovery, the developer of ensartinib, has treated over 100 subjects in the Phase 2 program and 
has a randomized Phase 3 ongoing.  An analysis of the subjects who reported drug-related rash 
in the Phase 2 study by severity and by duration indicated that 57 subjects developed rash; the 
majority (52/57 subjects) in the first month of treatment. Of these, the maximum grade was 
Grade 2 or 3 in 24 subjects. In this subset with grade 2 or higher rash, 19 subjects developed 
rash within the first 28 days, 3 between days 34 and 39 and one on day 47. One additional 
subject developed rash on day 544. Based on these data, it was decided that a run-in period of 
1 cycle Instead of 2 cycles) for ensartinib would be sufficient. 


 
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3 Experimental Plan 
3.1 Study Design 
This is an open-label, multicenter, Phase 1/2 study to evaluate the safety and preliminary 
efficacy of a targeted therapy for NSCLC in combination with a checkpoint inhibitor:  
• 
Ensartinib (X-396), an ALK Inhibitor and  
• 
Durvalumab (MEDI4736), an anti-PD-L1 antibody. 
There will be a pre-immunotherapy Run-in Period prior to starting the combination drug 
therapy.  During the Run-in Period, ensartinib will be given for one 28-day cycle as monotherapy 
prior to starting the combination therapy (durvalumab and ensartinib) in Cycle 1.   
The dose escalation phase will utilize a standard 3 + 3 design to determine the Recommended 
Combination Dose (RCD), followed by an expansion phase, in which the dose escalation cohort 
at the RCD will be expanded to 20 subjects (inclusive of the subjects from the dose escalation 
cohort).   
3.1.1 Study Phase 
Phase 1/2 
3.1.2 Enrollment/Randomization 
Enrollment will occur in a sequential fashion.  See Section 3.1.7.1 for a description of the Run-in 
Period.  After the RCD is determined, the expansion phase will start (n =20 subjects, inclusive of 
the subjects from the dose escalation cohort treated at the RCD).   
3.1.3 Blinding/Unblinding 
This is an open-label study. 
3.1.4 Subject Population 
Subjects with histologically confirmed metastatic NSCLC.  Subjects must have confirmed ALK 
rearrangement as assessed by immunohistochemistry (IHC).  Subjects may have had prior 
therapy with ALK inhibitors or be ALK inhibitor naïve.  ALK inhibitor naïve subjects will be 
informed of the availability of approved ALK inhibitors.  Details on subject eligibility are found in 
Section 5. 
3.1.5 Number of Sites/Subjects 
Up to 8 sites in the US, with a total of up to 32 subjects. 
3.1.6 Sample Size Considerations 
The dose escalation phase will utilize a standard 3 + 3 design, which will result in the enrollment 
of 9 to 18 subjects. 
In the expansion phase, 20 subjects are thought to provide sufficient data to adequately identify 
essential safety and preliminary efficacy signals.  Therefore, 14 additional subjects will be added 
to the 6 treated at the RCD of the dose escalation phase.  The sample size, n=20, for the 
expansion phase is deemed to provide sufficient precision for the estimation of incidence of 


 
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adverse events.  The Clopper Pearson confidence intervals (CI) for incidence of adverse events 
based on a sample size of 20 subjects are provided below: 
Number of Subjects 
with Event 
Incidence 
95% Confidence Interval 
(Clopper Pearson) 
1/20 
0.05 
(0.00127, 0.24873) 
2/20 
0.10 
(0.01235, 0.31698) 
3/20 
0.15 
(0.03207, 0.37893) 
4/20 
0.20 
(0.05733, 0.43661) 
5/20 
0.25 
(0.08657, 0.49105) 
6/20 
0.30 
(0.11893, 0.54279) 
7/20 
0.35 
(0.15391, 0.59219) 
8/20 
0.40 
(0.19119, 0.63946) 
9/20 
0.45 
(0.23058, 0.68472) 
10/20 
0.50 
(0.27196, 0.72804) 
11/20 
0.55 
(0.31528, 0.76942) 
12/20 
0.60 
(0.36054, 0.80881) 
13/20 
0.65 
(0.40781, 0.84609) 
14/20 
0.70 
(0.45721, 0.88107) 
15/20 
0.75 
(0.50895, 0.91343) 
16/20 
0.80 
(0.56339, 0.94267) 
17/20 
0.85 
(0.62107, 0.96793) 
18/20 
0.90 
(0.68302, 0.98765) 
19/20 
0.95 
(0.75127, 0.99873) 
 
3.1.7 Treatment Schema 
The study drugs used in this study are administered per cycle as shown below: 
Dosing Schedule: 
Period 
Cycle 
Ensartinib 
(p.o.) 
Durvalumab 
(i.v.) 
Run-in Period:  
see Section 3.1.7.1 
Run-in  
(-1) 
Daily for 28 days 
None 
Combination 
Treatment 
1 to 12 
Daily for 28 days each cycle 
Q4W on Cycle Day 1 (±3 days) 
p.o. = by mouth; i.v. = intravenous; Q4W = every 4 weeks 
 
Subjects will receive a monthly supply of ensartinib.  At each study visit, they will return the 
unused portion to the study site; the number of pills returned will be counted to determine 
compliance. 


 
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 Run-in Period 
Prior to starting durvalumab in Cycle 1 of the combination therapy, there will be a run-in period 
where ensartinib will be given as a monotherapy for 1 cycle (28 days, Cycle -1) in order to 
determine a safety signal that might compromise combination therapy and also to determine 
the effect of ALK inhibitor therapy on the immune tumor microenvironment. 
During the run-in period, subjects will be evaluated for rash, where a Grade ≥2 is a DLT.   
Subjects with no DLTs in the run-in period will proceed to Cycle 1 of the combination therapy 
(See Section 3.2.1, Flowchart for Subjects Who Proceed with Combination Therapy after Run-in).  
Subjects who experience a DLT during the run-in period will not go on to receive durvalumab in 
Cycle 1 of the combination therapy and will be replaced. In addition, subjects who experience 
any toxicity that requires a dose reduction of ensartinib (see Section 8.4) during the run-in 
period, will not go on to receive durvalumab in Cycle 1 of the combination therapy and will be 
replaced.  
The subjects who do not proceed with combination treatment, may continue treatment with 
ensartinib monotherapy after resolution of DLT.  See Section 3.2.2, Flowchart for Subjects who 
Continue Treatment with Ensartinib (X-396) Monotherapy after Run-in, for details on 
assessments during continued monotherapy treatment.  
Dose escalations and de-escalations for the determination of RCD will be performed according 
to Section 3.1.7.2.  For each dose level in the dose escalation phase, enrollment of Subjects 1-3 
will be staggered according to the 1-cycle run-in period (i.e., one subject will be enrolled every 1 
cycle to monotherapy with ensartinib). 
After 3 subjects have proceeded to the combination therapy, enrollment to the dose level 
cohort may be held if additional time is needed to determine the dose level for the next 3 
subjects according to the 3 + 3 design. 
 Dose Escalation Phase 
Each subject enrolled in the dose escalation cohorts of the study will be evaluated for DLTs, as 
defined in Section 3.1.9.  Dose escalations and de-escalations for the determination of RCD will 
be performed based on the available dose levels (see table below) and the respective rules for a 
standard 3 + 3 dose escalation study design (see Figure 1). 
The dose for durvalumab is based on the currently recommended dose of 1500 mg (see Section 
2.2.3).  If a subject’s body weight drops to ≤ 30 kg while on the study, the subject will receive 
weight-based dosing equivalent to 20 mg/kg of durvalumab as long as the body weight remains 
≤ 30 kg (e.g., a 30 kg subject would receive a 600 mg dose; a 25 kg subject would receive a 500 
mg dose; etc.).  When the weight improves to >30 kg, the subject may return to fixed dosing of 
durvalumab 1500 mg. 
Dose Level Table: 
Dose 
Level 
Doses 
Ensartinib 
Durvalumab 
-1 
150 mg 
1500 mg 
Starting 
200 mg 
1500 mg 
+1 
225 mg 
1500 mg 


 
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Dose Escalation and De-Escalation Schema (3 + 3 Design)
1
0
 ≤1   
>1
 >1 
Treat 3 
Subjects 
@ DL and 
assess 
DLTs
Expand 
to 6 
Subjects 
@ DL and 
assess 
DLTs
DL is unsafe
DL is safe
Is DL + 1 available
and not
previously declared unsafe?
Escalation
DL = DL + 1
Yes
No
DL = Starting 
Dose Level
Is DL + 1 available
and not
previously declared unsafe?
Yes
DL is RCD
No
Is DL - 1 
available?
No
RCD cannot be 
determined
Was DL - 1 
previously declared 
safe?
No
3 subjects already 
treated @ DL?
Yes
Yes
No
Yes
De-Escalation
DL = DL - 1
DL - 1 is RCD
DL = Dose Level (per DL Table)         DLT = (Subjects with) Dose Limiting Toxicities         RCD = Recommended Combination Dose (per DL Table)
 
Figure 1. Dose Escalation and De-Escalation Schema 
Per Figure 1, the RCD is defined as the highest dose level at which no more than 1 of 6 subjects 
(i.e., < 33%) experience DLTs.  The RCD cannot be determined if none of the predefined dose 
level cohorts fulfill that criterion. 
Upon determination of an RCD, respective intra-subject dose escalation or de-escalation for 
subjects still on study, and previously treated at dose levels other than the RCD, may be 
permitted upon agreement by the Sponsor and Investigator.  
 Dose Expansion Phase 
The RCD dose level cohort will be expanded to 20 subjects (14 subjects added to the 6 treated at 
the RCD in the dose escalation phase).   
3.1.8 Dosing Adjustments, Delays, and Discontinuations 
Individual subject dosing adjustments due to toxicity will be allowed/may be required in 
accordance with the “Dose Adjustment and Management Guidelines” for toxicity related to 
durvalumab and ensartinib, outlined in Section 8.3 and Section 8.4, respectively.  If a toxicity 
occurs that requires toxicity management in accordance with Sections 8.3 or 8.4, and the 
toxicity causing drug can be clearly identified, then the respective guideline should be followed. 
If the toxicity causing drug cannot be identified, then the more conservative guideline should be 
followed. 


 
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 Monitoring for Hepatic Toxicity During Combination Therapy 
During the ensartinib/durvalumab combination therapy, all hepatic toxicity events related at 
least to durvalumab will be considered and treated as immune-related events. In order to 
monitor the hepatic combination toxicities more closely, in addition to the ongoing 
measurements that occur every 4 weeks, liver function tests (ALT, AST, alkaline phosphatase, 
and total bilirubin) will be performed at 2 weeks after the durvalumab dose during Cycle 1 of the 
combination therapy.  
The main difference between monotherapy and combination therapy hepatic toxicities is that 
ensartinib dosing will not be stopped for Grade 2 hepatic toxicity during ensartinib 
monotherapy, whereas it will be held during combination therapy. 
Please refer to Sections 8.3 and 8.4 for general instructions and for respective monotherapy 
dose modifications. For hepatic toxicities following ensartinib/durvalumab combination 
treatment, follow the instructions given below: 
Grade 1 
No dose modification is required for a Grade 1 hepatic toxicity. 
Grade 2 
Hold ensartinib and durvalumab until resolution to ≤ Grade 1 (and after the end of any steroid 
taper), and discontinue drugs permanently if such resolution does not occur within 28 days.  
Upon resolution to ≤ Grade 1, ensartinib dosing may resume and durvalumb dosing may resume 
at the next scheduled dose. 
Grade 3 
In general, hold both drugs until resolution to ≤ Grade 1 (and after the end of any steroid 
taper). Upon resolution to ≤ Grade 1, ensartinib dosing may resume at a lower dose as outlined 
in Section 8.4; and durvalumb dosing may resume at the next scheduled dose. 
Discontinue ensartinib permanently for any of the following: 
• Grade 3 toxicity lasting longer than 7 days 
• Elevated ALT ≥3 x ULN in conjunction with a total bilirubin ≥2 x ULN, and no correctable, 
non-drug related cause 
Discontinue durvalumab permanently for any of the following: 
• Transaminases or bilirubin not resolving to ≤ Grade 1 or baseline within 14 days 
• Transaminases > 8 × the upper limit of normal (ULN) or bilirubin > 5 × ULN 
• Any case meeting Hy’s law criteria (as defined in FDA Guidance Document “Drug-Induced 
Liver Injury”) 
Grade 4 
Discontinue drugs permanently 
3.1.9 DLT and MTD/RCD for the Combination Therapy 
MTD will not be determined in this study.  Instead, the RCD will be determined in the context of 
the predefined dose levels used during the dose escalation phase as per Section 3.1.7.2. 


 
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DLTs will be observed over a period of the first 2 Cycles of the combination therapy, including 
the pre-dose assessment for Cycle 3, defined as the “DLT Evaluation Period.”  The decisions for 
dose escalations, de-escalations and RCD, as described in Section 3.1.7.2 will primarily be based 
on the number of subjects with DLTs occurring during the DLT Evaluation Period.  DLTs occurring 
outside the DLT Evaluation Period will also be evaluated and may impact such decisions. 
DLTs are defined as any adverse events that are possibly, probably, or definitely related to the 
administration of durvalumab or ensartinib and fulfill any of the following criteria: 
1. Any Grade ≥ 3 rash, colitis, pneumonitis, neurological event or uveitis. 
2. Any Grade 2 pneumonitis, neurological event or uveitis, with the following exception: 
• 
Grade 2 pneumonitis, neurological event or uveitis that downgrade to Grade ≤ 1 
within 3 days after onset, whereby maximal supportive care, including systemic 
corticosteroids, is permitted. 
3. Any other Grade ≥ 3 toxicity, with the following exceptions: 
• 
Grade 3 irAEs that downgrade to Grade ≤ 2 within 3 days, or to Grade ≤ 1 or 
baseline within 14 days after onset, whereby maximal supportive care, including 
systemic corticosteroids, is permitted. 
• 
Grade 3 endocrinopathy that becomes asymptomatic when managed with or 
without systemic corticosteroid therapy and/or hormone replacement therapy. 
• 
Grade 3 inflammatory reaction attributed to a local antitumor response (e.g., 
inflammatory reaction at sites of metastatic disease, lymph nodes, etc.). 
• 
Grade 3 fatigue for ≤ 7days. 
• 
Grade 3 infusion-related reaction (first occurrence and in the absence of steroid 
prophylaxis) that resolves within 6 hours with appropriate clinical management. 
• 
Liver transaminase elevation ≤ 8 times ULN that downgrades to Grade ≤ 2 (≤ 5 times 
ULN) within 7 days after onset, whereby maximal supportive care, including 
systemic corticosteroids, is permitted. 
• 
Total bilirubin ≤ 5 times ULN that downgrades to Grade ≤ 2 (≤ 3 times ULN) within 7 
days after onset, whereby maximal supportive care, including systemic 
corticosteroids, is permitted. 
• 
Grade ≥ 3 neutropenia that (1) is not associated with fever or systemic infection, (2) 
does not require medical intervention, and (3) improves to Grade 2 within 7 days. 
• 
Grade 3 and 4 lymphopenia. 
• 
Grade 3 thrombocytopenia that (1) is not associated with clinically significant 
bleeding, (2) does not require medical intervention, and (3) improves to Grade 2 
within 7 days. 
• 
Isolated Grade 3 electrolyte abnormalities that are not associated with clinical signs 
or symptoms and are reversed with appropriate maximal medical intervention 
within 3 days. 
• 
Any pre-existing laboratory abnormality that deteriorates to Grade 3/4, but where 
the increment of deterioration is considered not clinically significant by both 
Investigator and Sponsor. 
Immune-related AEs are defined as AEs of immune nature (i.e., inflammatory) in the absence of 
a clear alternative etiology.  In the absence of clinical abnormality, repeat laboratory testing will 
be conducted to confirm significant laboratory findings prior to designation as a DLT. 


 
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While rules for adjudicating DLTs are specified above, an AE that is Grade < 3 or listed as exempt 
above may also be defined as DLT after consultation with the Sponsor and Investigators, based 
on the emerging safety profiles of durvalumab and ensartinib.  Likewise, subjects who become 
not evaluable for DLT, because they discontinued or interrupted treatment due to toxicities 
other than DLTs, may be counted as DLT subjects, if the toxicities cannot be managed in 
accordance with the dosing modifications described in Section 3.1.8. 
Subjects who experience a DLT will be discontinued from study treatment and will enter the On 
Study and Post Study Follow-up (see Section 3.1.16).  However, if it is in the best interest of the 
subject, the Investigator, subject and Sponsor may agree to continue treatment with ensartinib, 
possibly at a lower dose level. 
3.1.10 Subject Withdrawal from Treatment or from Study 
A subject will be withdrawn from study treatment for any of the following reasons: 
1. Withdrawal of consent for further treatment 
2. Pregnancy or intent to become pregnant. 
3. DLT at any time (see Section 3.1.9). 
4. Progressive disease requiring alternative systemic treatment. 
5. Significant protocol violation or noncompliance that, in the opinion of the Investigator 
or Sponsor, warrants withdrawal. 
6. Development of intercurrent, non-cancer-related illnesses or complications that prevent 
either continuation of therapy or regular follow-up. 
7. Best medical interest of the subject (at the discretion of the Investigator) 
 
A subject will be withdrawn from the study for the following reasons: 
1. Best medical interest of the subject at the discretion of the Investigator  
2. Initiation of alternative anti-cancer therapy (marketed or investigational). 
3. Withdrawal of consent for all follow-up. 
4. Lost to follow-up. 
5. Death. 
Discontinuation from receiving study treatment does not mean that the subject is withdrawn 
from the study.  If applicable, subjects who are withdrawn from study treatment should undergo 
the planned On Study Follow-up procedures (see Study Flowchart, Section 3.2.1), followed by 
the Post Study follow-up period (see Section 3.1.16). 
Section 7.2.6 provides additional details regarding documentation for early subject withdrawal 
from study treatment and early withdrawal from study.  
See also Sections 8.3, and 8.4 for subject withdrawal from treatment due to necessary dosing 
interruptions or discontinuations. 
 Treatment beyond Progression 
Subjects meeting criteria for progression by RECIST 1.1 (Section 8.5) will be allowed to continue 
on therapy until confirmation of progression if the subject agrees and signs an appropriate 
informed consent form regarding continuation of treatment and as long as the following criteria 
are met at the discretion of the Investigator: 


 
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a. Absence of symptoms and signs (including worsening of laboratory values) indicating 
disease progression; 
b. No significant decline in ECOG performance status; 
c. Absence of rapid progression of disease or of progressive tumor at critical anatomical 
sites (e.g., cord compression) requiring urgent alternative medical intervention. 
See Section 8.5 for additional information regarding RECIST 1.1 and irRECIST. 
3.1.11 Subject Evaluability and Subject Replacements 
In the dose escalation phase, subjects are fully evaluable for DLT if they fulfill the criteria 
described for the Per-Protocol Population for DLT Assessment (as defined in Section 4.1.2). 
Subjects who are not fully evaluable for DLT per Section 4.1.2 will be replaced. 
Subjects are fully evaluable for secondary endpoints of PFS rate and ORR if they fulfill the 
criteria for the Per-Protocol Population for Clinical Efficacy (as defined in Section 4.2.2). 
Subjects who are not fully evaluable for PFS rate and ORR may be replaced. 
3.1.12 Optional Study Treatment Extension 
Subjects who still benefit from treatment at the end of the 12 cycles (Core Study) may continue 
treatment with ensartinib and/or durvalumab until progression, if agreed upon by subject, 
Sponsor and Investigator.  
See flowchart in Section 3.2.1 for assessments to be performed during this period. 
3.1.13 Interim Analysis 
Interim Safety Reviews will be performed to assess DLTs in the dose escalation cohorts (see 
Section 3.1.7.2). Interim analyses may be performed to analyze the 8- and 24-week ORR 
endpoints.  
3.1.14 Safety Monitoring and Study Stopping Rules 
In accordance with the Administrative, Legal, and Ethical Requirements section of the protocol 
(see Section 7), Safety Monitoring will be performed by an internal data safety monitoring panel, 
consisting of the Principal Investigators (and co-investigators as needed), the Sponsor’s Medical 
Monitor, and drug safety personnel from MedImmune/AstraZeneca, and Xcovery, providers of 
the study drugs.  Additional Investigators and staff, or additional Sponsor personnel and 
consultants, shall participate in reviews, if indicated.  The safety monitoring panel will 
communicate by phone and/or email on a regular basis, and in particular, to review the safety of 
individual cohorts for the purpose of dose escalation or de-escalation as per Section 3.1.7.2. 
An Independent Data Safety Monitoring Board will not be utilized for this open-label study. 
The study will be suspended or possibly stopped prematurely for any of the following reasons: 
1. A death that is unexpected and at least probably related to study drug. 
2. Severe anaphylactic reaction (i.e., with respiratory and cardiovascular failure) to any of 
the study drugs. 


 
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3. Any events that, in the judgment of the medical monitor, are deemed serious enough to 
warrant immediate review by the internal data safety monitoring panel.  This may 
include any symptomatic and/or irreversible treatment-related Grade 4 pneumonitis, 
colitis, dermatitis, or hepatitis or any symptomatic treatment-related Grade ≥ 3 
neurological toxicity or uveitis.  
4. Any other safety finding assessed as related to study drug that, in the opinion of the 
internal data safety monitoring panel, contraindicates further dosing of study subjects. 
5. Any interim findings that, in the opinion of the Investigators and the Sponsor, suggest 
that the study treatment has no clinical benefit for the subjects. 
General criteria for premature trial termination are outlined in the Administrative Sections. 
3.1.15 Duration of Study 
Length of Study per subject: 
Up to 16 months: 1 month for Run-in, 12 months for 
treatment and 3 months for On Study Follow-up  
(See Section 3.1.12 for optional treatment extension) 
Enrollment Period: 
24 months 
Length of Study: 
41 months 
Length of Survival Post Study 
Follow-up 
Up to 5 years from initiation of treatment 
3.1.16 On Study and Post-Study Follow-up 
All subjects, whether they complete the study as planned, discontinue treatment, or 
prematurely withdraw from the study as per Section 3.1.10, will be followed as per institutional 
guidelines in accordance with the usual standard of care principles.   
Subjects who complete study treatment or discontinue treatment prematurely will enter an On 
Study Follow-up, which will be conducted for 90 days after the last administration of study drug 
according to the flowchart in Section 3.2.1.  Refer to Section 7.1.5 for information on recording 
AEs during the On Study Follow-up. 
See Section 3.2.2 for Ensartinib On Study Follow-up for subjects who continue treatment with 
ensartinib monotherapy after run-in according to Section 3.1.7.1. 
If the determination is made to remove a subject from treatment at a visit that coincides with 
the first visit of the On-Study Follow-up Period, any assessments required in the first On Study 
Follow-up visit that are not covered as part of the last on-treatment visit (usually correlative 
labs) should be done as soon as possible.  If these assessments cannot be done on the same day, 
the subject should be brought back in at the earliest opportunity.  Any assessments or 
correlative samples required by both the last on-treatment visit and the first On Study Follow-up 
visit should not be repeated. 
In addition to the On Study Follow-up, there will be a Post Study Follow-up, during which clinical 
outcomes data (dates of progression/relapse and survival) will be collected at least every 6 
months for up to 5 years from initiation of treatment.  If after 5 years there are a significant 
number of subjects who are still alive, there will be an option to extend this period.   
The Post Study Follow-up will include a query to determine if there were any immune-related 
adverse events (irAEs) during the 90 days since the last administration of study drug. 


 
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See Section 3.2.2 for Ensartinib Post Study Follow-up for subjects who continue treatment with 
ensartinib monotherapy after run-in according to Section 3.1.7.1. 
For subjects who do not continue Post Study Follow-up at one of the study sites after the end of 
study, the Principal Investigators or the clinical team, under the supervision of the Principal 
Investigator, will obtain this data through review of outside records or communication with the 
subject or his/her physician.  
 End of Study Visit 
If a subject is withdrawn from study according to the criteria defined in Section 3.1.10, an End 
of Study visit must be conducted at the time of withdrawal. For subjects not yet in On Study 
Follow-up, this End of Study visit will be the first planned visit of the On Study Follow-up. For 
subjects already in On Study Follow-up, this End of Study visit will be the next planned visit of 
the On Study Follow-up. However, any procedures/assessments that were done within 7 days of 
the End of Study visit need not be repeated. All subjects of childbearing potential who withdraw 
from study must have a serum pregnancy test done at the End of Study visit, unless it was done 
within 7 days prior to End of Study visit. 
After the End of Study Visit, the subject will proceed into Post Study Follow-up as described 
above, unless otherwise unable to do so (e.g., subject withdraws consent for all follow-up). 
 
 


 
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3.2 Study Flowcharts 
3.2.1 Flowchart for Subjects Who Proceed with Combination Therapy after Run-in 
 
Cycle 2
Cycle 3
Cycle 4
Cycle 5
Cycle 6
Cycle Day 
1 (±3)
15 (±3)
1 (±3)
1 (±3)
1 (±3)
1 (±3)
1 (±3)
Cumulative Study  Day
-28
-14
1
15
29
57
85
113
141
Treatment 
Durvalumab (1500 mg)
X
X
X
X
X
X
Ensartinib (X-396) (oral; see Sections 3.1.7.1 and 3.1.7.2)
daily
daily
daily
daily
daily
daily
daily
daily
daily
Disease Staging (date/stage at 1st diagnosis and at study 
entry)
X
Disease Assessment  by  irRECIST/RECISTa
X
X
X
X
Study Procedures & Examinations
Eligibility Assessment and Informed Consent (IC)e
X
Demographics (incl. DoB; sex; height; race; ethnicity) 
X
Medical history
X
Physical Exam (incl. weight and ECOG Perf Status)b
X
X
X
X
X
X
X
X
X
12-Lead ECGa
X
X
X
X
X
X
Vital Signs (T, HR, BP, RR)g
X
X
X
X
X
X
X
X
X
Concomitant Medications / Procedures 
X
X
X
X
X
X
X
X
X
Adverse Events (starting or worsening after IC)f
X
X
X
X
X
X
X
X
X
Blood Hematology (CBC, differential, platelets)a
X
X
X
X
X
X
X
X
X
Chemistry (glucose, BUN, creat., Na, K, Cl, CO2, Ca, Mg, total 
protein, albumin, Tbili., AST, ALT,  ALP, LDH)a
X
X
X
X
X
X
X
X
X
AST, ALT, ALP, and Tbilia,J
X
Chemistry cont. (Free  T3, Free T4, TSH)a
X
X
X
X
X
X
X
X
Chemistry cont. (Amylase and lipase)a
X
X
X
X
X
X
X
X
Testosterone (males only)
X
Urinalysisa,c
X
X
X
X
X
X
X
X
Coagulation parameters (PT, aPTT, INR)a,d
X
Serum pregnancy test (Urine test only pre-dose on first day 
of ensartinib and first day of combination drug)a
Up to 1 week  
before Tx start 
X
X
X
X
Specimens for Other Peripheral Blood Assays
Whole blood for  (PBMC and plasma) for flow cytometry and 
biological assays) a
X
X
X
X
Blood for Biomarker analyses a
X
X
X
X
Biopsy (or FFPE slides) for tumor microenvironmenth
Xh
Xh
Overall Survival
Progression Free Survival
Long Term Follow-up
Tumor Biopsy
Treatment (4 weeks/cycle)
-2
Ensartinib 
Run-In 
(Cycle -1)
-4
1
5
9
Cycle 1
3
Tumor & Disease Assessments
Up to 28 days 
before Tx start
Specimens for Routine Laboratory Procedures
13
3.2.1 - Flowchart for Subjects who 
Proceed with Combination Therapy 
after Run-in 
Screening / 
Baseline
Study Week
17
21


 
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Cycle 7
Cycle 8
Cycle 9 Cycle 10 Cycle 11 Cycle 12
Cycle Day 
1 (±3)
1 (±3)
1 (±3)
1 (±3)
1 (±3)
1 (±3)
1 (±3)
Cumulative Study  Day
169
197
225
253
281
309
Treatment 
Durvalumab (1500 mg)
X
X
X
X
X
X
Xi
Ensartinib (X-396) (oral; see Sections 3.1.7.1 and 3.1.7.2)
daily
daily
daily
daily
daily
daily
daily
Tumor & Disease Assessments
Disease Staging (date/stage at 1st diagnosis and at study 
entry)
Disease Assessment  by  irRECIST/RECISTa
X
X
X
Q8W starting on 
Week 49  or SOC
Study Procedures & Examinations
Eligibility Assessment and Informed Consent (IC)e
Demographics (incl. DoB; sex; height; race; ethnicity) 
Medical history
Physical Exam (incl. weight and ECOG Perf Status)b
X
X
X
X
X
X
Xi
X
X
X
12-Lead ECGa
X
X
X
Q8W starting on 
Week 53
X
Vital Signs (T, HR, BP, RR)g
X
X
X
X
X
X
Xi
X
X
X
Concomitant Medications / Procedures 
X
X
X
X
X
X
Xi
X
X
X
Adverse Events (starting or worsening after IC)f
X
X
X
X
X
X
Xi
X
X
X
Specimens for Routine Laboratory Procedures
Blood Hematology (CBC, differential, platelets)a
X
X
X
X
X
X
Xi
X
X
X
Chemistry (glucose, BUN, creat., Na, K, Cl, CO2, Ca, Mg, total 
protein, albumin, Tbili., AST, ALT,  ALP, LDH)a
X
X
X
X
X
X
Xi
X
X
X
AST, ALT, ALP, and Tbilia,J
Chemistry cont. (Free  T3, Free T4, TSH)a
X
X
X
X
X
X
Xi
X
X
X
Chemistry cont. (Amylase and lipase)a
X
X
X
X
X
X
Xi
X
X
X
Testosterone (males only)
Urinalysisa,c
X
X
X
X
X
X
Xi
X
Coagulation parameters (PT, aPTT, INR)a,d
X
Serum pregnancy test (Urine test only pre-dose on first day 
of ensartinib and first day of combination drug)a
X
X
X
Q8W starting on 
Week 49  
X
X
Specimens for Other Peripheral Blood Assays
Whole blood for  (PBMC and plasma) for flow cytometry and 
biological assays) a
X
X
X
X
Week 49
X
Blood for Biomarker analyses a
X
X
X
X
Week 49
X
Biopsy (or FFPE slides) for tumor microenvironmenth
optional
Overall Survival
Progression Free Survival
Long Term Follow-up
X
Tumor Biopsy
X
Last Study Drug 
Dose +28
( ±4) days
Last Study Drug 
Dose +56  
(±4) days
Every 6 months up 
to 5 years post 
initiation of 
treatment
 Last Study Drug 
Dose + 91
( ±7) days  
End of  Study
Q8W starting 8 weeks after
 last disease assessment
Post Study 
Follow-up
On Study Follow-upf
29
Optional Study 
Treatment 
Extensioni
33
Treatment (4 weeks/cycle)
3.2.1 - Flowchart for Subjects who 
Proceed with Combination Therapy 
after Run-in (cont.)
Study Week
37
41
45
25


 
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Footnotes for Flowchart 3.2.1 
 
 
 
J: In addition to the pre-durvalumab testing Q4W, AST, ALT, ALP, and Tbili will be performed at  2 weeks after the durvalumab dose for Cycle 1 of the comb.therapy. See Section 3.1.8.1.
      are reviewed before dosing.
    will continue every 4 weeks starting on Week 49 (unless otherwise indicated) until PD or until  treatment is discontinued by the Investigator. 
e: Standard of Care procedures may be used for eligibility assessments provided they meet the criteria specified in either the inclusion criteria or flowchart
   -Optional core biopsies will be obtained at the time of tumor progression or at the completion of treatment from subjects who consent to this procedure.  
  14 days prior to initiation of durvalumab).  These biopsies should include a minimum of 3 cores from lung tissue and minimum 4 cores from any other site.
f:  See section 7.1.5  for details regarding collection of AEs for 90 days after last study drug administration
g: See Section 6.4 for assessment of vital signs before/during/after durvalumab
h: A fresh tissue biopsy will be required prior to treatment with ensartinib and following the run-in period but before initiation of durvalumab (up to
i: Dosing/assessments for subjects who continue treatment after completion of  12 cycles (Core Study).  Durvalumab dose and assessments for both drugs 
b: Full physical examination at baseline; targeted physical examination at other timepoints
c: Urinalysis performed at Screening, Day 1, every 4 weeks and as clinically indicated.
d: Coagulation tests: prothrombin time, aPTT and INR – only performed at Screening and as clinically indicated.
   -If possible, a minimum of 8 subjects will have fresh tissue sampling from which fine needle aspiration (FNA) can be also obtained for immune profiling
a: pre durvalumab dose, when applicable. Note: It is strongly recommended that hematology, chemistry and pregnancy test (when applicable) results
   If subjects are ALK inhibitor naïve, either archival tissue or pre-treatment biopsy will be acceptable. See Section 4.3.1.1 for details


 
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3.2.2 Flowchart for Subjects who Continue Treatment with Ensartinib (X-396) Monotherapy after Run-in 
 
 
 
Last dose of 
Ensartinib + 30 days
Every 6 months up to 5 
years post initiation of 
treatment
Treatment 
Ensartinib (X-396) – oral 
daily
Disease Assessment  by RECIST 
Q8W
X
Physical Exam (incl. weight and ECOG Perf Status) 
Q4W
X
12-Lead ECG 
Q8W
X
Vital Signs (T, HR, BP, RR)
Q4W
X
Concomitant Medication / Procedure 
Q4W
X
Adverse Events (starting or worsening after IC) 
Q4W
X
Blood Hematology (CBC, differential, platelets)
Q4W
X
Chemistry (glucose, BUN, creat., Na, K, Cl, CO2, Ca, Mg, total 
protein, albumin, Tbili., AST, ALT,  ALP, LDH)
Q4W
X
Urinalysis
Q8W
X
Serum pregnancy test
Q8W
X
Long Term Follow-up
Overall Survival
X
Progression Free Survival
X
 Note: It is strongly recommended that hematology, chemistry and pregnancy test (when applicable) results are reviewed at every assessment point
Post Study 
Follow-up
Specimens for Routine Laboratory Procedures
Q4W = every 4 weeks; Q8W =  every 8 weeks
     for 30 days after last dose of study drug.
Ensartinib On Study 
Follow-up 
Study Procedures & Examinations
Tumor & Disease Assessments
a: Drug administration/assessments for subjects who continue treatment with ensartinib (daily) after run-in period, according to Section 3.1.7.1; 
   - safety assessments will continue every 4 weeks (unless otherwise indicated) until PD or until  treatment is discontinued by the Investigator.
  - final safety assessments should be completed within 30 days of study completion; adverse events should continue to be collected 
Post Run-in 
Monotherapya
3.2.2 - Flowchart for Subjects who Continue Treatment 
with Ensartinib (X-396) Monotherapy after Run-in (and 
do not proceed with Combination Therapy)a 


 
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4 Study Objectives and Endpoints 
Primary Objective 
[Endpoints] 
Phase 1 Dose Escalation Phase: 
Recommended Combination Dose (RCD) 
Safety and Tolerability [CTCAE 4.03, including DLTs and RCD] 
Expansion Phase: 
Safety and Tolerability [CTCAE 4.03] 
Secondary Objectives 
[Endpoints] 
Dose Escalation and Expansion Phases (all subjects): 
Clinical Efficacy by irRECIST and RECIST 1.1 [PFS rate and ORR at 8 and 
24 weeks, overall best response, DCR, DoR, OS] 
Exploratory Objectives 
[Endpoints] 
Dose Escalation and Expansion Phases (all subjects): 
Biologic Activity [Effects on Tumor Microenvironment, Immune 
Response] 
DLT=Dose-limiting Toxicity; RCD=Recommended Combination Dose; ORR=Objective Response Rate; DCR=Disease 
Control Rate; DoR=Duration of Response; PFS=Progression-free Survival; OS=Overall Survival; CTCAE=National Cancer 
Institute Common Terminology Criteria for Adverse Events; RECIST = Response Evaluation Criteria in Solid Tumors; 
irRECIST=immune-related RECIST 
4.1 Safety and Tolerability 
Assessment of safety and tolerability will be performed by the internal data safety monitoring 
panel on an ongoing basis, based on data review and regular conference calls with the 
Investigators.   
4.1.1 Endpoints and Assessment Methods 
Clinical laboratory tests, vital signs and weight measurements, physical exams, ECG, ECOG 
performance status evaluation, imaging scans and any other medically indicated assessments, 
including subject interviews, will be performed to detect new abnormalities and deteriorations 
of any pre-existing conditions.  The Investigator will evaluate any laboratory abnormalities for 
clinical significance, and clinically significant abnormalities will be recorded as adverse events.  
All treatment-emergent clinically significant abnormalities and deteriorations from time of 
signing the informed consent to the end of study visit will be recorded in the Case Report Forms 
(CRFs) as adverse events and graded according to the CTCAE Version 4.03.  See further adverse 
event documentation and reporting requirements in Section 7.1. 
For the dose escalation phase, DLTs and RCDs will be assessed as per Sections 3.1.9 and 3.1.7.2, 
respectively. 
4.1.2 Subject Evaluation and Statistics 
The Per-Protocol (PP) Population for DLT assessment includes: 
• 
All subjects who experience a DLT at any time during the DLT Evaluation Period (as 
defined in Section 3.1.9 
• 
All subjects with no DLT who received at least 75% of the scheduled doses of 
durvalumab and ensartinib drugs as well as respective safety assessments, without 
major protocol violations, over the entire DLT Evaluation Period (as defined in Section 
3.1.9).   


 
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Refer to Section 3.1.11 for subject replacements.  
The Safety Population is defined as all subjects who receive at least one dose of either of the 
study drugs. 
In the Dose Escalation Phase, for the primary endpoint of determining DLTs and the RCD, the 
analysis of safety and tolerability will be based on the PP Population for DLT Assessment. 
In both phases (escalation and expansion), the overall analysis of safety and tolerability will be 
based on the Safety Population. 
Appropriate summaries of AEs, SAEs, laboratory data and vital signs data will be presented for 
the Safety Population overall and by cohort.  Adverse events will be coded using the MedDRA 
dictionary.  Incidences of treatment-emergent adverse events (TEAE, those events that started 
after dosing or worsened in severity after dosing) will be presented overall and by maximum 
severity and relationship to study drugs. 
For each continuous laboratory parameter, results will be categorized as low, normal, or high 
based on the laboratory normal ranges. Frequencies and percentages will be presented for the 
shifts in these categories (i.e., low to normal, low to high, high to low, etc.) from baseline to 
each post-treatment assessment time point. Additionally, for each continuous hematology and 
chemistry parameter, descriptive statistics will be presented for the changes from baseline to 
each post-treatment assessment time point.  Descriptive statistics will be presented for the 
changes in vital signs from baseline to each post-treatment assessment time point. 
4.2 Clinical Efficacy 
4.2.1 Endpoints and Assessment Methods 
Clinical efficacy will be assessed by irRECIST and RECIST 1.1 (see Section 8.5), measuring 
progression free survival (PFS) rate and objective response rate (ORR) at 8 and 24 weeks based 
on disease assessments at the scheduled Weeks 9 and 25 visits, as well as overall best response, 
disease control rate (DCR), duration of response (DoR), and overall survival (OS). Tumor disease 
assessments will be made at a minimum of every 8 weeks on study. See the sections below for 
additional details. 
For the primary analysis, all efficacy endpoints will be assessed at the completion of the On 
Study Follow-up or completion of 12 cycles of therapy. 
PFS and OS will be updated at yearly intervals during the Post Study Follow-up and can be 
provided as addenda to the final report.   
 Objective Response Rate (ORR) 
ORR is defined as the percentage of subjects meeting criteria of Complete Response (CR) or 
Partial Response (PR) with confirmation over a period of at least 4 weeks.   


 
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 Disease Control Rate (DCR) 
DCR is defined as the percentage of subjects meeting criteria of Stable Disease (SD), PR, or CR 
with confirmation over a period of at least 4 weeks.  
 Duration of Response (DoR) 
DoR is defined as the interval between the date of earliest determination of CR or PR to the date 
of earliest determination of PD, or to the date of death, if PD does not occur. 
 Progression-free Survival (PFS) 
PFS is defined as the interval between the date of first dose to the date of earliest determination 
of Progressive Disease (PD), or to the date of death, if PD does not occur.  Subjects without 
documentation of progression at the time of the analysis will be censored at the date of last 
response assessment. Subjects with no tumor response assessment will be censored at the start 
date of the treatment. Subjects who discontinued treatment or withdrew from the study for 
reasons other than documented PD or death will be censored at the date of last response 
assessment prior to discontinuation or withdrawal. 
 Overall Survival (OS) 
OS is defined as the interval between the date of first dose until the date of death or the date of 
last follow-up.  Subjects who are still alive will be censored on the date of last follow-up.  Every 
effort will be made to follow subjects for OS after they discontinue the study. 
4.2.2 Subject Evaluation and Statistics 
The Intent-To-Treat (ITT) Population is defined as all subjects who receive at least one dose of 
any of the study drugs.  The Per-Protocol (PP) Population for clinical efficacy is defined as all 
subjects who received at least 75% of the scheduled doses of the study drug over the first 2 
cycles of combination therapy, as well as, respective disease assessments, without major 
protocol violations. 
All efficacy analyses will be performed for both ITT and PP populations for all cohorts and for the 
expansion cohort separately.  Tumor Response will be summarized and analyzed descriptively.  
A 95% CI based on binomial distribution will be constructed for the estimated DCR and ORR at 8 
and 24 weeks. 
The number and percentage of subjects who died or had a confirmed progression, who survived 
without a confirmed progression, and who were lost to follow-up (unknown survival and/or 
progression status) will be summarized.  PFS rate at 8 and 24 weeks and the corresponding 95% 
CIs will be calculated based on Kaplan-Meier product limit estimates and will be displayed along 
with the corresponding number of subjects at risk.   
PFS and OS will be summarized using the 25th percentile, Median, and 75th percentile as well as 
the minimum and maximum survival time, calculated by Kaplan-Meier method, and will be 
displayed graphically. 
 


 
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4.3 Biological Activity 
4.3.1 Endpoints and Assessment Methods 
Samples for exploratory assessment of correlative immunologic response will be collected 
according to the Study Flowchart in Section 3.2.1.  Correlative data will be obtained to assess 
the effects of the regimen on the tumor microenvironment and biological activity in blood.  The 
exploratory assessments will help to determine whether protein expression, mutational burden, 
gene expression, soluble PD-L1 or immune cell profiling can be associated with clinical benefit or 
resistance to combination therapy. 
 Tumor Microenvironment 
This study will examine biopsies taken prior to ensartinib initiation, after ensartinib exposure 
(following the run-in period) and optionally at the time of progression or end of combination 
therapy (end of study, if clinically feasible) to evaluate PD-L1 expression as assessed by 
immunohistochemistry, neoantigen signature and immune biomarker expression in tissue, and 
to assess the correlation of these evaluations with clinical response as well as changes in 
profiling associated with resistance.  Analyses may include the following: 
• 
Mutational burden, gene expression profiling, and immune profiling from before 
therapy 
• 
Immune markers of response and resistance in pre-treatment and post-treatment 
tumor biopsies. 
A minimum of 25 slides (5-µm, formalin-fixed, paraffin embedded (FFPE)) will be required.   
A fresh tissue biopsy will be required prior to treatment with ensartinib and following the run-in 
period with ensartinib but before initiation of durvalumab (up to 14 days prior to initiation of 
durvalumab).  These biopsies should include a minimum of 3 cores from lung tissue and 
minimum 4 cores from any other site.  If subjects are ALK inhibitor naïve, either archival tissue 
or pre-treatment biopsy will be acceptable.  Optional core biopsies will be obtained at the time 
of tumor progression or at the completion of treatment from subjects who consent to this 
procedure. A minimum of 3 cores will be required. 
If possible and as determined by the Investigator, a minimum of 8 subjects will have fresh tissue 
sampling from which fine needle aspiration (FNA) will also be obtained for immune profiling.  
Remaining core biopsies will be formalin-fixed and paraffin-embedded as per institutional 
standards for further evaluation with IHC or tumor DNA/RNA extraction for sequencing or 
nanostring.   
4.3.1.1.1 Immunohistochemistry 
Quantitative immunofluorescence will be used to evaluate multiple immune biomarkers 
simultaneously in FFPE archival tissue or in pre- and post- treatment biopsy samples as 
available. 
PD-L1 has been examined in studies of PD-1/PD-L1 inhibitors with mixed results in terms of 
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attributed to variability in different assays and in different definitions of positivity.  It is unknown 
how the introduction of ALK inhibition may alter PD-L1 expression and the immune 
microenvironment and whether that may influence outcomes to combination therapy.  
In this study, a pre-treatment biopsy will allow the evaluation of PD-L1 and other immune 
biomarkers to determine correlation with response to combination therapy.  A post run-in 
biopsy will also be performed in order to assess changes in PD-L1 that may have occurred as a 
result of ALK inhibition.  In addition to PD-L1 immunohistochemistry, CD3 immunostaining will 
be performed to evaluate the degree of immune infiltrate in tumor specimens pre- and post-
therapy.  Finally, other markers of immune suppression (FoxP3 to stain T regulatory cells, TIM-3, 
Lag-3 and others) may be evaluated. 
4.3.1.1.2 DNA sequencing 
Whole-exome sequencing (WES) and targeted next-gen sequencing will be performed, as 
feasible, on pre-treatment, post run-in, and post combination treatment biopsies (as available). 
The targeted sequencing (Oncopanel) is a cancer genomic assay performed at Dana Farber 
Cancer Institute to detect somatic mutations, copy number variations, and structural variants in 
tumor DNA that surveys exonic DNA sequences of 275 cancer genes and 91 introns across 30 
genes for rearrangement detection. 
4.3.1.1.3 Gene expression 
Inflammatory or immune-related gene expression signatures may serve as predictors of clinical 
benefit beyond PD-L1 expression and may be evaluated in a subset of biopsies. 
4.3.1.1.4 Immune profiling 
Immune profiling in tumor biopsies collected pre and post durvalumab treatment (as clinically 
feasible) will be performed to evaluate correlates of response and resistance.  FNA samples will 
be used, if available. 
 Biological Activity in Blood Samples 
Blood samples (PBMCs and plasma) will be collected according to Section 3.2 for evaluation of 
PBMC profile by flow cytometry, cytokine profile, soluble PD-L1 analysis, and next-gen 
sequencing of circulating tumor DNA (to evaluate ALK, KRAS, EGFR fusions or mutations). Blood 
may also be used for the evaluation of cytokine profiles and exosomal profiling.   
4.3.2 Subject Evaluation and Statistics 
Only subjects who receive at least 1 dose of each drug and who provide the baseline and at least 
1 on-treatment sample (if applicable) will be evaluated.  As these analyses represent exploratory 
evaluations of potential biomarkers of response or resistance to therapy, descriptive statistics 
will be used to describe findings and potential relationships to outcomes to therapy. 
The exploratory pharmacodynamic assessment of the immunologic changes in the tumor 
microenvironment will include the correlation between clinical activity and the expression level 
of PD-L1 and tumor-infiltrating lymphocyte (TILs) changes in biopsies pre and post treatment. 
The association between response and PD-L1 expression overall and within each cohort will be 
assessed descriptively. Confidence intervals for the overall odds ratio and the odds ratio within 


 
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each cohort will be presented. The association between response and TILs changes (increase, 
decrease, or no change) will be evaluated similarly.  
All other exploratory results will be summarized descriptively. 


 
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5 Subject Eligibility 
NOTE: Standard of Care procedures may be used for eligibility assessments provided they meet the 
criteria specified in either the inclusion criteria or flowchart. 
5.1 Inclusion Criteria 
Eligible subjects must fulfill all of the following criteria: 
1. 
Histologic confirmation of metastatic NSCLC. Subjects must have confirmed ALK 
rearrangement as assessed by IHC.  Subjects may have had prior therapy with ALK 
inhibitors (other than ensartinib) or be ALK inhibitor naïve.  ALK inhibitor naïve subjects 
will be informed of the availability of approved ALK inhibitors. 
2. 
Measurable disease according to RECIST 1.1, defined as ≥ 1 lesion that can be 
accurately measured in at least 1 dimension (longest diameter to be recorded for non-
lymph node lesions, shortest diameter to be recorded for lymph node lesions).  Each 
lesion must be ≥ 10 mm when measured by CT, MRI, or caliper measurement by clinical 
examination or ≥ 20 mm when measured by chest x-ray. 
3. 
Willing to provide a fresh pre-treatment biopsy; however, if subject is ALK inhibitor 
naïve, either archival or pre-treatment biopsy will be acceptable. 
4. 
Asymptomatic subjects with surgically treated brain metastases must be ≥ 14 days post 
surgery at the time of first dosing, while clinically stable with no requirement for 
steroids.  
Asymptomatic subjects with radiation-treated brain metastases may enter the study 
immediately after completion of the radiation (and be off steroids, if applicable).  
Symptomatic subjects (those experiencing headache, seizure etc.), must have been 
relieved from all symptoms of their CNS disease, and must have completed radiation 
and be off steroids prior to first dosing (anti seizure medicine permitted).   
5. 
Laboratory parameters for vital functions should be in the normal range.  Laboratory 
abnormalities that are not clinically significant are generally permitted, except for the 
following laboratory parameters, which must be within the ranges specified, regardless 
of clinical significance: 
Hemoglobin 
≥ 9 g/dL 
Neutrophil count 
≥ 1.5 x 109/L 
Platelet count 
≥ 100,000/mm3 
Serum creatinine, or 
Creatinine Clearance 
≤ 1.5x Institutional Upper Limit of Normal (ULN), or 
≥ 50 mL/min (by Cockcroft-Gault formula) 
Serum total bilirubin 
≤ 1.5 × ULN (except for subjects with Gilbert’s 
syndrome who will be allowed after consultation 
with their physician)  
AST/ALT 
≤ 2.5 x ULN 
Alkaline phosphatase 
≤ 2.5 x ULN 
6. 
ECOG Performance Status ≤ 2. 
7. 
Age ≥ 18 years. 
8. 
Able and willing to provide valid written informed consent. 


 
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9. 
Subject is willing and able to comply with the protocol for the duration of the study 
including undergoing treatment and scheduled visits and examinations including follow 
up 
10. 
Body weight > 30 kg 
5.2 Exclusion Criteria 
Subjects may not enter the study if they fulfill any of the following criteria: 
1. 
Treatment with an investigational agent within 4 weeks of starting treatment, and any 
prior drug-related toxicity (except alopecia) should have recovered to Grade 1 or less. 
2. 
Prior treatment with anti-PD-1, PD-L1 (including durvalumab), or CTLA4, or ensartinib 
(X-396). 
3. 
Active, suspected or prior documented autoimmune disease (including but not 
restricted to inflammatory bowel disease, celiac disease, Wegner’s granulomatosis, 
Hashimoto’s thyroiditis, rheumatoid arthritis, systemic lupus, scleroderma and its 
variants, multiple sclerosis, myasthenia gravis).  Vitiligo, residual hypothyroidism due to 
autoimmune condition only requiring hormone replacement, psoriasis not requiring 
systemic treatment, or conditions not expected to recur in the absence of an external 
trigger are permitted. 
4. 
Subjects with clinically significant cardiovascular disease, including: 
a. New York Heart Association (NYHA) Class II or higher congestive heart failure. 
b. Myocardial infarction, unstable angina, cerebrovascular accident or transient 
ischemic attack within 6 months of start of study drug (Day -28). 
c. Clinically significant supraventricular or ventricular arrhythmia. 
d. QTcF ≥ 450 ms (male) or QTcF ≥ 470 ms (female). 
e. Clinically uncontrolled hypertension. 
5. 
History of pneumonitis or interstitial lung disease, or any unresolved immune-related 
adverse events following prior therapy. 
6. 
Major surgery within 4 weeks of starting treatment (or scheduled for surgery during the 
projected course of the study). 
7. 
Women of child bearing potential who are pregnant as evidenced by positive serum 
pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) or nursing.  
8. 
Female subjects of childbearing potential who are sexually active with a non-sterilized 
male partner must use at least one highly effective method of contraception (see table 
below) from the time of screening and must agree to continue using such precautions 
for 90 days after the final dose of investigational products.  Non-sterilized male partners 
of a female subject must use male condoms 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 trial and the drug 


 
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washout period is an acceptable practice; however, periodic abstinence, the rhythm 
method, and the withdrawal method are not acceptable methods of birth control. 
Female subjects should refrain from breastfeeding throughout the period described 
above. 
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.  
Females will be considered post-menopausal if they have been amenorrheic for 12 
months without an alternative medical cause.  The following age-specific requirements 
apply:  
• 
Females <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).  
• 
Females ≥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. 
Non-sterilized male subjects who are sexually active with a female partner of 
childbearing potential must use male condoms plus spermicide from screening through 
90 days after receipt of the final dose of investigational products.  Male subjects should 
refrain from sperm donation throughout this period. Female partners (of childbearing 
potential) of a male subject must use a highly effective method of contraception (see 
table below) 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 trial 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. 
Highly effective methods of contraception are described in the table below. A highly 
effective method of contraception is defined as one that results in a low failure rate (i.e. 
less than 1% per year) when used consistently and correctly. 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). 
Acceptable highly effective methods of contraception are described in the following 
table: 
 


 
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Highly Effectivea Methods of Contraception 
Barrier/Intrauterine Methods 
Hormonal Methods 
• 
Copper T intrauterine device 
• 
Levonorgesterel-releasing 
intrauterine system (e.g., 
Mirena®)b 
• 
“Implants”:Etonogestrel-releasing 
implants: e.g. Implanon® or Norplan® 
• 
“Intravaginal devices”: Ethinylestradiol 
and etonogestrel-releasing intravagibal 
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: e.g. 
Cerazette® 
a - Highly effective (i.e. failure rate of <1% per year)  
b - This is also considered a hormonal method 
c - Cerazette® is currently the only highly effective progesterone based pill. 
9. 
Subjects who are immunosuppressed, including those with known immunodeficiency. 
10. 
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).  Subjects with a past or 
resolved HBV infection (defined as the presence of hepatitis B core antibody [anti-HBc] 
and absence of HBsAg) are eligible.  Subjects positive for hepatitis C (HCV) antibody are 
eligible only if polymerase chain reaction is negative for HCV RNA 
11. 
History of severe allergic reactions to any unknown allergens or components of the 
study drugs. 
12. 
Other serious illnesses (e.g., serious infections requiring antibiotics, bleeding disorders). 
13. 
Mental impairment that may compromise compliance with the requirements of the 
study. 
14. 
Lack of availability for immunological and clinical follow-up assessment. 
15. 
Inability to swallow or retain oral medication, presence of active gastrointestinal (GI) 
disease or other condition that will interfere significantly with the absorption, 
distribution, metabolism, or excretion of ensartinib. 
16. 
Any condition that, in the clinical judgment of the treating physician, is likely to prevent 
the subject from complying with any aspect of the protocol or that may put the subject 
at unacceptable risk. 
17. 
History of allogeneic organ transplant 
18. 
Subjects must not donate blood while on study and for at least 90 days following the 
last durvalumab treatment. 
 
 


 
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5.3 Restrictions on Concomitant Therapies 
5.3.1 Non-Permitted Concomitant Therapies 
Subject may not receive the following concomitant therapies during the study: 
1. 
Systemic treatment with high-dose corticosteroids (greater than Prednisone 10 mg 
daily or equivalent) or other immunosuppressive treatments (e.g., methotrexate, 
chloroquine, azathioprine).  See Section 5.3.2 for exceptions.  [Wash-out period: 
2 weeks prior to Day -28 (start of study drug).] 
2. 
Other cancer therapy (e.g., drug, non-palliative radiation, or immunotherapy). 
[Wash-out period: 4 weeks or 5 half-lives (whichever is shorter) prior to Day -28 (start 
of study drug); 6 weeks for nitrosoureas, 7 days for ALK TKIs]. 
3. 
Live/attenuated vaccines 1 month prior to Day -28 (start of study drug) and for at least 
6 months after the last dose of treatment. 
The wash-out period prior to Day -28 (start of study drug) of the study for all non-permitted 
drugs should be at least 1 week, unless stated otherwise above. 
NOTE for ensartinib:  Although only minimal QTc prolongation has been observed with 
ensartinib therapy to date, subjects will be monitored with electrocardiograms and electrolytes, 
and caution should be exercised if concomitant medications with known risk of Torsades de 
Pointes (see Section 8.7) are to be administered. 
5.3.2 Permitted Concomitant Therapies 
Subject may receive the following concomitant therapies during the study: 
1. 
Inhaled or oral steroids for treating mild to moderate asthma or allergies, or topical 
steroids for localized (< 5% of body surface area) dermatitis, not to exceed 10mg/day 
prednisone or bioequivalent corticosteroid. 
2. 
Oral steroids for the treatment of ensartinib-associated rash is permitted during 
ensartinib monotherapy only.   
3. 
Physiologic replacement of glucocorticoids as maintenance therapy for adrenal 
insufficiency.  Standard doses of hydrocortisone for maintenance therapy are up to 10–
20 mg/m2/day divided 2–4 times per day.  For a subject with a body surface area (BSA) 
of 1.73 m2, this translates to a total dose of up to 34.6 mg of hydrocortisone per day. 
The equivalent dose of dexamethasone is up to 1.2 mg per day.  Some subjects may 
additionally receive mineralocorticoid-replacement maintenance therapy with 
fludrocortisone.  The maintenance dose of fludrocortisone for this indication is 0.05–0.1 
mg/day. 
4. 
NSAIDs, acetylsalicylic acid, and specific COX-2 inhibitors. 
5. 
Antihistamines and other non-steroidal anti-allergy medication. 
6. 
Hormone or hormone-related anti-cancer therapy. 
7. 
At the discretion of the Investigator, any drug or non-drug therapy necessary to treat 
any condition arising during the study, including high-dose corticosteroids to treat 
immune-mediated adverse reactions.  Subjects should receive full supportive care, 
including transfusions of blood and blood products, and treatment with antibiotics, 
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in accordance with their institutional guidelines.  Use of anticoagulants such as warfarin 
is permitted; however, caution should be exercised and additional international 
normalized ratio (INR) monitoring is recommended. 
All prescription and nonprescription drugs must be recorded in the concomitant medications 
section of the case report form (CRF), listing generic (preferably) or brand name, indication, 
dose, route, and dates of administration.  All non-drug therapies must be recorded in the 
respective sections of the CRF. 


 
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6 Study Drug Preparation and Administration 
All study drugs are supplied by the Sponsor (see Section 7.2.8). Commercially available water for 
injection (WFI) and 0.9% (w/v) saline or 5% (w/v) dextrose will be supplied by each site.  See 
Section 6.4 for monitoring of subjects after durvalumab doses. 
6.1 Durvalumab (MEDI4736) 
6.1.1 Study Drug Information 
Manufacturer 
MedImmune 
Expiration/Retest 
Date 
Expiration/retest dates are documented in the QA Disposition of 
Investigational Medicinal Product (IMP) Report. 
Container 
Description 
Type: 
Single use vial  
Material: 
Glass 
Size: 
10 mL 
Formulation 
Liquid solution containing 500 mg durvalumab per vial.  
The solution contains 50 mg/mL durvalumab, 26 mM 
histidine/histidine-HCl, 275 mM trehalose dihydrate, 0.02% 
(weight/volume [w/v]) polysorbate 80, at pH 6.0. 
Active Ingredient 
Content 
Mass/Weight: 
500 mg 
Volume: 
10mL 
Concentration: 
50 mg/mL 
Storage Conditions 
2°C–8°C (36°F–46°F) Do not freeze 
Labeling 
Product name, lot number, route of administration, and storage 
conditions 
6.1.2 Durvalumab Investigational Product Inspection 
Each vial of durvalumab selected for dose preparation should be inspected.  If there are any 
defects noted with the investigational product (IP), the Investigator and Sponsor should be 
notified immediately. Please see Section 7.2.8 for additional details. 
6.1.3 Durvalumab Preparation 
Preparation of durvalumab and preparation of the intravenous bag dose are to be performed by 
the IP manager or designated personnel using aseptic technique.  No incompatibilities between 
durvalumab and polyvinylchloride or polyolefin copolymers have been observed. 
Dose Calculation: 
Subjects will receive a fixed dose of durvalumab: 1500 mg Q4W for subjects > 30 kg.   
NOTE: If a subject’s body weight drops to ≤ 30 kg while on the study, the subject will receive 
weight-based dosing equivalent to 20 mg/kg of durvalumab as long as the body weight remains 
≤ 30 kg (e.g., a 30 kg subject would receive a 600 mg dose; a 25 kg subject would receive a 500 
mg dose; etc.).  When the weight improves to >30 kg, the subject may return to fixed dosing of 
durvalumab 1500 mg.   
The volume of durvalumab (in mL) to add to the IV bag is calculated as follows: 


 
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Volume of 
Durvalumab 
(mL) 
= 
Dose level (mg) 
 
÷ 
Durvalumab 
Concentration 
(nominal 50 mg/mL) 
 
Dose Preparation: 
Durvalumab will be administered using a 250 mL IV bag containing 0.9% (w/v) saline or 5% (w/v) 
dextrose, and delivered through an IV administration set with a 0.2 or 0.22 µm in-line filter.  A 
volume of diluent equal to the calculated volume of durvalumab to be added to the IV bag must 
be removed from the bag prior to addition of durvalumab.  The calculated volume of 
durvalumab is then added to the IV bag, and the bag is mixed by gentle inversion to ensure 
homogeneity of the dose in the bag. 
Example: For a 1500 mg dose (for subjects > 30 kg in weight), 30 mL of durvalumab is to be 
diluted in a 250 mL IV bag. First, 30.0 mL of diluent is removed from the IV bag, and then 30 mL 
of durvalumab is added to the bag.  The bag is mixed by gentle inversion to ensure homogeneity 
of the dose in the bag. 
Durvalumab does not contain preservatives; any unused portion must be discarded. 
6.1.4 Durvalumab Administration 
Following preparation of the dose, durvalumab will be administered according to the following 
guidelines: 
• 
A physician must be present at the site or immediately available to respond to 
emergencies during all administrations of investigational products. Fully functional 
resuscitation facilities should be available. 
• 
Prior to the start of the infusion, the IV bag contents must be at room temperature to 
avoid an infusion reaction due to the administration of the solution at low 
temperatures. 
• 
Durvalumab must not be administered via IV push or bolus but as an IV infusion. 
• 
Durvalumab solution should not be infused with other solutions or medications. 
• 
Durvalumab must be administered at room temperature by controlled infusion into a 
peripheral vein or central line. 
• 
The entire contents of the IV bag should be administered as an IV infusion over 
approximately 60 (± 5) minutes, using a 0.2- or 0.22-μm in-line filter.  An infusion time 
of less than 55 minutes is considered a deviation.   
• 
After the contents of the IV bag are fully administered, the IV line will be flushed with a 
volume of IV diluent equal to the priming volume of the infusion set used.  Alternatively, 
the infusion will be completed according to institutional policy to ensure the full dose is 
administered; documentation is required if the line was not flushed. 
• 
The total time between needle puncture of the durvalumab vial to 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).  Standard infusion time is 60 ± 5 minutes.  However, if there are 
interruptions during infusion, the total allowed time should not exceed 8 hours.  In the 
event that either preparation time or infusion time exceeds the time limits, a new dose 
must be prepared from new vials. 


 
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• 
Durvalumab does not contain preservatives, and any unused portion must be discarded. 
• 
The date, start time, interruption, and completion time of durvalumab administration 
must be recorded in the source documents.   
• 
Subjects will be monitored before, during and after infusion with assessment of vital 
signs according to Section 6.4. 
• 
In the event of a ≤Grade 2 infusion-related reaction, the infusion rate of study drug 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.  For subjects with a 
≤Grade 2 infusion-related reaction, subsequent infusions may be administered at 50% of 
the initial rate.  Acetaminophen and/or an antihistamine (e.g., 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, study 
drug will be discontinued. See Section 8.3.1. 
6.2 Ensartinib (X-396) 
6.2.1 Study Drug Information 
Manufacturer 
Xcovery 
Expiration/Retest Date 
Expiration/retest dates are documented on the Certificate of 
Analysis and/or stability certification. 
Container Description 
Type: 
Bottle 
Material: 
HDPE 
Size:  
60cc (30 capsules) 
Formulation 
Dry blend in capsule 
Active Ingredient Content 
Mass/Weight: 
25 or 100 mg  
Volume: 
Not applicable 
Concentration: 
Not applicable 
Storage Conditions 
Room temperature, 15°C to 30°C (59°F to 86°F) 
Labeling 
Product name, lot number, route of administration, and 
storage conditions 
6.2.2 Preparation  
Not applicable 
6.2.3 Administration 
Subjects will receive a 4-week supply of ensartinib.  At each study visit, they will return the 
unused portion to the study site; the number of pills returned will be counted to determine 
compliance. 
Ensartinib is taken orally, once per day. It may be taken with or without food; however, subjects 
may tolerate the drug better (i.e., have fewer gastrointestinal side effects), if it is taken with 
food.  It is recommended that the subjects take the medication at approximately the same time 
each day.  The time of day for administration of study medication should be consistent.   


 
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6.3 Estimated Study Requirements 
Drug 
Requirements 
Ensartinib  
(25 mg capsules) 
1,000 bottles  
(30 capsules/bottle) 
Ensartinib  
(100 mg capsules) 
1,000 bottles  
(30 capsules/bottle) 
Durvalumab 
350 kits (4 vials/kit) 
 
6.4 Monitoring of Durvalumab Dose Administration 
Subjects will be monitored before, during and after durvalumab infusion with assessment of 
vital signs according to the table below: 
Vital Signs Assessment on Study Drug Administration Days 
Drug 
Pre Dose 
During Infusion 
End of Infusion  
(± 5 minutes) 
30 (± 5) Minutes 
Post Infusion  
60 (± 5) Minutes 
Post Infusion  
Durvalumab  
X 
Every 15 (± 5) 
minutes 
X 
X 
x 
 
If a subject tolerates treatment well for the first 4 doses of durvalumab (i.e., no infusion 
reactions), subsequent infusions in that subject can be monitored according to the table below.  
A longer duration of observation after the end of infusion can be used if the Investigator deems 
it clinically necessary. 
Vital Signs Assessment 
on study drug 
administration days 
(after first 4 doses) 
Pre Dose 
During Infusion 
End of Infusion  
(± 5 minutes) 
15 (± 5) Minutes 
Post Infusion 
Durvalumab 
X 
Every 30 (± 5) 
minutes 
X 
X 
 
6.5 Drug Overdose Management 
There are no known antidotes available for durvalumab or ensartinib.  Any overdoses with these 
drugs should be managed symptomatically.  An overdose is defined as a subject receiving any 
dose in excess of that specified in this protocol by > 10%.  All such overdoses must be reported, 
with or without associated AEs/SAEs, according to Section 7.1.2.2.  
 


 
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7 Administrative, Legal and Ethical Requirements 
7.1 
Documentation and Reporting of Adverse Events 
7.1.1 Definitions 
An Adverse Event (AE) is any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product and that does not necessarily have a causal 
relationship with the 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 (investigational) product, whether or not related to the medicinal 
(investigational) product. 
N.B.: The definition above, provided for in the GCP-ICH Guideline E6, is being extended for the 
purpose of LICR studies to include any events, intercurrent diseases and accidents observed 
while the patient/subject is on study, i.e., during the actual treatment period, as well as during 
drug-free, pre- and post-treatment periods, under placebo or in a reference group receiving 
drug or non-drug therapy or no treatment. 
A Serious Adverse Event (SAE) is any untoward medical occurrence that: 
1. 
Results in death, 
2. 
Is life-threateningA, 
3. 
Requires inpatient hospitalization or prolongation of existing hospitalization, 
4. 
Results in persistent or significant disability or incapacity, 
5. 
Is a congenital anomaly / birth defect or 
6. 
Is another medically important conditionB. 
A 
The term “life-threatening” in the definition of “serious” refers to an event in which the 
patient/subject is at risk of death at the time of the event; it does not refer to an event, which 
hypothetically might have caused death if it were more severe. 
B 
Medically important conditions that may not result in death, be immediately life-
threatening or require hospitalization may be considered as SAE when, based upon appropriate 
medical judgment, they may jeopardize the patient/subject or may require intervention to 
prevent one of the outcomes listed in the definition above.  Examples of such events are 
intensive treatment in an emergency room or at home for allergic bronchospasm; blood 
dyscrasias or convulsions that do not result in hospitalization; or development of drug 
dependency or drug abuse. 
N.B.: The term “severe” is often used to describe the intensity (severity) of an event (such as: 
mild, moderate, or severe, e.g., pain).  The event itself may be of relatively minor medical 
significance (such as severe headache).  This is not the same as “serious”, which is based on 
patient/event outcome or action criteria usually associated with events that pose a threat to 
patient’s life or vital functions.  Seriousness (not severity) serves as a guide for defining 
regulatory reporting obligations. 


 
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7.1.2 Additional Expedited Reporting Requirements for this Study 
For the purpose of this study, the following events must be reported by phone or email to the 
Sponsor within 24 hours of knowledge of the event (see Section 7.1.6 for Sponsor contact 
information) and may result in submission of an SAE based on certain criteria outlined below: 
• 
Pregnancy 
• 
Overdose (as defined in Section 6.5) 
• 
Hepatic Function Abnormality (as defined in Section 7.1.8) 
 Pregnancy 
7.1.2.1.1 Maternal Exposure 
Female subjects should avoid becoming pregnant and breastfeeding during the study and for 
90 days after the final dose of investigational product (see Section 5.2, #8). 
If a subject becomes pregnant during the course of the study, the study drugs should be 
discontinued immediately.   
Pregnancy itself is not regarded as an AE unless there is a suspicion that the drug 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 (see section 7.1.6).  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 subject was discontinued from the study.   
If any pregnancy occurs in the course of the study, the Investigator or other site personnel 
should inform the Sponsor within 1 day, i.e., immediately, but no later than 24 hours of when 
he or she becomes aware of it.   
The Sponsor will work with the Investigator to ensure that all relevant information is provided 
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. 
7.1.2.1.2 Paternal Exposure 
Male subjects should refrain from fathering a child or donating sperm during the study and for 
90 days after the final dose of investigational product (see Section 5.2, #8).   
Pregnancy of the subject’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 90 days after the last dose 
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 subject’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.  


 
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 Overdose 
Any overdose (as defined in Section 6.5) of a study subject, with or without associated AEs/SAEs, 
is required to be reported within 24 hours of knowledge of the event to the Sponsor. If the 
overdose results in an AE, the AE must also be recorded as an AE according to Section 7.1.5. 
Overdose does not automatically make an AE serious, but if the consequences of the overdose 
are serious, for example death or hospitalization, the event is serious and must be recorded and 
reported as an SAE according to Section 7.1.6. There is currently no specific treatment in the 
event of an overdose of the study drugs. The Investigator will use clinical judgment to treat any 
overdose. See Section 6.5 for additional details. 
 Hepatic Function Abnormality 
Hepatic function abnormality (as defined in Section 7.1.8) in a study subject, with or without 
associated clinical manifestations, is required to be reported as “hepatic function abnormal” 
within 24 hours of knowledge of the event to the Sponsor, unless a definitive underlying 
diagnosis for the abnormality (e.g., cholelithiasis or bile duct obstruction) that is unrelated to 
investigational product has been confirmed (see Section 7.1.6 for Sponsor contact information). 
• 
If the definitive underlying diagnosis for the abnormality has been established and is 
unrelated to investigational product, the decision to continue dosing of the study 
subject will be based on the clinical judgment of the Investigator. 
• 
If no definitive underlying diagnosis for the abnormality is established, dosing of the 
study subject must be interrupted immediately. Follow-up investigations and inquiries 
must be initiated by the investigational site without delay. 
Each reported event of hepatic function abnormality will be followed by the Investigator and 
evaluated by the Sponsor and MedImmune/AstraZeneca. 
7.1.3 Severity of an Adverse Event 
The severity of all serious and non-serious adverse events should be assessed according to the 
National Cancer Institute CTCAE Scale (Version 4.03). 
7.1.4 Relationship of Adverse Events to Study Drug 
The relationship of all serious and non-serious adverse events to the investigational agent(s) will 
be determined by the Investigator on the basis of their clinical judgment, using one of the 
following terms (in accordance with NCI Guideline “Expedited Adverse Event Reporting 
Requirements for NCI Investigational Agents”, NCI Cancer Therapy Evaluation Program, January 
2001): 
Definitely related (The AE is clearly related to the investigational agent) 
Probably related (The AE is likely related to the investigational agent) 
Possibly related (The AE may be related to the investigational agent) 
Unlikely related (The AE is doubtfully related to the investigational agent) 
Unrelated (The AE is clearly not related to the investigational agent) 
N.B.: When making the assessment on causality, it should be taken into consideration that 
immune-therapeutic agents have the potential to cause very late and/or permanent effects on 


 
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the immune system, i.e., a causal relationship could exist despite a lack of apparent temporal 
relationship.  Information provided in the IB and/or in “Background” of this protocol may 
support these evaluations. 
7.1.5 General Reporting Requirements 
All serious and non-serious adverse events must be documented in the source records and on 
the respective section of the CRF, regardless of severity or the assumption of a causal 
relationship.  The documentation includes: dates of onset and resolution, severity, seriousness, 
study drug intervention, treatment and outcome, as well as, the causal relationship between the 
event and the study drug in accordance with Section 7.1.4.  This documentation is required for 
all AEs that occur: 
a. from the date of signing the informed consent, and 
b. until the off-study date or 90 days after the last administration of study drug, whichever 
is longer, or until a new treatment is initiated (see Section 3.1.10 for subjects who begin 
other anti-cancer treatment). 
Immune Related Adverse Events (irAEs) will be collected from the time of informed consent 
through 90 days after the last dose of the last study treatment (regardless of initiation of 
another therapy). 
7.1.6 Expedited Serious Adverse Event (SAE) Reporting Requirements 
In addition to the General Reporting Requirements specified in Section 7.1.5, all events 
meeting the criteria for an SAE per Section 7.1.1, irrespective of suspected causation, must be 
reported by the Investigator to the Sponsor’s Drug Safety Contact (primarily) or, alternatively, 
to the Primary Sponsor Contact, within 24 hours of becoming aware of the event (see contact 
information below). SAEs should be reported via the Medidata RAVE data capture system 
(which utilizes “Safety Gateway”), using the respective Adverse Event and Safety Case 
Summary electronic CRFs (eCRFs).  This includes any deaths that occur after the off-study date, 
but within 30 days of last study drug administration. In the event that the SAE cannot be 
reported via Medidata RAVE, the SAE should be reported using the “Initial Serious Adverse 
Event Report Form,” provided by the Sponsor. 
Note: If an SAE cannot be reported via Medidata RAVE or the “Initial Serious Adverse Event 
Report Form” within 24 hours of becoming aware of the event, the Sponsor’s Drug Safety 
Contact (primarily) or, alternatively, the Primary Sponsor Contact, must be contacted by 
phone or email within 24 hours of becoming aware of the event. In this case, the phone or 
email notification can then be followed up through Medidata RAVE or an “Initial Serious 
Adverse Event Report Form” within one working day of the event. 
If the “Initial Serious Adverse Event Report Form” is being used, the expedited reports should be 
directed by fax or e-mail to the Drug Safety Contact (primarily) or, alternatively, the Primary 
Sponsor Contact.  Studies utilizing Medidata RAVE (and the “Safety Gateway”) built into the 
eCRF, and respective SAE reporting procedures, do not require reporting by fax or email.  
Questions related to Medidata RAVE and “Safety Gateway” procedures should be directed to 
the Drug Safety Contact or Primary Sponsor Contact (see table below for contact information). 


 
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In urgent cases, pre-notification via phone or informal e-mail should be considered. 
Drug Safety Contact: 
Gary O’Donnell, MS 
Senior Manager, Drug Safety 
Clinical Trials Management 
Ludwig Institute for Cancer Research 
666 3rd Ave, 28th Floor 
New York, New York 10017 
Tel: 
+1 212 450 1551 
Fax: 
+1 212 450 1535 
godonnell@licr.org 
Primary Sponsor Contact: 
Mary Macri 
Director 
Clinical Trials Management 
Ludwig Institute for Cancer Research 
666 3rd Ave, 28th Floor 
New York, New York 10017 
Tel: 
+1 212 450 1546 
Fax: 
+1 212 450 1535 
mmacri@licr.org  
 
Serious adverse events must also be reported by the Principal Investigator to the respective 
Institutional Review Board after being assigned a serious adverse event tracking number by the 
Sponsor.  Institutional Review Boards may have specific rules on which Adverse Events need to 
be reported expeditiously, as well as, the time frames for such reporting. 
SAE Reports will be evaluated by the Sponsor’s Medical Monitor.  Regulatory authorities and 
other Investigators, as well as institutional and corporate partners, will be informed by the 
Sponsor as required by ICH guidelines, laws and regulations in the countries where the 
investigational agent is being administered.  In particular, SAEs that are unexpected and for 
which a causal relationship with the study drug cannot be ruled out, will be reported by the 
Sponsor within 15 calendar days; if they are life-threatening or fatal, they will be reported within 
7 Calendar days. 
Serious adverse event reporting to AstraZeneca/Medimmune is described in a separate 
agreement. 
7.1.7 Serious Adverse Event (SAE) Follow-up Requirements 
Subjects experiencing SAEs should be followed closely until the condition resolves or stabilizes, 
and every effort should be made to clarify the underlying cause.  Follow-up information related 
to SAEs must be submitted to the Sponsor as soon as relevant data are available. 
7.1.8 Adverse Events of Special Interest (AESIs) 
An adverse event of special interest (AESI) is one of scientific and medical interest specific to the 
understanding of the investigational products and may require close monitoring and rapid 
communication by the Investigator to the Sponsor. An AESI may be serious or non-serious. The 
rapid recording of all AEs, including AESIs, allows ongoing surveillance of these events in order 
to characterize and understand them in association with the use of the investigational products.   
AESIs for durvalumab 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-related adverse event (irAE) is defined as an adverse event 


 
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that is associated with drug exposure and is consistent with an immune-mediated mechanism of 
action and where there is no clear alternate aetiology. Serologic, immunologic, and histologic 
(biopsy) data, as appropriate, should be used to support an irAE diagnosis. Appropriate efforts 
should be made to rule out neoplastic, infectious, metabolic, toxin, or other etiologic causes of 
the irAE. 
If the Investigator has any questions in regards to an AE being an irAE, the Investigator should 
promptly contact the Medical Monitor. 
If an AESI also meets SAE criteria, the event will be reported as an SAE per Section 7.1.6. 
AESIs observed with durvalumab and those considered AESIs for the purpose of this study are 
listed below. Further information on these AESIs (e.g. presenting symptoms) can be found in the 
current version of the durvalumab (MEDI4736) Investigator’s Brochure (IB). Guidelines for the 
management of subjects experiencing toxicities for durvalumab can be found in Section 8.3 and 
in the following Medimmune guideline: “Medimmune’s Dosing Modification and Toxicity 
Management Guidelines for Immune- mediated, Infusion Related, and Non Immune-mediated 
Reactions (MEDI4736 (durvalumab) Monotherapy or Combination therapy with 
Tremelimumab or Tremelimumab monotherapy).” 
 
• 
Colitis/Gastrointestinal disorders 
Diarrhea and colitis are the most commonly observed treatment-emergent AEs 
following dosing with study medications.  In rare cases, colon perforation may occur 
that requires surgery (colectomy) or can lead to a fatal outcome, if not properly 
managed. 
• 
Pneumonitis/Interstitial lung disease (ILD) 
Adverse events of pneumonitis have been observed with anti-PD-1, and anti-PD-L1 
antibodies (see IB). Initial work-up should include high-resolution CT scan, ruling out 
infection, and pulse oximetry.  Typically, pulmonary consultation is required. 
• 
Hepatic Function Abnormality (Hepatitis, hepatotoxicity) 
Increased transaminases have been reported during treatment with anti-PD-L1/anti-PD-
1 antibodies (see IB).  Inflammatory hepatitis has been reported in 3% to 9% of subjects 
treated with anti-CTLA-4 monoclonal antibodies (e.g., ipilimumab).  The clinical 
manifestations of ipilimumab-treated subjects included general weakness, fatigue, 
nausea and/or mild fever and increased liver function tests such as AST, ALT, alkaline 
phosphatase, and/or total bilirubin. Hepatic function abnormality is defined as any 
increase in ALT or AST to greater than 3 × ULN and concurrent increase in total bilirubin 
to be greater than 2 × ULN.  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 concurrent or pre-existing disease (e.g., 
cholelithiasis and bile duct obstruction with distended gallbladder) or an agent other 
than the investigational product. Cases where a subject shows an AST or ALT ≥ 3 x ULN 
or total bilirubin ≥ 2 x ULN may need to be reported as SAEs. These cases should be 


 
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reported as SAEs if, after evaluation they meet the criteria for a Hy’s Law case or if any 
of the individual liver test parameters fulfill any of the SAE criteria. 
• 
Neurotoxicity (Neuropathy / neuromuscular toxicity) 
Immune-mediated nervous system events include encephalitis, peripheral motor and 
sensory neuropathies, Guillain-Barré, and myasthenia gravis. 
• 
Endocrine Disorders 
Immune-mediated endocrinopathies include hypo- and hyper-thyroidism, adrenal 
insufficiency, hypophysitis/hypopituitarism, diabetes insipidus, and Type 1 diabetes 
mellitus. 
Type 1 diabetes mellitus: For subjects with suspected diabetes mellitus, Investigators 
should obtain an endocrinology consult and institute appropriate management which 
may include the administration of insulin.  
• 
Dermatitis/Rash 
Prompt treatment with steroids (topical or systemic based on severity) is important as 
per current established toxicity management guidelines. 
• 
Nephritis and increases in serum creatinine 
A consult with a Nephrologist should be done as well as monitoring for signs and 
symptoms that may be related to changes in renal function (e.g., routine urinalysis, 
elevated serum BUN and creatinine, decreased creatinine clearance, electrolyte 
imbalance, decrease in urine output, proteinuria, etc.). Subjects should be thoroughly 
evaluated to rule out any alternative etiology (e.g., disease progression, infections, etc.). 
Steroids should be considered in the absence of clear alternative etiology even for low 
grade events (Grade 2), in order to prevent potential progression to higher grade event. 
• 
Pancreatic Disorders 
Immune-mediated pancreatitis includes autoimmune pancreatitis (or labs suggestive of 
pancreatitis - increased serum lipase, increased serum amylase). 
• 
Hypersensitivity and Infusion Reactions 
Hypersensitivity reactions as well as infusion-related reactions have been reported with 
anti-PD-L1 and anti-PD-1 therapy (see IB).  As with the administration of any foreign 
protein and/or other biologic agents, reactions following the infusion of monoclonal 
antibodies (MAbs) can be caused by various mechanisms, including acute anaphylactic 
(IgE-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, arthralgia, bronchospasm, wheeze, cough, 
dizziness, fatigue, headache, hypertension, myalgia, vomiting and unresponsiveness. 
• 
Other inflammatory responses that are rare with a potential immune-mediated aetiology 
include, but are not limited to, myocarditis, pericarditis, and uveitis. 
 
Guidelines for the management of subjects experiencing toxicities for durvalumab can be found 
in Section 8.3. Guidelines for ensartinib can be found in Section 8.4. 
 


 
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7.2 Administrative Sponsor Requirements 
7.2.1 Study Master Files 
The Investigator must retain a Sponsor-specified comprehensive and centralized filing system 
(“Study Master File”) of all trial-related documentation that is suitable for inspection by the 
Sponsor and regulatory authorities.  Upon completion of the trial, the Investigator is required to 
submit a summary report to the Sponsor. 
The Investigator must arrange for the retention of the Study Master File for a period of time 
determined by the Sponsor.  No part of the Study Master File shall be destroyed or relocated 
without prior written agreement between the Sponsor and the Investigator. 
7.2.2 Case Report Form Data Collection 
Electronic Case Report Forms (eCRF) will be completed in accordance with respective guidance 
and after training provided by the Sponsor.  The use of eCRFs encompasses electronic data 
entry, query management and sign-off.  Systems used for electronic data capture will be 
compliant with FDA regulations 21 CFR Part 11 and within the constraints of the applicable local 
regulatory agency guidelines (whichever provides the greatest protection to the integrity of the 
data). 
All subjects who sign an informed consent form, regardless of study procedures performed, will 
be assigned a screening number and have their data entered into the eCRF. 
The Investigator will sign and date the completed eCRF sections.  This signature will indicate a 
thorough inspection of the data in the eCRF and will certify its content. 
7.2.3 Language 
The protocol is written in English.  All correspondence between the study site and the Sponsor 
should be maintained in English.  Case Report Forms must be completed in English.  All written 
material to be used by subjects and para-clinical staff must use vocabulary that is clearly 
understood, and be in the language appropriate for the trial site. 
7.2.4 Monitoring 
The Sponsor will oversee the conduct of the study and perform clinical monitoring visits for site 
qualification, site initiation, routine monitoring and site close-out.  Clinical Monitors and/or 
other sponsor staff will meet with the Investigator staff and require direct access to source 
data/documents.  Such access may also be required for Institutional Review Board review, and 
regulatory inspection/audits.  Direct access is defined as permission to examine, analyze, verify, 
and reproduce any records and reports that are important to the evaluation of the study.  All 
reasonable precautions within the constraints of the applicable regulatory requirement(s) to 
maintain the confidentiality of subjects’ identities and sponsor’s proprietary information will be 
exercised. 
It is the Clinical Monitor’s responsibility to inspect the CRFs at regular intervals throughout the 
trial to verify adherence to the protocol, the completeness, accuracy and consistency of the 
data, and adherence to Good Clinical Practice guidelines.  The Clinical Monitor will have access 


 
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to patient charts, laboratory reports and other subject records needed to verify the entries on 
the CRFs (“source data verification”). 
7.2.5 Protocol Amendments 
Protocol amendments may be implemented only after approval by the Investigator, Sponsor, 
Institutional Review Board and, if required, the regulatory authorities.  Amendments that are 
intended to eliminate an apparent immediate hazard to subjects may be implemented prior to 
such approvals.  However, in this case, approval must be obtained as soon as possible after 
implementation.  Implementation of administrative amendments that do not affect the safety of 
the subjects do usually not require prior Institutional Review Board approval, just notification. 
When immediate deviation from the protocol is required to eliminate an immediate hazard(s) to 
subjects, the Investigator will contact the Sponsor if circumstances permit, to discuss the 
planned course of action.  Any departures from the protocol must be fully documented in the 
source documentation. 
7.2.6 Premature Subject Withdrawal from Treatment or from Study 
A subject may withdraw from study treatment or from the study at any time for any reason 
without prejudice to his/her future medical care by the physician or at the study site.  Likewise, 
the Investigator and/or Sponsor have the right to withdraw subjects from treatment or from the 
study.  Specific subject withdrawal criteria are listed in Section 3.1.10.  Should a subject (or a 
subject’s legally authorized representative) decide to withdraw from study treatment or from 
the study, all efforts will be made to complete the required study procedures and report the 
treatment observations as thoroughly as possible. 
For all subject withdrawals, a complete final evaluation should be made at the time of 
withdrawal.  The appropriate form in the CRF should be completed with an explanation of why 
the subject is withdrawing, and an attempt should be made to perform a follow-up evaluation. 
7.2.7 Early Trial Termination 
Sponsor and Investigator have the right to terminate the study early.  Specific study stopping 
rules are listed in Section 3.1.14.  In such case, one party must notify the other in advance in 
writing about the intent of and the reasons for the termination.  The Investigator must also 
notify the appropriate Institutional Review Board accordingly. 
7.2.8 Study Drug Shipments and Accountability 
Study drug shipments will be addressed to the Principal Investigator’s authorized designee, 
preferably, the site’s pharmacy.  The recipient will verify the amount and condition of the drug 
and will return a signed Acknowledgment of Receipt to the shipper. 
A drug dispensing log (inventory) will be kept by the study site, containing at least the following: 
• 
the subject’s identification (subject number and code) 
• 
date and quantity of drug dispensed 
• 
date and quantity of drug returned to the Investigator/pharmacy (if applicable) 
• 
date and quantity of accidental loss of drug (if any)  


 
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These inventories must be made available for inspection by the Clinical Monitor.  The 
Investigator is responsible for seeing to it that all used and unused trial supplies are accounted 
for.  At the end of the study, the Clinical Monitor will also collect the original study drug 
dispensing records. 
 
At the end of the study or as directed by the Sponsor, all used and unused supplies, including 
partially used or empty containers, will be disposed of or transferred as instructed by the 
Sponsor, and in accordance with local written procedures, if applicable.  Any disposal or transfer 
of investigational agent shall be noted on the investigational drug disposition log and signed-off 
by a second person.  At the end of the study, the Clinical Monitor will collect the original drug 
disposition logs. 
7.3 Regulatory, Legal and Ethical Requirements 
7.3.1 Good Clinical Practice (GCP), Laws and Regulations 
The Investigator must ensure that he/she and all authorized personnel for the study are familiar 
with the principles of Good Clinical Practice (GCP) and that the study is conducted in full 
conformity with the current revision of the Declaration of Helsinki, ICH Guidelines and 
applicable local laws and regulations, with the understanding that local laws and regulations 
take precedence over respective sections in the Declaration of Helsinki and/or the ICH 
Guidelines. 
7.3.2 Informed Consent 
The Investigator must obtain witnessed (if applicable) written informed consent from the 
subject or the subject’s legally authorized representative after adequate explanation of the 
aims, methods, anticipated benefits, and potential hazards of the study and before any study 
procedures are performed.  The subject should be given a copy of the informed consent 
documentation.  The original signed and dated informed consent form must be retained in the 
study records at the study site, and is subject to inspection by representatives of the Sponsor, or 
representatives from regulatory agencies. 
7.3.3 Institutional Review Board 
The Investigator must obtain written approval from the appropriate Institutional Review Board 
for the protocol and informed consent, and all amendments thereof, prior to recruitment of 
subjects and prior to shipment of investigational agents. 
The Investigator must report Serious Adverse Events (SAEs) to the appropriate Institutional 
Review Board in accordance with the Institutional Review Board’s rules and guidelines (see also 
Section 7.1). 
The Investigator must assure that continuing review (at least once per year) of the study is 
performed by the Institutional Review Board throughout the duration of the study.  If so 
required by the Institutional Review Board, the Investigator must provide study reports on an 
annual basis and upon completion of the study. 


 
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All correspondence with, and reports to, the Institutional Review Board must be maintained in 
the study files at the study site and copies must be sent to the Sponsor. 
7.3.4 Subject Confidentiality 
The Investigator must ensure that the subject’s privacy is maintained.  A subject should only be 
identified by their initials, date of birth and subject number on the CRFs or other documents 
submitted to the Sponsor.  Documents that are not submitted to the Sponsor (e.g., signed 
informed consent form) should be kept in a strictly confidential section of the study file by the 
Investigator. 
The Investigator shall permit the Sponsor and authorized representatives of regulatory agencies 
to review the portion of the subject’s medical record that is directly related to the study.  As 
part of the informed consent process, the subject must have given written consent that his/her 
records will be reviewed in this manner. 
 
 


 
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8 Appendices 
8.1 Protocol Version History 
Original Issue 
Issue date: 21-JUL-2016 
Summary of Changes: not applicable 
Amendment 1 
Issue date: 11-NOV-2016 
Summary of Changes:  
1. Synopsis and Section 4.0 (Study Objectives): The primary objective was clarified as follows 
(changes in bold): “Phase 1 Dose Escalation Phase:  
Recommended Combination Dose (RCD). The changes were added to clarify that an objective 
of Phase I is to determine the RCD.  
Safety and Tolerability [CTCAE 4.03, including DLTs and RCD] 
2. Section 3.1.8.1 (Monitoring for Hepatic Toxicity During Combination Therapy).  This section 
was added per FDA request. 
3. Section 3.1.16.1 (End of Study Visit): this section was added for clarification and to provide 
consistency with other protocols. 
4. Section 3.2 (Flowchart): Footnote J was added: “J: In addition to the pre-durvalumab testing, 
AST, ALT, ALP, and Tbili will be performed at 2 weeks after the durvalumab dose for Cycle 1 of 
the comb. therapy.”  This footnote was added per requirements in Section 3.1.8.1. 
5. Section 5.1 (Inclusion Criteria): Criterion #3 was changed FROM: “Availability of archival 
(diagnostic) specimens and willing to undergo a pre-treatment biopsy. If subjects are ALK 
inhibitor naïve, either archival or pre-treatment biopsy will be acceptable.” TO: “Willing to 
provide a fresh pre-treatment biopsy; however, if subject is ALK inhibitor naïve, either 
archival or pre-treatment biopsy will be acceptable.”  Rationale: This change was 
implemented to provide clarification and agreement with Section 4.3.1.1. 
6. Section 5.2 (Exclusion Criteria): for Criterion #8, additional contraception details/clarifications 
were added per current Medimmune guidelines 
7. Section 5.2 (Exclusion Criteria): The following criterion #18 was added “Subjects must not 
donate blood while on study and for at least 90 days following the last durvalumab 
treatment.” 
8. Section 6.1.3 (Durvalumab Preparation): Updates were made per current Medimmune 
recommendations 
a. The following sentence was updated (changes in bold): “No incompatibilities between 
durvalumab and polyethylene, polypropylene, polyvinylchloride, or polyolefin 
copolymers have been observed.” 
b. A note was added to indicate that dextrose may also be used as a diluent for durvalumab 
per current Medimmune guidelines. 
9. Section 6.1.4 (Durvalumab administration): additional details or clarifications were provided 
per current Medimmune guidelines. 
a. The following paragraph was added: “In the event of a ≤Grade 2 infusion-related 
reaction, the infusion rate of study drug 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.  For subjects with a ≤Grade 2 infusion-related reaction, 


 
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subsequent infusions may be administered at 50% of the initial rate.  Acetaminophen 
and/or an antihistamine (e.g., 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, study drug will be discontinued. 
See Section 8.3.1.” 
b. The following sentence was updated (changes in bold): “Investigational product(s) must 
be administered at room temperature by controlled infusion via an infusion pump into a 
peripheral vein or central line.” 
c. The following sentence was modified (changes in bold): “Since the compatibility of 
durvalumab with other IV medications and solutions, other than normal saline (0.9% 
[w/v] Sodium Chloride for Injection), is not known, the Durvalumab solution should not 
be infused through an IV line in which with other solutions or medications. are being 
administered 
d. The following sentence was changed FROM: “If durvalumab administration has to be 
delayed, temporally interrupted or the infusion rate decreased, or if administration time 
exceeds these limits, a new dose must be prepared from new vials.” TO: “Standard 
infusion time is 60 ± 5 minutes.  However, if there are interruptions during infusion, the 
total allowed time should not exceed 8 hours at room temperature.  In the event that 
either preparation time or infusion time exceeds the time limits, a new dose must be 
prepared from new vials.” 
10. Section 7.1.6 (Expedited Serious Adverse Event (SAE) Reporting Requirements): The following 
sentence was added “Serious adverse event reporting to AstraZeneca/Medimmune is 
described in a separate agreement.” This is per current protocol language. 
11. Section 8.3.1 (Durvalumab Dose Modification Due to Toxicity): table was updated according 
to current Medimmune guidelines, dated 19Aug2016. 
12. Section 8.3.2 (Durvalumab Dose Modification Not Due to Treatment-related Toxicities).  The 
section was updated for clarification and to provide consistency with other protocols.  
Changed FROM: “(1). If the subject misses 2 consecutive planned doses, the subject should 
be discontinued from treatment. (2) If the dosing interruption is ≤ half the planned dosing 
interval, the originally planned drug administration should be given.  The respective protocol 
deviation should be documented. (3) If the dosing interruption is greater than half the 
planned dosing interval, the dosing should be skipped and the next scheduled drug 
administration should be performed.  The respective protocol deviation should be 
documented.”  TO: 
(1) The originally planned visit/treatment schedule should be maintained in general, i.e., 
dosing interruptions should not reset the original treatment schedule. Exceptions may be 
made only for individual dosing days, whereby the interval between any two doses shall 
be no less than 21 days. All resulting protocol deviations should be documented. 
(2) If the dosing interruption causes 2 consecutive planned doses to be missed, the 
treatment should be discontinued. 
(3) If the dosing interruption is ≤ half the planned dosing interval, the originally planned 
dose should be given and the next dose(s) should be adjusted in accordance with #1, if 
necessary. 
(4) If the dosing interruption is greater than half the planned dosing interval, the dose 
should be skipped and the next dose(s) should be adjusted in accordance with #1, if 
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Amendment 2 
Issue date: 14-AUG-2017 
Summary of Changes: 
1. Per rationale provided in Section 2.3, the Run-in period for ensartinib monotherapy was 
changed from 2 cycles to 1 cycle. This change was made in the Synopsis and Sections 3.1, 
3.1.7, 3.1.7.1, 3.1.15, and 3.2. Section 2.3 was added. 
2. Per current Medimmune recommendations, the language was updated for durvalumab 
dosing of subjects whose body weight drops to ≤ 30 kg while on the study; in these cases, 
durvalumab dose will be weight based.  Previously a fixed dose of 600 mg was recommended 
for ≤ 30 kg. This change was made in the Synopsis and Sections 2.2.3, 3.1.7.2, and 6.1.3. The 
following clarification was added in Sections 3.1.7.2 and 6.1.3: “If a subject’s body weight 
drops to ≤ 30 kg while on the study, the subject will receive weight-based dosing equivalent 
to 20 mg/kg of durvalumab as long as the body weight remains ≤ 30 kg (e.g., a 30 kg subject 
would receive a 600 mg dose; a 25 kg subject would receive a 500 mg dose; etc.).  When the 
weight improves to >30 kg, the subject may return to fixed dosing of durvalumab 1500 mg.”   
3. Section 3.1.16, On Study and Post Study Follow-up.  
a. The 3rd paragraph was clarified (changes in bold): “See Section 3.2.2 for Ensartinib On 
Study Follow-up for subjects who continue treatment with ensartinib monotherapy after 
run-in according to Section 3.1.7.1.” 
b. The following paragraph was added before the last paragraph: “See Section 3.2.2 for 
Ensartinib Post Study Follow-up for subjects who continue treatment with ensartinib 
monotherapy after run-in according to Section 3.1.7.1. 
4. Section 3.2.1, Flowchart 
a. Deleted Run-in Cycle -2, per changes described in point #1. Cumulative study days for 
Cycle -1 were corrected to -28 for Week -4 and -14 for Week -2. 
b. An additional column was added to indicate that testing described in footnote J occurs in 
Study Week 3 
c. Footnote h was updated to indicate that the post ensartinib biopsy may be taken up to 
14 days prior to start of durvalumab (changed from 28 days).  This was done per the 
change of ensartinib monotherapy from 2 cycles to 1 cycle. 
d. Footnote h was updated to clarify timing of optional tumor biopsies (see changes to 
Section 4.1.3.1.) 
e. Optional tumor biopsy was removed from Cycle 12 per change to Section 4.3.1.1 
f. Screening window was changed from 1 month to 28 days (for clarification and agreement 
with cycles). 
5. Section 3.2.2 Flowchart 
a. Third column was relabeled as Ensartinib On Study Follow-up to distinguish it from the 
On Study Follow-up in Section 3.2.1 
b. The Post Study Follow-up column was added; long term follow-up assessments were 
added. 
c. Note was clarified to indicate (changes in bold) “It is strongly recommended that 
hematology, chemistry and pregnancy test (when applicable) results are reviewed before 
dosing at every assessment point.” 


 
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6. Section 4.3.1.1 (Tumor Microenvironment), 3rd paragraph:  
a. First sentence was updated (changes in bold): “A fresh tissue biopsy will be required prior 
to treatment with ensartinib and following the run-in period with ensartinib but before 
initiation of durvalumab (up to 28 14 days prior to initiation of durvalumab).”  This was 
done per the change of ensartinib monotherapy from 2 cycles to 1 cycle. 
b. 4th sentence was updated to clarify timing of optional tumor progressions (changes in 
bold): Optional core biopsies will be obtained at the time of tumor progression or at the 
end of the study completion of treatment from subjects who consent to this procedure.   
7. Section 5.1, Inclusion Criterion # 4 was changed FROM: “Subjects with treated brain 
metastases must have been treated with surgery and/or radiation therapy ≥ 21 days pre-
study and must be clinically stable with no requirement for steroids.” TO: “Asymptomatic 
subjects with surgically treated brain metastases must be ≥ 14 days post surgery at the time 
of first dosing, while clinically stable with no requirement for steroids.  Asymptomatic 
subjects with radiation-treated brain metastases may enter the study immediately after 
completion of the radiation (and be off steroids, if applicable). Symptomatic subjects (those 
experiencing headache, seizure etc.), must have been relieved from all symptoms of their 
CNS disease, and must have completed radiation and be off steroids prior to first dosing (anti 
seizure medicine permitted).”  The change was implemented to provide requirement 
clarification for subjects receiving surgery vs those receiving radiation therapy and to further 
clarify the requirement for symptomatic vs asymptomatic subjects.   
8. Section 5.2, Exclusion Criteria: 
a. #1 was clarified (changes in bold): “Treatment with an investigational agent within 4 
weeks of starting treatment, and any prior drug-related toxicity (except alopecia) should 
have recovered to Grade 1 or less.” 
b. #4: Start of study drug was changed from Day -57 to -28.  This was based on change of 
run-in. 
9. Section 5.3.1, Non-permitted Concomitant Therapies; Start of study drug was changed from 
Day -57 to -28. This was based on change of run-in. 
10. Sections 6.1.1 (Study Drug Information), 6.1.2 (Durvalumab Investigational Product 
Inspection), 6.1.3 (Durvalumab Preparation) and 6.1.4 (Durvalumab Administration): Sections 
were clarified and/or reorganized per current Medimmune recommendations and to 
maintain consistency with current protocols.  
11. Section 7.1.8 (AESIs): section was updated and descriptions of AESIs were expanded per 
current Medimmune recommendations. Diabetes insipidus was added to endocrine 
disorders.  The following bullet was added:  
• 
Other inflammatory responses that are rare with a potential immune-mediated 
aetiology include, but are not limited to, myocarditis, pericarditis, and uveitis. 
12. Section 8.3.1 (Durvalumab Dose Modification due to toxicity) 
a. added myocarditis to Pneumonitis/ILD bullet In Grades 1, 2, and 3.  
b. For Infusion related reactions Grades 1 and 2, the phrase “total infusion time not to 
exceed 4 hours.” was deleted per Medimmune current guidelines.  
13. Administrative: Spelling, grammar and typographical errors were corrected; formatting 
changes were implemented, as applicable.  
 
 
 


 
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8.2 Participating Study Sites, Investigators and Staff, Laboratories, and 
Sponsor Information 
This information is provided in the Clinical Study File. 
 
 


 
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8.3 Dose Adjustments and Delays for Durvalumab 
If a toxicity occurs that requires toxicity management in accordance with Sections 8.3 or 8.4, and 
the toxicity causing drug can be clearly identified, then the respective guideline should be 
followed. If the toxicity causing drug cannot be identified, then the more conservative guideline 
should be followed. 
8.3.1 Durvalumab Dose Modification Due to Toxicity 
Durvalumab (MEDI4736) administration may be modified or discontinued as a result of toxicities 
as described in the table below.  
Additional information and guidance regarding dose modification due to toxicity are provided 
from MedImmune in the following guidelines: 
“MedImmune’s Dosing Modification and Toxicity Management Guidelines for Immune-
mediated, Infusion Related, and Non Immune-mediated Reactions (MEDI4736 (durvalumab) 
Monotherapy or Combination therapy with Tremelimumab or Tremelimumab monotherapy).” 
Dose modifications will not be required for AEs that are clearly not attributed to durvalumab 
(such as an accident) or for laboratory abnormalities that are not deemed to be clinically 
significant. 
Durvalumab (D) Dose Modification Due to Toxicity 
Note: If D dosing is held temporarily until resolution of the event as per instructions below, 
treatment should resume at the next scheduled treatment date. 
Immune-related Adverse Events (irAEs) 
Immune-related adverse events are defined as AEs of immune nature (i.e., inflammatory) in 
the absence of a clear alternative etiology.  Maximum supportive care, including 
immunosuppressive medications, such as high dose steroids, is allowed to induce resolution 
of the event.  However, infliximab should not be used for management of immune-related 
hepatitis. 
In addition to the criteria for permanent discontinuation of D depicted below, permanently 
discontinue D also for:  
• Any Grade rash with bullous skin formations. 
• 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/regimen. 
• Recurrence of a previously experienced Grade 3 treatment-related AE following 
resumption of dosing. 
Grade 1 
• 
In general, no dose modification required. 
• 
For pneumonitis/interstitial lung disease and myocarditis, consider holding D dosing as clinically 
appropriate and during diagnostic work-up for other etiologies. 


 
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Durvalumab (D) Dose Modification Due to Toxicity 
Grade 2 
• 
In general, hold D until resolution to ≤ Grade 1 and after the end of any steroid taper, and 
discontinue D permanently if such resolution does not occur within 60 days (30 days for 
neurotoxicities).  Criteria for temporary hold or permanent discontinuation of D may differ by 
event as detailed below. 
• 
For pneumonitis/interstitial lung disease and myocarditis, the decision to reinitiate D upon 
resolution shall be based upon treating physician’s clinical judgment (as long as the event does not 
meet DLT criteria). 
• 
For peripheral neuromotor syndromes, such as Guillain-Barre and Myasthenia Gravis, follow 
general instructions above, but always discontinue D permanently if there are signs of respiratory 
insufficiency or autonomic instability. 
• 
For endocrinopathies, other than isolated hypothyroidism, follow general instructions above, but 
subjects may be retreated if the endocrinopathy is controlled and the subject is clinically stable 
while requiring steroid doses of ≤ 10 mg/day prednisone equivalent. 
• 
For isolated hypothyroidism managed with hormone replacement therapy, and for sensory 
neuropathy/neuropathic pain, holding D is at the discretion of the Investigator. 
• 
For elevated creatinine or rash, D should be held until resolution to ≤ Grade 1 or baseline. 
• 
For vitiligo, no dose modification required. 
Grade 3 
• 
In general, hold D until resolution to ≤ Grade 1, and after the end of any steroid taper, and 
discontinue D permanently if such resolution does not occur within 60 days (30 days for 
neurotoxicities and rash).  Criteria for permanent discontinuation of D may differ by event as 
detailed below. 
• 
For peripheral neuromotor syndromes (such as Guillain-Barre and Myasthenia Gravis), apply 
respective Grade 2 rules. 
• 
For endocrinopathies, follow Grade 2 instructions above. 
• 
For pneumonitis/interstitial lung disease, myocarditis, diarrhea/enterocolitis and elevated serum 
creatinine (e.g., nephritis or renal dysfunction), always discontinue D permanently. 
• 
For asymptomatic increases of amylase or lipase levels, hold D, and if complete work up shows no 
evidence of pancreatitis, D may be continued. 
• 
For hepatitis, discontinue D permanently for (1) transaminases or bilirubin not resolving to ≤ Grade 
1 or baseline within 14 days, (2) transaminases > 8 × the upper limit of normal (ULN) or bilirubin 
> 5 × ULN, or (3) any case meeting Hy’s law criteria (as defined in FDA Guidance Document “Drug-
Induced Liver Injury”). 
• 
For rash, D should be held until resolution to ≤ Grade 1 or baseline. 
Grade 4 
• 
In general, discontinue D permanently. 
• 
For endocrinopathies, follow Grade 2 instructions above. 
• 
For asymptomatic increases of amylase or lipase levels, hold D, and if complete work up shows no 
evidence of pancreatitis, D may be continued.  


 
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Durvalumab (D) Dose Modification Due to Toxicity 
Infusion-related Reactions 
Grade 1 
• 
The infusion rate of D may be decreased 50% or temporarily interrupted until resolution of the 
event. 
• 
Acetaminophen and/or antihistamines may be administered per institutional standards at the 
discretion of the Investigator. 
• 
Premedication for subsequent doses should be considered. 
• 
Steroids should not be used for routine premedication of ≤Grade 2 infusion reactions. 
Grade 2: 
• 
Same as Grade 1, but consider giving subsequent infusions at 50% of the initial infusion rate. 
Grade 3 and 4: 
• 
The infusion must be stopped immediately and treatment permanently discontinued. 
• 
Manage severe infusion-related reactions per institutional standards (e.g., IM epinephrine, 
followed by IV diphenhydramine and ranitidine, and IV glucocorticoid). 
All other Adverse Events 
Grade 1 
• 
No dose modification required. 
Grade 2 
• 
Hold D until resolution to ≤ Grade 1 or baseline, and discontinue D permanently if such resolution 
does not occur within 60 days. 
Grade 3 
• 
Hold D. If AEs downgrade to ≤ Grade 2 within 7 days or resolve to ≤ Grade 1 or baseline within 14 
days, resume D administration at next scheduled dose. Otherwise, discontinue D permanently. 
Grade 4 
• 
In general, discontinue D permanently. 
• 
For isolated lab results, decision to discontinue should be based on accompanying clinical 
signs/symptoms and per Investigator’s clinical judgment in consultation with the Sponsor. 
 
8.3.2 Durvalumab Dose Modification Not Due to Treatment-related Toxicities 
Durvalumab administration may be modified or discontinued as a result of events other than 
toxicity, e.g., intercurrent illness or logistical/administrative reasons, whereby the following 
rules should apply: 
(1) The originally planned visit/treatment schedule should be maintained in general, i.e., 
dosing interruptions should not reset the original treatment schedule. Exceptions may 
be made only for individual dosing days, whereby the interval between any two doses 
shall be no less than 21 days. All resulting protocol deviations should be documented. 
(2) If the dosing interruption causes 2 consecutive planned doses to be missed, the 
treatment should be discontinued. 


 
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(3) If the dosing interruption is ≤ half the planned dosing interval, the originally planned 
dose should be given and the next dose(s) should be adjusted in accordance with #1, if 
necessary. 
(4) If the dosing interruption is greater than half the planned dosing interval, the dose 
should be skipped and the next dose(s) should be adjusted in accordance with #1, if 
necessary   
 
 


 
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8.4 Ensartinib (X-396) Toxicity Management and Dose Modification 
If a toxicity occurs that requires toxicity management in accordance with Sections 8.3 or 8.4, and 
the toxicity causing drug can be clearly identified, then the respective guideline should be 
followed. If the toxicity causing drug cannot be identified, then the more conservative guideline 
should be followed. 
Dose reductions or holds and initiation of supportive care are allowed as clinically indicated by 
the treating physician.  
NOTE: Up to 2 dose reductions (225 to 200 mg; 200 to 150 mg; or 150 to 100 mg) per subject 
are allowed.  
Subjects whose treatment is delayed due to drug-related toxicity will discontinue study drug or 
will resume treatment when toxicity has improved (as long as the toxicity resolves within 
4 weeks) according to the dose modifications below.  Treatment with ensartinib will be held in 
any subject experiencing a DLT as described in Section 3.1.9 at any time during the study.   
As noted, dose reductions for toxicity or based on the clinical judgment of the treating physician 
will be allowed.  If persistent toxicity occurs despite the dose reductions, the Investigator should 
consider removing the subject from the study. 
Dose Modifications Due to Drug-Related Hematologic Toxicity 
If drug-related hematologic toxicity occurs, treatment with ensartinib should be held (see table 
below) and re-evaluated in at least 1 week.  Absolute neutrophil count (ANC) and platelets 
should be monitored as is clinically appropriate, but at least weekly, until recovery.  For 
resumption of treatment, see table below.  If ANC and/or platelets do not recover within 4 
weeks, the subject should be permanently discontinued from trial treatment. 
Dose Modifications Due to Drug-related Hematologic Toxicities 
Event 
Ensartinib Dose c 
Neutropenia (ANC) 
 
ANC <0.5 x 109/L (Grade 4) 
Hold dose a until recovery to ≤ Grade 2 [ANC ≥1.0 x 109/L], then 
resume ensartinib at one lower dose level b. 
Recurrence of  
ANC <0.5 x 109/L (Grade 4) 
Hold dose a until ANC recovery to ≤ Grade 2 [ANC ≥1.0 x 109/L], then 
resume ensartinib at one lower dose level b. 
Thrombocytopenia 
 
Platelets <50 x 109/L  
(Grade 3) 
 
Hold dose a until improvement to Platelets ≥75 x 109/L 
• If resolved in ≤5 days, then resume without a dose reduction b. 
• If resolved in >5 days but <4 weeks, then resume dose at one 
lower dose level b. 
a 
Hold ensartinib treatment; do at least weekly CBC with differential until toxicity resolves (ANC recovery ≥1.0 x 
109/L and Platelets ≥75 x 109/L). 
b 
Re-treatment criteria = ANC recovery ≥1.0 x 109/L and Platelets ≥75 x 109/L.  Dose reduction(s) (up to 2 per 
subject): 225 to 200 mg; 200 to 150 mg; or 150 to 100 mg. 
c 
Any subjects who require a treatment delay of more than 4 weeks due to treatment-related toxicity will be 
discontinued from trial treatment.  


 
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Dose Modifications Due to Drug-Related Non-Hematologic Toxicities 
Grade 3 or 4 Non-Hematologic Toxicity 
The dose reduction guidelines for drug-related non-hematologic toxicities are shown in the table 
below.  If a Grade 3 non-hematologic toxicity that is expected to be manageable and reversible 
with dose reduction occurs, treatment with ensartinib should be held until the toxicity resolves 
to ≤ Grade 1.  If the Grade 3 non-hematologic toxicity lasts longer than 7 days, study drug will be 
discontinued.  Subjects with Grade 3 non-hematologic toxicity lasting ≤7 days that does not 
resolve to ≤ Grade 1 within 4 weeks should also be removed from the trial treatment.  If a Grade 
4 non-hematologic toxicity occurs, study drug will be discontinued. 
Specific Recommendations for Rash: 
To date, the most common drug-related adverse event with ensartinib has been rash, primarily 
Grade 1-2.  Although different types of rash have been reported (rash, erythema, erythematous 
rash, follicular rash, macular rash, maculopapular rash, pruritic rash, acneiform dermatitis, 
exfoliative rash, pustular rash), the predominant type of rash seems to be the erythematous 
rash, described sometimes as a sunburn-type rash (however, it does not appear to be 
phototoxicity).  Some of these have been Grade 3, generally with pruritus and sometimes with 
peeling.  It has begun as early as Cycle 1 Day 4 and in other cases not until Cycle 2. 
Based on the experience to date, the recommendations for treating rashes considered related 
to ensartinib are as follows.  For Grade 3 rash, hold ensartinib until resolution to ≤ Grade 1, then 
resume treatment at a reduced dose.  For Grade 1-2 rashes, topical corticosteroids may be used, 
if appropriate.  If it is felt that short-term courses of oral corticosteroids are needed, it is 
suggested that the dose of ensartinib be held until improvement to ≤ Grade 1, then resume 
ensartinib at a reduced dose.  Of course, the Investigator should treat the subject as he/she 
feels is most appropriate, including the use of allowed concomitant medications and holding 
and/or reducing the dose of ensartinib. 
Specific Recommendations for Nausea, Vomiting and Diarrhea: 
For subjects with Grade 3 nausea, vomiting, and/or diarrhea, ensartinib should be held and 
supportive care initiated.  If the Grade 3 toxicity lasts ≤7 days, subjects may restart ensartinib at 
a reduced dose when toxicity returns to ≤ Grade 1.  If the subject has recurrent Grade 3 toxicity 
despite supportive care, the subject will restart ensartinib at the next lower dose level once 
toxicity has resolved to ≤ Grade 1. 
Specific Recommendations for Liver Function Test Abnormalities: 
For subjects with Grade 3 liver enzyme elevations (AST/ALT), ensartinib should be held until the 
values recover to ≤ Grade 1.  Subjects with an elevation of ALT ≥3 x ULN in conjunction with a 
bilirubin ≥2 x ULN may remain in the study if a correctable, non-drug related cause of the liver 
test evaluations can be documented; otherwise, the subject must be discontinued from the trial. 


 
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Specific Recommendations for Pneumonitis: 
For pneumonitis of any grade not attributable to NSCLC progression, other pulmonary disease, 
infection, or radiation effect, or other treatment, trial treatment must be discontinued. 
Dose Modifications for Drug-related Non-Hematologic Toxicities 
Toxicity Grade 
Ensartinib Dose 
Grade 0, 1, or 2 
None 
Grade 3 and expected to be manageable and 
reversible with dose reduction 
Hold a 
If toxicity remains Grade 3 toxicity for longer than 
7 days 
Discontinue study drug 
If Grade 3 toxicity lasts ≤7 days and resolves to  
≤ Grade 1  
Reduce one dose level c 
Grade 3 and not expected to be manageable and 
reversible with dose reduction (e.g., cardiac failure) 
Discontinue study drug 
Recurrence of Grade 3 toxicity 
Reduce one dose level or discontinue 
treatment a, c 
Elevated ALT ≥3 x ULN in conjunction with a bilirubin 
≥2 x ULN, and no correctable, non-drug related cause 
Discontinue study drug   
Grade 4 
Discontinue study drug 
Pneumonitis of any grade b 
Discontinue study drug 
a  Ensartinib should be held until toxicity resolves to ≤ Grade 1.  Any subject who develops toxicity that does not 
resolve to ≤ Grade 1 within 4 weeks should be removed from the trial treatment.   
b  For pneumonitis of any grade not attributable to NSCLC progression, other pulmonary disease, infection, or 
radiation effect, or other treatment, discontinue study drug. 
c Dose reduction(s) (up to 2 per subject): 225 to 200 mg; 200 to 150 mg; or 150 to 100 mg 
 
Other Dose Modifications 
If the subject misses a dose of study medication, the subject should take the dose as soon as 
possible, but not less than 12 hours before the next dose is due.  If the next dose is due in less 
than 12 hours, the subject should skip the missed dose and take the next dose as scheduled. 
If vomiting occurs after taking the study medication, the subject should be instructed not to 
retake the dose.  Subjects should take the next scheduled dose of study medication.  If vomiting 
persists, the subject should contact the Investigator.  No routine prophylactic antiemetics will be 
given.  However, antiemetics may be administered with nausea and vomiting when they occur, 
and may be given prophylactically afterwards. 
 
 


 
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8.5 RECIST 1.1 and irRECIST Guidelines  
The Response Evaluation Criteria in Solid Tumors (RECIST) guidelines were revised in 2009 as 
RECIST 1.1.(29) These guidelines have been the widely accepted criteria to assess response and 
progression in solid tumors; however, limitations have been noted in the use of RECIST 1.1 for 
immunotherapy trials. With immunotherapeutic agents, clinical trials have shown that complete 
response, partial response, or stable disease status can still be achieved after an initial increase 
in overall tumor burden, and regression of initial lesions may occur despite development of new 
lesions. The Immune-related Response Criteria (irRC) were developed to address the need for 
response criteria in an immunotherapy setting.(30)  The main difference with irRC was that it 
considered the subject's total tumor burden at each subsequent assessment and required 
confirmation of suspected disease progression with subsequent imaging, approximately four 
weeks later.  In addition, a greater number of lesions (10 vs. 5) were measured in a 
bidimensional manner instead of unidimensionally as in RECIST 1.1.  In 2013, Nishino et al. 
demonstrated that immune-related response criteria using unidimensional measurements were 
highly concordant with the bidimensional results of irRC, but with less measurement 
variability.(31)  Based on these findings and in order to utilize both the established criteria of 
irRC and RECIST 1.1, the two systems have been adapted, modified, and combined into the 
Immune-related Response Evaluation Criteria in Solid Tumors (irRECIST).(32)  The adapted 
irRECIST criteria are modifications to the irRC, incorporating the findings of Nishino et al. and the 
advantages of RECIST 1.1 while overcoming the shortcomings of each of the other guidelines.   
The guidelines for RECIST 1.1 are summarized below, followed by a summary for irRECIST. 
RECIST 1.1 
The following section outlines the RECIST 1.1 guidelines as published (29) and as summarized by 
National Cancer Institute for CTEP-involved clinical trials.   
I. 
Disease Parameters for RECIST 1.1 
Changes in the largest diameter (unidimensional measurement) of the tumor lesions and the 
shortest diameter in the case of malignant lymph nodes are used in the RECIST 1.1 criteria. 
Measurable disease.  Measurable lesions are defined as those that can be accurately measured 
in at least one dimension (longest diameter to be recorded) as >20 mm by chest x-ray, as >10 
mm with CT scan, or >10 mm with calipers by clinical exam.  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.  If the Investigator thinks it appropriate to include them, the conditions 
under which such lesions should be considered must be defined in the protocol. 
NOTE for irRECIST: During target lesion selection the radiologist will consider information on 
the anatomical sites of previous intervention (e.g. previous irradiation, RF-ablation, TACE, 
surgery, etc.). Lesions undergoing prior intervention will not be selected as target lesions 
unless there has been a demonstration of progress in the lesion. 


 
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Malignant lymph nodes.  To be considered pathologically enlarged and measurable, a lymph 
node must be >15 mm in short axis when assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 5 mm).  At baseline and in follow-up, only the short axis 
will be measured and followed. 
Non-measurable disease.  All other lesions (or sites of disease), including small lesions (longest 
diameter <10 mm or pathological lymph nodes with ≥ 10 to <15 mm short axis), are considered 
non-measurable disease.  Bone lesions, leptomeningeal disease, ascites, pleural/pericardial 
effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, and abdominal masses 
(not followed by CT or MRI), are considered as non-measurable. 
Note:  Cystic lesions that meet the criteria for radiographically defined simple cysts should not 
be considered as malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts.  ‘Cystic lesions’ thought to represent cystic metastases can be 
considered as measurable lesions, if they meet the definition of measurability described above. 
However, if non-cystic lesions are present in the same subject, these are preferred for selection 
as target lesions. 
NOTE for irRECIST:  
Lesions that are partially cystic or necrotic can be selected as target lesions. The longest 
diameter of such a lesion will be added to the Total Measured Tumor Burden (TMTB) of all 
target lesions at baseline. If other lesions with a non-liquid/non-necrotic component are 
present, those should be preferred. 
Brain lesions detected on brain scans can be considered as both target or non-target lesions 
depending on the protocol definition. 
Target lesions.  All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in 
total, representative of all involved organs, should be identified as target lesions and recorded 
and measured at baseline.  Target lesions should be selected on the basis of their size (lesions 
with the longest diameter), be representative of all involved organs, but in addition should be 
those that lend themselves to reproducible repeated measurements.  It may be the case that, 
on occasion, the largest lesion does not lend itself to reproducible measurement in which 
circumstance the next largest lesion which can be measured reproducibly should be selected.  A 
sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters.  If lymph nodes are to be 
included in the sum, then only the short axis is added into the sum.  The baseline sum diameters 
will be used as reference to further characterize any objective tumor regression in the 
measurable dimension of the disease. 
Non-target lesions.  All other lesions (or sites of disease) including any non-measureable as well 
as measurable lesions over and above the 5 target lesions should be identified as non-target 
lesions and should also be recorded at baseline.  Measurements of these lesions are not 
required, but the presence, absence, or in rare cases unequivocal progression of each should be 
noted throughout follow-up.  


 
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II. 
Methods for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation using a ruler or calipers.  All 
baseline evaluations should be performed as closely as possible to the beginning of treatment 
and never more than 4 weeks before the beginning of the treatment. 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is 
preferred to evaluation by clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam. 
Clinical lesions:  Clinical lesions will only be considered measurable when they are superficial 
(e.g., skin nodules and palpable lymph nodes) and ≥10 mm diameter as assessed using calipers 
(e.g., skin nodules).  In the case of skin lesions, documentation by color photography, including a 
ruler to estimate the size of the lesion, is recommended.  
Chest x-ray:  Lesions on chest x-ray are acceptable as measurable lesions when they are clearly 
defined and surrounded by aerated lung.  However, CT is preferable.  
Conventional CT and MRI:  This guideline has defined measurability of lesions on CT scan based 
on the assumption that CT slice thickness is 5 mm or less.  If CT scans have slice thickness 
greater than 5 mm, the minimum size for a measurable lesion should be twice the slice 
thickness.  MRI is also acceptable in certain situations (e.g. for body scans).   
Use of MRI remains a complex issue.  MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which greatly 
impact image quality, lesion conspicuity, and measurement.  Furthermore, the availability of 
MRI is variable globally.  As with CT, if an MRI is performed, the technical specifications of the 
scanning sequences used should be optimized for the evaluation of the type and site of disease.  
Furthermore, as with CT, the modality used at follow-up should be the same as was used at 
baseline and the lesions should be measured/assessed on the same pulse sequence.  It is 
beyond the scope of the RECIST guidelines to prescribe specific MRI pulse sequence parameters 
for all scanners, body parts, and diseases.  Ideally, the same type of scanner should be used and 
the image acquisition protocol should be followed as closely as possible to prior scans.  Body 
scans should be performed with breath-hold scanning techniques, if possible. 
PET-CT:  At present, the low dose or attenuation correction CT portion of a combined PET-CT is 
not always of optimal diagnostic CT quality for use with RECIST measurements.  However, if the 
site can document that the CT performed as part of a PET-CT is of identical diagnostic quality to 
a diagnostic CT (with IV and oral contrast), then the CT portion of the PET-CT can be used for 
RECIST measurements and can be used interchangeably with conventional CT in accurately 
measuring cancer lesions over time.  Note, however, that the PET portion of the CT introduces 
additional data which may bias an investigator if it is not routinely or serially performed.   
Ultrasound:  Ultrasound is not useful in assessment of lesion size and should not be used as a 
method of measurement.  Ultrasound examinations cannot be reproduced in their entirety for 
independent review at a later date and, because they are operator dependent, it cannot be 
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the next.  If new lesions are identified by ultrasound in the course of the study, confirmation by 
CT or MRI is advised.  If there is concern about radiation exposure at CT, MRI may be used 
instead of CT in selected instances. 
Endoscopy, Laparoscopy:  The utilization of these techniques for objective tumor evaluation is 
not advised.  However, such techniques may be useful to confirm complete pathological 
response when biopsies are obtained or to determine relapse in trials where recurrence 
following complete response (CR) or surgical resection is an endpoint. 
Tumor markers:  Tumor markers alone cannot be used to assess response.  If markers are 
initially above the upper normal limit, they must normalize for a subject to be considered in 
complete clinical response.  Specific guidelines for both CA-125 response (in recurrent ovarian 
cancer) and PSA response (in recurrent prostate cancer) have been published.(33-35)  In 
addition, the Gynecologic Cancer Intergroup has developed CA-125 progression criteria which 
are to be integrated with objective tumor assessment for use in first-line trials in ovarian 
cancer.(36)  
Cytology, Histology:  These techniques can be used to differentiate between partial responses 
(PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor types, such as 
germ cell tumors, where known residual benign tumors can remain). 
The cytological confirmation of the neoplastic origin of any effusion that appears or worsens 
during treatment when the measurable tumor has met criteria for response or stable disease is 
mandatory to differentiate between response or stable disease (an effusion may be a side effect 
of the treatment) and progressive disease. 
FDG-PET:  While FDG-PET response assessments need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in 
assessment of progression (particularly possible 'new' disease).  New lesions on the basis of 
FDG-PET imaging can be identified according to the following algorithm:  
a) Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD based 
on a new lesion. 
b) No FDG-PET at baseline and a positive FDG-PET at follow-up:  If the positive FDG-PET at 
follow-up corresponds to a new site of disease confirmed by CT, this is PD.  If the 
positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, additional 
follow-up CT scans are needed to determine if there is truly progression occurring at 
that site (if so, the date of PD will be the date of the initial abnormal FDG-PET scan).  If 
the positive FDG-PET at follow-up corresponds to a pre-existing site of disease on CT 
that is not progressing on the basis of the anatomic images, this is not PD. 
c) FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy in 
cases where a residual radiographic abnormality is thought to represent fibrosis or 
scarring.  The use of FDG-PET in this circumstance should be prospectively described in 
the protocol and supported by disease-specific medical literature for the indication.  
However, it must be acknowledged that both approaches may lead to false positive CR 
due to limitations of FDG-PET and biopsy resolution/sensitivity. 


 
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Note:  A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake greater than 
twice that of the surrounding tissue on the attenuation corrected image. 
III. 
Response Criteria for RECIST 1.1 
 
A. Evaluation of Target Lesions 
Complete Response (CR):  Disappearance of all target lesions.  Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to <10 mm.   
Partial Response (PR):  At least a 30% decrease in the sum of the diameters of target lesions, 
taking as reference the baseline sum diameters 
Progressive Disease (PD):  At least a 20% increase in the sum of the diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline sum if that is the 
smallest on study).  In addition to the relative increase of 20%, the sum must also demonstrate 
an absolute increase of at least 5 mm.  (Note:  the appearance of one or more new lesions is 
also considered progressions). 
Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on study 
B. Evaluation of Non-Target Lesions 
Complete Response (CR):  Disappearance of all non-target lesions and normalization of tumor 
marker level.  All lymph nodes must be non-pathological in size (<10 mm short axis) 
Note:  If tumor markers are initially above the upper normal limit, they must normalize for a 
subject to be considered in complete clinical response. 
Non-CR/Non-PD:  Persistence of one or more non-target lesion(s) and/or maintenance of tumor 
marker level above the normal limits 
Progressive Disease (PD):  Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions.  Unequivocal progression should not normally trump 
target lesion status.  It must be representative of overall disease status change, not a single 
lesion increase.   
Although a clear progression of “non-target” lesions only is exceptional, the opinion of the 
treating physician should prevail in such circumstances, and the progression status should be 
confirmed at a later time by the review panel (or Principal Investigator). 
C. Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started).  The subject's best response assignment 
will depend on the achievement of both measurement and confirmation criteria. 


 
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1. For Subjects with Measurable Disease (i.e., Target Disease) 
Target 
Lesions 
Non-Target Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response when 
Confirmation is Required* 
CR 
CR 
No 
CR 
>4 wks. Confirmation** 
CR 
Non-CR/Non-PD 
No 
PR 
>4 wks. Confirmation** 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-PD/not evaluated 
No 
PR 
SD 
Non-CR/Non-PD/not evaluated 
No 
SD 
documented at least once >4 
wks. from baseline** 
PD 
Any 
Yes or No 
PD 
no prior SD, PR or CR 
Any 
PD*** 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
*      See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
**    Only for non-randomized trials with response as primary endpoint. 
***  In exceptional circumstances, unequivocal progression in non-target lesions may be accepted as disease 
progression. 
Note: 
Subjects with a global deterioration of health status requiring discontinuation of treatment without 
objective evidence of disease progression at that time should be reported as “symptomatic 
deterioration.”  Every effort should be made to document the objective progression even after 
discontinuation of treatment. 
 
2. For Subjects with Non-Measurable Disease (i.e., Non-Target Disease) 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
* ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is increasingly used as an end-
point for assessment of efficacy in some trials so to assign this category when no lesions can be measured is not 
advised. 
 
D. Duration of Response 
Duration of overall response:  The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first date that 
recurrent or progressive disease is objectively documented (taking as reference for progressive 
disease the smallest measurements recorded since the treatment started). 
The duration of overall CR is measured from the time measurement criteria are first met for CR 
until the first date that progressive disease is objectively documented. 
Duration of stable disease:  Stable disease is measured from the start of the treatment until the 
criteria for progression are met, taking as reference the smallest measurements recorded since 
the treatment started, including the baseline measurements.  
 


 
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irRECIST 
Immune-related RECIST (irRECIST) guidelines according to Bohnsack et al. (32) are presented 
below. 
I. 
Baseline Assessments in irRECIST 
In irRECIST, baseline assessment and measurement of measurable/non-measurable and 
target/non-target lesions and lymph nodes are in line with RECIST 1.1. One new definition is 
added: If a subject has no measurable and no non-measurable disease at baseline the radiologist 
will assign ‘No Disease’ (irND) as the overall tumor assessment for any available follow-up time 
points unless new measurable lesions are identified and contribute to the total measured tumor 
burden (TMTB).  irND is a valid assessment in studies with adjuvant setting where the protocol 
and study design allow the inclusion of subjects with no visible disease. 
II 
Follow-up Assessments in irRECIST 
A. Follow-up recording of target and new measurable lesions 
A key difference in irRECIST is that the appearance new lesions does not automatically 
indicate progression.  Instead, all measured lesions (baseline-selected target lesions and new 
measurable lesions) are combined into the total measured tumor burden (TMTB) at follow-up.  
Baseline-selected target lesions and new measurable lesions are NOT assessed separately. 
Measurements of those lesions are combined into the TMTB, and one combined assessment 
provided. 
In order to be selected as new measurable lesions (≤ 2 lesions per organ, ≤ 5 lesions total, per 
time point), new lesions must meet criteria as defined for baseline target lesion selection and 
meet the same minimum size requirements of 10 mm in long diameter and minimum 15 mm in 
short axis for new measurable lymph nodes. New measurable lesions should be prioritized 
according to size, and the largest lesions elected as new measured lesions.  
B. Follow-up non-target assessment 
RECIST 1.1 definitions for assessment of non-target lesions apply.  The response of non-target 
lesions primarily contributes to the overall response assessments of irCR and irNon-CR/Non-PD 
(irNN). Non-target lesions do not affect irPR and irSD assessments. Only a massive and 
unequivocal worsening of non-target lesions alone, even without progress in the TMTB is 
indicative of irPD.  In alignment with RECIST 1.1, baseline selected non-target lesions can never 
convert to measurable lesions, not even if they increase in size at subsequent time points and 
become measurable. Only true new lesions can be measured and contribute to the TMTB. 
C. Follow-up for New Non-Measurable Lesions  
All new lesions not selected as new measurable lesions are considered new non-measurable 
lesions and are followed qualitatively. Only a massive and unequivocal progression of new non-
measurable lesions leads to an overall assessment of irPD for the time point. Persisting new 
non-measurable lesions prevent irCR.  


 
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III 
Overall Assessments for irRECIST 
The irRECIST overall tumor assessment is based on TMTB of measured target and new lesions, 
non-target lesion assessment and new non-measurable lesions. 
At baseline, the sum of the longest diameters (SumD) of all target lesions (up to 2 lesions per 
organ, up to total 5 lesions) is measured.  At each subsequent tumor assessment, the SumD of 
the target lesions and of new, measurable lesions (up to 2 new lesions per organ, total 5 new 
lesions) are added together to provide the total measurable tumor burden (TMTB). 
Overall Assessments by irRECIST 
Complete Response 
(irCR) 
Complete disappearance of all measurable and non-measurable lesions. Lymph 
nodes must decrease to < 10 mm in short axis. 
Partial Response 
(irPR) 
Decrease of ≥ 30% in TMTB relative to baseline, non-target lesions are irNN, and 
no unequivocal progression of new non-measurable lesions 
• 
If new measurable lesions appear in subjects with no target lesions at 
baseline, irPD will be assessed. That irPD time point will be considered a new 
baseline, and all subsequent time points will be compared to it for response 
assessment. irPR is possible if the TMTB of new measurable lesions 
decreases by ≥ 30% compared to the first irPD documentation 
• 
irRECIST can be used in the adjuvant setting, in subjects with no visible 
disease on CT/MRI scans. The appearance of new measurable lesion(s) 
automatically leads to an increase in TMTB by 100% and leads to irPD. These 
subjects can achieve a response if the TMTB decreases at follow-up, as a sign 
of delayed response. 
• 
Based on the above, sponsors may consider enrolling subjects with no 
measurable disease and/or no visible disease in studies with response 
related endpoints. 
Stable Disease 
(irSD) 
Failure to meet criteria for irCR or irPR in the absence of irPD 
Progressive Disease 
(irPD) 
Minimum 20% increase and minimum 5 mm absolute increase in TMTB 
compared to nadir, or irPD for non-target or new non-measurable lesions. 
Confirmation of progression is recommended minimum 4 weeks after the first 
irPD assessment. An irPD confirmation scan may be recommended for subjects 
with a minimal TMTB %-increase over 20% and especially during the flare time-
window of the first 12 weeks of treatment, depending on the compound efficacy 
expectations, to account for expected delayed response. 
• 
In irRECIST a substantial and unequivocal increase of non-target lesions is 
indicative of progression. 
• 
IrPD may be assigned for a subject with multiple new non-measurable 
lesions if they are considered to be a sign of unequivocal massive worsening 
Other 
irNE: used in exceptional cases where insufficient data exist.  
irND: in adjuvant setting when no disease is detected 
irNN:, no target disease was identified at baseline, and at follow-up the subject 
fails to meet criteria for irCR or irPD 
 
 


 
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8.6 Exploratory Assessment of Correlative Immunologic Research 
Please refer to the Study Laboratory Manual for information on testing to be done and 
instructions on specimen handling and logistics. 
 
 


 
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8.7 Drugs with Known Risk of Torsades de Pointes 
The following list is taken from www.crediblemeds.org (17 Dec 2015).  This may not be a 
comprehensive list.  For more details and periodic updates, see www.crediblemeds.org. 
Amiodarone (Cordarone® and others) 
Anagrelide (Agryline® and others) 
Arsenic trioxide (Trisenox®) 
Astemizole (Hismanal®) 
Azithromycin (Zithromax® and others) 
Bepridil (Vascor® and others) 
Chloroquine (Aralen®) 
Chlorpromazine (Thorazine® and others) 
Cilostazol (Pletal®) 
Ciprofloxacin (Cipro® and others) 
Cisapride (Propulsid®) 
Citalopram (Celexa® and others) 
Clarithromycin (Biaxin® and others) 
Cocaine (Cocaine) 
Disopyramide (Norpace®) 
Dofetilide (Tikosyn®) 
Domperidone (Motilium® and others) 
Donepezil (Aricept®) 
Dronedarone (Multaq®) 
Droperidol (Inapsine® and others) 
Erythromycin (E.E.S.® and others) 
Escitalopram (Cipralex® and others) 
Flecainide (Tambocor® and others) 
Fluconazole (Diflucan® and others) 
Gatifloxacin (Tequin®) 
Grepafloxacin (Raxar®) 
 
Halofantrine (Halfan®) 
Haloperidol (Haldol® (US & UK) and others) 
Ibutilide (Corvert®) 
Levofloxacin (Levaquin® and others) 
Levomeprazine (Nosinan®, Nozinan®, 
Levoprome®) 
Levomethadyl (Orlaam®) 
Mesoridazine (Serentil®) 
Methadone (Dolophine® and others) 
Moxifloxacin (Avelox® and others) 
Ondansetron (Zofran® and others) 
Oxaliplatin (Eloxatin®) 
Papaverine HCl 
Pentamidine (Pentam®) 
Pimozide (Orap®) 
Probucol (Lorelco®) 
Procainamide (Pronestyl® and others) 
Propofol (Diprivan® and others) 
Quinidine (Quinaglute® and others) 
Sevoflurane (Ulane® and others) 
Sotalol (Betapace® and others) 
Sparfloxacin (Zagam®) 
Sulpiride (Dogmatil® and others) 
Terfenadine (Seldane®) 
Thioridazine (Mellaril® and others) 
Vandetanib (Caprelsa®) 
 
 
 
 


 
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8.8 ECOG Performance Status 
Eastern Cooperative Oncology Group Performance Status   
Grade 
ECOG PS 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work 
of a light or sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities. 
Up and about more than 50% of waking hours 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking 
hours 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair 
5 
Dead 
Reference: (37) 
 
 
 


 
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8.9 List of Abbreviations 
AE 
adverse event 
AESI 
adverse event of special interest 
ALCL 
Anaplastic large cell lymphoma  
ALK 
Anaplastic lymphoma kinase 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
AUC 
area under the concentration time curve 
CD 
Cluster of differentiation 
CI 
confidence intervals  
Cmax 
peak concentration 
Cmin 
trough concentration  
CNS 
Central nervous system 
CR 
Complete response 
CRC 
Colorectal Cancer  
CRF 
Case report form  
CTC 
Circulating tumor cell 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTLA-4 
Cytotoxic T lymphocyte-associated antigen 4  
DC 
Dendritic cell 
DCR 
Disease control rate 
DLT 
dose-limiting toxicity 
DoR 
Duration of Response 
ECLA 
Electrochemiluminescence assay 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
EGFR 
epidermal growth factor receptor 
FDA 
Food and Drug Administration 
FDG-PET 
fluorodeoxyglucose (FDG)-positron emission tomography (PET) 
FNA 
Fine needle aspiration 
EML4 
Echinoderm microtubule associated protein-like 4  
FFPE 
Formalin-fixed paraffin-embedded 
FIH 
First in human 
GCP 
Good Clinical Practice 
GMP 
Good manufacturing practice 
HCC 
hepatocellular carcinoma 
HDT 
High dose therapy 
HLA 
Human Leukocyte Antigen 
IB 
Investigator Brochure 


 
C O N F I D E N T I A L  
SOP-C01-TMP-3 version 3  
LUD2014-012-ALK Protocol Amendment 2 (Final, 14-AUG-2017) 
Page 81 of 85 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IGSF 
Immunoglobulin superfamily 
IHC 
Immunohistochemistry 
IL 
interleukin 
IMiD 
Immune modulatory drug 
IMT 
inflammatory myofibroblastic tumors  
IND 
Investigational new drug 
irAE 
Immune-related adverse event 
irRC 
irRC immune-related response criteria 
IV (i.v.) 
intravenous 
IRB 
Institutional Review Board 
LICR 
Ludwig Institute for Cancer Research 
LTK 
leukocyte tyrosine kinase  
mAb 
Monoclonal antibody 
MDSC 
myeloid derived suppressor cells 
MedDRA 
Medical Dictionary for Regulatory Activities 
MSD 
Meso Scale Discovery 
MET 
MNNG HOS transforming gene or c-Met 
MTD 
maximum tolerated dose 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse 
Events 
NPM 
nucleophosmin 
NSCLC 
Non-small cell lung cancer 
NK 
Natural killer 
ORR 
Objective Response Rate 
OS 
Overall survival 
PBMC 
Peripheral blood mononuclear cell 
PD 
Progressive disease 
PD-1 
Programmed death-1  
PD-L1 
Programmed death ligand 1 
PFS 
Progression free survival 
PD 
Pharmacodynamics  
PK 
Pharmacokinetics 
p.o. 
By mouth 
PD 
Progressive disease 
PR 
Partial response 
Q4W 
Every 4 weeks 
QTc 
corrected QT interval 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RCC 
Renal cell carcinoma 


 
C O N F I D E N T I A L  
SOP-C01-TMP-3 version 3  
LUD2014-012-ALK Protocol Amendment 2 (Final, 14-AUG-2017) 
Page 82 of 85 
RCD 
Recommended combination dose 
RTK 
receptor tyrosine kinase  
SAE 
Serious Adverse Event 
SCCHN 
squamous cell carcinoma of the head and neck 
SD 
Stable disease 
SOC 
Standard of care 
TIL 
tumor-infiltrating lymphocyte 
TKI 
tyrosine kinase inhibitor 
TMA 
thrombotic microangiopathy  
TME 
tumor microenvironment  
TMTB 
Total Measured Tumor Burden  
ULN 
Upper limit of normal 
WFI 
Water for Injection 
 
 
 


 
C O N F I D E N T I A L  
SOP-C01-TMP-3 version 3  
LUD2014-012-ALK Protocol Amendment 2 (Final, 14-AUG-2017) 
Page 83 of 85 
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