A Biomarker-Driven Protocol for Previously Treated ALK-Positive Non-Squamous NSCLC Patients: The NCI-NRG ALK Protocol
Phase: PHASE2
Conditions: Lung Non-Squamous Non-Small Cell Carcinoma, Stage IV Lung Cancer AJCC v8, Stage IVA Lung Cancer AJCC v8, Stage IVB Lung Cancer AJCC v8
Sponsor: National Cancer Institute (NCI)

For Protocol Amendment 8 of:  NRG-LU003, “A Biomarker-Driven Protocol for Previously 
Treated NSCLC ALK Positive Patients: The NCI-NRG-ALK Protocol” 
 
NCI/Local Protocol #:  NRG-LU003 
 
NCI Protocol Version Date:  January 20, 2022 
 
Request for Rapid Amendment (RRA) for studies using ensartinib and for studies using 
lorlatinib:   
 
Section 
Change 
7.3.5 
In response to a CTEP Request for Rapid Amendment (RRA) for 
studies using ensartinib, the following NOTE was added: 
• NOTE:  This study is closed to accrual and patients who 
received ensartinib are no longer receiving treatment; 
therefore the CAEPR will not be further updated.   
7.3.6 
In response to a CTEP Request for Rapid Amendment (RRA) for 
studies using lorlatinib, the CAEPR for lorlatinib (version 2.2, June 
24, 2020) was revised as follows: 
 
• Added New Risk: 
o Rare but Serious: Central nervous system necrosis; 
Hyperglycemia; Hyperlipidemia 
o Also Reported on Lorlatinib Trials But With Insufficient 
Evidence for Attribution: Anorexia; Bronchopulmonary 
hemorrhage; Cardiac disorders - Other (cardiac tamponade); 
- Cardiac disorders - Other (left ventricular dysfunction); 
Chest pain - cardiac; Cholecystitis; Heart failure; 
Hepatobiliary disorders - Other (cholelithiasis); 
Hepatobiliary disorders - Other (hepatic function 
abnormal); Injury, poisoning and procedural complications - 
Other (traumatic intracranial hemorrhage, intentional self-
injury); Ischemia cerebrovascular; Mucositis oral; 
Neoplasms benign, malignant and unspecified (incl cysts 
and polyps) - Other (neoplasm progression, pericardial 
effusion malignant); Nervous system disorders - Other 
(neurological symptom, carpal tunnel syndrome); 
Neutrophil count decreased; Palpitations; Pericardial 
effusion; Sinus bradycardia; Small intestinal obstruction; 
Surgical and medical procedures - Other (radiotherapy to 
bone); Vascular disorders - Other (thrombosis); Voice 
alteration; White blood cell decreased 
 
• Increase in Risk Attribution 
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to: 
for patients receiving lorlatinib only (day 1 of cycles 1-3, and every 
3 cycles thereafter) 
 
5.2.1 
A new paragraph was added to define “missed dose,” for clarity. 
5.4.2 
Prohibited therapies for brigatinib were revised to match the FDA 
label as follows:   
• Bullet 1 – deleted “or moderate” and added “or inducers” 
• Bullet 2 – deleted  
15.4 
Paragraph 4, 1st sentence – the time of the assessment was 
corrected to after the trial has “accrued 100 patients”. 
APPENDIX XVI 
The PDF Wallet Card was updated to be a fillable form. 
Informed Consents 
There are no changes to the sample contents for alectinib,   
brigatinib, ceritinib, crizotinib, ensartinib, pemetrexed, and 
screening except the version dates were changed to be consistent 
with the amended protocol.   
 
CTEP issued a Request for Rapid Amendment (RRA) for studies 
using ensartinib, but the risk profile was not revised because the 
study is closed to accrual and patients who received ensartinib are 
no longer receiving treatment. 
 
For changes to the sample consent for lorlatinib, see the summary 
of changes attached to that consent.   
 
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Protocol Agent 
Agent 
Supply 
NSC # 
IND # 
 
IND Sponsor  
Alectinib 
PMB 
794611 
 
DCTD, NCI 
Brigatinib 
PMB 
784728 
LDK378 (Ceritinib) 
PMB 
802646 
Ensartinib 
PMB 
784729 
Lorlatinib 
PMB 
803411 
Crizotinib 
PMB 
749005 
Pemetrexed 
Commercial 
698037 
Cisplatin 
Commercial 
119875 
Carboplatin 
Commercial 
241240 
 
Participating Sites 
 U.S. 
 Canada 
 Approved International Member Sites 
 
Document History  
 
Version Date 
Amendment 8 
January 20, 2022 
Amendment 7 
August 11, 2020 
Amendment 6 
June 29, 2020 
Amendment 5 
February 17, 2020 
Amendment 4 
November 13, 2019 
Amendment 3 
September 9, 2019 
Amendment 2 
June 21, 2019 
Amendment 1 
May 20, 2019 
Pre-activation revision 
March 4, 2019 
Initial 
November 19, 2018 
 
 
 
 
  
 
 
This protocol was designed and developed by NRG Oncology. It is intended 
to be used only in conjunction with institution-specific IRB approval for 
study entry.  No other use or reproduction is authorized by NRG Oncology 
nor does NRG Oncology assume any responsibility for unauthorized use of 
this protocol. 
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NRG ONCOLOGY 
 
NRG-LU003 (11-AUG-2020) 
 
A BIOMARKER-DRIVEN PROTOCOL FOR PREVIOUSLY TREATED ALK-
POSITIVE NON-SQUAMOUS NSCLC PATIENTS: THE NCI-NRG ALK  PROTOCOL  
 
CONTACT INFORMATION (20-JAN-2022) 
 
For regulatory 
requirements: 
For patient enrollments: 
For data submission: 
Regulatory documentation 
must be submitted to the 
CTSU via the Regulatory 
Submission Portal.  
 
Sign in at www.ctsu.org, and 
select Regulatory > 
Regulatory Submission.  
 
Institutions with patients 
waiting that are unable to use 
the Portal should alert the 
CTSU Regulatory Office 
immediately at 1-866-651-
2878 to receive further 
instruction and support. 
 
Contact the CTSU 
Regulatory Help Desk at 1-
866-651-2878 for regulatory 
assistance. 
Refer to the patient enrollment 
section of the protocol for 
instructions on using the 
Oncology Patient Enrollment 
Network (OPEN).  OPEN is 
accessed at 
https://www.ctsu.org/OPEN S
YSTEM/ or 
https://OPEN.ctsu.org. 
 
Contact the CTSU Help Desk 
with any OPEN-related 
questions by phone or email: 
1-888-823-5923, or 
ctsucontact@westat.com. 
 
Data collection for this study 
will be done exclusively 
through Medidata Rave.  
Refer to the data submission 
section of the protocol for 
further instructions.  
 
The most current version of the study protocol and all supporting documents must be 
downloaded from the protocol-specific page located on the CTSU member’s website (located at 
https://www.ctsu.org).  Access to the CTSU members’ website is managed through the Cancer 
Therapy and Evaluation Program - Identity and Access Management (CTEP-IAM) registration 
system and requires user log in with CTEP-IAM username and password.  
For clinical questions (i.e. patient eligibility or treatment-related) Contact the Study PI of 
the Lead Protocol Organization. 
For non-clinical questions (i.e. unrelated to patient eligibility, treatment, or clinical data 
submission) contact the CTSU Help Desk by phone or e-mail:  
CTSU General Information Line – 1-888-823-5923, or ctsucontact@westat.com.  All calls and 
correspondence will be triaged to the appropriate CTSU representative.  
 
 
 
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TABLE OF CONTENTS 
NRG ONCOLOGY ..........................................................................................................................1 
SCHEMA  ........................................................................................................................................8 
1. 
OBJECTIVES ......................................................................................................................9 
1.1 
Primary Objective ....................................................................................................9 
1.2 
Secondary Objectives ...............................................................................................9 
1.3 
Correlative Science Objective ..................................................................................9 
2. 
BACKGROUND .................................................................................................................9 
2.1 
Alectinib .................................................................................................................11 
2.2 
Brigatinib ...............................................................................................................15 
2.3 
LDK378 (Ceritinib) ...............................................................................................19 
2.4 
Crizotinib ...............................................................................................................21 
2.5 
Ensartinib (X-396) .................................................................................................22 
2.6 
Lorlatinib................................................................................................................24 
2.7 
Summary of NRG-LU003  .....................................................................................26 
3. 
ELIGIBILITY AND INELIGIBILITY CRITERIA ..........................................................27 
3.1       Patient Selection Guidelines ..................................................................................27 
3.2 
Eligibility Criteria ..................................................................................................28 
3.3 
Ineligibility Criteria ...............................................................................................29 
4. 
REQUIREMENTS FOR STUDY ENTRY, TREATMENT, AND FOLLOW-UP ..........30 
5.        TREATMENT PLAN/Regimen description .......................................................................33 
5.1 
ALK Inhibitor Therapy  .........................................................................................33 
5.2 
Agent Administration  ............................................................................................35 
5.3 
Integrated Assay/Biomarker ..................................................................................36 
5.4 
General Concomitant Medication and Supportive Care Guidelines  .....................37 
5.5 
Duration of Therapy ...............................................................................................38 
6. TREATMENT MODIFICATIONS/managEment .....................................................................39 
6.1 
Dose Modifications and Toxicity Management for Alectinib ...............................39 
6.2       Dose Modifications and Toxicity Management for Brigatinib ..............................41 
6.3       Dose Modifications and Toxicity Management for LDK378 (ceritinib) ...............44 
6.4       Dose Modifications and Toxicity Management for Crizotinib ..............................45 
6.5       Dose Modifications and Toxicity Management for Ensartinib ..............................47 
6.6       Dose Modifications and Toxicity Management for Lorlatinib ..............................50 
6.7       Dose Modifications and Toxicity Management for Pemetrexed ...........................52 
7. 
ADVERSE EVENTS REPORTING REQUIREMENTS .................................................54 
7.1   
Protocol Agents ......................................................................................................54 
7.2  
Adverse Events and Serious Adverse Events ........................................................54 
7.3 
Comprehensive Adverse Events and Potential Risks (CAEPR) List for 
CTEP Study Agents  ..............................................................................................55 
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7.4 
Expedited Reporting of Adverse Events  ...............................................................77 
8. 
REGISTRATION AND STUDY ENTRY PROCEDURES  ............................................80 
8.2       Patient Enrollment .................................................................................................83 
8.3       Digital Data Submission of Images to NRG Using TRIAD  .................................84 
9.0 
DRUG INFORMATION ...................................................................................................85 
9.1 
Agent Ordering and Agent Accountability ............................................................85 
9.2 
Investigational Study Agent: Alectinib (
, NSC #794611)  ..............86 
9.3 
Investigational Study Agent: Brigatinib (
, NSC #784728) ..............88 
9.4 
Investigational Study Agent: LDK378 (ceritinib) (
, NSC 
#802646)  ...............................................................................................................89 
9.5 
Investigational Study Agent: Crizotinib (
, NSC #749005)  .............92 
9.6 
Investigational Study Agent: Ensartinib (
, NSC #784729) .............93 
9.7 
Investigational Study Agent: Lorlatinib (
, NSC #803411) ........95 
9.8 
Commercial Agent: Pemetrexed (NSC# 698037)..................................................97 
9.9 
Commercial Agent: Cisplatin (NSC# 119875) ......................................................97 
9.10 
Commercial Agent: Carboplatin (NSC# 241240)..................................................97 
10. 
PATHOLOGY/BIOSPECIMEN  ......................................................................................98 
10.1 
Mandatory Central Pathology Review for Integrated Marker Testing  .................98 
10.2 
Biospecimen Submission Tables  ........................................................................100 
11. 
MODALTY REVIEWS ...................................................................................................103 
12. 
SPECIAL STUDIES (NON-TISSUE) .............................................................................104 
13. 
ASSESSMENT OF EFFECT ..........................................................................................104 
13.1 
Antitumor Effect – Solid Tumors ........................................................................104 
13.2 
Response Criteria .................................................................................................107 
14. 
DATA AND RECORDS  ................................................................................................110 
14.1 
Data Management/Collection  .............................................................................110 
14.2 
Instructions for Patients who Do Not Start Assigned Protocol Treatment ..........111 
14.3 
Summary of Data Submission .............................................................................111 
14.4 
Data Quality Portal  .............................................................................................111 
14.5 
Rave-CTEP-AERS integration  ...........................................................................112 
14.6 
Global Reporting/Monitoring ..............................................................................113 
15. 
STATISTICAL CONSIDERATIONS.............................................................................113 
15.1 
Study Design  .......................................................................................................113 
15.2 
Study Endpoints ...................................................................................................114 
15.3 
Primary Objectives Study Design  .......................................................................115 
15.4 
Study Monitoring of Primary Objectives  ............................................................116 
15.5 
Accrual/Study Duration Considerations ..............................................................118 
15.6 
Secondary Endpoints and Statistical Analysis Plans ...........................................118 
15.7 
Gender/Ethnicity/Race Distribution .....................................................................120 
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REFERENCES  ...........................................................................................................................121 
APPENDIX I: Analysis Plans for cfDNA Results ......................................................................124 
APPENDIX II: Techical specifications for FoundationOne®CDx Solid tumor assay  ..............127 
APPENDIX III: Specimen instructions for FoundationOne®CDx Solid tumor assay  ..............129 
APPENDIX IV: technical specifications for foundationone®Liquid  blood-based assay  .........131 
APPENDIX V: Specimen instructions for foundationONe®Liquid  blood-based assay  ...........133 
APPENDIX VI: CTEP Collaborative Agreements Language .....................................................134 
APPENDIX VII: NRG-LU003 PILL diary for alectinib .............................................................136 
APPENDIX VIII: NRG-LU003 PILL diary for brigatinib ..........................................................137 
APPENDIX IX: NRG-LU003 PILL diary for Crizotinib ............................................................138 
APPENDIX X: NRG-LU003 PILL diary for Ensartinib  ............................................................139 
APPENDIX XI: NRG-LU003 PILL diary for LDK378 (CERitinib) ..........................................140 
APPENDIX XII: NRG-LU003 PILL diary for lorlatinib ............................................................141 
APPENDIX XIII: Prohibited therapies, herbal supplements  ......................................................142 
APPENDIX XIV:  PATIENT DRUG INFORMATION HANDOUT AND WALLET CARD 
FOR ENSARTINIB  ........................................................................................................145 
APPENDIX XV:  PATIENT CLINICAL TRIAL WALLET CARD  ........................................147 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
NRG-LU003 
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STEP 1 REGISTRATION 
Submission of tissue and blood* 
 
STEP 2 REGISTRATION 
Patients will be randomized to one of the agents based on their mutation 
 
STRATIFICATION 
By ALK resistance mutation as described in section 15.1  
 
  
ALK TKI targeting 
mutations noted in Table 
5.1  
  
Patients with ALK 
L1198F or METamp 
will receive 
Crizotinib 
  
Patients with no 
ALK or METamp 
Mutation will be 
randomized to a 
different next 
generation ALK 
TKI or pemetrexed 
+ cisplatin or 
carboplatin 
SCHEMA (17-FEB-2020) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
*Tissue and blood must be sent after a patient is registered to the study so that an NRG-LU003 
patient identifier may be sent with the samples. 
 
Based on the identified ALK mutation(s), patients will be assigned to treatment with the 
indicated ALK inhibitors as described in Section 5.1 and Section 15.1. If no ALK-resistance 
mutations are identified, patients will be randomized to receive either a next-generation ALK 
inhibitor they have not received or pemetrexed based chemotherapy. 
Next-generation ALK inhibitor = 2nd or 3rd generation 
 
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1. OBJECTIVES 
1.1 
Primary Objective 
• To assess whether ALK kinase domain mutations (G1202/C1156Y /I1171/L1196/ 
V1180/ F1174/ compound mutation) associated with drug resistance are 
prognostic for objective response to subsequent ALK inhibitor therapy.  
• To assess whether subsequent pemetrexed based chemotherapy improves 
objective response comparing to ALK inhibitor therapy for no ALK mutation 
patients 
• To evaluate objective responses of patients with specific genetic alterations 
(ALKL1198F/MET double mutation or high-level MET gene amplification) 
treated with crizotinib.   
 
1.2 
Secondary Objectives 
• Progression-free survival (PFS) 
• Duration of response (DOR) 
• Overall survival (OS) 
• Intracranial objective response rate (ORR) 
• Safety and tolerability 
 
1.3 
Correlative Science Objective 
• Establish concordance between tumor and liquid biopsies 
 
2. BACKGROUND 
Prospective molecular testing for ALK rearrangements and therapeutic targeting with small 
molecule tyrosine kinase inhibitors (TKIs) of ALK inhibitors are now the standard of care for 
those patients with advanced non-small cell lung cancer (NSCLC) with ALK –rearranged 
(i.e., ALK-positive). However, the optimal treatment strategy and sequence of these agents 
for , particularly in the setting of acquired resistance, has not yet been established. Although 
ALK-positive NSCLC patients live longer due to the availability of ALK targeted therapies, 
most will eventually relapse and die of the disease. 
 
To date, at least 27 different ALK fusion variants have been reported in the literature, of 
which echinoderm microtubule associated protein like 4 (EML4) is the predominant fusion 
partner (Ou et al, 2012).  Published studies in unselected patients with NSCLC report an ALK 
fusion prevalence between 2.7% (Perner et al, 2008; Varella Garcia et al, 2010) and 8% (Kris 
et al, 2014). The largest study to date in unselected NSCLC patients (Gainor et al, 2013), 
estimated the prevalence of ALK fusion-positive NSCLC to be 4.4%, in line with the range 
described above. 
Currently, the first generation multi-targeted ALK inhibitor crizotinib, alectinib and LDK378 
(ceritinib) and second generation ALK inhibitors are approved by the US FDA for first line 
treatment of advanced ALK-positive NSCLC. Unfortunately, most patients develop acquired 
therapeutic resistance to crizotinib, often within the first year of treatment. More potent, 
second-generation ALK inhibitors (LDK378 (ceritinib), alectinib and brigatinib) are 
approved after crizotinib failure in this patient population.  Several randomized phase III 
trials have recently completed comparing second-generation inhibitors versus standard of 
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care in the first-line setting.  For example, LDK378 (ceritinib) was recently shown to be 
superior to standard first-line platinum/pemetrexed chemotherapy (ASCEND-4), and 
alectinib was found to be superior to crizotinib in two separate studies of crizotinib-naïve, 
ALK-positive NSCLC patients (J-ALEX and global ALEX; Hida et al, 2017; Peters et al.. 
2017). Additional second-generation ALK inhibitors like brigatinib and ensartinib, as well as 
third-generation inhibitors like lorlatinib, are at various stages of clinical development, with 
all three currently in randomized phase 3 trials against crizotinib in the first line setting.  Of 
note, crizotinib is known to have limited activity in the central nervous system (CNS), 
whereas the class of next generation inhibitors has shown robust activity in patients with 
CNS metastases.  Overall, next generation inhibitors, specifically LDK378 (ceritinib) and 
alectinib are moving into the front-line setting for metastatic ALK-positive NSCLC; 
however, many patients around the world are still receiving sequential treatment with first-
line crizotinib followed by a next-generation ALK inhibitor.   
 
Numerous studies have examined mechanisms of resistance to first and next-generation ALK 
inhibitors.  In patients whose disease has relapsed on crizotinib, approximately 20% have 
acquired a secondary mutation within the ALK tyrosine kinase domain (Gainor et al. 2016). 
Over 10 distinct crizotinib-resistant mutations have now been reported. Acquired ALK 
mutations that have been reported to confer resistance to crizotinib include L1196M, 
G1202R, S1206Y, G1269A, F1174C and 1151Tins. By contrast, in patients who have 
relapsed on second-generation ALK inhibitors; close to 50% have acquired a secondary ALK 
resistance mutation (Gainor et al. 2016). The spectrum of ALK resistance mutations seen 
with second-generation ALK inhibitors is narrower than that of crizotinib, with ALK 
G1202R being the predominant resistance mutation emerging after all second-generation 
ALK inhibitors. As first- and next-generation ALK inhibitors are structurally distinct, their 
potencies against specific ALK resistance mutations varies widely. For example, alectinib 
has little activity against ALK I1171 mutations, which are commonly identified in alectinib-
resistant tumors; LDK378 (ceritinib) retains potency against I1171 mutations and can 
effectively overcome these mutations in preclinical and early clinical studies.  Numerous 
other examples of differential activity have been reported, including ALK G1123S (resistant 
to LDK378 (ceritinib) but sensitive to alectinib) and V1180L (resistant to alectinib but 
sensitive to LDK378 (ceritinib) (Dong X, et al., 2016).  
 
Most patients who relapse on crizotinib remain sensitive to more potent, next generation 
ALK inhibitors, suggesting that most crizotinib-resistant tumors remain ALK dependent.  
Indeed, LDK378 (ceritinib), alectinib and brigatinib are currently approved for crizotinib-
resistant patients, without requirement for a biopsy or molecular testing.  However, in the 
setting of relapse on a second-generation ALK inhibitor, preclinical studies using clinical 
resistant specimens and patient-derived cell lines indicates that about one-half of tumors 
remain ALK-dependent (typically those tumors harboring ALK resistance mutations), 
whereas the remaining one-half have become ALK-independent (typically those tumors 
without ALK resistance mutations)(Gainor et al, 2016). The latter have upregulation of other 
oncogenic pathways as the primary mechanisms of resistance, or phenotypic changes 
including epithelial to mesenchymal transition or rarely small cell transformation. Those 
ALK-dependent tumors may still be sensitive to another ALK inhibitor (if appropriately 
matched to the ALK mutation), whereas ALK-independent tumors are likely no longer 
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responsive to another ALK inhibitor.  This preclinical work has yet to be validated clinically.      
 
Taken together, these studies suggest that ALK resistance mutations may serve as a critical 
biomarker to guide selection of subsequent therapy, particularly in the setting of relapse on a 
second-generation ALK inhibitor. As second-generation ALK inhibitors are already widely 
used in crizotinib-resistant patients, and are moving rapidly into the first-line setting, there is 
an urgent need to understand how best to treat patients who have become resistant to a 
second-generation ALK inhibitor.  
 
2.1 Alectinib 
Clinical data in the crizotinib-refractory and crizotinib-naïve settings 
Alectinib is FDA-approved for the treatment of patients with ALK+ NSCLC who have 
progressed on, or are intolerant to, crizotinib and for first-line treatment of ALK+ NSCLC.  
The initial approval of alectinib was based on two phase 1/2 single-arm studies (NP28673 
and NP28761). The global NP28673 alectinib study reported an objective response rate 
(ORR) of 50.8%, median duration of response of 15.1 months and median progression-free 
survival (PFS) of 8.9 months (Ou et al., 2016). The North American NP28761 study reported 
an ORR of 52.2%, median duration of response of 13.5 months and median PFS of 8.1 
months (Shaw A, et al., 2016). With longer follow-up, pooled analysis of the two phase 2 
studies demonstrated an ORR of 51%, Disease Control Rate (DCR) of 79%, median DOR of 
14.9 months, and median PFS of 8.3 months (Yang et al., 2017).  
 
Alectinib has also shown significant CNS activity, with CNS ORR in patients with 
measurable CNS disease at baseline of 58.8% in NP28673 and 75% in NP28761. CNS 
duration of response was 11.1 months in both studies.  
 
Alectinib is well tolerated, with the most common AEs (all grades) being constipation (38%); 
fatigue (32%) and peripheral edema (28%) (Yang JC et al, 2017). Most AEs are grade 1 and 
grade 2 in severity, with G3-5 AEs occurring in 40% of patients, the most common being 
dyspnea (4%), blood creatinine phosphokinase increased (4%) and AST and ALT increased 
(3% each). AEs leading to treatment withdrawal were reported in 6% of patients (n=14). 
  
Two recently reported phase 3 studies, J-ALEX and ALEX, have established alectinib as a 
new standard of care for newly diagnosed ALK-positive NSCLC patients (Hida, et.al, 2017; . 
In both studies, crizotinib-naïve patients were randomized to receive either alectinib or 
crizotinib as first-line therapy. While there were a number of differences in the study designs 
and study populations, the efficacy results were remarkably similar. Median PFS was 
approximately 26 months with alectinib in both studies. The hazard ratio for progression was 
0.4-0.5 favoring alectinib. Consistent with its known intracranial activity, alectinib was 
shown to significantly delay time to CNS progression, with a cause-specific hazard ratio of 
0.16. Overall, both drugs were reasonably well tolerated, but there were fewer serious 
adverse events with alectinib in both studies. Approval of first line alectinib was given US 
regulatory approval in November 2017.  
 
Molecular predictors of response and resistance to alectinib 
Recently, the efficacy of alectinib in ALK-positive NSCLC patients with different ALK 
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Figure #1: NP28761* and NP28673* Pooled Mutation Analysis in Crizotinib-Failed 
ALK-Positive NSCLC: Change in Allele Frequency During Alectinib Treatment (cont.) 
 
 
 
Several known resistance mutations increased in frequency in plasma samples following 
alectinib treatment in one patient: APCG871V, EML4-ALK, ALK G1202R C>T and C>G. 
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The convergent evolution of two different sub-clones of G1202R suggests strong selective 
pressure to develop the G1202R mutation in response to alectinib.  In contrast, ALK I1171T, 
KCNN3-ALK and ALKC1156F decreased after alectinib treatment. 
 
Analysis of ALK mutations in response to alectinib using plasma samples from the additional 
phase 2 plasma samples revealed 47 missense SNVs in 21 different patients. The change in 
allele frequency (AF) while on alectinib generally matched the expected pattern. SNVs 
known to be resistant to alectinib (e.g. G1202R, I1171N/S) increased in AF during treatment, 
while those known to be sensitive to alectinib (e.g. F1174V, G1269A) decreased in AF 
during treatment (Table 2 and Figure 1). 
 
In the additional phase 2 samples, R1209Q, a variant in the ALK catalytic domain, was 
detected in six patients; in five of these patients, the variant was only detected after 
progression on alectinib, suggesting it may be a novel resistance mechanism. Patient 
was the only patient with an R1209Q mutation that showed a reduction in AF 
during alectinib treatment; however, known resistance variants (G1202R and I1171N) 
increased in AF, suggesting that a different subclone showed stronger resistance to alectinib.  
 
Taken together, these data demonstrate that alectinib is clinically active against native ALK 
and several ALK variants that can cause resistance to crizotinib. Resistance mutations 
including I1171S/N, G1202R and the novel R1209Q may occur during treatment with 
alectinib. These analyses also show that in the absence of tissue samples, assessing tumor 
DNA in plasma samples may be an alternative non-invasive way to monitor for the 
appearance of resistance mutations during therapy, some of which may be targetable by other 
ALK inhibitors.  
 
2.2 Brigatinib (20-JAN-2022) 
Clinical data 
Brigatinib is FDA-approved for patients with ALK+ NSCLC who have progressed on or are 
intolerant to crizotinib and for first-line use. The relationship between ALK mutation status 
and efficacy of brigatinib has been evaluated in two ongoing studies: a first-in-human phase 
1/2 study (AP26113-11-101), which assessed a variety of dose levels (30 mg to 300 mg 
daily), and a phase 2 study (“ALTA”; AP26113-13-201) (Gettinger, 2016). In the ALTA 
study, patients with ALK+ NSCLC who had progressed on crizotinib, were randomized to 
one of two regimens of brigatinib: 90 mg QD and 180 mg QD with 7-day lead-in at 90 mg 
QD (90 mg QD → 180 mg QD). These studies included 71 and 222 patients, respectively, 
with ALK+ NSCLC and prior treatment with crizotinib. As shown in Figure 2, tumor tissue 
samples collected after crizotinib therapy (baseline; n=32 total) were used to assess the 
efficacy of brigatinib according to baseline mutation status. Tumor tissue samples collected 
after disease progression on brigatinib (post-baseline; n=6 total) were used to identify 
potential mechanisms of resistance to brigatinib. All samples were analyzed using the 
FoundationOne®CDx next generation sequencing (NGS) platform to assess the presence of 
secondary mutations in ALK kinase domain (KD) (as well as the presence of ALK 
rearrangements) or mutations in other genes. 
 
 
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Figure #3: Confirmed Responses Observed in Patients with and without ALK 
Mutations at Baseline 
 
*ALK fusion negative by NGS at baseline. †PIK3CA E545K mutation, §EGFR amplification, ׀׀BRAF 
G596R mutation detected at baseline.  ‡Patient receiving brigatinib for 29 days; tumor scan taken 32 days 
after last dose.  
 
Figure #4: Durable Responses Observed in Patients with and without ALK 
Mutations at Baseline 
 
 
*Patients with a PFS event who remain on study.  
†Patients who discontinued treatment or were otherwise censored before PFS event.  
 
Analysis of Post-Baseline Samples 
Best overall response:          PD         SD         Confirmed PR         Confirmed CR
WT
L1196M
WT
WT
S1206F
WT
F1174L
G1269A
WT
WT
WT
WT
WT
WT
F1174L
WT
WT
WT
WT
F1245V
WT
G1202R
WT
WT
L1196M
WT
WT
WT
WT
F1174L
WT
WT
Phase 1/2
ALTA
100
50
–50
–100
Best Change From Baseline 
in Target Lesions, %
0
100
50
–50
–100
Best Change From Baseline 
in Target Lesions, %
0
*,†
‡
*,§
*
*,  
*
0
6
12
18
24
30
WT
L1196M
WT
WT
F1174L
WT
WT
WT
F1174L
WT
S1206F
G1269A
WT
WT
WT
PFS, Months
Baseline Secondary ALK Mutation 
0
3
6
9
12
15
F1245V
WT
F1174L
WT
WT
G1202R
WT
WT
WT
L1196M
WT
WT
WT
WT
WT
WT
WT
PFS, Months
Baseline Secondary ALK Mutation 
†
†
*
*
*
†
*
†
†
Phase 1/2
ALTA
Patients without a PFS event who remain on study
Best overall response:          PD         SD         Confirmed PR         Confirmed CR
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Evaluable post-baseline samples have been analyzed from 5 patients in the phase 1/2 study 
and 1 patient in the ALTA study. Table 4 shows a summary of the results of the post-baseline 
mutation analysis (red box), along with additional details regarding patient treatment and 
outcome that assist in interpretation of the results, such as the brigatinib dosing regimen, time 
to progression, time to post-baseline biopsy, and time to brigatinib discontinuation. All 6 
patients achieved a confirmed response on brigatinib. Note that baseline biopsies were only 
available from 2 of these 6 patients. 
 
Table #4: Summary of Post-Baseline Mutation Analysis of Brigatinib Treated Patients 
 
 
aAll PBL samples collected while on or within 3 days of D/C of brigatinib therapy; bALTA patient 
c180 mg QD with 7 day lead-in at 90 mg QD; KD=kinase domain; D/C=discontinuation;  BL=baseline; PBL=post-
baseline 
 
In the first two patients (patient IDs
, no new ALK mutations were 
detected at progression, suggesting the possible emergence of an ALK-independent 
mechanism of resistance in these patients. Note that patient
had F1174L detected at 
baseline (18%), achieved a confirmed PR, and after progression on brigatinib had F1174L 
detected after 11.3 months of treatment, though at a lower level (5%). In the absence of the 
baseline sample one could have concluded, erroneously, that this provided evidence that 
F1174L is a resistance mutation for brigatinib. This is clearly not the case since, as noted 
above, 3/3 patients with an F1174L mutation at baseline achieved confirmed responses on 
brigatinib. 
 
In the next 2 patients (patient IDs
, multiple ALK mutations were 
detected at progression, suggesting the possible emergence of compound mutations, that is 2 
(or more) mutations in the same ALK allele. Since baseline tumor samples were not provided 
it cannot be determined whether any of the single mutants, or the compound mutants 
themselves, developed on brigatinib treatment or were pre-existing. Both patients had a 
Patient 
ID
BL secondary 
ALK KD 
mutation status
(% of reads)
Brigatinib 
Regimen
(mg)
Best 
Confirmed 
Response 
Time to 
Progression
(days)
Time to 
PBL biopsy#
(days)
Time to 
Brigatinib D/C
(days)
PBL secondary ALK 
KD mutation status
(% of reads)
Comment
No tissue
120 QD
PR
165
394
609
None
Possible emergence of ALK-independent 
resistance
F1174L (18%)
180 QDc
PR
335
344
487
F1174L (5%)
Possible emergence of ALK-independent 
resistance
No tissue
180 QDc
PR
165
261
258
I1171H (11%)
D1203N (8%)
G1269A (6%)
Possible compound mutation in ALK 
kinase domain
No tissue
90 QD
PR
225
267
277
F1174L (54%)
E1210K (27%)
Possible compound mutation in ALK 
kinase domain
WT
90 QD
PR
331
575
616
G1202R (14%)
PBL sample collected 9.7months after
brigatinib dose escalation to 120 mg BID
No tissue
60 BID
PR
867
964
Ongoing
G1202R (4%)
BRAF G469A mutation (2%) also detected 
in PBL sample
Lesion regression following brigatinib 
dose escalation to 240mg QD
*ALTA patient; D/C: discontinuation; # All PBL samples collected while on, or within 3 days of discontinuation of brigatinib therapy
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confirmed PR but progressed after 5.4 and 7.4 months of treatment. 
 
In the last 2 patients, a G1202R mutation was detected at progression. In patient
 no 
ALK mutation was detected at baseline, indicating that G1202R emerged during brigatinib 
treatment. This patient achieved a confirmed PR at the initial dose of 90 mg QD, and then 
escalated to 120 mg BID upon progression after ~11 months of treatment. G1202R was 
subsequently detected in a tumor biopsy collected after 18.9 months of treatment. Since there 
were no intervening biopsies, the kinetics with which G1202R emerged, and whether or not 
dose escalation had an effect on those kinetics, is not known. 
 
Finally, in patient
 G1202R was detected in a biopsy collected nearly 32 months 
after the start of brigatinib treatment. This patient achieved a confirmed PR at the initial dose 
of 60 mg BID that was maintained until month 28.5. Upon detection of a G1202R mutation 
in a biopsy collected at month ~32, the brigatinib dose was escalated to 240 mg QD. 
Regression of the lesion was observed upon dose escalation. 
 
In summary, by a variety of assessments that relate exposure levels achieved in patients to 
inhibitory concentrations required in cellular assays, 180 mg QD brigatinib is predicted to 
lead to levels of exposure sufficient to inhibit native ALK and all single resistance mutants, 
consistent with the profile of brigatinib as a pan-ALK mutant inhibitor. These include 
mutants associated with preclinical and/or clinical resistance to LDK378 (ceritinib) (such as 
L1152R/P, L1198F, and F1174C/L/V) and alectinib (such as T1151ins, I1171N, and 
V1180L). Importantly, there is limited data suggesting activity of brigatinib against G1202R. 
However, in this case, preclinical results suggest that optimal efficacy of brigatinib against 
G1202R may be dose-dependent. 
 
The presence of compound ALK mutations, or ALK independent mechanisms, appears to be 
associated with brigatinib resistance. In addition, G1202R was clearly acquired during 
brigatinib treatment in one patient. However it was detected in a biopsy collected nearly 19 
months after treatment initiation and for the first 10 months the patient was dosed with 90 
mg, not at the currently recommended dose of 180 mg. G1202R was also detected in another 
patient after a long duration of brigatinib treatment (31.7 months) and direct evidence that a 
higher than standard dose of brigatinib could induce tumor regression was obtained in that 
patient. 
 
2.3 LDK378 (Ceritinib) 
LDK378 (ceritinib) was the first of the second-generation ALK inhibitors to be granted FDA 
approval for the treatment of advanced, crizotinib-pretreated ALK+ NSCLC.  LDK378 
(ceritinib) is approximately 20 times more potent than crizotinib in vitro and inhibits the most 
common ALK resistance mutations, including L1196M and G1269A.  In the phase 1 study 
(ASCEND-1), LDK378 (ceritinib) achieved durable systemic and intracranial responses in 
both crizotinib-naïve and crizotinib-pretreated patients (Kim, 2016).  The median PFS with 
crizotinib was 18.4 months and 6.9 months in crizotinib-naïve and crizotinib-pretreated 
patients, respectively.   
 
To understand genetic determinants of response to LDK378 (ceritinib), tumor biopsies from 
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2.4 Crizotinib 
Crizotinib has received traditional or conditional approval for the treatment of patients with 
advanced ALK-positive NSCLC in many countries, including the United States (US), Europe 
(EU), and Japan. Crizotinib has also received traditional approval for the treatment of 
patients with advanced ROS1-positive NSCLC in the US. 
 
Crizotinib is a selective ATP-competitive small-molecule inhibitor of ALK, ROS1, and c-
MET/Hepatocyte Growth Factor Receptor (HGFR) tyrosine kinases and their oncogenic 
variants (eg, ALK or ROS1 fusion proteins or c-MET/HGFR mutant variants). Consistent 
with this mechanism of action, crizotinib inhibited phosphorylation of c-MET/HGFR and 
selected ALK fusion or mutant variants in tumor cells both in vitro and in vivo, and ROS1 in 
vitro. Crizotinib exhibited potent and selective growth inhibitory activity against tumor cells 
exhibiting translocation/inversion or selected mutations involving the ALK gene locus 
(EML4-ALK or nucleophosmin [NPM]-ALK fusion variants). 
 
Oral dosing of crizotinib 250 mg twice daily (BID) showed plasma concentrations reach 
steady state within 15 days and remain stable. The mean apparent terminal half-life was 42 
hours in cancer patients after a single dose. Crizotinib is absorbed with a peak plasma 
concentration occurring between 4 and 6 hours under fasting conditions. Crizotinib is a 
substrate of P- glycoprotein and is predominately metabolized by CYP3A4/5. Elimination of 
crizotinib was related to its hepatic, and possibly gastrointestinal, metabolism with a mean of 
63.1% of [14C] crizotinib excreted in the feces and 22.2% in the urine (crizotinib 
Investigator’s Brochure [IB]). 
 
Overall, the adverse events (AEs) reported for crizotinib in clinical studies were considered 
generally tolerable and manageable. For single-agent crizotinib, the most common AEs 
(≥20% of patients) reported as of March 2015 from 1761 (95.7%) of the 1840 patients with 
advanced NSCLC as treatment-related were vision disorders (60.4%), nausea (49.1%), 
diarrhea (48.1%), vomiting (43.9%), edema (38.1%), constipation (32.4%), elevated 
transaminases (30.4%), fatigue (21%), and neutropenia (20.4%). The majority of AEs were 
Grades 1 or 2 in severity, while treatment-related AEs of Grades 3, 4, or 5 in severity were 
observed among 701 (38.1%) advanced NSCLC patients who received at least 1 dose of 
single-agent crizotinib 250 mg BID. The most common (≥ 2%) Grade 3 treatment-related 
AEs were neutropenia, elevated transaminases, hypophosphatemia, lymphopenia, leukopenia, 
and fatigue. The most common (≥ 1%) Grade 4 treatment-related AEs were neutropenia, and 
elevated transaminases. The Grade 5 treatment-related AEs were interstitial lung disease 
(ILD) (0.4%), death (0.2%), and pneumonia, hepatotoxicity, lung infection, disseminated 
intravascular coagulation, arrhythmia, dyspnea, pulmonary embolism and deep vein 
thrombosis (0.1% each) (crizotinib IB). 
 
Clinical trials of crizotinib in both the first- and second-line ALK-positive NSCLC settings 
showed high rates of objective tumor response, and the responses were rapid and durable 
(PROFILE 1007 and PROFILE 1014). However, essentially all patients relapse on crizotinib, 
many within the first year of treatment. To date, numerous mechanisms of crizotinib 
resistance have been reported. While most crizotinib-resistant tumors remain ALK-
dependent, only 20-30% of resistant tumors acquire a secondary ALK resistance mutation. 
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Numerous crizotinib-resistant mutations have now been reported, including ALK L1196M 
(the gatekeeper mutation), G1269A, I1151Tins, L1152R, C1156Y, I1171T/N/S, 
F1174C/L/V, V1180L, G1202R, S1206Y, and E1210K, among others. More potent second- 
and third-generation ALK inhibitors can overcome many of these mutations. 
 
While alectinib has become the new standard of care for newly diagnosed patients with 
advanced ALK+ NSCLC (Peters et al., NEJM 2017), crizotinib may still play an important 
role in specific settings. First, as noted above, crizotinib is a potent MET inhibitor. Second 
and third generation ALK inhibitors (with the exception of ensartinib) do not inhibit MET, 
and indeed, MET amplification has been shown to function as a bypass mechanism 
mediating resistance to next generation inhibitors such as alectinib. In one case report, a 
patient who had developed resistance to alectinib due to MET amplification responded to 
crizotinib (Gouji et al., JTO 2014), validating the role of MET in driving resistance.   
 
Crizotinib may also play a role in patients who have received sequential ALK inhibitors and 
have developed compound (i.e., double) ALK mutations including ALK L1198F. This was 
first demonstrated in a case report of a patient who had been treated with crizotinib, LDK378 
(ceritinib) and lorlatinib (Shaw et al., NEJM 2016). This patient developed the ALK C1156Y 
resistance mutation after failing on crizotinib. She did not respond to LDK378 (ceritinib), but 
did respond durably to lorlatinib. However, when she relapsed on lorlatinib, her tumor had 
acquired the compound ALK C1156Y/L1198F mutation. In vitro studies showed that this 
L1198F compound mutation conferred resistance to lorlatinib and other next generation ALK 
inhibitors, but unexpectedly conferred sensitivity to the less potent ALK inhibitor crizotinib. 
Indeed, the patient was treated with crizotinib and experienced a dramatic and durable 
response. Additional in vitro studies have demonstrated that ALK L1198F can resensitize 
other crizotinib-resistance mutations including ALK L1196M and even ALK G1202R (Shaw 
et al., NEJM 2016). Thus, crizotinib may be an effective therapeutic option for patients when 
their resistance is due to an ALK L1198F-containing compound mutation.   
 
2.5 Ensartinib (X-396) (17-FEB-2020) 
Ensartinib is a potent, novel and specific ALK inhibitor.  In biochemical assays, ensartinib 
was tested against ALK and all alterations available in the Reaction Biology panel (Reaction 
Biology Corp.). It showed potent inhibition of all of them with IC50 <4 nM. The wild-type, 
and F1174, C1156Y, L1196M, S1206R, and T1151 mutants are particularly sensitive to 
ensartinib with IC50 of <0.4 nM, while the G1202R mutant is least sensitive (IC50 = 3.8 
nM). Besides ALK, ensartinib also potently inhibits TRKA fusions, TRKC, and ROS1. 
Kinases inhibited at higher concentrations are EphA2, EphA1, EphB1 and c-MET. Compared 
to crizotinib, ensartinib was approximately 10-fold more potent in in vitro assays (Lovly et 
al. 2011). It is particularly potent against the L1198F mutant, which is resistant to lorlatinib 
(1.1 nM for ensartinib vs. 26.7 nM for crizotinib) (Lovly, unpublished data). 
 
In pre-clinical studies, ensartinib exhibited a favorable efficacy profile, including anti-tumor 
activity against multiple ALK variants including those that are resistant to crizotinib.  Data 
from animal studies support the potential utility of ensartinib in crizotinib-resistant tumors 
and the potential use of ensartinib for the treatment of NSCLC tumors that have metastasized 
to the brain. 
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Clinical Efficacy in ALK+ NSCLC Patients 
There is an ongoing Phase 1/2 study with ensartinib (NCT01625234).  In this trial, responses 
have been observed in patients with ALK-positive NSCLC, including patients who are 
crizotinib-naïve, patients who have received prior crizotinib, and in patients with CNS 
metastases.  In addition, the drug has generally been well tolerated.   
 
As of Feb. 15, 2017, 97 patients have been enrolled in the ongoing Phase I/II study, with 60 
ALK+ efficacy evaluable patients dosed at ≥200mg once daily. To be evaluable for efficacy, 
patients must have completed at least 1 cycle of treatment (each cycle is approximately 28 
days) and had a post baseline response assessment. Among the 15 patients who didn't receive 
a prior ALK TKI, 12 achieved a partial response (PR), a response rate (RR) of 87%. Two 
patients who did not respond were ALK negative via plasma next generation sequencing 
(NGS). Among the 29 patients who received prior crizotinib but no other ALK TKI, 20 had a 
PR (RR: 69%), 8 had stable disease (SD), and 1 had progressive disease (PD) as best 
response, yielding an overall disease control rate (DCR) of 97%. Four of the 16 patients who 
received multiple ALK TKIs had a PR, and another 4 had SD, a DCR of 50%. Fourteen 
patients (3 were ALK TKI naïve, 8 had prior crizotinib only, 3 had multiple ALK TKIs) had 
CNS target lesions at baseline. Of these 14 patients, 2 had a complete intracranial response 
(CR), 7 achieved a PR, and 4 had SD, a 64% RR and a DCR of 93% (Horn 2018). 
 
The overall median PFS for ALK-positive evaluable patients was 9.2 months. In the ALK 
TKI naive patients, the median PFS was 26.2 months. Of the patients with prior crizotinib 
only, the median PFS was 9.0 months. Within the subgroup that received prior crizotinib and 
a second-generation ALK TKI, the median PFS was 1.9 months (Horn et al. In Press). 
 
NGS was performed by Resolution Bioscience on ctDNA from plasma samples on some 
patients who had prior ALK TKI(s), and various responses were observed as summarized 
below (Table 6). NGS panel targeted actionable mutations and rearrangements found in 
NSCLC. 
 
Table 6: Activity Seen in Patients with ALK Kinase Domain Mutations 
ALK 
Resistant 
Mutation 
Best 
Response 
Prior ALK 
TKI 
Dose 
(mg) 
PFS* 
(mo) 
DOR* 
(mo) 
%CFB* 
Best 
Response 
L1196M 
PR 
crizotinib 
225 
5.6 
3.7 
-47.4 
L1196M, 
G1269A 
PR 
crizotinib 
225 
7.4 
5.6 
-53.7 
T1151M 
PR 
crizotinib 
250 
3.7 
1.9 
-48.5 
G1202R 
PR 
crizotinib and 
LDK378 
(ceritinib) 
225 
5.7 
3.9 
-36.4 
L1152V, 
G1269A 
PR 
crizotinib and 
alectinib 
225 
3.6 
1.9 
-91.4 
F1174V 
PR 
crizotinib 
225 
15.5 
12 
-40 
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S1206F 
SD 
crizotinib 
225 
2.6 
- 
0 
E1154K 
SD 
crizotinib 
225 
5.7 
- 
-26.8 
G1202R 
PD 
crizotinib and 
LDK378 
(ceritinib) 
225 
1.8 
- 
13.2 
D1203N, 
C1156Y 
PD 
crizotinib and 
LDK378 
(ceritinib) 
225 
1.7 
- 
39.2 
* PFS (progression free survival); DOR (duration of response); CFB (change from baseline) 
 
2.6 Lorlatinib 
Preclinical Data 
Lorlatinib (PF-06463922) is a selective, ATP competitive small molecule inhibitor of ALK 
and c-ROS oncogene 1 (ROS1) receptor tyrosine kinases that was specifically designed to 
address mechanisms of resistance.  In preclinical studies, lorlatinib demonstrated potent and 
selective inhibitory activity against wild-type ALK, most known acquired crizotinib-resistant 
ALK mutations (Johnson et al, 2014; Zou et al, 2015; Toyokawa 2014). Lorlatinib was also 
capable of penetrating the blood-brain barrier (BBB) in preclinical animal models (Johnson 
et al, 2014; Zou et al, 2015).  
 
In vitro, lorlatinib potently inhibited catalytic activities of wild-type ALK and 15 different 
ALK mutant kinases in recombinant enzyme and cell-based assays (Ki or 50% inhibitive 
concentration [IC50] ranged from <0.07 nM to 113 nM) (Zou et al, 2015; Gainor et al, 2016).  
The 15 ALK mutants analyzed included crizotinib-resistant mutations 1151Tins, L1152R, 
C1156Y, L1196M, G1202R, S1206Y, E1210K, and G1269A; LDK378 (ceritinib)-resistant 
mutations F1174L, F1174C, G1202del, and D1203N;  as well as the alectinib-resistant 
I1171T/N/S mutations.  Among these mutations, 1151Tins and G1202R confer high levels of 
resistance to almost all of the second generation ALK inhibitors tested, including LDK378 
(ceritinib) and alectinib (Shaw & Engelman, 2013; Friboulet et al, 2014; Ou et al, 2014; 
Gainor et al, 2016).  In instances of LDK378 (ceritinib) resistance, it was reported that 5 of 
11 patients (46%) whose tumors developed resistance to therapy acquired ALK mutations of 
either G1202R or F1174L, and that C1156Y and L1152R ALK mutants conferred resistance 
to LDK378 (ceritinib) (Friboulet et al, 2014).  For alectinib resistance, in addition to 
G1202R, mutations at amino acid position I1171 have been reported to be the most common 
(Ou et al, 2015; Gainor et al, 2016).  
 
Lorlatinib also showed potent growth inhibitory activity and induced apoptosis in human 
H3122 NSCLC and Ba/F3 pro B cells engineered to express various ALK mutants (IC50 = 
2.4 nM to 80 nM).  Compared with crizotinib and the second generation ALK inhibitors, 
LDK378 (ceritinib), alectinib, and lorlatinib showed significantly improved inhibitory 
activity against wild type or mutant forms of ALK (Zou et al, 2015).  In H3122 human 
NSCLC cells harboring an endogenous EML4-ALK V1 (E13:A20) fusion proteins, lorlatinib 
was >10-fold more potent than crizotinib, LDK378 (ceritinib), and alectinib at inhibiting both 
the ALK kinase activity and cell growth.  In a panel of Ba/F3 cell lines engineered to express 
various mutant forms of ALK fusion, lorlatinib inhibited cell proliferation mediated by 
EML4-ALKF1174L and EML4-ALKS1206Y at IC50 values >4-fold more potent than that of 
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crizotinib, LDK378 (ceritinib) or alectinib, and it was >3-fold more potent than crizotinib, 
LDK378 (ceritinib) or alectinib against EML4-ALK C1156Y, EML4-ALK 1151Tins or 
EML4-ALK G1202R driven Ba/F3 cell growth (Zou et al, 2015). 
 
In vivo, lorlatinib demonstrated marked cytoreductive activity in mice bearing tumor 
xenografts that express EML4-ALK, EML4-ALK L1196M, EML4-ALK G1269A, 
EML4-ALK G1202R, EML4-ALK I1171T, or NPM-ALK at low nanomolar free plasma 
concentrations.  These effects were associated with significant decreases in cellular Ki67 
expression and increased cleaved-caspase3 levels in tumors.  In addition, lorlatinib achieved 
brain exposure of 20-30% of plasma levels in mice and rats.  In mice bearing orthotopic 
EML4-ALK or EML4-ALK L1196M positive brain tumor implants, lorlatinib caused tumor 
shrinkage and prolonged survival (Zou et al, 2015).  The overall anti-tumor efficacy of 
lorlatinib was dose dependent and strongly correlated with inhibition of ALK 
phosphorylation and downstream signal transduction.  
 
Lorlatinib Clinical Evidence 
The First in Patient (FIP) single-agent dose escalation and expansion study 
(Study B7461001) began on 23 January 2014.  This Phase 1/2 study is enrolling patients with 
advanced ALK-positive NSCLC and patients with advanced ROS1-positive NSCLC, with or 
without asymptomatic CNS (central nervous system) metastases.   
 
As of the data cutoff of 15 January 2016, lorlatinib has been administered to 54 patients in 
the Phase 1 part of this study across 7 QD doses of 10 mg, 25 mg, 50 mg, 75 mg, 100 mg, 
150 mg, and 200 mg and 3 twice a day (BID) doses of 35 mg BID, 75 mg BID, and 100 mg 
BID.   Of the 3 patients enrolled in the 200 mg QD cohort, 1 dose-limiting toxicity (DLT) 
occurred in a patient who failed to receive 16 of the planned 21 doses of lorlatinib due to 
Grade 1 and Grade 2 central nervous system adverse events (AEs).  A decision was made 
among the Sponsor and investigators to re-test lower doses to better understand and evaluate 
the CNS effects observed at the higher dose levels.  Lower doses of 50 mg QD, 75 mg QD, 
and 100 mg QD were evaluated and BID regimens tested were 35 mg BID, 75 mg BID, and 
100 mg BID. A food effect cohort was tested at 100 mg QD (planned as 6 patients). 
 
Additionally, based on the PK data observed, simulated patient exposure suggested that 
the100-mg QD dose was the lowest dose that would exceed the lorlatinib efficacious 
concentration (Ceff ) of 150 ng/mL during the majority of the dosing interval once steady 
state was reached.  The Ceff of 150 ng/mL was a plasma concentration predicted to result in 
>80% tumor growth inhibition of the ALK G1202R resistance mutation.  Further, lorlatinib 
demonstrated durable clinical activity at 100-mg QD dose, which indicated that this 
compound has anti-tumor activity both intra- and extracranially.  The 100-mg QD dose was 
chosen as the RP2D based on the entirety of the safety, efficacy, and clinical pharmacology 
data.   
 
In the phase 1 study, lorlatinib has demonstrated a confirmed ORR of 46% among ALK-
positive patients treated with two or more ALK inhibitors.  Median duration of response was 
11.7 months, and median PFS among the 26 ALK-positive patients treated with 2 or more 
ALK TKIs was 9.2 months.  In addition, lorlatinib demonstrated marked intracranial activity, 
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with durable responses noted in ALK-positive patients who had failed multiple ALK TKIs, 
including LDK378 (ceritinib) and alectinib (Shaw et al., 2017). 
 
Of note, early in the phase 1 study, lorlatinib was noted to be active in patients harboring 
G1202R-positive tumors who had failed prior LDK378 (ceritinib), alectinib, and brigatinib.  
To examine molecular correlates of response to lorlatinib in ALK-positive patients who had 
failed 2 or more ALK TKIs, Pfizer analyzed 12 patients who had undergone a biopsy on the 
last TKI received. Eight of the 12 samples were found to harbor known ALK resistance 
mutations. In the remaining 4 cases, no genetic mutation in ALK was detected. As shown in 
Figure 5A (below), tumor regression was observed in all patients with lung cancers 
harboring ALK resistance mutations, including 5 tumors with ALK G1202R or G1202del. In 
patients without detectable ALK resistance mutations, none demonstrated tumor regression. 
Consistent with this data, the duration of treatment with lorlatinib was longer in those 
patients with ALK resistance mutations compared to those without (mean 448 vs 42 days, 
respectively, p=0.027; Figure 5B).  
 
Figure 5A-B. Response to Lorlatinib and Correlation with ALK Resistance Mutations 
in Patients Treated with ≥2 ALK TKI.  (A) Best systemic response.  (B) Duration of 
treatment 
 
 
Resistance to lorlatinib 
In a brief report, Shaw et al (2016) described a patient with crizotinib resistance due to the 
ALK C1156Y mutation who subsequently responded to lorlatinib. When the tumor relapsed, 
sequencing of the resistant tumor revealed an ALK L1198F mutation in addition to the 
C1156Y mutation. The L1198F substitution confers resistance to lorlatinib through steric 
interference with drug binding. However, L1198F paradoxically enhances binding to 
crizotinib, negating the effect of C1156Y and resensitizing resistant cancers to crizotinib. The 
patient received crizotinib again, and she achieved a durable (~6 month) response.  
 
2.7 Summary of NRG-LU003 (17-FEB-2020) 
The NCI-NRG-ALK Protocol proposes to study ALK positive non-squamous NSCLC 
patients who develop progression on a second-generation ALK inhibitor, and to establish a 
treatment algorithm for these patients based on resistance mechanisms identified by tissue 
biopsies. The patients may have received the second-generation ALK inhibitor as first- or 
second-line therapy. Initially, patients will undergo tissue biopsy (if they do not have residual 
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tissue available from a biopsy obtained within the last 3 months) along with blood sampling 
for cfDNA analysis. The sensitivity of circulating-free (cf) DNA testing has not been 
established for routine clinical use in ALK positive non-squamous NSCLC. The 
implementation of cfDNA testing may be challenging given the multiple and heterogenous 
mechanisms of resistance to ALK inhibitors. Based on the results of tissue biopsy testing, 
patients will be assigned to a specific treatment group (see Table in Section 5.1). Treatments 
will be selected based on preclinical and in some cases, clinical data demonstrating activity 
of the treatment against the specific ALK mutation or resistance mechanism identified.  If no 
ALK-resistance mutations are identified, patients will be randomized to receive either a next-
generation ALK inhibitor they have not received or Pemetrexed based therapy with or 
without cisplatin or carboplatin. The response rate in the cohort receiving chemotherapy will 
be compared to the response rates of each of the second-generation ALK inhibitors among 
patients with no ALK-resistance mutations identified.  
 
Patients whose tissue is insufficient will need to have a repeat biopsy if feasible, as per their 
treating physician; otherwise, they will not be eligible for this trial. We have anticipated 
about 10% of patients may have insufficient tissue from a tissue biopsy for mutational 
testing, and have taken this into consideration when calculating sample size. cfDNA will be 
collected on all cases.  
 
After the first 200 patients are enrolled, we will analyze the concordance of cfDNA and 
tissue biopsy. If a high degree of concordance is found with confidence, we will amend the 
protocol and select patients based on cfDNA only. At that time, tumor biopsy will become 
optional, but recommend if possible. This will be decided with input from CTEP and the 
FDA. 
 
3. ELIGIBILITY AND INELIGIBILITY CRITERIA (20-MAY-2019) 
 
 
Note: Per NCI guidelines, exceptions to inclusion and exclusion criteria are not 
permitted.  For questions concerning eligibility, please contact the Biostatistical/Data 
Management Center (see protocol cover page).  
 
3.1       Patient Selection Guidelines (21-JUNE-2019) 
3.1.1    Submission of blood and tumor tissue is required for all patients. This requirement may 
change to blood only after the first 200 patients have been analyzed.  Investigators should 
check with their site Pathology department regarding release of biospecimens before 
approaching patients about participation in the trial. (See details of tissue and blood 
submissions in Section 10.) 
 
3.1.2 Use of prohibited therapies listed in Appendix XIII should be taken into consideration 
when screening and enrolling patients in NRG-LU003. Sites will report at step 1 
registration whether enrolling patients require the use of any CYP interacting agents, and 
any prohibited ALK inhibitors will be removed from assignment consideration for these 
patients 
Because the lists of these agents are constantly changing, it is important to regularly 
consult a frequently-updated medical reference.  As part of the enrollment/informed 
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consent procedures, the patient will be counseled on the risk of interactions with other 
agents, and what to do if new medications need to be prescribed or if the patient is 
considering a new over-the-counter medicine or herbal product. 
 
3.2 
Eligibility Criteria (17-FEB-2020) 
A patient cannot be considered eligible for this study unless ALL of the following 
conditions are met. 
 
Prior to Step 1 Registration 
3.2.1 Patients must have histologically or cytologically confirmed stage IV ALK-positive non-
squamous NSCLC (includes M1a, M1b, M1c stage disease, AJCC 8th edition). ALK 
rearrangement must have been demonstrated by an FDA approved assay (Vysis FISH or 
Ventana IHC) or by next generation sequencing (NGS).  
3.2.2 Patient must be willing and able to undergo a fresh biopsy, or if patient has had a biopsy 
after progression on current TKI within 3 months of study enrollment (and has continued 
TKI for clinical benefit per treating physician) this tissue may be used. Must have 
sufficient tissue. 
3.2.3 Age ≥ 18.  
3.2.4 Patient must have progressive disease as defined by RECIST 1.1 after one second 
generation ALK inhibitor, including LDK378 (ceritinib), alectinib, ensartinib, and 
brigatinib (may not have received more than one second-generation ALK inhibitor). 
Patient may have received prior crizotinib; however, the second generation ALK inhibitor 
received must be the last treatment given prior to study enrollment.   
o Prior lorlatinib (third-generation ALK inhibitor) is not allowed. 
3.2.5 Prior chemotherapy is not allowed except for one prior cycle received at the time of 
original diagnosis of metastatic NSCLC with no evidence of disease progression 
following the cycle.  NOTE:  prior adjuvant or neoadjuvant chemotherapy is allowed if 
last dose was received more than 12 months prior to enrollment. 
3.2.6 The patient or a legally authorized representative must provide study-specific informed 
consent prior to Step 1 Registration. 
 
Prior to Step 2 Registration 
3.2.7 Adequate hematologic function within 28 days prior to step 2 registration defined as 
follows: 
• 
ANC ≥ 1500cells/mm3 
• 
Platelets ≥ 100,000cells/mm3 
3.2.8 Adequate renal function within 28 days prior to step 2 registration defined as follows: 
• Estimated creatinine clearance > 60mL/min by the Cockcroft Gault formula below: 
 
  
3.2.9 Adequate hepatic function within 28 days prior to step 2 registration defined as follows: 
• Total Bilirubin ≤ 1.5 x ULN (except for patients with documented Gilbert’s 
syndrome). 
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• 
Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 2.5 x 
ULN; < 5 x ULN if liver metastases are present. 
3.2.10 Patients with asymptomatic treated or untreated brain metastases are eligible. Treated 
brain metastases are eligible as long as patients have measurable disease outside the brain 
according to RECIST 1.1. Patients must be on a stable or decreasing dose of steroids for 
at least 7 days prior to step 2 registration. Anticonvulsants are allowed as long as the 
patient is neurologically stable and not deteriorating.   
3.2.11 Patients enrolled with asymptomatic brain mets must have at least one measurable target 
extracranial lesion according to RECIST 1.1.  
3.2.12 ECOG performance status 0-2 
3.2.13 Acute effects of any prior therapy resolved to baseline severity or to CTCAE Grade ≤1 
(except for alopecia, hearing loss). 
3.2.14 Not taking any medications identified in Section 5.4.2 that may interact with selected 
study medication based on stratification in Section 15.1 
3.2.15 Patients must be able to take oral medications (i.e. swallow whole tablets/capsules) 
3.2.16  All females of childbearing potential must have a blood test or urine study within 14 days 
prior to Step 2 Registration to rule out pregnancy. Refer to section 9 for requirements on 
the length of time patients should maintain adequate contraception for after the last dose 
of each medication. A female of childbearing potential is any woman, regardless of 
sexual orientation or whether they have undergone tubal ligation, who meets the 
following criteria:  
• Has not undergone a hysterectomy or bilateral oophorectomy; or  
• Has not been naturally postmenopausal for at least 24 consecutive months (i.e., has 
had menses at any time in the preceding 24 consecutive months) 
• Women must not be pregnant or breast-feeding due to potential harm to the fetus or 
infant from ALK inhibitors and the unknown risk. Women of childbearing potential 
and sexually active males must agree to use an accepted and effective method of 
contraception or to abstain from sexual intercourse for the duration of their 
participation in the study. 
 
3.3 
Ineligibility Criteria (20-JAN-2022) 
Patients with any of the following conditions are NOT eligible for this study. 
 
 
3.3.1   Major surgery within 2 weeks of study entry. Minor surgical procedures (eg, port insertion, 
pleurex catheter placement) are allowed and all wounds must not show signs of infection 
or draining. 
3.3.2 Palliative bone RT (<10 fractions) must have been completed at least 48 hours prior to 
study entry. Stereotactic or small field brain irradiation must have completed at least 1 
week prior to study entry.  Whole brain RT or other palliative RT must have been 
completed at least 2 weeks prior to study entry.   
3.3.3 Prior dose of second-generation ALK inhibitor (LDK378 (ceritinib), alectinib, ensartinib) 
within 5 days prior to step 2 registration. Prior dose of brigatinib within 7 days prior to 
step 2 registration.  
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3.3.4 History of interstitial lung disease or interstitial fibrosis, including a history of pneumonitis, 
obliterative bronchiolitis, pulmonary fibrosis.  Patients with a history of prior radiation 
pneumonitis are not excluded.  
3.3.5 Active inflammatory gastrointestinal disease (such as Crohns, ulcerative colitis), chronic 
diarrhea, symptomatic diverticular disease, or any gastrointestinal disease that would affect 
the absorption of oral medications or increase the risk of toxicity.  
3.3.6 Clinically significant cardiovascular abnormalities, as determined by the 
treating/registering physician, such as uncontrolled hypertension, congestive heart failure 
NYHA classification of 3, unstable angina or poorly controlled arrhythmia, or myocardial 
infarction within 6 months.  
3.3.7 Active and clinically significant bacterial, fungal, or viral infection  
3.3.8 Patients with active or chronic pancreatitis based on lipase elevation, symptoms, and 
radiographic findings 
3.3.9 Other concomitant serious illness or organ system dysfunction that in the opinion of the 
investigator would either compromise patient safety or interfere with the evaluation of the 
safety of the study drug.  
3.3.10 Patients must not plan to receive any other investigational agents during the course of 
therapy.  
 
3.3.11 Patients with active malignancy other than ALK-positive non-squamous NSCLC within 
the last 2 years are excluded (note: adequately treated basal cell or squamous cell skin 
cancer, in situ cervical cancer, papillary thyroid cancer treated with curative intent, 
adequately treated Stage I or II cancer from which the patient is currently in complete 
remission, or any other cancer from which the patient has been disease free for 2 years are 
eligible). 
3.3.12 No chemotherapy and/or immunotherapy allowed after step 1 registration. 
 
4. REQUIREMENTS FOR STUDY ENTRY, TREATMENT, AND FOLLOW-UP 
 
PRE-TREATMENT ASSESSMENTS (20-JAN-2022) 
Assessments 
Prior to Step 1 
Registration 
  
Prior to Step 2 Registration 
(up to 28 calendar days) 
Medical history/concurrent meds 
 
 X 
Physical Exam, ECOG Performance 
Status and vital signs (to include 
heart rate and blood pressure) 
 
 X 
Toxicity Assessment 
 
X 
Brain MRI* (see Section 8.3 for 
instructions for collection of images) 
 
X 
Chest/abdomen (include pelvis if 
clinically indicated) CT scan 
contrast enhanced (see Section 8.3 
instructions for collection of images) 
 
X 
EKG 
 
 X 
Complete Metabolic Panel, 
(including creatinine, bilirubin, 
 
 X 
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ALT, AST, calcium,  glucose, 
magnesium, phosphorous  
CBC with Differential (to include 
ANC, platelets) 
 
 X 
Serum or Urine Pregnancy Test for 
women of childbearing potential 
 
X (within 14 days) 
Tumor biopsy**  
X  
 
MANDATORY: Peripheral Blood 
(two 8.5mL Roche cell-free DNA 
collection tubes) see section 10 and 
Appendix IV for collection details ** 
X 
 
Tissue sample (for patients who 
consent to biobanking) 
X (see section 10) 
 
  
*If contraindicated, Head CT with contrast acceptable 
** Biopsy and blood taken within 3 months.  If patient has a biopsy after progression on current 
TKI within 3 months of study enrollment (and continued TKI for clinical benefit per treating 
physician) this tissue may be used. Must have sufficient tissue.  Note that tissue and blood 
samples must not be sent to Foundation Medicine, Inc. until after the patient is registered, so that 
unique NRG-LU003 patient identifiers may be sent with the samples.  It is important to label 
these samples appropriately; please refer to the specimen Requisition Forms for detailed 
instructions.  The Forms are posted on the Case Report Forms tab of the NRG-LU003 page of 
the CTSU website.  
 
 
 
ASSESSMENTS DURING TREATMENT (20-JAN-2022) 
Assessments 
Day 1 of Each Cycle (+/- 3 
days) 
Day 1 of Every Odd Cycle 
Starting with Cycle 3 (+/- 3 
days) 
Medical history/Concurrent 
meds  
X 
 
Physical Exam and vital 
signs/ECOG Performance 
Status 
X 
 
Toxicity Assessment 
X 
 
FOR PATIENTS WITH 
BRAIN METS: 
Contrast enhanced Brain MRI* 
(see Section 8.3 for instructions 
for collection of images) 
 
X 
(Every 2 cycles for the first 6 
months, then every 3 cycles 
thereafter)  
 
FOR PATIENTS WITHOUT  
BRAIN METS: 
Contrast enhanced Brain MRI* 
(see Section 8.3 for instructions 
 
As clinically indicated 
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for collection of images) 
Chest/abdomen (include pelvis 
if clinically indicated) CT scans 
with RECIST (see Section 13.0, 
and see Section 8.3 for 
instructions for collection of 
images) 
 
X 
(Every 2 cycles for the first 6 
months with first repeat scan 
prior to Cycle 3, Day 1, then 
every 3 cycles thereafter) 
Complete Metabolic Panel, 
(including creatinine, bilirubin, 
ALT, AST, glucose**, calcium) 
magnesium, phosphorous 
X 
 
Amylase, lipase 
X [for patients receiving 
brigatinib, LDK378 
(ceritinib) or lorlatinib] 
 
Lipid Panel (fasting) 
X (for patients receiving 
lorlatinib only day 1 of 
cycles 1-3, and every 3 
cycles thereafter) 
 
CBC with Differential 
X 
 
CPK 
X (For patients receiving 
alectinib and brigatinib) 
 
EKG 
 
X (for patients receiving 
ensartinib, LDK378 
(ceritinib), crizotinib and 
lorlatinib; as clinically 
indicated for alectinib and 
brigatinib) 
Serum or Urine Pregnancy Test 
for women of childbearing 
potential 
X 
(CYCLE 1 ONLY) 
 
MANDATORY: Peripheral 
Blood (two 8.5mL Roche cell-
free DNA collection tubes)  See 
Section 10 and Appendix IV for 
collection details 
 
X (at progression) 
Tumor biopsy (if patient 
consents, see Section 10) 
 
X (at progression)*** 
Optional plasma collection (for 
patients who consent) 
 
X (at progression) 
Optional whole blood collection 
(for patients who consent) 
X (Cycle 3, Day 1) 
 
 
*If contraindicated Head CT with contrast acceptable 
**For patients receiving LDK378 (ceritinib) or brigatinib, prior to cycle 1, evaluate fasting 
glucose, then periodically thereafter as clinically indicated. Refer to section 6 for hyperglycemia 
mangagement guidelines. 
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website. 
 
5.2 
Agent Administration (20-JAN-2022) 
Protocol treatment must begin within 2 weeks after Step 2 Registration. 
All patients will receive their assigned ALK inhibitor at the standard dose. All ALK 
inhibitors are orally administered. Starting doses and dose reductions are summarized in 
Section 6.  One treatment cycle will consist of 21 consecutive days. Treatment will 
continue until disease progression or unacceptable toxicity.  
 
5.2.1 ALK Inhibitors 
If a dose is missed or vomiting occurs after dosing, do not administer an additional dose 
and take the next dose at the schedule time.  
 
A dose is considered missed after 6 hours for a drug that is dosed twice a day, or after 12 
hours for a drug that is dosed once a day. 
 
 
Alectinib 
Administration:  600 mg orally twice daily with food at similar times each day (i.e. 
breakfast and dinner); administer until disease progression or unacceptable toxicity. 
 
Do not open or dissolve capsule contents. 
 
 
LDK378 (ceritinib) 
Administration:  450 mg orally once a day with food; administer until disease progression 
or unacceptable toxicity. 
 
If a dose is missed or vomiting occurs after dosing, do not administer an additional dose 
and continue with the next scheduled dose of LDK378 (ceritinib). 
 
 
Brigatinib 
Administration:  90 mg orally once a day for the first 7 days; if tolerated, with no 
respiratory symptoms, increase the dose to 180 mg once daily; administer until disease 
progression or unacceptable toxicity. 
 
If brigatinib is delayed for 14 days or longer for reasons other than toxicity, resume 
treatment at 90 mg once daily for 7 days before increasing to the previously tolerated 
dose. 
 
Brigatinib may be taken with or without food; do not crush or chew tablets, swallow 
whole. 
 
 
Ensartinib 
Administration:  225 mg orally once a day with or without food; administer until disease 
progression or unacceptable toxicity. 
 
 
Lorlatinib 
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Administration:  100 mg orally once a day with or without food or beverage; administer 
until disease progression or unacceptable toxicity. 
 
 
Crizotinib 
Administration:  250 mg orally twice daily; administer until disease progression or 
unacceptable toxicity. 
 
Crizotinib may be taken with or without food. Swallow capsules whole. Do not open or 
dissolve capsule contents. If vomiting occurs after dosing, do not administer an additional 
dose and continue with the next scheduled dose of crizotinib. 
 
5.2.2 Pemetrexed based chemotherapy with cisplatin or carboplatin 
Administration: Pemetrexed 500 mg/m2 administered by IV over 10 minutes on Day 1 of 
a 21 day cycle with cisplatin or carboplatin. Doses can be rounded per institution policy. 
NOTE: Pemetrexed administration requires vitamin supplementation initiated one week 
prior to first dose of pemetrexed with the following:  
• Folic acid 1000 mcg PO once daily continuously for duration of chemotherapy 
and should continue for 21 days after last dose of pemetrexed. 
• Administer vitamin B, B12, 1000 mcg IM intramuscularly, 1 week prior to the 
first dose of pemetrexed and every 9 weeks. 
• Administer dexamethasone per institutional guidelines  
 
Cisplatin  
Administration: 75 mg/m2 IV once every 3 weeks (on Day 1 of a 21 day cycle with 
pemetrexed). Prepare and administer per institution policy. Doses can be rounded per 
institution policy. 
 
Carboplatin 
Administration: AUC5 once every 3 weeks (on Day 1 of a 21 day cycle with 
pemetrexed). Prepare and administer per institution policy. Doses can be rounded per 
institution policy. Carboplatin dose will be calculated using the Calvert formula. For the 
purposes of this protocol, the glomerular filtration rate is considered equivalent to the 
creatinine clearance calculated by Cockcroft-Gault and is capped at 125 mL/min. 
 
Duration of Treatment: Patients will initially receive 4-6 cycles of pemetrexed with 
cisplatin or carboplatin.  
 
5.2.3 Maintenance Pemetrexed 
Maintenance treatment of pemetrexed (as a single agent) may continue until progression 
or significant toxicity as determined by clinical findings through physical examination, 
imaging, etc. 
 
5.3 
Integrated Assay/Biomarker (20-May-2019) 
 
FoundationOne®CDx utilizes a hybrid-capture, next-generation sequencing testing 
method on solid tissue biopsies. 
 
FoundationOne®Liquid  utilizes a hybrid-capture, next-generation sequencing testing 
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method on liquid (blood) biopsies. 
 
 
For further information related to technical specifications and sample processing, please 
refer to Appendices I-IV. 
 
 
The first 200 patients enrolled into the trial will be randomized, described in Section 
15.1, based upon NGS from baseline FoundationOne®CDx testing. Concomitant 
concordance testing will occur with the FoundationOne®Liquid  assay to determine 
whether subsequent patients enrolled into the trial can be randomized based upon 
baseline blood-based genomic testing as opposed to tissue-based testing. 
 
5.4 
General Concomitant Medication and Supportive Care Guidelines (20-JAN-2022) 
5.4.1 Permitted Supportive/Ancillary Care and Concomitant Medications 
 
All supportive therapy for optimal medical care will be given during the study period at 
the discretion of the attending physician(s) within the parameters of the protocol and 
documented on each site’s source documents as concomitant medication.  
▪ Anticonvulsants 
▪ Antiemetics may be administered according to standard practice.  
▪ Anticoagulants 
▪ Antidiarrheals 
▪ Analgesics 
▪ Hematopoietic Growth Factors 
▪ Highly active antiretroviral therapy (HAART) 
▪ Supported therapies for toxicities associated with pemetrexed, according to the FDA 
approved label or institutional practice. 
 
5.4.2 Prohibited Concomitant Therapies (by Agent)  
▪ Alectinib 
▪ None 
▪ Brigatinib 
▪ 
Avoid concomitant use of brigatinib with strong CYP3A inhibitors or inducers. 
▪  
▪ As brigatinib inhibits P-gp, BCRP, OCT1, MATE1, MATE2k, and induces 
CYP3A and 2C, use caution with administered agents that are P-gp, BCRP, 
OCT1, MATE1, MATE2K, CYP3A, or 2C substrates. 
▪ LDK378 (ceritinib) 
▪ Avoid concurrent use of LDK378 (ceritinib) with strong CYP3A4/5 inhibitors or 
inducers; avoid concurrent use of certitinib with CYP3A4/5  or CYP2C9 
substrates with narrow therapeutic indices. 
▪ Co-administration of medications with known potential for QTc prolongation should 
be avoided. 
▪ Crizotinib 
▪ Avoid concurrent use of crizotinib with strong CYP3A inhibitors or inducers. 
Avoid concurrent use of crizotinib with CYP3A4/5  substrates with narrow 
therapeutic indices. 
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▪ Ensartinib 
To be used with caution: 
▪ Drugs that are CYP3A4/5   substrates with narrow therapeutic indices. 
▪ Drugs that are strong CYP3A4/5   inhibitors. 
▪ Drugs that are strong CYP3A4/5   inducers 
▪ Concomitant treatment with medications with a known risk for Torsades de 
Pointes should be used with caution. 
▪ As ensartinib inhibits CYP2C9, drugs metabolized by CYP2C9 with narrow 
therapeutic indices should be used with caution. 
▪ Lorlatinib 
▪ Strong CYP3A inducers are contraindicated. 
▪ Avoid concomitant use with moderate CYP3Ainducers. 
▪ Avoid concomitant use with strong CYP3A inhibitors. 
▪ Avoid concomitant use of lorlatinib with CYP3A substrates with narrow 
therapeutic indices. 
▪ Avoid concomitant use of lorlatinib with P-gp substrates with narrow therapeutic 
indices. 
▪ Pemetrexed with cisplatin or carboplatin 
▪ Ibuprofen increases exposure (AUC) of pemetrexed. Avoid administration of 
ibuprofen for 2 days before, the day of and 2 days following administration of 
pemetrexed. Monitor patients more frequently for myelosuppression, renal, and 
gastrointestinal toxicity, if concomitant administration of ibuprofen cannot be 
avoided. 
 
Because there is a potential for interaction with other concomitantly administered drugs, 
the case report form must capture the concurrent use of all other drugs, over-the-counter 
medications, or alternative therapies.  The Principal Investigator should be alerted if the 
patient is taking any agent known to affect or with the potential for drug interactions.  
The study team should check a frequently-updated medical reference for a list of drugs to 
avoid or minimize use of.  Appendix XIV (Patient Drug Information Handout and Wallet 
Card for Ensartinib) should be provided to patients assigned to ensartinib.  Appendix XV 
(Patient Clinical Trial Wallet Card) should be provided to all other patients.  
 
5.4.3 Participation in Other Trials  
 
Participation in other clinical trials of anti-neoplastic therapy is not allowed. 
 
5.5 
Duration of Therapy 
In the absence of treatment delays due to adverse event(s), treatment may continue as 
specified in the above treatment modality sections or until one of the following criteria 
applies: 
▪ 
Disease progression, 
▪ 
Intercurrent illness that prevents further administration of treatment, 
▪ 
Unacceptable adverse event(s), as described in Section 6 
▪ 
Patient decides to withdraw consent for participation in the study, or 
▪ 
General or specific changes in the patient's condition render the patient unacceptable 
for further treatment in the judgment of the investigator. 
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Progression is determined based on RECIST 1.1.  Patients will be allowed to continue on 
study treatment beyond RECIST defined PD if the treating investigator believes the 
patient is deriving clinical benefit.  Response is determined by RECIST 1.1. 
 
6. TREATMENT MODIFICATIONS/MANAGEMENT 
 
For all drugs, permanently discontinue if treatment is held for greater than 21 days 
with or without resolution of toxicity. Only up to two dose reductions are allowed and dose 
re-escalation is not allowed.  
 
ALK inhibitor 
Starting dose 
First dose 
reduction 
Second dose 
reduction 
Alectinib 
600 mg PO twice 
daily 
450 mg PO twice 
daily 
300 mg PO twice 
daily 
LDK378 (ceritinib) 
450 mg PO once 
daily 
300 mg PO once 
daily 
150 mg PO once 
daily 
Brigatinib 
90 mg PO once 
daily x 1 week 
60 mg once daily  
Permanently 
discontinue  
180 mg PO once 
daily 
120mg once daily 
90 mg PO once daily  
Ensartinib 
225 mg PO once 
daily 
200 mg PO once 
daily 
150mg PO once daily 
Lorlatinib 
100 mg PO once 
daily 
75 mg PO once 
daily 
50 mg PO once daily 
Crizotinib 
250 mg PO twice 
daily 
200 mg PO twice 
daily 
250 mg PO once 
daily 
Pemetrexed 
500 mg/m2 IV 
once every 3 
weeks 
375 mg/m2 IV 
once every 3 
weeks.. 
250 mg/m2 IV once 
every 3 weeks..  
Cisplatin 
75 mg/m2 IV once 
every 3 weeks 
60 mg/m2 IV once 
every 3 weeks 
48 mg/m2 IV once 
every 3 weeks 
Carboplatin 
AUC5 once every 
3 weeks 
AUC=4 once every 
3 weeks 
AUC=3.2 once every 
3 weeks 
 
6.1 
Dose Modifications and Toxicity Management for Alectinib 
Hepatic Toxicity 
Grade  
Dose Modification 
Grade 3 AST or ALT elevation of greater 
than 5 times upper limit of normal 
(ULN) with total bilirubin less than or 
equal to 2 times ULN 
Temporarily withhold until recovery to 
baseline or to less than or equal to 3 times 
ULN, then dose will be reduced by one dose 
level, per table in section 6. 
Grade 2 ALT or AST elevation greater 
than 3 times ULN with total bilirubin 
Permanently discontinue alectinib. 
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elevation greater than 2 times ULN in 
the absence of cholestasis or 
hemolysis 
Grade 3 Total bilirubin elevation of 
greater than 3 times ULN 
Temporarily withhold until recovery to 
baseline or to less than or equal to 1.5 times 
ULN, then dose will be reduced by one 
level as per section 6. 
Interstitial Lung Disease/Pneumonitis 
Grade  
Dose Modification 
Any grade treatment-related interstitial 
lung disease (ILD)/pneumonitis 
Permanently discontinue alectinib. 
Renal Toxicity 
Grade  
Dose Modification 
Grade 3 renal impairment 
Temporarily withhold until serum creatinine 
recovers to less than or equal to 1.5 times 
ULN, then dose will be reduced by one 
level. 
Grade 4 renal impairment 
Permanently discontinue alectinib. 
Cardiac Toxicity 
Grade  
Dose Modification 
Grade 2 or Grade 3  
Symptomatic sinus bradycardia 
Withhold alectinib until recovery to 
asymptomatic bradycardia or to a heart rate 
of 60 bpm or above. If contributing 
concomitant medication is identified and 
discontinued, or its dose is adjusted, resume 
alectinib at previous dose upon recovery to 
asymptomatic bradycardia or to a heart rate 
of 60 bpm or above. If no contributing 
concomitant medication is identified, or if 
contributing concomitant medications are 
not discontinued or dose modified, resume 
alectinib by reducing one dose level (see 
section 6) upon recovery to asymptomatic 
bradycardia or to a heart rate of 60 bpm or 
above. 
Grade 4 Sinus bradycardia (life-
threatening consequences, urgent 
intervention indicated) 
Permanently discontinue alectinib if no 
contributing concomitant medication is 
identified. If contributing concomitant 
medication is identified and discontinued, or 
its dose is adjusted, resume alectinib by 
reducing one dose level (see section 6) upon 
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recovery to asymptomatic bradycardia or to 
a heart rate of 60 bpm or above, with 
frequent monitoring as clinically indicated. 
Permanently discontinue alectinib in case of 
recurrence. 
Blood Creatinine Phosphokinase (CPK) 
Grade  
Dose Modification 
Grade 3 CPK elevation greater than 5 
times ULN 
Temporarily withhold until recovery to 
baseline or to less than or equal to 2.5 times 
ULN, then resume at same dose. 
Grade 4 CPK elevation greater than 10 
times ULN or second occurrence of 
CPK elevation of greater than 5 times 
ULN 
Temporarily withhold until recovery to 
baseline or to less than or equal to 2.5 times 
ULN, then reduce by one dose level per 
section 6. 
 
6.2 Dose Modifications and Toxicity Management for Brigatinib 
Avoid concomitant use of strong CYP3A inhibitors during treatment with brigatinib. If 
concomitant use of a strong CYP3A inhibitor cannot be avoided, reduce the brigatinib once 
daily dose by approximately 50% (i.e., from 180 mg to 90 mg, or from 90 mg to 60 mg). 
After discontinuation of a strong CYP3A inhibitor, resume the brigatinib dose that was 
tolerated prior to initiating the strong CYP3A inhibitor. 
 
Interstitial Lung Disease (ILD)/Pneumonitis 
Grade  
Dose Modification 
Grade 1 
• If new pulmonary symptoms occur during the first 7 
days of treatment, withhold brigatinib until recovery 
to baseline, then resume at same dose and do not 
escalate to 180 mg if ILD/pneumonitis is suspected.  
• If new pulmonary symptoms occur after the first 7 
days of treatment, withhold ALUNBRIG until 
recovery to baseline, then resume at same dose.  
• If ILD/pneumonitis recurs, permanently discontinue 
brigatinb 
Grade 2 
• If new pulmonary symptoms occur during the first 7 
days of treatment, withhold brigatinib until recovery 
to baseline. Resume at next lower dose (per section 
5.1.1) and do not dose escalate if ILD/pneumonitis is 
suspected.  
• If new pulmonary symptoms occur after the first 7 
days of treatment, withhold brigatinib until recovery 
to baseline. If ILD/pneumonitis is suspected, resume 
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at next lower dose (section 6); otherwise, resume at 
same dose.  
• If ILD/pneumonitis recurs, permanently discontinue 
Grade 3 or 4 
Permanently discontinue brigatinib for 
ILD/pneumonitis 
Hypertension 
Grade  
Dose Modification 
Grade 3  
• Withhold brigantinib until hypertension has 
recovered to Grade 1 or less (SBP less than 140 
mmHg and DBP less than 90 mmHg), then resume 
brigatinib at next lower dose (section 6).  
• Recurrence: withhold brigatinib until recovery to 
Grade 1 or less, and resume at next lower dose 
(section 6) or permanently discontinue treatment. 
Grade 4  
• Withhold brigatinib until recovery to Grade 1 or less, 
and resume at next lower dose (section 6) or 
permanently discontinue treatment.  
• Recurrence: permanently discontinue brigatinib for 
recurrence of Grade 4 hypertension. 
Bradycardia (HR less than 60 bpm) 
Grade  
Dose Modification 
Grade 2 or Grade 3 
Symptomatic sinus 
bradycardia 
• Withhold brigatinib until recovery to asymptomatic 
bradycardia or to a resting heart rate of 60 bpm or 
above.  
• If a concomitant medication known to cause 
bradycardia is identified and discontinued or dose-
adjusted, resume brigatinib at same dose upon 
recovery to asymptomatic bradycardia or to resting 
heart rate of 60 bpm or above.  
• If no concomitant medication known to cause 
bradycardia is identified, or if contributing 
concomitant medications are not discontinued or dose-
adjusted, resume brigatinib at next lower dose (see 
section 6) upon recovery to asymptomatic bradycardia 
or to resting heart rate of 60 bpm or above. 
Grade 4  
• Permanently discontinue brigatinib if no contributing 
concomitant medication is identified.  
• If contributing concomitant medication is identified 
and discontinued or dose-adjusted, resume brigatinib 
at next lower dose (see section 6) upon recovery to 
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asymptomatic bradycardia or to a resting heart rate of 
60 bpm or above, with frequent monitoring as 
clinically indicated. 
 • Recurrence: permanently discontinue brigatinib 
Visual Disturbances 
Grade  
Dose Modification 
Grade 2 or 3 visual 
disturbance 
Withhold  brigatinib until recovery to Grade 1 or 
baseline, then resume at the next lower dose (see 
section 6) 
Grade 4 visual disturbance 
Permanently discontinue brigatinib 
Creatinine Phosphokinase (CPK) Elevation 
Grade  
Dose Modification 
Grade 3  
Withhold brigatinib until recovery to Grade 1 or less 
(less than or equal to 2.5 x ULN) or to baseline, then 
resume brigatinib at same dose 
Grade 4 or recurrence of 
Grade 3 elevation 
Withhold brigatinib until recovery to Grade 1 or less 
(less than or equal to 2.5 × ULN) or to baseline, then 
resume brigatinib at next lower dose (see section 6) 
Lipase or Amylase Elevation 
Grade  
Dose Modification 
Grade 3  
Withhold brigatinib until recovery to Grade 1 or less 
(less than or equal to 1.5 × ULN) or to baseline, then 
resume brigatinib at same dose. 
Grade 4 or recurrence of 
Grade 3  
Withhold brigatinib until recovery to Grade 1 or less 
(less than or equal to 1.5 × ULN) or to baseline, then 
resume brigatinib at next lower dose (see section 6) 
Hyperglycemia 
Grade  
Dose Modification 
Grade 3 or greater 
If adequate hyperglycemic control cannot be achieved 
with optimal medical management, withhold 
brigatinib until adequate hyperglycemic control is 
achieved and consider reduction to the next dose (see 
section 6) or permanently discontinue brigatinib. 
Other Toxicity related to Brigatinib 
Grade  
Dose Modification 
Grade 3 
• Withhold brigatinib until recovery to baseline, then 
resume at same dose.  
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• Recurrence: withhold brigatinib until recovery to 
baseline, then resume at next lower dose or 
discontinue brigatinib (see section 6). 
Grade 4 
• First occurrence: either withhold brigatinib until 
recovery to baseline and resume at next lower dose 
(see section 6) or permanently discontinue.  
• Permanently discontinue brigatinib for recurrence. 
 
6.3 Dose Modifications and Toxicity Management for LDK378 (ceritinib) 
Gastrointestinal Adverse Reaction 
Grade 
Dose Modification 
Grade 2 Lipase or amylase increase 
Withhold and monitor serum lipase and 
amylase. Resume LDK378 (ceritinib) with a 
150mg dose reduction after recover to less 
than 1.5 times ULN. 
Grade 3 or greater, severe or intolerable 
nausea, vomiting or diarrhea despite 
optimal antiemetic or antidiarrheal 
therapy 
Withhold until improved, then resume 
LDK378 (ceritinib) with a 150 mg dose 
reduction. 
Hyperglycemia 
Grade 
Dose Modification 
Grade 3 despite optimal 
antihyperglycemic therapy 
Withhold until hyperglycemia is 
adequately controlled, then resume 
LDK378 (ceritinib) with a 150 mg dose 
reduction. If adequate hyperglycemic 
control cannot be achieved with optimal 
medical management, discontinue 
LDK378 (ceritinib).  
Pneumonitis  
Grade 
Dose Modification 
Any Grade treatment-related 
ILD/pneumonitis 
Permanently discontinue LDK378 
(ceritinib) 
Cardiac Arrhythmias 
Grade 
Dose Modification 
Grade 3 QT corrected interval prolonged 
QTc interval > 500 ms  
Withhold until QTc interval is less than 
481 msec or recovery to baseline if 
baseline QTc is greater than or equal to 
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481 msec, then resume LDK378 
(ceritinib) with a 150 mg dose reduction 
Grade 4 QTc QT corrected interval 
prolonged 
Permanently discontinue LDK378 
(ceritinib). 
Grade 2 Symptomatic bradycardia  
Withhold until recovery to asymptomatic 
bradycardia or to a heart rate of 60 bpm or 
above, evaluate concomitant medications 
known to cause bradycardia, and resume 
LDK378 (ceritinib) with a 150mg dose 
reduction, with frequent monitoring. 
Grade 3 Clinically significant 
bradycardia requiring intervention or 
Grade 4 life-threatening bradycardia in 
patients taking a concomitant medication 
also known to cause bradycardia or a 
medication known to cause hypotension 
Withhold until recovery to asymptomatic 
bradycardia or to a heart rate of 60 bpm or 
above. If the concomitant medication can 
be adjusted or discontinued, resume 
certinib with a 150 mg dose reduction, 
with frequent monitoring. 
Grade 4 Life-threatening bradycardia in 
patients who are not taking a concomitant 
medication also known to cause 
bradycardia or known to cause 
hypotension 
Permanently discontinue LDK378 
(ceritinib). 
Hepatotoxicity 
Grade 
Dose Modification 
Grade 3 ALT or AST elevation greater 
than 5 times ULN with total bilirubin 
elevation less than or equal to 2 times 
ULN 
Withhold until recovery to baseline or less 
than or equal to 3 times ULN, then resume 
LDK378 (ceritinib) with a 150 mg dose 
reduction. 
Grade 2 ALT or AST elevation greater 
than 3 times ULN with total bilirubin 
elevation greater than 2 times ULN in the 
absence of cholestasis or hemolysis 
Permanently discontinue LDK378 
(ceritinib). 
 
6.3.1 LDK378 (ceritinib) Dose Modification for Strong CYP3A Inhibitors  
Avoid concurrent use of strong CYP3A inhibitors during treatment with LDK378 
(ceritinib). If concomitant use of a strong CYP3A inhibitor is unavoidable, reduce the 
LDK378 (ceritinib) dose by one dose level. After discontinuation of a strong CYP3A 
inhibitor, resume the LDK378 (ceritinib) dose that was taken prior to initiating the strong 
CYP3A inhibitor.  
 
6.4 Dose Modifications and Toxicity Management for Crizotinib 
 
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* Except lymphopenia (unless associated with clinical events, e.g., opportunistic infections). 
 
Hematologic Toxicities* 
Grade 
Dose Modification 
Grade 3 
Withhold until recovery to Grade 2 or less, then 
resume at the same dose schedule 
Grade 4 
Withhold until recovery to Grade 2 or less, then 
resume at next lower dose 
Hepatotoxicity 
Grade 
Dose Modification 
Grade 3 Alanine 
aminotransferase (ALT) or 
aspartate aminotransferase 
(AST) elevation greater than 5 
times upper limit of normal 
(ULN) with total bilirubin less 
than or equal to 1.5 times ULN 
Withhold until recovery to baseline or less than or 
equal to 3 times ULN, then resume at reduced dose. 
Grade 2 ALT or AST elevation 
greater than 3 times ULN with 
concurrent total bilirubin 
elevation greater than 1.5 times 
ULN (in the absence of 
cholestasis or hemolysis) 
Permanently discontinue. 
ILD/Pneumonitis 
Grade 
Dose Modification 
Any grade drug-related 
interstitial lung 
disease/pneumonitis 
Permanently discontinue. 
Cardiac Toxcitity 
Grade 
Dose Modification 
Grade 3 QT corrected interval 
prolonged 
Withhold until recovery to baseline or to a QTc less 
than 481 ms, then resume at reduced dose. 
Grade 4  QT corrected interval 
prolonged 
Permanently discontinue. 
Grade 2 or Grade 3 
Bradycardia* (symptomatic, may 
be severe and medically 
Withhold until recovery to asymptomatic bradycardia 
or to a heart rate of 60 bpm or above. 
 
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*Heart rate less than 60 beats per minute (bpm). 
†Permanently discontinue for recurrence. 
 
6.5 Dose Modifications and Toxicity Management for Ensartinib 
 
Drug-related Hematologic Toxicities 
Grade  
Dose Modification* 
Grade 3 ANC decrease 
Withhold ensartinib until recovery to Grade ≤ 2, then 
resume at the same dose level. 
Grade 4 ANC decrease 
Withhold ensartinib until recovery to < Grade 2, then 
resume at a one dose level reduction. 
Grade 3 Platelet count decrease 
Withhold ensartinib until recovery to ≤ Grade 2, then 
resume at the same dose level. 
Grade 4 Platelet count decrease 
Withhold ensartinib until recovery to ≤ Grade 2, then 
resume at a one dose level reduction. 
Drug-related Non-Hematologic Toxicities 
significant, medical intervention 
indicated) 
Evaluate concomitant medications known to cause 
bradycardia, as well as antihypertensive medications. 
 
If contributing concomitant medication is identified 
and discontinued, or its dose is adjusted, resume at 
previous dose upon recovery to asymptomatic 
bradycardia or to a heart rate of 60 bpm or above. 
 
If no contributing concomitant medication is 
identified, or if contributing concomitant medications 
are not discontinued or dose modified, resume at 
reduced dose upon recovery to asymptomatic 
bradycardia or to a heart rate of 60 bpm or above. 
Grade 4 Bradycardia*,† (life-
threatening consequences, urgent 
intervention indicated) 
Permanently discontinue if no contributing 
concomitant medication is identified. 
 
If contributing concomitant medication is identified 
and discontinued, or its dose is adjusted, resume at 
250 mg once daily upon recovery to asymptomatic 
bradycardia or to a heart rate of 60 bpm or above, with 
frequent monitoring. 
Visual Toxicity 
Grade 
Dose Modification 
Visual Loss (Grade 4 Ocular 
Disorder) 
Discontinue during evaluation of severe vision loss. 
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Transaminase Elevations 
Grade  
Dose Modification* 
Grade 3 ALT or AST elevation 
> 5 times ULN with total 
bilirubin elevation ≤ 2x ULN 
Withhold ensartinib until recovery to baseline or ≤ 3x 
ULN, then resume at a one dose level reduction. 
 Grade 2 ALT or AST elevation 
> 3x ULN in conjunction with 
total bilirubin elevation > 2x 
ULN (in absence of cholestasis 
or hemolysis), and no 
correctable, non-drug related 
cause 
Permanently discontinue ensartinib 
Pneumonitis 
Grade  
Dose Modification* 
Pneumonitis of any grade** 
Permanently discontinue ensartinib 
Rash*** 
Grade  
Dose Modification* 
Grade 1 (mild) 
Continue ensartinib at same dose, follow, and, if 
necessary, use topical treatments. 
Grade 2 (moderate and 
symptomatic) 
Continue ensartinib at same dose; topical 
corticosteroids may be used. If, after 1 week, the rash 
is worse or there is no improvement, give a 5 day 
course of tapering oral corticosteroids. If, one week 
later, it is not improved to at least mild (≤ Grade 1), 
withhold ensartinib until at least mild (≤ Grade 1). At 
that time, resume ensartinib at a one dose level 
reduction. 
Grade 3 (severe) 
Withhold ensartinib. Topical treatments may be used. 
Oral corticosteroids may be considered. When 
improved to at least mild (≤ Grade 1), resume 
ensartinib at a one dose level reduction. 
Nausea, Vomiting and Diarrhea 
Grade  
Dose Modification* 
Grade 3 or greater 
Withhold ensartinib and initiate supportive care. If 
Grade 3 toxicity lasts ≤ 7 days, resume ensartinib at a 
one dose level reduction when toxicity recovers to ≤ 
Grade 1. 
QTcF Prolongation 
Grade 
Dose Modification 
QTcF >500 ms on at least 2 
separate ECGs 
Withhold until recovery to baseline or to a QTcF <481 
ms, then resume at one dose level reduction. 
QTcF >500 ms or ≥60 ms 
change from baseline with 
Torsade de pointes or 
Permanently discontinue. 
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polymorphic ventricular 
tachycardia or signs/symptoms 
of serious arrhythmia 
Bradycardia 
Grade 
Dose Modification 
Bradycardia: heart rate <60 
beats per minute (symptomatic, 
may be severe and medically 
significant, medical intervention 
indicated) 
Withhold until recovery to asymptomatic bradycardia 
or to a heart rate of 60 bpm or above. 
Evaluate concomitant medications known to cause 
bradycardia, as well as antihypertensive medications. 
If contributing concomitant medication is identified 
and discontinued, or its dose is adjusted, resume at 
previous dose upon recovery to asymptomatic 
bradycardia or to a heart rate of 60 bpm or above. 
If no contributing concomitant medication is identified, 
or if contributing concomitant medications are not 
discontinued or dose modified, resume at one level 
dose reduction upon recovery to asymptomatic 
bradycardia or to a heart rate of 60 bpm or above. 
Bradycardia: recurrent heart 
rate <60 beats per minute (life-
threatening consequences, 
urgent intervention indicated) 
Permanently discontinue if no contributing 
concomitant medication is identified. 
If contributing concomitant medication is identified 
and discontinued, or its dose is adjusted, resume at one 
level dose reduction upon recovery to asymptomatic 
bradycardia or to a heart rate of 60 bpm or above, with 
frequent monitoring. 
Visual Loss 
Grade 
Dose Modification 
Visual Loss (Grade 4 Ocular 
Disorder) 
Discontinue during evaluation of severe vision loss.  
Any patient that experiences severe visual loss (best 
corrected vision less than 20/200 in one or both eyes) 
or other serious visual complaints should have an 
ophthalmological evaluation consisting of best 
corrected visual acuity, retinal photographs, visual 
fields, optical coherence tomography (OCT) and other 
evaluations as appropriate for new onset of severe 
visual loss.  There is insufficient information to 
characterize the risks of resumption of treatment in 
patients with a severe visual loss; a decision to resume 
treatment should consider the potential benefits to the 
patient. 
Severe Renal Dysfunction 
Grade 
Dose Modifications  
Severe renal dysfunction (CL 
<30 mL/min) not requiring 
dialysis (not thought to be 
related to study medication) 
Hold dose until creatinine clearance returns to < grade 
3 (CL ≥30 mL/min).  If this occurs within 4 weeks, 
resume at a 1 level dose reduction.  When CL 
improves to ≥50 mL/min, dose may be escalated back 
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to the pre-dose modification level, if appropriate. 
Grade 3 renal dysfunction not 
requiring dialysis (thought to be 
study drug-related) and 
expected to be manageable and 
reversible with dose reduction 
Withhold ensartinib until recovery to < Grade 1. If 
toxicity remains Grade 3 for > 7 days, permanently 
discontinue ensartinib*. If Grade 3 toxicity lasts ≤ 7 
days and resolves to ≤ Grade 1, resume at a one dose 
level reduction. 
Grade 3 renal dysfunction not 
requiring dialysis (thought to be 
study drug-related) and not 
expected to be manageable and 
reversible with dose reduction 
Permanently discontinue ensartinib. 
Grade 4 renal dysfunction not 
requiring dialysis (thought to be 
study drug-related) 
Permanently discontinue ensartinib. 
Other Toxicity related to Ensartinib 
Grade  
Dose Modification* 
Grade 3 and expected to be 
manageable and reversible with 
dose reduction 
Withhold ensartinib. If toxicity remains Grade 3 for > 
7 days, permanently discontinue ensartinib*. If Grade 
3 toxicity lasts ≤ 7 days and resolves to baseline or ≤ 
Grade 1, resume at a one dose level reduction. 
Grade 3 and not expected to be 
manageable and reversible with 
dose reduction 
Permanently discontinue ensartinib 
Recurrence of Grade 3 toxicity 
Withhold ensartinib until resolves to baseline or ≤ 
Grade 1, then resume at a one dose level reduction or 
permanently discontinue ensartinib. 
Grade 4 
Permanently discontinue ensartinib* 
* Any patient who develops toxicity that does not resolve to baseline or ≤ Grade 1 within 4 
weeks or requires a treatment delay of more than 4 weeks due to treatment-related toxicity 
should be discontinued from trial treatment. In the case of either Grade 3 toxicity lasting 
longer than 7 days or Grade 4 toxicity, if the investigator feels that it is appropriate for the 
patient to continue treatment with ensartinib, this may be allowed after discussion with the 
Study Chair. 
** For pneumonitis of any grade not attributable to other causes, such as NSCLC 
progression, other pulmonary disease, infection, or radiation effect, discontinue ensartinib. 
*** For rash severity, rather than using CTCAE criteria based on BSA, consider severity 
based on symptoms and intensity. 
 
6.6 Dose Modifications and Toxicity Management for Lorlatinib 
 
Central Nervous System Effects  
Grade 
Dose Modification 
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Grade 1 
Continue at the same dose or withhold the dose 
until recovery to baseline. Resume lorlatinib at 
the same dose or at a 
reduced dose. 
Grade 2 OR Grade 3 
Withhold dose until Grade 0 or 1. Resume 
lorlatinib at a 
reduced dose. 
Grade 4 
Permanently discontinue lorlatinib. 
Hyperlipidemia  
Grade 4 hypercholesterolemia OR 
Grade 4 hypertriglyceridemia 
Withhold lorlatinib until recovery of 
hypercholesterolemia and/or 
hypertriglyceridemia to less than or equal to 
Grade 2. 
Resume lorlatinib at the same dose. 
If severe hypercholesterolemia and/or 
hypertriglyceridemia recurs, resume lorlatinib 
at a reduced dose. 
Atrioventricular (AV) Block 
Second-degree AV block 
Withhold lorlatinib until PR interval is less than 
200 ms. 
Resume lorlatinib at a reduced dose. 
First occurrence of complete AV block 
Withhold lorlatinib until 
• pacemaker placed OR 
• PR interval less than 200 ms. 
If a pacemaker is placed, resume lorlatinib at 
the same dose. 
If no pacemaker is placed, resume lorlatinib at 
a reduced dose. 
Recurrent complete AV block 
Place pacemaker or permanently discontinue 
lorlatinib. 
Interstitial Lung Disease (ILD)/Pneumonitis  
Any Grade treatment–related 
ILD/Pneumonitis 
Permanently discontinue lorlatinib. 
Other Adverse Reactions 
Grade 1 OR Grade 2 
Continue lorlatinib at same dose or reduced dose. 
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Grade 3 OR Grade 4 
Withhold lorlatinib until symptoms resolve to less 
than or 
equal to Grade 2 or baseline. Resume lorlatinib 
at one level dose reduction. 
 
6.7 Dose Modifications and Toxicity Management for Pemetrexed  
 
Adverse Event 
Dose Modification 
Myelosuppressive toxicity 
ANC less than 500 mm3 and 
platelets greater than or equal to 
50,000/mm3 
OR 
Platelet count less than 
50,000/mm3 without bleeding. 
 Hold dose until recovered then 375 mg/m2 
Platelet count less than 
50,000/mm3 with bleeding 
 Hold dose until recovered then 250 mg/m2 
Recurrent Grade 3 or 4 
myelosuppression after 2 dose 
reductions 
Discontinue 
Non-hematologic toxicity 
Any Grade 3 or 4 toxicities 
EXCEPT mucositis or 
neurologic toxicity 
   OR 
Diarrhea requiring 
hospitalization 
 Hold dose until recovered then 375 mg/m2 
Grade 3 or 4 mucositis 
 Hold dose until recovered then 250 mg/m2 
Renal toxicity 
Withhold until creatinine clearance is 45 mL/min or 
greater 
Grade 3 or 4 neurologic toxicity 
Permanently discontinue 
Recurrent Grade 3 or 4 non-
hematologic toxicity after 2 dose 
reductions 
Permanently discontinue 
Severe and life-threatening Skin 
Toxicity 
Permanently discontinue 
Interstitial Pneumonitis 
Permanently discontinue 
 
6.8 Dose Modifications and Toxicity Management for Cisplatin 
The table below is recommended dose adjustments for cisplatin.  
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Adverse Event 
Dose Modification 
Myelosuppressive toxicity 
ANC less than 500 mm3 OR 
Platelet count less than 
50,000/mm3 without bleeding. 
Hold dose until recovered then 60 mg/m2 
Platelet count less than 
50,000/mm3 with bleeding 
Hold dose until recovered then 37.5 mg/m2 
Recurrent Grade 3 or 4 
myelosuppression after 2 dose 
reductions 
Discontinue 
Non-hematologic toxicity 
Any Grade 3 or 4 toxicities  
    
Hold dose until recovered then 48 mg/m2 
Renal toxicity 
CrCl 46-60 mL/min  give 75% dose (56 mg/m2) 
CrCl 30-45 mL/min  give 50% dose (37.5mg/m2) 
< 30 mL/min - discontine 
  
Grade 3 or 4 neurologic toxicity 
Permanently discontinue 
Recurrent Grade 3 or 4 non-
hematologic toxicity after 2 dose 
reductions 
Permanently discontinue 
 
6.9 Dose Modifications and Toxicity Management for Carboplatin 
The table below is recommended dose adjustments for carboplatin.  
 
Adverse Event 
Dose Modification 
Myelosuppressive toxicity 
ANC less than 500 mm3 OR 
Platelet count less than 
75,000/mm3 without bleeding. 
Hold dose until recovered then AUC=4 
Platelet count less than 
50,000/mm3 with bleeding 
Hold dose until recovered then AUC =3.2 
Recurrent Grade 3 or 4 
myelosuppression after 2 dose 
reductions 
Discontinue 
Non-hematologic toxicity 
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Any Grade 3 or 4 toxicities  
    
Hold dose until recovered then AUC = 3.2 
Grade 3 or 4 neurologic toxicity 
Permanently discontinue 
Recurrent Grade 3 or 4 non-
hematologic toxicity after 2 dose 
reductions 
Permanently discontinue 
 
7. ADVERSE EVENTS REPORTING REQUIREMENTS 
7.1   
Protocol Agents 
Investigational Agents 
The investigational agents administered in NRG-LU003 are being made available under 
an IND sponsored by CTEP.  For lorlatinib, LDK378 (ceritinib), alectinib, brigatinib, 
crizotinib, and ensartinib determination of whether an adverse event meets expedited 
reporting criteria, see the reporting table in section 7.4 of the protocol.  
7.2  
Adverse Events and Serious Adverse Events 
7.2.1 This study will utilize the NCI Common Terminology Criteria for Adverse Events 
(CTCAE) version 5.0 for CTEP-AERS (CTEP Adverse Event Reporting System) CAERs 
and routine reporting of adverse events (AEs), located on the CTEP web site, 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. All 
appropriate treatment areas should have access to a copy of the CTCAE version 5.0. 
 
7.2.2 Definition of an Adverse Event (AE) 
Any untoward medical occurrence associated with the use of a drug in humans, whether 
or not considered drug related.  Therefore, an AE can 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 
considered related to the medicinal (investigational) product (attribution of unrelated, 
unlikely, possible, probable, or definite). (International Conference on Harmonisation 
[ICH], E2A, E6).  
 
For multi-modality trials, adverse event reporting encompasses all aspects of protocol 
treatment including radiation therapy, surgery, device, and drug. 
 
Due to the risk of intrauterine exposure of a fetus to potentially teratogenic agents, the 
pregnancy of a study participant must be reported via CTEP-AERS in an expedited 
manner. 
 
7.2.3    Adverse Events of Special Interest for Alectinib 
The following adverse events must be reported expeditiously within 24h of awareness 
regardless of grade or seriousness criteria: 
 
Drug-Induced Liver Injury (DILI) 
Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice as defined by Hy's Law 
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Hyperglycemia; Hyperkalemia; Hypertriglyceridemia; Hypoalbuminemia; Hypocalcemia; 
Hypokalemia; Hyponatremia; Hypophosphatemia; Metabolism and nutrition disorders - Other 
(hyperammonemia); Metabolism and nutrition disorders - Other (malnutrition) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthralgia; Back 
pain; Musculoskeletal and connective tissue disorder - Other (hemiparesis) 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND 
POLYPS) - Tumor hemorrhage 
NERVOUS SYSTEM DISORDERS - Dizziness; Edema cerebral; Nervous system disorders - 
Other (cerebral ventricle dilatation); Seizure; Stroke; Syncope 
PSYCHIATRIC DISORDERS - Confusion; Insomnia 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Cough; Dyspnea; 
Respiratory, thoracic and mediastinal disorders - Other (obstructive airways disorder) 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Dry skin; Pruritus 
VASCULAR DISORDERS - Thromboembolic event 
 
Note: Alectinib hydrochloride in combination with other agents could cause an exacerbation of 
any adverse event currently known to be caused by the other agent, or the combination may 
result in events never previously associated with either agent. 
 
7.3.2    Brigatinib 
 
Comprehensive Adverse Events and Potential Risks list (CAEPR) 
 for  
Brigatinib (AP26113, NSC 784728)  
 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single list of 
reported and/or potential adverse events (AE) associated with an agent using a uniform 
presentation of events by body system. In addition to the comprehensive list, a subset, the 
Specific Protocol Exceptions to Expedited Reporting (SPEER), appears in a separate column and 
is identified with bold and italicized text. This subset of AEs (SPEER) is a list of events that are 
protocol specific exceptions to expedited reporting to NCI (except as noted below).  Refer to the 
'CTEP, NCI Guidelines: Adverse Event Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf for 
further clarification.  Frequency is provided based on 492 patients. Below is the CAEPR for 
Brigatinib (AP26113). 
 
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses 
next to the AE in the SPEER.  If this CAEPR is part of a combination protocol using multiple 
investigational agents and has an AE listed on different SPEERs, use the lower of the grades 
to determine if expedited reporting is required. 
 
Version 2.2, May 7, 20201 
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CARDIAC DISORDERS - Palpitations; Sinus tachycardia 
GASTROINTESTINAL DISORDERS - Dry mouth; Dyspepsia; Flatulence; Gastric 
hemorrhage; Mucositis oral; Pancreatitis 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Death NOS; 
Edema limbs; Fever; Generalized edema3; Multi-organ failure; Non-cardiac chest pain; Pain; 
Sudden death NOS 
INFECTIONS AND INFESTATIONS - Meningitis; Sepsis; Upper respiratory infection; 
Urinary tract infection 
INVESTIGATIONS - Activated partial thromboplastin time prolonged; Blood lactate 
dehydrogenase increased; Cholesterol high; Creatinine increased; Electrocardiogram QT 
corrected interval prolonged; Neutrophil count decreased; Platelet count decreased; Weight loss; 
White blood cell decreased 
METABOLISM AND NUTRITION DISORDERS - Hypercalcemia; Hypokalemia; 
Hypomagnesemia; Hyponatremia; Metabolism and nutrition disorders - Other 
(hyperinsulinemia) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthralgia; 
Musculoskeletal and connective tissue disorder - Other (musculoskeletal chest pain, 
musculoskeletal stiffness); Myalgia; Pain in extremity 
NERVOUS SYSTEM DISORDERS - Dizziness; Dysgeusia; Memory impairment; Nervous 
system disorders - Other (peripheral neuropathy); Stroke 
PSYCHIATRIC DISORDERS - Confusion; Insomnia 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Adult respiratory 
distress syndrome; Respiratory failure 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Dry skin; Photosensitivity; Pruritus; 
Rash acneiform 
VASCULAR DISORDERS - Thromboembolic event 
 
Note: Brigatinib (AP26113) in combination with other agents could cause an exacerbation of any 
adverse event currently known to be caused by the other agent, or the combination may result in 
events never previously associated with either agent. 
 
7.3.3    LDK378 (ceritinib)  
 
Comprehensive Adverse Events and Potential Risks list (CAEPR) 
for LDK378 (ceritinib, NSC 802646) 
 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single list of 
reported and/or potential adverse events (AE) associated with an agent using a uniform 
presentation of events by body system. In addition to the comprehensive list, a subset, the 
Specific Protocol Exceptions to Expedited Reporting (SPEER), appears in a separate column and 
is identified with bold and italicized text. This subset of AEs (SPEER) is a list of events that are 
protocol specific exceptions to expedited reporting to NCI (except as noted below).  Refer to the 
'CTEP, NCI Guidelines: Adverse Event Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf for 
further clarification. Frequency is provided based on 1770 patients. Below is the CAEPR for 
LDK378 (ceritinib). 
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Hyperesthesia, Hypoesthesia, Hyporeflexia, Hypotonia, Ischemic neuropathy, Loss of 
proprioception, Miller Fisher syndrome, Mononeuritis, Mononeuropathy, Mononeuropathy 
multiplex, Motor dysfunction, Multifocal motor neuropathy, Muscle atrophy, Muscular 
weakness, Myelopathy, Nerve conduction studies abnormal, Nerve degeneration, Neuralgia, 
Neuritis, Neuromuscular toxicity, Neuromyopathy, Neuropathy peripheral, Neuropathy vitamin 
B6 deficiency, Neurotoxicity, Paresthesia, Peripheral motor neuropathy, Peripheral nerve lesion, 
Peripheral nerve palsy, Peripheral nervous system function test abnormal, Peripheral 
sensorimotor neuropathy, Peripheral sensory neuropathy, Peroneal muscular atrophy, Peroneal 
nerve palsy, Phrenic nerve paralysis, Polyneuropathy, Polyneuropathy chronic, Polyneuropathy 
idiopathic progressive, Radiation neuropathy, Sensorimotor disorder, Sensory disturbance, 
Sensory loss, Skin burning sensation, Temperature perception test decreased, Tinel’s sign, Toxic 
neuropathy, and Ulnar neuritis. 
 
4Treatment-related rash may include erythematous rash, rash maculo-papular, and pruritus. 
 
Adverse events reported on crizotinib (PF-02341066) trials, but for which there is 
insufficient evidence to suggest that there was a reasonable possibility that crizotinib (PF-
02341066) caused the adverse event: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Blood and lymphatic system 
disorders - Other (basophilia); Disseminated intravascular coagulation; Eosinophilia; 
Leukocytosis 
CARDIAC DISORDERS - Atrial fibrillation; Cardiac arrest; Chest pain - cardiac; Myocarditis; 
Pericardial effusion; Supraventricular tachycardia 
EYE DISORDERS - Cataract; Optic nerve disorder; Papilledema 
GASTROINTESTINAL DISORDERS - Colitis; Dysphagia; Gastric ulcer; Gastroesophageal 
reflux disease; Gastrointestinal disorders - Other (gastrointestinal amyloidosis); Ileus 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Fever; General 
disorders and administration site conditions - Other (failure to thrive); Malaise; Non-cardiac 
chest pain 
HEPATOBILIARY DISORDERS - Hepatobiliary disorders - Other (cholestasis); 
Hepatobiliary disorders - Other (hepatitis) 
IMMUNE SYSTEM DISORDERS - Autoimmune disorder 
INFECTIONS AND INFESTATIONS - Abdominal infection; Infections and infestations - 
Other (peridiverticular abscess); Kidney infection; Lung infection; Sepsis; Skin infection; 
Urinary tract infection 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Injury, poisoning and 
procedural complications - Other (traumatic lung injury); Spinal fracture; Wound complication 
INVESTIGATIONS - Blood lactate dehydrogenase increased; CPK increased; GGT increased; 
Investigations - Other (monocyte count increased); Investigations - Other (platelet count 
increased); Platelet count decreased 
METABOLISM AND NUTRITION DISORDERS - Dehydration; Hyperglycemia; 
Hyperkalemia; Hypermagnesemia; Hypertriglyceridemia; Hypoalbuminemia; Hypocalcemia; 
Hypokalemia; Hyponatremia; Hypophosphatemia; Metabolism and nutrition disorders - Other 
(hypoproteinemia) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthralgia; 
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Musculoskeletal and connective tissue disorder - Other (myopathy); Myalgia; Pain in extremity 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND 
POLYPS) - Treatment related secondary malignancy; Tumor hemorrhage 
NERVOUS SYSTEM DISORDERS - Intracranial hemorrhage; Ischemia cerebrovascular; 
Pyramidal tract syndrome; Seizure; Stroke 
PREGNANCY, PUERPERIUM AND PERINATAL CONDITIONS - Pregnancy loss 
PSYCHIATRIC DISORDERS - Confusion; Delirium; Euphoria 
RENAL AND URINARY DISORDERS - Acute kidney injury; Hematuria; Renal calculi; 
Urinary retention 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Bronchopulmonary 
hemorrhage; Dyspnea; Pleural effusion; Respiratory failure; Respiratory, thoracic and 
mediastinal disorders - Other (pneumomediastinum); Respiratory, thoracic and mediastinal 
disorders - Other (respiratory distress) 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Skin and subcutaneous tissue 
disorders - Other (drug eruption) 
VASCULAR DISORDERS - Hematoma; Hypotension; Phlebitis; Thromboembolic event; 
Vasculitis 
 
 
Note: Crizotinib (PF-02341066) in combination with other agents could cause an exacerbation of 
any adverse event currently known to be caused by the other agent, or the combination may 
result in events never previously associated with either agent. 
 
7.3.5    Ensartinib  
NOTE:  This study is closed to accrual and patients who received ensartinib are no longer 
receiving treatment; therefore the CAEPR will not be further updated.   
 
Comprehensive Adverse Events and Potential Risks list (CAEPR) 
for  
Ensartinib (X-396 hydrochloride, NSC 784729) 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single list 
of reported and/or potential adverse events (AE) associated with an agent using a uniform 
presentation of events by body system. In addition to the comprehensive list, a subset, the 
Specific Protocol Exceptions to Expedited Reporting (SPEER), appears in a separate 
column and is identified with bold and italicized text. This subset of AEs (SPEER) is a list 
of events that are protocol specific exceptions to expedited reporting to NCI (except as 
noted below).  Refer to the 'CTEP, NCI Guidelines: Adverse Event Reporting 
Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf 
for further clarification. Frequency is provided based on 490 patients. Below is the CAEPR 
for Ensartinib (X-396 hydrochloride). 
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in 
parentheses next to the AE in the SPEER. If this CAEPR is part of a combination 
protocol using multiple investigational agents and has an AE listed on different 
SPEERs, use the lower of the grades to determine if expedited reporting is 
required. 
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GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Chills; Flu like 
symptoms; Gait disturbance; General disorders and administration site conditions - Other 
(hyperthermia); General disorders and administration site conditions - Other (nodule); General 
disorders and administration site conditions - Other (temperature intolerance); Generalized 
edema; Localized edema; Malaise; Non-cardiac chest pain; Pain 
HEPATOBILIARY DISORDERS - Hepatic failure; Hepatobiliary disorders - Other (liver 
injury) 
IMMUNE SYSTEM DISORDERS - Autoimmune disorder 
INFECTIONS AND INFESTATIONS - Conjunctivitis; Folliculitis; Fungemia; Lung infection; 
Otitis media; Paronychia; Pharyngitis; Rash pustular; Shingles; Sinusitis; Skin infection; Upper 
respiratory infection; Urinary tract infection; Viremia  
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Injury, poisoning and 
procedural complications - Other (nail bed bleeding); Injury, poisoning and procedural 
complications - Other (sunburn); Wound complication 
INVESTIGATIONS - Activated partial thromboplastin time prolonged; Blood lactate 
dehydrogenase increased; Blood prolactin abnormal; Cardiac troponin I increased; Cholesterol 
high; Ejection fraction decreased; Electrocardiogram QT corrected interval prolonged; 
Electrocardiogram T wave abnormal; Hemoglobin increased; Investigations - Other (alpha 
hydroxybutyrate dehydrogenase increased); Investigations - Other (blood chloride increased); 
Investigations - Other (blood fibrinogen increased); Investigations - Other (blood follicle 
stimulating hormone increased); Investigations - Other (blood luteinizing hormone decreased); 
Investigations - Other (blood luteinizing hormone increased); Investigations - Other (blood urea 
increased); Investigations - Other (c-reactive protein increased); Investigations - Other 
(creatinine renal clearance); Investigations - Other (electrocardiogram high voltage); 
Investigations - Other (estradiol decreased); Investigations - Other (estradiol increased); 
Investigations - Other (fibrin D dimer increased); Investigations - Other (gamma-
glutamyltransferase decreased); Investigations - Other (monocyte count increased); 
Investigations - Other (nitrite urine present); Investigations - Other (platelet count increased); 
Investigations - Other (progesterone decreased); Investigations - Other (progesterone increased); 
Investigations - Other (protein total decreased); Investigations - Other (thrombin time 
prolonged); Investigations - Other (total bile acids increased); Investigations - Other 
(urobilinogen urine increased); Investigations - Other (white blood cells urine positive); Lipase 
increased; Lymphocyte count decreased; Lymphocyte count increased; Neutrophil count 
decreased; Platelet count decreased; Serum amylase increased; Urine output decreased; Weight 
gain; Weight loss; White blood cell decreased  
METABOLISM AND NUTRITION DISORDERS - Dehydration; Hyperglycemia; 
Hyperkalemia; Hyperlipidemia; Hypermagnesemia; Hyperphosphatemia; Hypertriglyceridemia; 
Hyperuricemia; Hypocalcemia; Hypokalemia; Hypomagnesemia; Hyponatremia; 
Hypophosphatemia; Metabolism and nutrition disorders - Other (hypochloremia); Metabolism 
and nutrition disorders - Other (hypoproteinemia); Metabolism and nutrition disorders - Other 
(hypouricemia) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthralgia; Arthritis; 
Back pain; Bone pain; Chest wall pain; Generalized muscle weakness; Muscle cramp; Muscle 
weakness lower limb; Musculoskeletal and connective tissue disorder - Other (mastication 
disorder); Musculoskeletal and connective tissue disorder - Other (muscle atrophy); Myalgia; 
Neck pain; Pain in extremity 
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NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND 
POLYPS) - Skin papilloma 
NERVOUS SYSTEM DISORDERS - Anosmia; Dizziness; Dysesthesia; Dysphasia; Edema 
cerebral; Headache; Nervous system disorders - Other (osmotic demyelination syndrome); 
Nervous system disorders - Other (poor quality sleep); Nervous system disorders - Other (visual 
field defect); Paresthesia; Peripheral motor neuropathy; Peripheral sensory neuropathy 
PSYCHIATRIC DISORDERS - Anxiety; Insomnia 
RENAL AND URINARY DISORDERS - Acute kidney injury; Dysuria; Glucosuria; 
Hematuria; Proteinuria; Urinary tract pain 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Breast pain; Reproductive 
system and breast disorders - Other (vulvovaginal erythema) 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Cough; Dyspnea; 
Epistaxis; Nasal congestion; Pleural effusion; Pneumonitis; Pulmonary hypertension; 
Respiratory, thoracic and mediastinal disorders - Other (chronic obstructive pulmonary disease); 
Respiratory, thoracic and mediastinal disorders - Other (nasal dryness); Respiratory, thoracic and 
mediastinal disorders - Other (tachypnea); Voice alteration 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Bullous dermatitis; Eczema; 
Erythema multiforme; Hyperhidrosis; Nail changes; Nail discoloration; Nail loss; Nail ridging; 
Palmar-plantar erythrodysesthesia syndrome; Photosensitivity; Purpura; Rash acneiform; Skin 
and subcutaneous tissue disorders - Other (drug eruption); Skin and subcutaneous tissue 
disorders - Other (drug rash with eosinophilia & systemic symptoms); Skin and subcutaneous 
tissue disorders - Other (lichenoid keratosis); Skin and subcutaneous tissue disorders - Other 
(scab); Skin and subcutaneous tissue disorders - Other (skin discoloration); Skin and 
subcutaneous tissue disorders - Other (skin fissures); Skin and subcutaneous tissue disorders - 
Other (skin fragility); Skin and subcutaneous tissue disorders - Other (skin irritation); Skin and 
subcutaneous tissue disorders - Other (skin lesion); Skin and subcutaneous tissue disorders - 
Other (skin mass); Skin atrophy; Skin hyperpigmentation; Skin ulceration; Telangiectasia; 
Urticaria 
VASCULAR DISORDERS - Flushing; Hypertension; Hypotension; Thromboembolic event; 
Vascular disorders - Other (jugular vein distension) 
 
Note: Ensartinib (X-396 hydrochloride) in combination with other agents could cause an 
exacerbation of any adverse event currently known to be caused by the other agent, or the 
combination may result in events never previously associated with either agent. 
 
7.3.6 Lorlatinib 
 
Comprehensive Adverse Events and Potential Risks list (CAEPR) 
for  
Lorlatinib (PF-06463922, NSC 803411) 
 
 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single list of 
reported and/or potential adverse events (AE) associated with an agent using a uniform 
presentation of events by body system. In addition to the comprehensive list, a subset, the 
Specific Protocol Exceptions to Expedited Reporting (SPEER), appears in a separate column and 
is identified with bold and italicized text. This subset of AEs (SPEER) is a list of events that are 
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Other (left ventricular dysfunction); Chest pain - cardiac; Heart failure; Palpitations; Pericardial 
effusion; Sinus bradycardia 
EAR AND LABYRINTH DISORDERS - Tinnitus 
EYE DISORDERS - Blurred vision; Cataract; Eye disorders - Other (diplopia); Flashing lights; 
Floaters; Photophobia; Vision decreased 
GASTROINTESTINAL DISORDERS - Abdominal distension; Constipation; Dry mouth; 
Gastritis; Gastroesophageal reflux disease; Mucositis oral; Nausea; Small intestinal obstruction; 
Vomiting 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Gait 
disturbance; Generalized edema  
HEPATOBILIARY DISORDERS - Cholecystitis; Hepatic failure; Hepatobiliary disorders - 
Other (cholelithiasis); Hepatobiliary disorders - Other (hepatic function abnormal) 
INFECTIONS AND INFESTATIONS - Lung infection; Skin infection; Wound infection 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Injury, poisoning and 
procedural complications - Other (traumatic intracranial hemorrhage, intentional self-injury) 
INVESTIGATIONS - Alkaline phosphatase increased; CPK increased; Electrocardiogram QT 
corrected interval prolonged; GGT increased; Neutrophil count decreased; Platelet count 
decreased; Serum amylase increased; White blood cell decreased 
METABOLISM AND NUTRITION DISORDERS - Anorexia; Hyperkalemia; 
Hyperuricemia; Hypophosphatemia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Generalized muscle 
weakness; Myalgia; Myositis 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND 
POLYPS) - Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other 
(neoplasm progression, pericardial effusion malignant) 
NERVOUS SYSTEM DISORDERS - Amnesia; Concentration impairment; Dizziness; 
Dysarthria; Dysesthesia; Dysgeusia; Dysphasia; Intracranial hemorrhage; Ischemia 
cerebrovascular; Headache; Nervous system disorders - Other (neurological symptom, carpal 
tunnel syndrome); Neuralgia; Presyncope; Stroke; Vagus nerve disorder 
PSYCHIATRIC DISORDERS - Agitation; Anxiety; Confusion; Delirium; Depression; 
Euphoria; Insomnia; Irritability; Personality change; Psychiatric disorders - Other (mental status 
changes); Psychiatric disorders - Other (schizophreniform disorder) 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Bronchopulmonary 
hemorrhage; Dyspnea; Respiratory failure; Voice alteration 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Rash maculo-papular 
SURGICAL AND MEDICAL PROCEDURES - Surgical and medical procedures - Other 
(radiotherapy to bone) 
VASCULAR DISORDERS - Thromboembolic event; Vascular disorders - Other (thrombosis) 
 
 
Note: Lorlatinib (PF-06463922) in combination with other agents could cause an exacerbation of 
any adverse event currently known to be caused by the other agent, or the combination may 
result in events never previously associated with either agent. 
 
7.3.7  Pemetrexed: Below is a list of most common adverse events.  Refer to the approved 
package insert for a list of comprehensive adverse events.  
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• Tiredness 
• Nausea 
• Loss of appetite 
 
7.3.8 Cisplatin: Below is a list of most common adverse events.  Refer to the approved package 
insert for a list of comprehensive adverse events. 
• Joint pain 
• Loss of balance 
• Ringing in ears 
• Swelling of feet or lower legs 
• Trouble in hearing 
• Unusual tiredness or weakness 
• Nausea and vomiting 
 
 
7.3.9 Carboplatin: Below is a list of most common adverse events.  Refer to the approved 
package insert for a list of comprehensive adverse events. 
• Pain at place of injection 
• Nausea and vomiting 
• Unusual tiredness and weakness 
 
7.4 
Expedited Reporting of Adverse Events (20-May-2019) 
All adverse events (AEs) are submitted for expedited reporting protocol-specific rules 
evaluation using the Medidata Rave data management system. All AEs will be evaluated 
by the Cancer Therapy Evaluation Program Adverse Event Reporting System (CTEP-
AERS) to determine whether expedited reporting is recommended based on a set of 
programmed expedited reporting rules. AEs identified as meeting the programmed 
expedited reporting requirements can then be submitted in CTEP-AERS. A deep link in 
Rave will take the user directly to CTEP-AERS where the expedited report may be 
completed and submitted via CTEP-AERS. 
 
All serious adverse events that meet expedited reporting criteria defined in the reporting 
table below will be reported via the CTEP Adverse Event Reporting System, CTEP-
AERS, accessed via the link in RAVE. CTEP-AERS is also accessed via the CTEP web 
site, but all expedited reports must be initiated in RAVE ,  
https://eapps-ctep.nci.nih.gov/ctepaers/pages/task?rand=1390853489613 
 
Submitting a report via CTEP-AERS serves as notification to the NRG 
Biostatistical/Data Management Center and satisfies NRG requirements for expedited 
adverse event reporting. 
 
In the rare event when Internet connectivity is disrupted, a 24-hour notification must be 
made to the NRG Oncology by phone at 1-215-574-3191 and the NCI (301-897-7497). 
An electronic report must be submitted immediately upon re-establishment of the Internet 
connection.  
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o 
“10 Calendar Days” - A complete expedited report on the AE must be submitted within 10 calendar days of learning 
of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of investigational agent/intervention and have 
an attribution of possible, probable, or definite require reporting as follows:  
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
• 
All Grade 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
• 
Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization  
• 
Grade 3 adverse events 
2For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive half-lives, rounded UP to the 
nearest whole day, after the agent/intervention was last administered.  Footnote “1” above applies after this reporting period. 
Effective Date:  May 5, 2011 
 
 
7.4.3 Reporting to the Site IRB/REB 
Investigators will report serious adverse events to the local Institutional Review Board 
(IRB) or Research Ethics Board (REB) responsible for oversight of the patient according 
to institutional policy. 
 
7.4.4 Secondary Malignancy  
A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., 
treatment with investigational agent/intervention, radiation or chemotherapy). A 
secondary malignancy is not considered a metastasis of the initial neoplasm.  
 
CTEP requires all secondary malignancies that occur during or subsequent to treatment 
with an agent under an NCI IND/IDE be reported via CTEP-AERS . In addition, 
secondary malignancies following radiation therapy must be reported via CTEP-AERS. 
Three options are available to describe the event: 
• 
Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic leukemia 
[AML])  
• 
Myelodysplastic syndrome (MDS) 
• 
Treatment-related secondary malignancy 
Any malignancy possibly related to cancer treatment (including AML/MDS) should also 
be reported via the routine reporting mechanisms outlined in each protocol.  
 
Second Malignancy:  
A second malignancy is one unrelated to the treatment of a prior malignancy (and is NOT 
a metastasis from the initial malignancy).  Second malignancies require ONLY routine 
AE reporting unless otherwise specified. 
 
7.4.5  Pregnancy 
Investigators should report a pregnancy, suspected pregnancy, or positive/ inconclusive 
pregnancy test, including a male participant’s impregnation of his partner, expeditiously 
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practice sites on the FDA Form 1572 in RCR to allow the following: 
• Addition to a site roster; 
• Assign the treating, credit, consenting, or drug shipment (IVR only) tasks in OPEN; 
• Act as the site-protocol Principal Investigator (PI) on the IRB approval; and 
In addition, all investigators acting as the Site-Protocol PI (investigator listed on the IRB 
approval), consenting/treating/drug shipment investigator in OPEN, must be rostered at the 
enrolling site with a participating organization. 
 
Additional information is located on the CTEP website at 
https://ctep.cancer.gov/investigatorResources/default.htm. For questions, please contact the RCR 
Help Desk by email at RCRHelpDesk@nih.gov. 
 
8.1  CTSU Registration Procedures (20-JAN-2022) 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
 
IRB Approval:   
For CTEP and Division of Cancer Prevention (DCP) studies open to the National Clinical Trials 
Network (NCTN) and NCI Community Oncology Research Program (NCORP) Research Bases 
after March 1, 2019, all U.S.-based sites must be members of the NCI Central Institutional 
Review Board (NCI CIRB). In addition, U.S.-based sites must accept the NCI CIRB review to 
activate new studies at the site after March 1, 2019.  Local IRB review will continue to be 
accepted for studies that are not reviewed by the CIRB, or if the study was previously open at the 
site under the local IRB. International sites should continue to submit Research Ethics Board 
(REB) approval to the CTSU Regulatory Office following country-specific regulations. 
Sites participating with the NCI CIRB must submit the Study Specific Worksheet for Local 
Context (SSW) to the CIRB using IRBManager to indicate their intent to open the study locally. 
The NCI CIRB’s approval of the SSW is automatically communicated to the CTSU Regulatory 
Office, but sites are required to contact the CTSU Regulatory Office at 
CTSURegPref@ctsu.coccg.org to establish site preferences for applying NCI CIRB approvals 
across their Signatory Network. Site preferences can be set at the network or protocol level. 
Questions about establishing site preferences can be addressed to the CTSU Regulatory Office by 
emailing the email address above or calling 1-888-651-CTSU (2878). 
Sites using their local IRB or REB, must submit their approval to the CTSU Regulatory Office 
using the Regulatory Submission Portal located in the Regulatory section of the CTSU website. 
Acceptable documentation of local IRB/REB approval includes: 
• Local IRB documentation; 
• IRB-signed CTSU IRB Certification Form; and/or 
• Protocol of Human Subjects Assurance Identification/IRB Certification/ 
Declaration of Exemption Form. 
In addition, the Site-Protocol Principal Investigator (PI) (i.e. the investigator on the IRB/REB 
approval) must meet the following criteria in order for the processing of the IRB/REB approval 
record to be completed: 
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• Holds an Active CTEP status; 
• Rostered at the site on the IRB/REB approval and on at least one participating 
roster; 
• If using NCI CIRB, rostered on the NCI CIRB Signatory record; 
• Includes the IRB number of the IRB providing approval in the Form FDA 1572 in 
the RCR profile; and 
• Holds the appropriate CTEP registration type for the protocol.  
 
  Additional Requirements for Protocol NRG-LU003 Site Registration 
  Additional requirements to obtain an approved site registration status include: 
• An active Federal Wide Assurance (FWA) number; 
• An active roster affiliation with the Lead Protocol Organization (LPO) or a 
Participating Organization (PO); and 
• Compliance with all protocol-specific requirements (PSRs). 
 
  Upon site registration approval in RSS, the enrolling site may access OPEN to complete      
enrollments. The enrolling site will select their credentialed provider treating the subject in the 
OPEN credentialing screen, and may need to answer additional questions related to treatment in 
the eligibility checklist.   
 
   Downloading Site Registration Documents:   
   Download the site registration forms from the protocol-specific page located on the CTSU  
members’ website. Permission to view and download this protocol and its supporting 
documents is restricted based on person and site roster assignment. To participate, the 
institution and its associated investigators and staff must be associated with the LPO or a 
Protocol Organization (PO) on the protocol.  One way to search for a protocol is listed below. 
• Log on to the CTSU members’ website (https://www.ctsu.org) using your CTEP-
IAM username and password; 
• Click on Protocols in the upper left of the screen 
o Enter the protocol number in the search field at the top of the protocol tree, 
or 
o Click on the By Lead Organization folder to expand, then select NRG 
Oncology and protocol number NRG-LU003; 
• 
Click on Documents, select Site Registration, and download and complete the 
forms provided. (Note: For sites under the CIRB initiative, IRB data will load 
automatically to the CTSU as described above.)  
 
Submitting Regulatory Documents:  
Submit required forms and documents to the CTSU Regulatory Office via the Regulatory 
Submission Portal on the CTSU website.  
To access the Regulatory Submission Portal log on to the CTSU members’ website,go to the 
Regulatory section and select Regulatory Submission. 
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Institutions with patients waiting that are unable to use the Regulatory Submission Portal 
should alert the CTSU Regulatory Office immediately at 1-866-651-2878 in order to receive 
further instruction and support. 
 
Checking Your Site’s Registration Status: 
Site registration status may be verified on the CTSU members’ website.   
•  
• Click on Regulatory at the top of the screen;  
• Click on Site Registration; and 
• Enter the site’s 5-character CTEP Institution Code and click on Go 
o Additional filters are available to sort by Protocol, Registration Status, Protocol 
Status, and/or IRB Type. 
 
Note: The status shown only reflects institutional compliance with site registration 
requirements as outlined above. It does not reflect compliance with protocol requirements for 
individuals participating on the protocol or the enrolling investigator’s status with the NCI or 
their affiliated networks. 
 
8.2       Patient Enrollment 
Patient registration can occur only after evaluation for eligibility is complete, eligibility 
criteria have been met, and the study site is listed as ‘approved’ in the CTSU RSS.  Patients 
must have signed and dated all applicable consents and authorization forms.   
 
8.2.1 Oncology Patient Enrollment Network (OPEN) 
The Oncology Patient Enrollment Network (OPEN) is a web-based registration system 
available on a 24/7 basis. OPEN is integrated with CTSU regulatory and roster data and 
with the Lead Protocol Organization (LPOs) registration/randomization systems or 
Theradex Interactive Web Response System (IWRS) for retrieval of patient 
registration/randomization assignment. OPEN will populate the patient enrollment data in 
NCI’s clinical data management system, Medidata Rave. 
Requirements for OPEN access:   
• A valid CTEP-IAM account; 
• To perform enrollments or request slot reservations:  Be on a LPO roster, ETCTN 
Corresponding roster, or PO roster with the role of Registrar. Registrars must hold 
a minimum of an AP registration type; 
• Have an approved site registration for a protocol prior to patient enrollment. 
 
To assign an Investigator (IVR) or Non-Physician Investigator (NPIVR) as the treating, 
crediting, consenting, drug shipment (IVR only), or receiving investigator for a patient 
transfer in OPEN, the IVR or NPIVR must list the IRB number used on the site’s IRB 
approval on their Form FDA 1572 in RCR.  
Prior to accessing OPEN, site staff should verify the following: 
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• Patient has met all eligibility criteria within the protocol stated timeframes; and  
• All patients have signed an appropriate consent form and HIPAA 
authorization form (if applicable). 
Note:  The OPEN system will provide the site with a printable confirmation of 
registration and treatment information. Please print this confirmation for your records.  
Access OPEN at https://open.ctsu.org or from the OPEN link on the CTSU members’ 
website. Further instructional information is in the OPEN section of the CTSU website at 
https://www.ctsu.org or https://open.ctsu.org. For any additional questions, contact the 
CTSU Help Desk at 1-888-823-5923 or ctsucontact@westat.com. 
 
 
In the event that the OPEN system is not accessible, participating sites can contact NRG 
web support for assistance with web registration: websupport@acr.org or call the NRG 
Registration Desk 215-574-3191 Monday through Friday, 8:30 a.m. to 5:00 p.m. ET. The 
registrar will ask the site to fax in the eligibility checklist and will need the registering 
individual’s e-mail address and/or return fax number. This information is required to assure 
that mechanisms usually triggered by the OPEN web registration system (e.g. drug shipment 
and confirmation of registration) will occur.  
 
8.3       Digital Data Submission of Images to NRG Using TRIAD (11-AUG-2020) 
Transfer of Images and Data (TRIAD) is the American College of Radiology’s 
(ACR) image exchange application. TRIAD provides sites participating in clinical 
trials a secure method to transmit images. TRIAD anonymizes and validates the 
images as they are transferred. 
TRIAD Access Requirements: 
• A valid CTEP-IAM account.  
• Registration type of:  Associate (A), Associate Plus (AP), Non-Physician 
Investigator (NPIVR), or Investigator (IVR). Refer to the CTEP 
Registration Procedures section for instructions on how to request a 
CTEP-IAM account and complete registration in RCR. 
• TRIAD Site User role on an NCTN or ETCTN roster. 
 
All individuals on the Imaging and Radiation Oncology Core provider roster have access 
to TRIAD, and may submit images for credentialing purposes, or for enrollments to 
which the provider is linked in OPEN. 
 
TRIAD Installation: 
To submit images, the individual holding the TRIAD Site User role will need to 
install the TRIAD application on their workstation. TRIAD installation 
documentation is available at https://triadinstall.acr.org/triadclient/. 
This process can be done in parallel to obtaining your CTEP-IAM account  and 
RCR registration. 
For questions, contact TRIAD Technical Support staff via email TRIAD-
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Support@acr.org or 1-703-390-9858. 
 
9.0       DRUG INFORMATION  
 
9.1 
Agent Ordering and Agent Accountability 
NCI-supplied agents may be requested by eligible participating Investigators (or their 
authorized designee) at each participating institution. The CTEP-assigned protocol 
number must be used for ordering all CTEP-supplied investigational agents. The eligible 
participating investigators at each participating institution must be registered with CTEP, 
DCTD through an annual submission of FDA Form 1572 (Statement of Investigator), 
NCI Biosketch, Agent Shipment Form, and Financial Disclosure Form (FDF). If there are 
several participating investigators at one institution, CTEP-supplied investigational 
agents for the study should be ordered under the name of one lead investigator at that 
institution. Submit agent requests through the PMB Online Agent Order Processing 
(OAOP) application. Access to OAOP requires the establishment of a CTEP Identity and 
Access Management (IAM) account and the maintenance of an “active” account status, a 
“current” password, and active person registration status. For questions about drug 
orders, transfers, returns, or accountability, call or email PMB any time. Refer to the 
PMB’s website for specific policies and guidelines related to agent management. 
 
 
9.1.1 Starter supplies are not being provided. Patients must be registered in Step 2 prior 
to sites ordering study agents.   
Refer to the Policy and Guidelines for Investigational Agent Ordering and the 
contact information below for order processing time and conditions. Normal order 
processing time is two business days. An express courier account number must be 
provided for next-day delivery.  
 
CTEP Forms, Templates, Documents: http://ctep.cancer.gov/forms/  
NCI CTEP Investigator Registration: RCRHelpDesk@nih.gov  
PMB policies and guidelines: 
http://ctep.cancer.gov/branches/pmb/agent management.htm 
 
PMB Online Agent Order Processing (OAOP) application: 
https://ctepcore.nci.nih.gov/OAOP/ 
CTEP Identity and Access Management (IAM) account: 
https://ctepcore.nci.nih.gov/iam/  
CTEP IAM account help: ctepreghelp@ctep.nci.nih.gov  
PMB email: PMBAfterHours@mail.nih.gov  
PMB phone and hours of service: (240) 276-6575 Monday through Friday between 
8:30 am and 4:30 pm (ET)  
 
The investigator, or a responsible party designated by the investigator, must maintain a 
careful record of the receipt, dispensing and final disposition of all agents received from 
the PMB using the appropriate NCI Investigational Agent (Drug) Accountability Record 
(DARF) available on the CTEP forms page. Store and maintain separate NCI 
Investigational Agent Accountability Records for each agent, strength, formulation and 
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ordering investigator on this protocol. 
 
9.1.2 To supplement the toxicity information contained in this document, investigators must 
obtain the current version of the investigator brochure (IB), if available, for 
comprehensive pharmacologic and safety information. The current version of the 
Investigator Brochure (IB) will be accessible to site investigators and research staff 
through the PMB Online Agent Order Processing (OAOP) application. Access to OAOP 
requires the establishment of a CTEP Identity and Access Management (IAM) account 
and the maintenance of an “active” account status, a “current” password, and active 
person registration status. Questions about IB access may be directed to the PMB IB 
Coordinator via email to ibcoordinator@mail.nih.gov or the IB Coordinator may be 
contacted at 240-276-6575. 
 
9.2 
Investigational Study Agent: Alectinib (
, NSC #794611) (13-NOV-2019) 
Sites must refer to the Investigator Brochure for detailed pharmacologic and safety 
information. The Investigator Brochure will be provided by the Pharmaceutical 
Management Branch (PMB). See section 9.1.2. 
 
Chemical Name: 9-Ethyl-6,6-dimethyl-8-[4-(morpholin-4-yl)piperidin-1-yl]-11-oxo- 
6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile hydrochloride 
 
Other Names: RO5424802, CH5424802, ALECENSA® 
 
Classification: tyrosine kinase inhibitor 
 
Molecular Formula: C30H35ClN4O2 (hydrochloride salt)  
 
M.W.: 519.08 g/mol (hydrochloride salt); 482.62 g/mol (free base form) 
 
Mode of Action: tyrosine kinase inhibitor targeting ALK and RET 
 
Description:  Alectinib hydrochloride is a white to yellow reddish white powder or 
powder with lumps. 
 
How Supplied:  Genentech supplies and CTEP, DCTD, NCI distributes alectinib as white 
colored, hard capsules containing 150 mg of alectinib as the free base (equivalent to 
161.3 mg of alectinib HCl) and the following inactive ingredients: lactose monohydrate, 
hydroxypropylcellulose, sodium lauryl sulfate, magnesium stearate, and 
carboxymethylcellulose calcium. The capsule shell is composed of hypromellose, 
carrageenan, potassium chloride, titanium dioxide, corn starch, and carnauba wax. "ALE 
150 mg" is printed on the capsules with black ink. The printing ink contains red iron 
oxide (E172), yellow iron oxide (E172), FD&C Blue No. 2 aluminum lake (E132), 
carnauba wax, white shellac, and glyceryl monooleate.  Each bottle contains 240 
capsules. 
 
Storage: Do not store above 30°C. Store in original container to protect from light and 
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moisture. 
 
If a storage temperature excursion is identified, promptly return alectinib to Controlled 
Room Temperature (CRT) and quarantine the supplies.  Provide a detailed report of the 
excursion (including documentation of temperature monitoring and duration of the 
excursion) to PMBAfterHours@mail.nih.gov for determination of suitability. 
 
Stability:  Refer to the package label for expiration.  Dispense in the original container. 
 
Route of Administration: Oral 
 
Method of Administration: Alectinib must be taken with food for optimal absorption. 
Capsules should be swallowed whole. Do not open or dissolve the contents of the capsule. 
 
Potential Drug Interactions: In vitro studies indicate that neither alectinib nor its major 
metabolite (M4) inhibit CYP1A2, CYP2B6, CYP2C9, CYP2C19, or CYP2D6 at clinically 
relevant concentrations. Alectinib is a competitive inhibitor of CYP2C8.  Alectinib and M4 
showed a weak time-dependent inhibition of CYP3A4. However, the coadministration of 
alectinib did not affect the pharmacokinetics of CYP3A and CYP2C8 sensitive substrates.  
Alectinib also has the potential for moderate induction of CYP3A4 and CYP2B6 at clinical 
concentrations.  Systemic exposure to alectinib was not affected when co-administered 
with a strong CYP3A inhibitor or inducer. 
 
Alectinib is not a substrate of the efflux transporters P-glycoprotein (P-gp) or breast 
cancer resistance protein (BCRP), whereas M4 is a substrate of P-gp but not of BCRP.  
Alectinib and M4 are inhibitors of P-gp and BCRP.  Appropriate monitoring is 
recommended when administering alectinib with P-gp or BCRP substrates.. Alectinib did 
not inhibit OATP1B1, OATP1B3, OAT1, OAT3, or OCT2 transport activity in vitro. 
 
The co-administration of PPIs and other agents that raise gastric pH have no clinically 
relevant impact on alectinib pharmacokinetics.     
 
Patient Care Implications: An extra dose should not be taken if a patient misses a dose or 
vomits after taking a dose.  The next dose should be taken at the next regular scheduled 
time. 
 
Females of reproductive potential must use effective contraception during treatment and 
for a minimum of one (1) week after the final dose.  Males with female partners of 
reproductive potential must use effective contraception during treatment and for a 
minimum of three (3) months following the final dose. 
 
9.2.1 Subjects must be enrolled and assigned to the alectinib treatment arm prior to 
submitting the agent request to PMB. See section 9.1.1 
 
9.2.2 Availability/Supply  
Alectinib capsules are provided by Genentech and distributed by the DCTD/NCI. 
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Alectinib will be supplied to patients on study free of charge. 
 
 
9.3 
Investigational Study Agent: Brigatinib 
, NSC #784728) 
 
Sites must refer to the Investigator Brochure for detailed pharmacologic and safety 
information. The Investigator Brochure will be provided by the Pharmaceutical 
Management Branch (PMB). See section 9.1.2. 
 
Chemical Name or Amino Acid Sequence: 5-chloro-N4-[2-
(dimethylphosphoryl)phenyl]-N2-{2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-
yl]phenyl}pyrimidine-2, 4-diamine 
 
Other Names: AP26113 
 
Classification: anaplastic lymphoma kinase (ALK) inhibitor 
 
CAS Registry Number: 1197953-54-0 
 
Molecular Formula: C29H39ClN7O2P 
 
M.W.: 584.10 g/mol 
 
Approximate Solubility: pH dependent (>165.2 mg/ml at pH 2.5, >355.2 mg/mL at pH 
4.5, 3 mg/ml at pH 7) 
 
Mode of Action: Brigatinib is an oral tyrosine kinase inhibitor (TKI) targeting activated 
variants of ALK including the L1196M gatekeeper mutation and c-ros oncogene 1 
(ROS1) kinase.  It also inhibits certain variants of epidermal growth factor receptor 
(EGFR) and insulin-like growth factor receptor 1 (IGF-1R). 
 
How Supplied: Brigatinib is supplied by Takeda Pharmaceuticals and distributed by the 
Pharmaceutical Management Branch, CTEP/DCTD/NCI.  Brigatinib is available as 30 
mg film coated tablets packaged in 60-count HDPE bottles. The inactive ingredients are 
lactose monohydrate, microcrystalline cellulose, sodium starch glycolate, hydrophobic 
colloidal silica, and magnesium stearate. The tablet film-coating is comprised of talc, 
propylene glycol, polyvinyl alcohol, and titanium dioxide.  
 
Storage: Store at controlled room temperature 20°C – 25°C. Excursions permitted 
between 15°C – 30°C. 
 
If a storage temperature excursion is identified, promptly return brigatinib to below 30°C 
and quarantine the supplies.  Provide a detailed report of the excursion (including 
documentation of temperature monitoring and duration of the excursion) to 
PMBAfterHours@mail.nih.gov for determination of suitability. 
 
Stability: Stability studies are ongoing.  Dispense in the original container. 
 
Route and Method of Administration: Oral with or without food. Swallow whole, do 
not crush. 
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Potential Drug Interactions: Brigatinib is primarily metabolized by CYP2C8 and 
CYP3A4 in vitro, and a minor extent by CYP3A5. It is also a substrate of P-gp, BCRP, 
and OATP1A2 but not OATP1B1, OATP1B3, OATP2B1, OAT1, OAT3, OCT1, OCT2, 
MATE1, MATE2K, BSEP, or NTCP. P-gp, BCRP, and OATP1A2 inhibitors are unlikely 
to increase the plasma concentration of brigatinib due to high solubility and permeability 
in vitro. In vivo, CYP2C8 does not appear to contribute meaningfully to clearance of 
brigatinib. Strong inhibitors and inducers of CYP3A4 should be avoided.  Strong 
inhibitors and inducers of CYP2C8 should be used with caution. 
 
Brigatinib inhibits P-gp, BCRP, MATE1, MATE2K, and OCT1 in vitro.  Brigatinib and 
its metabolite AP26123 do not inhibit CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A4/5 at 
clinically relevant drug concentrations in vitro. Brigatinib also did not inhibit OATP1B1, 
OATP1B3, OAT1, OAT3, OCT2, or BSEP.  Use caution when administered with agents 
that are P-gp, BCRP, OCT1, MATE1, and MATE2K substrates. 
 
Brigatinib induces CYP3A and 2C enzymes through activation of the pregnane X 
receptor (PXR) and is a weak inducer of CYP1A2 and 2B6.  Use caution when 
administered with agents that are CYP3A or 2C substrates. 
 
Patient Care Implications: Females of childbearing potential should use effective 
contraception during treatment with brigatinib and for at least 4 months after the last dose 
of brigatinib. A non-hormonal method of contraception should be used as brigatinib can 
render some hormonal contraceptives ineffective. Males with female partners of 
reproductive potential should use effective contraception during treatment with brigatinib 
and for at least 3 months after the last dose of brigatinib. Lactating women should not 
breastfeed their children during treatment with brigatinib and for 1 week following the 
last dose. 
 
9.3.1 Subjects must be enrolled and assigned to the brigatinib treatment arm prior to 
submitting the agent request to PMB. See section 9.1.1 
 
9.3.2 Availability/Supply  
Brigatinib tablets are provided by Ariad Pharmaceuticals, Inc., a wholly owned subsidiary 
of Takeda Pharmaceutical Company Limited and distributed by the DCTD/NCI. Brigatinib 
will be supplied to patients on study free of charge. 
 
 
9.4 
Investigational Study Agent: LDK378 (ceritinib) (
 NSC #802646) (13-
NOV-2019) 
 
 
Sites must refer to the investigator brochure for detailed pharmacologic and safety 
information. The Investigator Brochure will be provided by the Pharmaceutical 
Management Branch (PMB). See section 9.1.2. 
 
Chemical Name: 5-Chloro-2-N-{5-methyl-4-(piperidin-4-yl)-2-[(propan-2-
yl)oxy]phenyl}-4-N-[2-(propane-2-sulfonyl)phenyl]pyrimidine-2,4-diamine 
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Other names: LDK378-NXA, Zykadia® 
 
Classification: anaplastic lymphoma kinase (ALK) inhibitor 
 
Molecular Formula: 
C28H36N5O3ClS 
M.W.: 558.14 (free base) 
 
Approximate Solubility: The 150 capsule is completely soluble in 250 mL of acidic 
media (pH=1) and much less soluble in 250 mL of neutral media (0.05 mg at pH=6.8). 
Mode of Action: ALK is a receptor tyrosine kinase linked to the genesis of several 
cancers through genetic aberrations involving translocation of the kinase domain with 
multiple fusion partners or activating mutations that result in ligand-independent 
constitutive activation. LDK378 (ceritinib) is an oral, highly selective and potent ALK 
kinase inhibitor which inhibits autophosphorylation of ALK, and consequently ALK-
mediated phosphorylation of downstream signaling proteins and proliferation of ALK-
dependent cancer cells.  
 
How Supplied: Novartis supplies and the Pharmaceutical Management Branch, CTEP, 
DCTD, NCI distributes LDK378 (ceritinib) as 150 mg hard gelatin capsules (HGC). 
Capsules are contained in 35-count HDPE bottles with induction seals.  
 
LDK378 (ceritinib) capsules contain drug substance, cellulose, 
microcrystalline/microcrystalline cellulose:low-substituted hydroxypropyl cellulose, 
magnesium stearate, sodium starch glycolate (type A)/sodium starch glycolate, silica and 
colloidal anhydrous/colloidal silicon dioxide. Capsule shells contain the following: 
gelatin; titanium dioxide (E171); indigotine (E132)/FD&C Blue No. 2 (for blue-white 
capsules).  
 
LDK378 (ceritinib) 150 mg capsules are white opaque size #00 HGC with a blue opaque 
cap. Capsules are marked with “LDK 150MG” on the cap and “NVR” on the body in a 
black radial rectified imprint. Printing ink contains the following components: 
ammonium hydroxide 28%; iron oxide black (E172)/ferric oxide, black; propylene 
glycol; and shellac (bleached, de-waxed) glaze 45%. 
 
Storage: Store below 25°C (77°F). 
If a storage temperature excursion is identified, promptly return LDK378 (ceritinib) to 
below 25°C (77°F) and quarantine the supplies.  Provide a detailed report of the 
excursion (including documentation of temperature monitoring and duration of the 
excursion) to PMBAfterHours@mail.nih.gov for determination of suitability. 
 
Stability:  Stability studies are ongoing.  Dispense in the original container. 
 
Route and Method of Administration:  Oral. Take LDK378 (ceritinib) once daily with 
food. Swallow LDK (ceritinib) capsules whole and without chewing or crushing. 
 
If a dose of LDK378 (ceritinib) is missed, make up that dose unless the next dose is due 
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within 12 hours. If vomiting occurs during the course of treatment, do not administer an 
additional dose and continue with the next scheduled dose of LDK378 (ceritinib). 
 
            Potential Drug Interactions:  Based on clinical data, CYP3A4/5 was the major enzyme 
responsible for metabolic clearance of LDK378 (ceritinib). Strong CYP3A4/5 inhibitors 
increased the systemic exposure of LDK378 (ceritinib) and strong inducers decreased 
systemic exposure of LDK378 (ceritinib). If concomitant use of strong CYP3A4/5 
inhibitors or inducers is unavoidable, refer to the protocol document for LDK378 (ceritinib) 
dose adjustments. Patients should avoid ingesting grapefruit or grapefruit juice since 
inhibition of CYP3A4/5 in the gut wall may increase the bioavailability of LDK378 
(ceritinib).   
 
Based on in vitro data, LDK378 (ceritinib) is a substrate of the efflux transporter P-
glycoprotein (P-gp), but not BCRP, MRP2, OCT1, OCT2, OAT2 or OATP1B1. Exercise 
caution with concomitant use of P-gp inhibitors and inducers and carefully monitor 
adverse drug reactions. 
 
LDK378 (ceritinib) may inhibit CYP3A and CYP2C9 at clinical concentrations. Avoid 
concurrent use of CYP3A and CYP2C9 substrates known to have narrow therapeutic 
indices or substrates primarily metabolized by CYP3A and CYP2C9 during treatment 
with LDK378 (ceritinib). 
 
In vitro studies show that LDK378 (ceritinib) does not inhibit transporters BCRP, P-gp or 
MRP2 at pH of 7.4 or OATP1B1, OATP1B3, OCT1, OCT2, OAT1, OAT2 or OAT3. 
Follow-up in vitro studies at pH 6.0 show that LDK378 (ceritinib) inhibits intestinal P-gp 
and BCRP, but not MRP2. LDK378 (ceritinib) also inhibits MATE-1, but not MATE2-K, 
suggesting that LDK378 (ceritinib) could lead to increased serum creatinine elevations by 
blocking in vivo clearance.  
 
Co-administration of LDK378 (ceritinib) and proton pump inhibitors showed a decrease in 
AUC and Cmax. Further subgroup analysis across multiple trials showed similar steady-
state exposure of LDK378 (ceritinib) in patients with and without proton pump inhibitors. 
 
Since LDK378 (ceritinib) may increase the exposure of drugs which are metabolized via 
CYP3A4/5, avoid concomitant administration with QTc prolonging medications which are 
metabolized by CYP3A4/5. Refer to the protocol document for dose adjustments and 
management of QT prolongation. Avoid co-administration with other agents known to cause 
bradycardia. 
 
            Patient Care Implications: Women should not breastfeed during treatment and for 2 
weeks following completion of therapy. Advise females of reproductive potential to use 
effective contraception during treatment with LDK378 (ceritinib) and for 6 months 
following completion of therapy. Advise males with female partners of reproductive 
potential to use condoms during treatment with LDK378 (ceritinib) and for 3 months 
following completion of therapy. Refer to the protocol document for further details. 
 
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9.4.1 Subjects must be enrolled and assigned to the LDK378 (ceritinib) treatment arm 
prior to submitting the agent request to PMB. See section 9.1.1 
 
9.4.2 Availability/Supply  
LDK378 (ceritinib) capsules are provided by Novartis and distributed by the DCTD/NCI. 
LDK378 (certinib) will be supplied to patients on study free of charge. 
 
9.5 
Investigational Study Agent: Crizotinib (
, NSC #749005) (13-NOV-
2019) 
 
Sites must refer to the investigator brochure for detailed pharmacologic and safety 
information. The Investigator Brochure will be provided by the Pharmaceutical 
Management Branch (PMB). See section 9.1.2. 
 
Chemical Name: (R)-3-[1-(2,6-Dichloro-3-fluoro-phenyl)-ethoxy]-5-(1-piperidin-4-yl-
1H-pyrazol-4-yl)-pyridin-2-ylamine  
Other Names: Xalkori®, PF-02341066 
 
Classification: ALK inhibitor 
 
CAS Registry Number: 8773999-52-5 
 
Molecular Formula: 
C21H22Cl2FN5O  
 
M.W.: 450.34 daltons 
Mode of Action: Crizotinib is a selective ATP-competitive small –molecule inhibitor of 
anaplastic lymphoma kinase (ALK), c-Met/hepatocyte growth factor receptor (HGFR) and 
Recepteur d’Origine Nantais (RON), and ROS1 receptor tyrosine kinases and their oncogenic 
variants. Translocations of these genes can result in expression of oncogenic fusion proteins 
that contribute to increased cell proliferation and survival. Antitumor efficacy of crizotinib is 
correlated to pharmacodynamic inhibition of phosphorylation of ALK fusion variants or c-
Met/HGFR in tumors in vivo. 
 
Description: white to pale yellow powder 
 
How Supplied: Crizotinib capsules are supplied by Pfizer, Inc. and distributed by the 
Pharmaceutical Management Branch, CTEP/DCTD/NCI.  Capsules are packaged in 60-
count bottles with colloidal silicon dioxide, microcrystalline cellulose, anhydrous dibasic 
calcium phosphate, sodium starch glycolate, and magnesium stearate as inactive 
ingredients in the following strengths: 
• 200 mg hard gelatin capsule (size 1) white opaque body and pink opaque cap, with 
"Pfizer" on the cap and "CRZ 200" on the body. 
• 250 mg hard gelatin capsule (size 0) pink opaque cap and body, with "Pfizer" on the 
cap and "CRZ 250" on the body. 
 
The pink opaque capsule shell components contain gelatin, titanium dioxide, and red iron 
oxide. The white opaque capsule shell components contain gelatin, and titanium dioxide. 
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The printing ink contains shellac, propylene glycol, strong ammonia solution, potassium 
hydroxide, and black iron oxide. 
 
Storage: Store at room temperature 20° to 25°C (68° to 77°F), excursions permitted between 
15 to 30°C (59 to 85°F). 
 
If a storage temperature excursion is identified, promptly return crizotinib to between 15 and 
30°C and quarantine the supplies.  Provide a detailed report of the excursion (including 
documentation of temperature monitoring and duration of the excursion) to 
PMBAfterHours@mail.nih.gov for determination of suitability. 
 
Stability: Refer to the package label for expiration.  Dispense in the original container. 
 
Route of Administration:  Take by mouth with or without food. 
Potential Drug Interactions:  Crizotinib is primarily metabolized by CYP 3A4/5 with minor 
contributions from CYP2C8, CYP2C19, and CYP2D6.  Avoid concomitant use of strong 
CYP3A inhibitors and inducers.  Use of potent CYP3A inducers should be avoided for at 
least 12 days prior to the first dose of crizotinib.  Use of strong CYP3A inhibitors should 
be avoided for at least 7 days prior to the first dose of crizotinib.  Exercise caution with 
concomitant use of moderate CYP3A inhibitors.  Crizotinib moderately inhibits CYP3A4 in 
a time-dependent fashion.  Avoid use with patients who receive CYP3A4 substrates with a 
narrow therapeutic index.   
 
Crizotinib is an inhibitor of CYP2B6 in vitro. Use caution with co-administered drugs that 
are predominantly metabolized by CYP2B6. 
 
Studies demonstrate that crizotinib is a substrate of P-gp and a weak BCRP inhibitor, 
however the potential to cause drug-drug interactions at therapeutic doses is low.  
Crizotinib inhibited P-gp, OCT1, and OCT2 in vitro at clinically relevant concentrations.  
Use caution with coadministration of P-gp, OCT1, and OCT2 substrates.   
 
Patient Care Implications: Females of childbearing potential must use adequate 
contraception for 90 days after the last dose of crizotinib. 
 
9.5.1 Subjects must be enrolled and assigned to the crizotinib treatment arm prior to 
submitting the agent request to PMB. See section 9.1.1 
 
9.5.2 Availability/Supply 
Crizotinib capsules are provided by Pfizer Pharma and distributed by the DCTD/NCI 
Crizotinib will be supplied to patients on study free of charge. 
 
9.6 
Investigational Study Agent: Ensartinib (
, NSC #784729) (13-NOV-
2019) 
Sites must refer to the investigator brochure for detailed pharmacologic and safety 
information. The Investigator Brochure will be provided by the Pharmaceutical 
Management Branch (PMB). See section 9.1.2. 
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Chemical Name or Amino Acid Sequence: 6-amino-5-(R)-(2,6-dichloro-3-
fluorophenyl)ethoxy-N-(4-(3R,5S)-3,5-dimethylpiperazine-1-
carbonyl)phenyl)pyridazine-3-carboxamide HCl salt 
 
Other Names: X0396, X-0396, X396 
 
Classification: anaplastic lymphoma kinase (ALK) inhibitor 
 
Molecular Formula: C26H27Cl2FN6O3 *2HCl 
M.W.: 634.4 (HCl salt) 561.4 (free base)  
 
Approximate Solubility: pH and solvent dependent [(27.5 mg/mL in purified water, 8.2 
mg/ml at pH 1.2 (simulated gastric fluid without enzymes)] 
 
Mode of Action: A potent and selective 2nd generation ALK inhibitor with additional 
activity against MET, ABL T315I, Ax1, EPHA2, and ROS1. ALK translocations can result 
in increased cell proliferation and survival.  Ensartinib inhibits cell growth and ALK 
receptor phosphorylation. 
 
Description: White to off-white solid.  Ensartinib (X-396 HCl) is hygroscopic. 
 
How Supplied: Xcovery Holding Company, LLC supplies and CTEP, DCTD, NCI 
distributes ensartinib (X-396 HCl) as 25 mg capsules (white opaque, size 2) and 100 mg 
capsules (yellow opaque body with blue opaque cap, size 0).  Inactive components consist 
of microcrystalline cellulose and stearic acid.  The capsules are packaged in 40 cc (25 mg) 
and 60 cc (100 mg) HDPE bottles containing 30 capsules per bottle with a desiccant, 
induction seal, and child resistant screw cap. 
 
Storage: Stored at controlled room temperature (15ºC-30ºC/59ºF-86ºF) 
 
If a storage temperature excursion is identified, promptly return ensartinib to controlled 
room temperature and quarantine the supplies.  Provide a detailed report of the excursion 
(including documentation of temperature monitoring and duration of the excursion) to 
PMBAfterHours@mail.nih.gov for determination of suitability. 
 
Stability: Stability studies are ongoing. Dispense in the original container. 
 
Route and Method of Administration: Oral with or without food.  
 
Potential Drug Interactions: Ensartinib is primarily metabolized by CYP3A4 with a minor 
contribution from 2C19 in vitro.  Use caution when administered with strong inhibitors and 
inducers of CYP3A4.   
 
In vitro, ensartinib did not inhibit cytochrome P450 isozymes CYP 1A2 or 2D6 but did 
inhibit 3A4 by 22% and 2C9 by 43% at 10 μM. While drug-drug interactions via 
cytochrome P450 isozymes are not expected at concentrations achieved in the clinic, 
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substrates of CYP3A4 and 2C9 should be used with caution.  
 
Plasma protein binding ranged from 90.2% to 97%. Use caution in patients who are 
receiving concomitant medications that are also highly protein-bound. 
 
Patient Care Implications: Females of childbearing potential and male participants with 
female partners should use adequate contraception for at least 1 week after the last dose 
of ensartinib.  
 
9.6.1 Subjects must be enrolled and assigned to the ensartinib treatment arm prior to 
submitting the agent request to PMB. See section 9.1.1 
 
9.6.2 Availability/Supply  
Ensartinib capsules are provided by Xcovery Pharma and distributed by the DCTD/NCI. 
Ensartinib will be supplied to patients on study free of charge. 
 
 
9.7 
Investigational Study Agent: Lorlatinib (
, NSC #803411) (11-AUG-
2020) 
 
 
Sites must refer to the investigator brochure for detailed pharmacologic and safety 
information. The Investigator Brochure will be provided by the Pharmaceutical 
Management Branch (PMB). See section 9.1.2. 
 
Chemical Name: (10R)-7-amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-
tetrahydro-2H-8,4-(metheno)pyrazolo[4,3-h][2,5,11]benzoxadiazacyclotetradecine-3-
carbonitrile 
 
Other Names: Lorbrena®, PF-06463922 
 
Classification: ALK inhibitor 
 
Molecular Formula: C21H19FN6O2  
M.W.: 406.41 daltons 
 
Mode of Action: Lorlatinib is a selective ATP-competitive small –molecule inhibitor of 
anaplastic lymphoma kinase (ALK) and c-ROS oncogene 1 (ROS1) kinase that also 
potently inhibits ALK kinase domain mutations responsible for resistance to ALK 
inhibitor treatment in non-small cell lung cancer.  Lorlatinib is able to cross the blood 
brain barrier. 
 
Description: The lorlatinib drug substance is a white to off-white powder. 
 
How Supplied:  Lorlatinib is supplied by Pfizer, Inc. and distributed by the Pharmaceutical 
Management Branch, CTEP/DCTD/NCI.  Tablets contain drug substance, microcrystalline 
cellulose, dibasic calcium phosphate anhydrous, sodium starch glycolate, and magnesium 
stearate. Tablets are packaged in 30-count bottles in the following strengths: 
• 25 mg tablet: 8 mm round, tan, immediate release film-coated, debossed with “Pfizer” 
on one side and “25” and “LLN” on the other side  
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• 100 mg tablet: 8.5 mm × 17 mm oval, lavender, immediate release, film-coated, 
debossed with “Pfizer” on one side and “LLN 100” on the other side  
 
The film-coating contains hydroxypropyl methylcellulose (HPMC) 2910/hypromellose, 
lactose monohydrate, macrogol/polyethylene glycol (PEG) 3350, triacetin, titanium 
dioxide, ferrosoferric oxide/black iron oxide, and iron oxide red. 
 
Storage: Store at room temperature 20° to 25°C (68° to 77°F), excursions permitted 
between 15 to 30°C (59 to 85°F). 
 
If a storage temperature excursion is identified, promptly return lorlatinib to between 15 and 
30°C and quarantine the supplies.  Provide a detailed report of the excursion (including 
documentation of temperature monitoring and duration of the excursion) to 
PMBAfterHours@mail.nih.gov for determination of suitability. 
 
Stability: Refer to the package label for expiration.  Dispense in the original container. 
 
Route of Administration: Oral administration.  May be administered without regard to 
food.  
 
Potential Drug Interactions: Lorlatinib is primarily metabolized by CYP3A4 and 
UGT1A4, with minor contributions from CYP2C8, CYP2C19, CYP3A5, CYP1A2, and 
UGT1A3.  Avoid concomitant use of strong CYP3A4/5 inhibitors and strong to moderate 
CYP3A4/5 inducers.  Exercise caution with concomitant use of moderate CYP3A4/5 
inhibitors.  Lorlatinib is a time-dependent inhibitor as well as inducer of CYP3A4/5.  
Avoid concomitant use of CYP3A4/5 substrates with a narrow therapeutic index.  
Lorlatinib is a weak inducer of CYP2B6, CYP2C9, and UGT isoforms.  Use caution with 
coadministration of CYP2B6, CYP2C9, and UGT substrates.  Lorlatinib is a moderate 
inducer of P-gp.  Coadministration of lorlatinib with P-gp substrates with narrow 
therapeutic indices should be avoided. 
 
Lorlatinib may have the potential to inhibit P-gp, BCRP, OCT1, MATE1, OATP1B1, 
OATP1B3, and OAT3.  In vitro studies indicate that clinical interactions with substrates 
of these transporters are unlikely to occur. 
 
 
Patient Care Implications: Females of childbearing potential and partners of patients 
during treatment must use adequate contraception during treatment and for a minimum of 
3 months after the last dose of lorlatinib. 
 
9.7.1 Subjects must be enrolled and assigned to the lorlatinib treatment arm prior to 
submitting the agent request to PMB. See section 9.1.1 
 
9.7.2 Availability/Supply  
Lorlatinib tablets are provided by Pfizer Pharma and distributed by the DCTD/NCI. 
Lorlatinib will be supplied to patients on study free of charge.  
 
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9.8 
Commercial Agent: Pemetrexed (NSC# 698037) 
9.8.1 Product Description 
 
Dosage Form: 50mg or 100mg as a white to light-yellow or green-yellow lypholized 
powder in single-dose vials for reconstitution for intravenous infusion. 
 
Active ingredient: pemetrexed 
 
Inactive ingredients: mannitol, hydrochloric acid and/or sodium hydroxide may be 
added to adjust pH. 
 
Packaging: carton containing one single-dose vial of 50mg or 100mg pemetrexed 
 
9.8.2 Availability/Supply 
 
Drug will be supplied commercially. Please see Section 5.2 for administration 
instructions. Please refer to the current FDA approved package insert provided with each 
drug and the site-specific pharmacy for toxicity information and instructions for drug 
preparation, handling and storage. 
 
Patient Care Implications: Females of childbearing potential must use adequate 
contraception for 6 months during treatment and after the last dose. Males with female 
partners must use adequate contraception during treatment and for 3 months after the last 
dose. 
 
9.9 
Commercial Agent: Cisplatin (NSC# 119875) 
9.9.1 Product Description 
 
Dosage Form: Intravenous infusion; intravenous powder for solution 
 
Active ingredient: cisplatin 
 
Inactive ingredients: sodium chloride, hydrochloric acid, sodium hydroxide, water 
 
Packaging: 50mL or 100mL per vial 
 
9.9.2 Availability/Supply 
 
Drug will be supplied commercially. Please see Section 5.2 for administration 
instructions. Please refer to the current FDA approved package insert provided with each 
drug and the site-specific pharmacy for toxicity information and instructions for drug 
preparation, handling and storage. 
 
Patient Care Implications: Females of childbearing potential must use adequate 
contraception during treatment and for 6 months after the last dose. Male patients must 
use highly effective contraception for a total of 6 months after last dose of chemotherapy. 
 
9.10 
Commercial Agent: Carboplatin (NSC# 241240) 
9.10.1 Product Description 
 
Dosage Form: Intravenous infusion; intravenous powder for solution 
 
Active ingredient: carboplatin 
 
Inactive ingredients: mannitol, water 
Packaging: Injectable solution is packaged in vials of 50, 150, 450 and 600mg. 
 
9.10.2 Availability/Supply 
 
Drug will be supplied commercially. Please see Section 5.2 for administration 
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instructions. Please refer to the current FDA approved package insert provided with each 
drug and the site-specific pharmacy for toxicity information and instructions for drug 
preparation, handling and storage. 
 
Patient Care Implications: Females of childbearing potential must use adequate 
contraception during treatment and for 6 months after the last dose. Male patients must 
use highly effective contraception for a total of 6 months after last dose of chemotherapy. 
 
10. PATHOLOGY/BIOSPECIMEN (17-FEB-2020) 
10.1 
Mandatory Central Pathology Review for Integrated Marker Testing (17-FEB-2020)  
10.1.1 Prospective Review: Submission of tissue and blood to Foundation Medicine after 
patient enrollment is mandatory for all patients.  
• Foundation Medicine (FMI) performs pathology review on all samples received and 
analyzed as per standard quality control procedures. Please refer to Appendices I-IV 
for guidelines around appropriate tissue preparation and specifications around 
FoundationOne®CDx and FoundationOne®Liquid testing.  
• For all samples tested at Foundation Medicine, pathology review is included in the 
average turn-around-time of 14 calendar days from time of sample receipt to sample 
reporting.   
• Standard Foundation Medicine testing requires the submission of a complete 
pathology report for each patient. Foundation Medicine will perform an initial 
pathology review of all submitted samples to confirm appropriate disease ontology 
classification. 
▪ Any discrepancies between Foundation Medicine pathology review and diagnosis 
noted on the original pathology report will be immediately communicated to the 
ordering provider.  The final report diagnosis is at the discretion of the ordering 
provider and their pathologist. 
• Special Foundation Medicine FFPE and Blood Kits with prepaid labels can be 
requested from the Foundation Medicine 
(clinical.operations@foundationmedicine.com) 
 
10.1.2 Please refer to Section 15 for markers to be tested and their usage. 
10.1.3 Testing requirements and reporting: 
• Samples should be shipped in kit provided by Foundation Medicine. H&E Slide and 
block or H&E slide and 10 unstained slides (5 microns thick). See Appendix II for 
further details. 
• Blood samples collected in special tubes, in the kit provided by Foundation Medicine 
(See Appendix IV)  
• Samples must be sent to Foundation Medicine after the patient is enrolled to NRG-
LU003. 
• All testing will be performed in a CLIA-certified and licensed testing facility, with 
results reported to NRG Oncology. 
• NRG Oncology will then notify the enrolling institution they may proceed to step 2 
registration. 
• In the event that a patient experiences progression following study entry, the 
complete report from Foundation Medicine may be requested from NRG Oncology 
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Data Management (see cover page for contact information). 
 
10.1.4 Testing must be completed within 14-21 days upon receipt. Method of testing: [e.g., 
IHC, RT-PCR, FISH, etc.] 
o FoundationOne®CDx utilizes a hybrid-capture, next-generation sequencing 
testing method on solid tissue biopsies. For more information, please refer to 
the technical specifications as described in Appendix I.  
o FoundationOne®Liquid  utilizes a hybrid-capture, next-generation sequencing 
testing method on liquid (blood) biopsies. For more information, please refer 
to the technical specifications as described in Appendix III.  
o Specimen requirements FoundationOne®CDx: please refer to the specimen 
preparation instructions as described in Appendix II. 
o FoundationOne®Liquid : please refer to the specimen preparation instructions 
as described in Appendix IV.    
• Test report range  
o Results from FoundationOne®CDx and FoundationOne®Liquid  testing will 
specify genomic alterations, as listed in Table 1 of Section 15.1.  
• Actionable values 
o FoundationOne®CDx: please refer to the performance specifications as 
described in Appendix I. 
o FoundationOne®Liquid : please refer to the performance specifications as 
described in Appendix III.  
• Invalid test results:  When testing cannot be performed within the validated 
parameters of a test, the result is an “invalid” result.   
 
Failed Reports: 
o If Foundation Medicine is unable to detect any genomic alterations in the 
specimen, either an alternate sample, if provided, will be tested, or a failed report 
will be generated. 
 
Qualified Reports:  
o In certain instances, Foundation Medicine does issue a Qualified Report which 
includes detected alterations but may reflect the potential of additional alterations 
that may have been detected had the specimen been of higher quality. Factors 
which may lead to a Qualified Report include the following: A second DNA 
signature: The presence of a second individual's DNA in the tested patient's 
specimen. The “contamination” can occur as a result of a past transplant 
procedure, or specimen mishandling by the outside institution. In cases where 
contamination is suspected, the ordering provider may be consulted to clarify 
transplant history. 
o Gender discordance: Gender is confirmed as part of standard quality control 
metrics. The sex chromosome signals are expected to match the reported gender 
(e.g. if the patient is male, Foundation Medicine would expect to detect the Y 
chromosome in the subject’s sample). If there is not a match, the ordering 
provider may be consulted to clarify the transplant history. 
o Low coverage: If is specimen is of suboptimal quality, often the Foundation 
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Medicine laboratory will be unable to read over each part of the DNA sequence 
enough times for the assay's requirements. For FoundationOne®CDx, median 
coverage must be ≥ 250X or the report may be qualified. For FACT, median 
coverage must be ≥ 5000X. 
o GC bias: With a suboptimal sample, there may be more GC nucleotide signals 
than AT signals. If the sample has been exposed to excessive heat while being 
embedded, is an older sample, or has been oxidized, an artificially higher signal 
level ("GC bias") can be created, which gives the impression of a copy number 
amplification when one is not actually present. This results in a reduced ability to 
detect low-level copy number amplifications. 
o Low tumor purity: Tumor content is assessed by both the Foundation Medicine 
Pathology and Computational Biology teams. If the tumor purity is determined to 
be less than 20%, the ability to detect all present genomic alterations will be 
dramatically reduced.  
o Low Reference Coverage: Two quality control samples are sequenced concurrent 
to test samples in order to confirm median coverage. If both control samples fail 
to report a median coverage of at least 250x, all samples on the plate would be 
considered unsuccessful. 
 
• Location of testing 
FoundationOne®CDx and FoundationOne®Liquid testing will occur in a Foundation 
Medicine Laboratory. Samples should be shipped after the patient is enrolled to 
NRG-LU003 and with the NRG-LU003 patient identifier to:  
 
• Cambridge Accessioning 
Foundation Medicine, Inc 
150 Second Street 
Cambridge, MA 02141, USA 
 
• Contact Information: 
Email: clinical.operations@foundationmedicine.com 
Phone: 617.418.2200 
 
10.1.5 Tissue Submission for testing:  See Biospecimen Submission tables below in Section 
10.2. 
 
10.2 
Biospecimen Submission Tables (17-FEB-2020) 
10.2.1 Mandatory Specimen Submissions: Submission of tissue and blood to Foundation 
Medicine is mandatory after enrollment to NRG-LU003 for all patients. 
See Appendix II and Appendix IV for Foundation medicine detailed specimen 
collection/processing/shipping instructions. 
 
Mandatory Study Description #1 [for eligibility determination] 
 
1) H&E slide and unstained slides are required to be submitted in a Foundation Medicine kit for 
central review for eligibility  
2) Peripheral blood is required to be submitted in a Foundation Medicine Kit for blood analysis 
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3) Required Forms: Specimen Transmittal (SP) form, pathology report. All forms must be 
completely filled out with an NRG Label including the Study #, Case #, NRG Institution name 
and # or Institution NCI ID, and patient initials. The pathology accession number and date of 
procedure must remain visible on the pathology report but all other PHI information must be 
redacted/removed. 
4) Kits: FFPE and Blood Kits should be requested from Foundation Medicine in advance of patient 
enrollment (clinical.operations@foundationmedicine.com) 
5) Shipping costs: Fedex label will be provided in the Foundation Medicine kit for samples being 
shipped to Foundation Medicine. Foundation Medicine will incur cost of returns. 
6) Results will be reported to NRG Oncology within 14 days of receipt of samples. 
7) Residual Material:  
a. All residual material will be shipped to the NRGBB-San Francisco (NRGBB-SF) by 
Foundation Medicine following analysis. Samples will be banked for patients who 
consented to banking, or if requested by site, will be returned or destroyed. 
 
Ship all biospecimens for mandatory central review in the Foundation Medicine kit for this trial to:  
Cambridge Accessioning Foundation Medicine Inc 
150 Second Street 
Cambridge, MA 02141 
clinical.operations@foundationmedicine.com 
phone: 617.418.2200 
 
Do NOT ship the required Foundation Medicine samples to the NRGBB, this will result in delays in 
central review testing. 
Specimen Type  
Collection 
Time Points 
Collection Information 
and  
Requirements/Instructions 
for Site 
Shipping  
See protocol-specific website for detailed 
specimen collection and shipment 
instructions 
FoundationOne®C
Dx 
 
FFPE Tissue: H&E 
Slide and Block 
(including core-
needle biopsies, 
fine-needle 
aspirates, and 
effusion cytologies) 
 
or  
 
10 unstained slides 
(4-5 microns thick) 
+ 1 H&E slide  
Prior to Step 
1 registration 
Please refer to Appendix II 
for Specimen Instructions 
 
Ship by overnight using prepaid labels 
provided in kit. Refer to Appendix II for 
sample shipment information.  
FoundationOne®Li
quid   
 
Peripheral whole 
blood (two 8.5mL 
tubes) 
 
Prior to Step 
1 Registration 
and 30 days 
post-
treatment (at 
progression) 
 
Please refer to Appendix IV 
for Specimen Instructions 
Ship Ambient with cold pack by overnight 
courier to Foundation Medicine using prepaid 
labels in kit: 
 
Tracking information must be sent day of 
shipment to  
clinical.operations@foundationmedicine.com 
 
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10.2.2 Optional Specimen Submissions 
DO NOT Ship required Foundation Medicine kits to the NRGBB, please send required 
specimens to Foundation Medicine as per section 10.2.1 Only optional banking samples 
should be shipped to NRGBB-SF. 
 
Patients must be offered the opportunity to consent to optional specimen collection. If the 
patient consents to participate, the site is required to submit the patient’s specimens as 
specified per protocol. Sites are not permitted to delete the specimen component from the 
protocol or from the sample consent. 
 
No studies will be conducted with the optional biospecimens without prior approval from 
CTEP.  An amendment for any correlative science studies to be performed on biological 
samples will be submitted to CTEP, NCI for review and approval according to NCTN 
guidelines. Amendments to the protocol and/or proposals for use of banked tissue or 
blood samples will include the appropriate background, experimental plans with assay 
details, and a detailed statistical section. Samples for testing will not be released for 
testing until the appropriate NCI approvals have been obtained. 
 
See detailed specimen collection/processing/shipping instructions on the protocol-
specific website. 
 
Specimen Collection for Banking for Future Research 
Specimens are being collected for future translational research projects. 
1) Required Forms: For FFPE samples: For patients that consented to banking an ST form 
and redacted pathology report must be also submitted to the NRGBB-SF at 
NRGBB@ucsf.edu or fax 415-476-5271. All forms must be completely filled out with an 
NRG Label including the Study #, Case #, NRG Institution name and # or Institution NCI 
ID, and patient initials. The pathology accession number and date of procedure must 
remain visible on the pathology report but all other PHI information must be 
redacted/removed. 
2) Banking kits are available for frozen biospecimens from the NRGBB-SF. Sites should 
include the following information in their email:  Sites ship to Fed Ex address with room 
number, confirm site has IRB approval for study, how many patients site enrolled in past 
month.  
Detailed Processing and shipping instructions are provided on the protocol-specific page 
of the CTSU website.   
3) Shipping days for Frozen Specimens: Monday-Wednesday (U.S. sites). Check NRG 
Broadcasts for bank holiday closures. We are unable to accept shipments on Saturdays or 
holidays. Check Fed Ex site for storm delays and do not ship during severe weather. 
4) Shipping costs: A single use prepaid Fed Ex label is included for banking samples from 
each case in LU003 kits provided to the site for batch shipping frozen biospecimens to 
the NRGBB-SF. Ship all Biospecimens for banking only to: 
NRG Oncology Biospecimen Bank – San Francisco 
2340 Sutter Street- Room S341 
UCSF  
San Francisco, CA 94115 
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415-476-7864/Fax 415-476-5271 
Email: NRGBB@ucsf.edu 
 
DO NOT Ship required Foundation Medicine kits to the NRGBB. 
 
For questions about banking biospecimens contact:  
NRG Oncology Biospecimen Bank – San Francisco 
NRGBB@ucsf.edu   
Phone: 415-476-7864/Fax 415-476-5271 
Specimen Type   
Collection Time Points 
 
Collection Information and  
Requirements/Instructions for 
Site 
Shipping 
 
H&E slide(s) of 
Primary tumor and 
FFPE block or 
unstained slides 
 
Pre-treatment and at 
progression 
 
Forms: ST Forms, Pathology 
Forms: Copies of submission 
Forms and  Pathology reports 
should be emailed to the NRGBB  
 
For patients that consented to 
banking- These pre-treatment 
samples will come from 
Foundation Medicine after testing 
is completed. The progression 
sample should be sent to 
NRGBB-San Francisco for 
banking.  
 
 
Forms should be 
emailed/faxed to 
NRGBB@ucsf.edu / 415-
476-5271 for all patients 
who consented to 
banking.  
 
The leftover pre-treatment 
tissue will be shipped 
from Foundation 
Medicine to NRGBB-San 
Francisco. Sites do not 
have to ship these to the 
NRGBB. 
 
Sites must ship the 
progression FFPE sample 
Ambient to NRGBB-San 
Francisco.  Use of cold 
packs are encouraged 
during warm weather.  
Whole Blood- one 5-
10 ml EDTA tube 
 
Cycle 3, Day 1 during 
treatment 
 
30 days post treatment 
(+/- 3 days) 
 
Collect blood, mix and aliquot 1-
1.5 ml of whole blood per vial 
into three 2ml cryovials.  Store at 
-80°C 
(-70°C to -90°C) until ready to 
batch ship on Dry ice.  
 
Ship on dry ice by 
overnight courier to 
NRGBB-San Francisco  
Plasma- EDTA tube 
 
5-10 mL of 
anticoagulated whole 
blood in EDTA tube #1 
(purple/ lavender top) 
and centrifuge 
 
At progression 
 
Frozen plasma samples containing 
minimum 0.5 mL per aliquot in 1 
mL cryovials (five) 
 
Plasma sent frozen in batch 
shipments on dry ice via 
overnight carrier to NRGBB-
SF 
 
11. MODALITY REVIEWS 
The Medical Oncology study chairs will perform a Quality Assurance Review after NRG 
Headquarters has received complete data for the first 20 cases enrolled. The Medical Oncology 
study chairs will perform the next review after NRG Headquarters has received complete data 
for the next 20 cases enrolled. The final cases will be reviewed within 3 months after this study 
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has reached the target accrual or as soon as NRG Headquarters has received complete data for 
all cases enrolled, whichever occurs first. 
 
12. SPECIAL STUDIES (NON-TISSUE) 
Not applicable for this protocol. 
 
13. ASSESSMENT OF EFFECT 
13.1 
Antitumor Effect – Solid Tumors  
For the purposes of this study, patients should be re-evaluated for response every 2 cycles  
Response and progression will be evaluated in this study using Response Evaluation 
Criteria in Solid Tumors (RECIST) guideline (version 1.1)  
The following general principles must be followed: 
1. To assess objective response, it is necessary to estimate the overall tumor burden at 
baseline to which subsequent measurements will be compared. All baseline 
evaluations should be performed as closely as possible to the beginning of treatment 
and never more than four weeks before registration. 
2. Measurable disease is defined by the presence of at least one measurable lesion. 
3. All measurements should be recorded in metric notation by use of a ruler or calipers.  
4. The same method of assessment and the same technique must be used to characterize 
each identified lesion at baseline and during follow-up.  
 
13.1.1 Definitions 
Intracranial response 
Intracranial response will be determined using modified RECIST 1.1 (Long et al, 2012) 
 
Evaluable for Objective Response 
Only those patients who have measurable disease present at baseline and have begun 
protocol therapy will be considered evaluable for response. These patients will have their 
response classified according to the definitions stated below. 
 
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. 
NOTE: 
Tumor lesions that are situated in a previously irradiated area might or might 
not be considered measurable. If the investigator thinks it appropriate to include them, the 
conditions under which such lesions should be considered must be defined in the 
protocol. 
 
Malignant Lymph Nodes 
To be considered pathologically enlarged and measurable, a lymph node must be ≥ 15 
mm in short axis when assessed by CT scan (CT scan slice thickness recommended to be 
no greater than 5 mm).  At baseline and in follow-up, only the short axis will be 
measured and followed. 
 
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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 of the diameters will be used as reference to further characterize any 
objective tumor regression in the measurable dimension of the disease. 
 
Non-target Lesions 
All other lesions (or sites of disease) including any measurable lesions over and above the 
5 target lesions should be identified as non-target lesions and should also be recorded at 
baseline.  Measurements of these lesions are not required, but the presence or absence of 
unequivocal progression of each should be noted throughout follow-up.  
 
13.1.2 Methods for Evaluation of 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 up to 4 weeks before step 2 registration. 
The same method of assessment and the same technique must 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 in 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.  
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 
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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 must 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. 
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:  
1. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of 
PD based on a new lesion. 
2. 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. 
3. 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. 
 
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. 
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13.2 
Response Criteria 
13.2.1 Evaluation of Target Lesions 
Complete Response (CR): Disappearance of all target lesions. Any pathological lymph 
nodes (whether target or non-target) must have reduction in short axis to < 10 mm. 
Partial Response (PR): At least a 30% decrease in the sum of the diameters of target 
lesions, taking as reference the baseline sum diameters 
Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target 
lesions, taking as reference the smallest sum on study (this includes the baseline sum if 
that is the smallest on study). In addition to the relative increase of 20%, the sum must 
also demonstrate an absolute increase of at least 5 mm. 
NOTE: The appearance of one or more new lesions is also considered progression. 
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. (Note: a 
change of 20% or more that does not increase the sum of the diameters by 5 mm or more 
is coded as stable disease) 
To be assigned a status of stable disease, measurements must have met the stable disease 
criteria at least once after study entry at a minimum interval of six weeks.  
 
13.2.2  Evaluation of Non-Target Lesions 
Complete Response (CR): Disappearance of all non-target lesions. All lymph nodes must 
be non-pathological in size (< 10 mm short axis) 
Non-CR/Non-PD: Persistence of one or more non-target lesion(s. 
Progressive Disease (PD): Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions (see Section 6.1.4.3). Unequivocal progression 
should not normally trump target lesion status. It must be representative of overall disease 
status change, not a single lesion increase. 
When the patient also has measurable disease, there must be an overall level of 
substantial worsening in non-target disease such that, even in the presence of SD or PR in 
target disease, the overall tumor burden has increased sufficiently to merit 
discontinuation of therapy.  A modest “increase” in the size of one or more non-target 
lesions is usually not sufficient to qualify for unequivocal progression status. The 
designation of overall progression solely on the basis of change in non-target disease in 
the face of SD or PR of target disease will therefore be extremely rare. 
When the patient only has non-measurable disease, the increase in overall disease burden 
should be comparable in magnitude to the increase that would be required to declare PD 
for measurable disease: i.e., an increase in tumor burden from “trace” to “large”, an 
increase in nodal disease from “localized” to “widespread”, or an increase sufficient to 
require a change in therapy. 
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). 
 
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13.2.3 Evaluation of New Lesions 
The appearance of new lesions constitutes Progressive Disease (PD). 
A growing lymph node that did not meet the criteria for reporting as a measurable or non-
measurable lymph node at baseline should only be reported as a new lesion (and therefore 
progressive disease) if it:  
a) Increases in size to ≥ 15 mm in the short axis, or  
b) There is new pathological confirmation that it is disease (regardless of size). 
c) New effusion or ascites that appears during treatment should only be reported as a 
new lesion (and therefore progressive disease) if it has cytological confirmation of 
malignancy. 
 
13.2.4 Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the treatment 
until disease progression/recurrence or non-protocol therapy (taking as reference for 
progressive disease the smallest measurements recorded since the treatment started). The 
patient’s best response assignment will depend on the achievement of both measurement 
and confirmation criteria. 
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For Patients with Measurable Disease (i.e., Target Disease) 
Target 
Lesions 
Non-Target  
Lesions 
New 
Lesions* 
Best Overall 
Response 
Remarks  
CR 
CR 
No 
CR 
 
CR 
Non-CR/Non-PD*** 
No 
PR 
 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD***/not evaluated 
No 
PR 
SD 
Non-PD***/not evaluated 
No 
SD 
Documented at least 
once ≥ X wks. from 
study entry 
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. 
** In exceptional circumstances, unequivocal progression in non-target lesions may be 
accepted as disease progression. 
***PD in non-target lesions should not normally trump target lesion status. It must be 
representative of overall disease status change, not a single lesion increase. Please refer to 
the Evaluation of Non-Target Lesions – Progressive Disease section for further 
explanation. 
NOTE: Patients with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be 
reported as “symptomatic deterioration.” Every effort should be made to document 
the objective progression even after discontinuation of treatment. 
 
13.2.5 Duration of Response 
Duration of Overall Response 
The duration of overall response is measured from the time measurement criteria are met 
for CR or PR (whichever is first recorded) until the first date that recurrent or progressive 
disease is objectively documented (taking as reference for progressive disease the 
smallest measurements recorded since the treatment started). 
 
The duration of overall CR is measured from the time measurement criteria are first met 
for CR until the first date that progressive disease is objectively documented. 
 
 
Duration of Stable Disease 
Stable disease is measured from the start of the treatment until the criteria for progression 
are met, taking as reference the smallest measurements recorded since the treatment 
started, including the baseline measurements.  
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To be assigned a status of stable disease, measurements must have met the stable disease 
criteria at least once after study entry at a minimum interval of eight weeks 
 
14. 
DATA AND RECORDS (20-MAY-2019) 
14.1 
Data Management/Collection (20-JAN-2022) 
Medidata Rave is a clinical data management system being used for data collection for this 
trial/study. Access to the trial in Rave is controlled through the CTEP-IAM system and 
role assignments.  
 
Requirements to access Rave via iMedidata: 
• 
A valid CTEP-IAM account; and  
• Assigned a Rave role on the LPO or PO roster at the enrolling site of: Rave CRA, 
Rave Read Only, Rave CRA (LabAdmin), Rave SLA, or Rave Investigator. 
              
            Rave role requirements: 
• Rave CRA or Rave CRA (Lab Admin) role must have a minimum of an Associate 
Plus (AP) registration type; 
• Rave Investigator role must be registered as a non-Physician Investigator 
(NPIVR) or Investigator (IVR); and 
• Rave Read Only role must have an Associates (A) registration type. 
 
Refer to https://ctep.cancer.gov/investigatorResources/default.htm for registration types 
and documentation required. 
Upon initial site registration approval for the study in Regulatory Support System (RSS), 
all persons with Rave roles assigned on the appropriate roster will be sent a study 
invitation e-mail from iMedidata. To accept the invitation, site staff must log in to the 
Select Login (https://login.imedidata.com/selectlogin) using their CTEP-IAM username 
and password, and click on the accept link in the upper right-corner of the iMedidata 
page. Site staff will not be able to access the study in Rave until all required Medidata 
and study specific trainings are completed. Trainings will be in the form of electronic 
learnings (eLearnings), and can be accessed by clicking on the link in the upper right 
pane of the iMedidata screen. If an eLearning is required and has not yet been taken, the 
link to the eLearning will appear under the study name in iMedidata instead of the Rave 
EDC link; once the successful completion of the eLearning has been recorded, access to 
the study in Rave will be granted, and a Rave EDC link will display under the study 
name.  
Site staff that have not previously activated their iMedidata/Rave account at the time of 
initial site registration approval for the study in RSS will also receive a separate invitation 
from iMedidata to activate their account. Account activation instructions are located on 
the CTSU website in the Data Management section under the Rave resource materials 
(Medidata Account Activation and Study Invitation Acceptance). Additional information 
on iMedidata/Rave is available on the CTSU members’ website in the Data Management 
> Rave section at www.ctsu.org/RAVE/ or by contacting the CTSU Help Desk at 1-888-
823-5923 or by e-mail at ctsucontact@westat.com.  
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14.2 
Instructions for Patients who Do Not Start Assigned Protocol Treatment  
If a patient does not receive any assigned protocol treatment, baseline and follow-up data 
will still be collected and must be submitted through Medidata Rave according to the 
schedule Completion Guidelines. 
 
14.3 
Summary of Data Submission 
Adverse event data collection and reporting, which are required as part of every clinical 
trial, are done to ensure the safety of patients enrolled in the studies as well as those who 
will enroll in future studies using similar agents. Adverse events are reported in a routine 
manner at scheduled times during the trial using Medidata Rave®. Additionally, certain 
adverse events must be reported in an expedited manner for more timely monitoring of 
patient safety and care. See Section 7 for information about expedited and routine 
reporting.  Summary of Data Submission: Refer to the CTSU website. 
 
See Section 8.3 for TRIAD account access and installation instructions. All imaging, 
anonymized via TRIAD, is securely stored in the IROC image archive at IROC 
Philadelphia QA Center. 
 
Summary of All Data Submission: Refer to the CTSU website  
 
14.4 
Data Quality Portal (20-JAN-2022) 
The Data Quality Portal (DQP) provides a central location for site staff to manage 
unanswered queries and form delinquencies, monitor data quality and timeliness, 
generate reports, and review metrics.  
 
The DQP is located on the CTSU members’ website under Data Management. 
The Rave Home section displays a table providing summary counts of Total 
Delinquencies and Total Queries. DQP Queries, DQP Delinquent Forms and the 
DQP Reports modules are available to access details and reports of unanswered 
queries, delinquent forms, and timeliness reports. Review the DQP modules on a 
regular basis to manage specified queries and delinquent forms. 
 
The DQP is accessible by site staff that are rostered to a site and have access to 
the CTSU website. Staff that have Rave study access can access the Rave study 
data using a direct link on the DQP. 
 
To learn more about DQP use and access, click on the Help icon displayed on the 
Rave Home, DQP Queries, and DQP Delinquent Forms modules. 
Note: Some Rave protocols may not have delinquent form details or reports specified on 
the DQP. A protocol must have the Calendar functionality implemented in Rave by the 
Lead Protocol Organization for delinquent form details and reports to be available on the 
DQP. Site staff should contact the LPO Data Manager for their protocol regarding 
questions about Rave Calendaring functionality.   
 
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14.5 
Rave-CTEP-AERS integration (20-JAN-2022) 
The Rave Cancer Therapy Evaluation Program Adverse Event Reporting System 
(CTEP-AERS) integration enables evaluation of post-baseline Adverse Events 
(AE) entered in Rave to determine whether they require expedited reporting, and 
facilitates entry in CTEP-AERS for those AEs requiring expedited reporting.    
All AEs that occur after baseline are collected in Medidata Rave using the 
Adverse Event form, which is available for entry at each treatment or reporting 
period, and used to collect AEs that start during the period or persist from the 
previous reporting period. The Clinical Research Associate (CRA) will enter AEs 
that occur prior to the start of treatment on a baseline form that is not included in 
the Rave-CTEP-AERS integration. AEs that occur prior to enrollment must begin 
and end on the baseline Adverse Events form and should not be included on the 
standard Adverse Events form that is available at treatment unless there has been 
an increase in grade. 
Prior to sending AEs through the rules evaluation process, site staff should verify 
the following on the Adverse Event form in Rave: 
• The reporting period (course/cycle) is correct; and 
• AEs are recorded and complete (no missing fields) and the form is query free.  
The CRA reports AEs in Rave at the time the Investigator learns of the event. If 
the CRA modifies an AE, it must be re-submitted for rules evaluation. 
Upon completion of AE entry in Medidata Rave, the CRA submits the AE for 
rules evaluation by completing the Expedited Reporting Evaluation form. Both 
NCI and protocol-specific reporting rules evaluate the AEs submitted for 
expedited reporting. A report is initiated in CTEP-AERS using information 
entered in Medidata Rave for AEs that meet reporting requirements. The CRA 
completes the report by accessing CTEP-AERS via a direct link on the Medidata 
Rave Expedited Reporting Evaluation form. 
In the rare occurrence, that Internet connectivity is lost; a 24-hour notification is 
to be made to CTEP by telephone at 301-897-7497. Once Internet connectivity is 
restored, the 24-hour notification that was phoned in must be entered immediately 
into CTEP-AERS using the direct link from Medidata Rave. 
Additional information about the CTEP-AERS integration is available on the 
CTSU website: 
• Study specific documents: Protocols > Documents> Education and 
Promotion; and   
• Expedited Safety Reporting Rules Evaluation user guide: Resources > CTSU 
Operations Information> User Guides. 
NCI requirements for SAE reporting are available on the CTEP website:  
• 
NCI Guidelines for Investigators: Adverse Event Reporting Requirements is 
available at 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeg
uidelines.pdf. 
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14.6 
Global Reporting/Monitoring 
This study will be monitored by the Clinical Data Update System (CDUS) version 3.0. 
Cumulative CDUS data will be submitted quarterly to CTEP by electronic means. 
Reports are due January 31, April 30, July 31, and October 31. 
 
15. 
STATISTICAL CONSIDERATIONS 
15.1 
Study Design (17-FEB-2020) 
This is a phase II biomarker-driven protocol designed to simultaneously evaluate the 
efficacy of multiple biomarker/ALK inhibitor combinations in previously treated ALK-
positive non-squamous NSCLC patients.  Depending on the mutation detected (including 
no mutation detected), patients will be either deterministically assigned to a particular 
agent or randomized to one of multiple agents, based on Table 15.1.  For patients with a 
given mutation, they will be assigned to ALK inhibitors according the pre-specified 
priority (denoted as “A”, “B”, “C” in Table 15.1) as they are sequentially accrued into the 
study over time.  Patients who have failed on a particular ALK inhibitor before will not 
be assigned to the same agent even if it is available for assignment per Table 15.1.  When 
randomization is used for treatment assignments, e.g., patients with mutation G1202, 
I1171, L1196 or no ALK mutation, their respective randomization ratio will be initially 
set with equal weights, and gradually adjusted during the trial conduct to minimize any 
difference between the numbers of patients treated with different  drugs, as patients’ prior 
ALK inhibitor treatment history are unknown.  The purpose of such adaptive 
randomization is to maximize the statistical power to address the primary objective, e.g., 
evaluating if a specific mutation is prognostic for a specific ALK inhibitor therapy (as 
compared to no ALK mutation).   
 
We assume 660 patients will be screened with 600 evaluable mutation analyses, and 
approximately 50% of these patients would be expected to have a relevant mutation. For 
patients with a mutation, the maximum number of evaluable patients to be treated with 
any ALK inhibitor/mutation combination is 40.  For patients with no ALK resistance 
mutations, the maximum number of evaluable patients to be treated with any ALK 
inhibitor is 60.  
 
Table 15.1: Treatment assignments based on tumor mutations (600 evaluable patients 
total)  
A= initially available for assignment (not applicable if previously treated with that agent) 
B= available for assignment only after A slots filled for that mutation (not applicable if 
previously treated with that agent) 
C= available for assignment only after A and B slots filled for that mutation (not 
applicable if previously treated with that agent) 
 
 
Mutation 
Projected 
Prevalence 
(%)* 
lorlatinib 
LDK378 
(ceritinib) 
alectini
b 
brigatinib 
ensartinib 
crizotinib 
Pemetrexed 
+ 
Cisplatin or 
Carboplatin 
G1202 
23.6 
A 
 
 
A 
 
 
 
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(including 
G1202del and 
G1202R)  
C1156Y 
1.8 
A 
 
C 
B 
 
 
 
I1171  
7.3 
A 
A 
 
A 
 
 
 
L1196 
(including 
L1196M) 
5.5 
A 
C 
B 
A 
A 
 
 
V1180 
1.8 
A 
C 
 
B 
 
 
 
F1174 
1.8 
B 
 
A 
C 
 
 
 
Compound 
mutation 
5.5 
A 
 
 
 
 
 
 
ALK L1198F 
mutation 
(alone or in 
combination 
with another 
ALK 
mutation) 
 
3.6 
 
 
 
 
 
A 
 
MET 
amplification 
7.3 
 
 
 
 
 
A 
 
No ALK-
resistance 
mutations** 
41.8 
A 
A 
A 
A 
A 
 
A 
 
*For illustration purpose only.  The mutation prevalence are based on literature or 
personal communications, which may be inaccurate.    
**Including no MET amplifications    
 
Compound mutation = two or more resistance mutation excluding those with L1198F 
L1189F/MET amplification = L1198F mutation alone or in combination, or no ALK 
mutation but any MET amplification 
 
If additional relevant information becomes available, patients with a specified mutation 
may be able to be treated with more than of the 5 agents specified in Table 1.  If other 
ALK mutations and relevant agents are discovered during the course of the trial, 
consideration by the trial investigators will be given to adding them to the trial by 
amendment. 
 
15.2 
Study Endpoints 
15.2.1 Primary Endpoint 
• Objective Response Rate (ORR), per investigator assessment 
 
15.2.2  Secondary Endpoints 
• Progression Free Survival (PFS), per investigator assessment 
• Duration of Response (DOR), per investigator assessment 
• Overall Survival (OS) 
• Intracranial Objective Response Rate, per investigator assessment  
• Safety profile 
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15.2.3 Correlative Science Endpoint 
• Agreement of biopsy mutation result and cfDNA mutation result 
 
15.3 
Primary Objectives Study Design (17-FEB-2020) 
15.3.1 Primary Hypothesis and Endpoints 
For each subsequent ALK inhibitor therapy, the primary hypothesis is that the presence 
of a relevant resistance mutation (G1202/C1156Y /I1171/L1196/ V1180/ F1174/ 
compound mutation) is prognostic for objective response.  
 
For the no ALK-resistance mutation patients, the primary hypothesis is to assess whether 
subsequent pemetrexed based chemotherapy improves objective responses as compared 
to ALK inhibitor therapies.  
 
For the mutated cohorts (ALK L1189F or MET amplification) treated with crizotinib, the 
primary hypothesis is that crizotinib will result in a non-negligible response rate in 
respective patient cohorts. 
 
The objective response rate (ORR) is defined as the number of subjects whose best 
overall response (BOR) of complete response (CR) or partial response (PR) divided by 
the number of evaluable subjects. BOR is defined as the best response designation, as 
determined by the investigators, recorded between the date of second step registration 
and the date of objectively documented progression per RECIST 1.1 or the date of 
subsequent anticancer therapy, whichever occurs first. For subjects without documented 
progression or subsequent anticancer therapy, all available response designations will 
contribute to the BOR determination. 
 
15.3.2 Primary Endpoint Analysis Plan 
For each ALK inhibitor therapy, the primary analysis is to compare the response rate for 
those patients who have the relevant mutation (G1202/C1156Y /I1171/L1196/ 
V1180/F1174/compound mutation) to those patients who receive the same ALK inhibitor 
therapy who have no mutations using Fisher’s exact test. All patients who receive at least 
one dose of an ALK inhibitor therapy will be included. We anticipate the ORR in the 
mutation group to be high (e.g., 50%), and the non-mutation group to be low (e.g., 10%). 
One-sided alpha level of 0.05 will be used.   
 
For the no ALK-resistance mutation patients, the primary analysis is to compare patients 
who are randomized concurrently to the pemetrexed with cisplatin or carboplatin arm and 
the respective ALK inhibitor therapy arm, e.g., intent-to-treatment population.  The 
response rates will be compared using Fisher’s exact test. We anticipate the ORR in the 
non-targeted therapy to be moderately high (e.g., 35%), and the ALK inhibitor group to 
be low (e.g., 10%).  One-sided alpha level of 0.05 will be used.   
 
For cohorts with ALK mutation of L1189F or MET amplification, the primary analysis 
will be based on the optimal Two-Stage design testing the null hypothesis that ORR≤20% 
vs. the alternative ORR≥50% (See Section 15.4).  All patients who receive at least one 
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dose of their assigned treatment regimen will be included.   
 
The primary analysis of each mutation/agent combination cohort will be conducted when 
each cohort meets its accrual target and are potentially followed for at least 24 weeks 
follow-up for the purpose of evaluating BOR status.  The ORR for each 
mutation/regimen combination and the associated 95% confidence intervals (using 
Clopper-Pearson method) will also be reported.   
 
15.3.3 Sample Size and Power Calculations 
 
Given the limited knowledge of the ALK mutation prevalence, this study cannot be 
designed to make an explicit hypothesis testing with uniform power and type 1 error 
consideration across all possible mutation/ALK inhibitor combinations.  Instead, the 
study is designed to exploit the logistical efficiency of a protocol to simultaneously 
evaluate as many mutation/ALK inhibitor combinations as possible (with proper 
prioritizations).   
 
For the primary objective of evaluating the prognostic value of mutations with respect to 
any specific ALK inhibitor, the statistical power for a particular comparison depends on 
the sample sizes actually accrued and the one-sided type 1 error specified.  For example, 
for each ALK inhibitor, with one-sided 0.05 level testing, there would be 90% power to 
detect an improvement in response rates from 10% (n=40, no mutations) to 45% (n=25, a 
specific mutation), but only 81% power to detect an improvement in response rates from 
10% (n=40, no mutations) to 50% (n=12, a specific mutation).   
 
For the primary objective of evaluating the preferred regimen for no ALK-resistance 
mutation patients, with one-sided type 1 error of 0.05, there would be 78% power to 
detect an improvement in response rates from 10% to 35% (n=40 for each no mutation 
cohort).    
 
These analyses need to be considered hypothesis generating because there are different 
mixes of patients in each group (in particular, different proportions of prior treatments). 
 
 
For patients with a mutation, the maximum number of evaluable patients to be treated 
with any ALK inhibitor/mutation combination is 40.  For patients with no ALK resistance 
mutations, the maximum number of evaluable patients to be treated with any ALK 
inhibitor or pemetrexed based chemotherapy is 60.  These maximum number of evaluable 
patients to be treated are chosen to address the primary objectives and be consistent with 
two-stage designs for each mutation/drug combination cohorts as delineated in Section 
15.4. 
 
15.4 
Study Monitoring of Primary Objectives (20-JAN-2022) 
For each mutation (or no resistance mutation)/regimen, a two-stage design will be used to 
provide an opportunity to stop accrual early if we see too few responses such that we can 
minimize the number of patients treated with highly unlikely efficacious agents.  The 
stopping criteria, however, are different for a mutation cohort and the no-ALK- mutation 
cohort. 
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For a no ALK-resistance mutation cohort treated with any ALK inhibitor or pemetrexed 
based chemotherapy, we consider an optimal two-stage design to evaluate non-negligible 
response rate by testing the null hypothesis that ORR≤5% vs. the alternative ORR≥20%. 
Such design has an expected sample size of 23.49 and a probability of early termination 
of 0.540.  If a given ALK inhibitor or pemetrexed based chemotherapy is actually not 
effective, there is a 0.093 probability of concluding that it is (the target 1-sided alpha was 
0.100). If the drug is actually effective, there is a 0.098 probability of concluding that it is 
not (the target power was 90%).  After 12 eligible patients have been accrued and treated 
with at least one cycle of a given ALK inhibitor, accrual to that inhibitor will be 
suspended.  Accrual will resume when at least one BOR of CR or PR is observed from 
the first 12 eligible patients; if one patient was already reported as having a BOR of CR 
or PR when the 12 patient accrual goal is reached, then accrual will not be suspended.   
Otherwise this no-mutation/drug combination cohort will be closed to accrual if none 
experience a BOR of either CR or PR after up to 24 weeks follow-up, in which case 
patients with no ALK-resistance mutations accrued in the future will be randomly 
assigned to the remaining available regimens. If patient accrual resumes after the stage 1 
assessment, the stage 2 analysis of the two-stage design will be conducted for a given 
regimen or pemetrexed based chemotherapy when 37 eligible patients become analyzable 
(treated with at least 1 cycle of the inhibitor and potentially followed for at least 24 
weeks).  The drug will be considered inactive if less than or equal to 3 patients with a 
BOR of CR or PR are observed out of the 37 patients. For a no-mutation cohort treated 
with any ALK inhibitor or pemetrexed based chemotherapy, the accrual will remain open 
until the stage 2 analysis demonstrates the inhibitor is inactive, or a total of 60 patients 
have been accrued in this mutation/inhibitor cohort.   
 
For a mutation cohort treated with any ALK inhibitor, we similarly consider an optimal 
two-stage design but with a higher bar of efficacy, i.e., to test the null hypothesis that 
ORR≤20% vs. the alternative ORR≥50% response rates. Such design has an expected 
sample size of 8.41 and a probability of early termination of 0.655.  If the ALK inhibitor 
is actually not effective for this particular mutation, there is a 0.085 probability of 
concluding that it is (the target 1-sided alpha was 0.100). If the ALK inhibitor is actually 
effective, there is a 0.184 probability of concluding that it is not (the target power was 
80%).  After 6 eligible patients have been enrolled and treated with at least one cycle of 
the ALK inhibitor, the accrual to that inhibitor will be suspended.  The accrual will 
resume when at least 2 BORs of CR or PR are observed from the first 6 eligible patients; 
if two patients were already reported as having a BOR of CR or PR when the 6 patient 
accrual goal is reached, then accrual will not be suspended.  If no or one response is 
observed from the first 6 eligible patients after up to 24 weeks follow-up, this 
mutation/ALK inhibitor cohort will be closed to accrual, in which case patients with the 
same mutation accrued in the future will be randomly assigned to the remaining available 
ALK inhibitors (when applicable).  If no ALK inhibitors are available for treatment 
assignment (including those with priority “B” or “C”), the accrual may remain open but 
the patients accrued after the patients required to complete the first stage analysis will not 
be included in the analysis of the first stage results.  If patient accrual resumes after the 
stage 1 assessment, the stage 2 analysis of the two-stage design will be conducted when 
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13 eligible patients become analyzable (treated with at least 1 cycle of the ALK inhibitor 
and potentially followed for at least 24 weeks).  The ALK inhibitor will be considered 
inactive for this mutation if less than or equal to 4 patients with a BOR of CR or PR are 
observed out of the 13 eligible patients. The accrual will remain open until the stage 2 
analysis demonstrates the inhibitor is inactive, or a total of 40 patients have been accrued 
in this mutation/inhibitor cohort.   
 
After the trial has accrued 100 patients, the accrual and frequency of mutations will be 
assessed.  If it appears that an insufficient number of patients are being seen with a given 
mutation, a protocol amendment may be considered to adjust the slot assignments to 
ensure sufficient patients are seen in the highest priority agents at that time.  For example, 
if it appears that insufficient I1171 patients are being seen, the three “A” slots for this 
mutation may be prioritized as A, B, and C slots instead. 
 
The NRG Oncology Data Monitoring Committee (DMC) will be informed when the 2-
stage design futility boundaries are met for each mutation/inhibitor cohort and no-
mutation/drug cohort.  In addition, DMC will review the study twice a year with respect 
to patient accrual and morbidity. An interim study summary report will be prepared at 
each meeting accordingly until all initial study results have been released.  In general, the 
interim reports will contain information about patient accrual rate, a projected completion 
date for the accrual phase, patient exclusion rates and reasons following registration, 
compliance rate of treatment delivery, distributions of pretreatment characteristics and 
important prognostic baseline variables, and the frequencies and severity of treatment-
related adverse events.  The interim reports will not contain the results of any efficacy 
analyses. 
 
The DMC also will review the study on an “as needed” basis.  
 
15.5 
Accrual/Study Duration Considerations 
Guarding against up to a 10% rate of patients whose biopsies are unsuitable for mutation 
assessment, the total number of patients to be screened is up to 660. During the first 6 
months following activation, little accrual is anticipated while the trial is being approved 
by institutional review boards (IRBs). Assuming a uniform monthly accrual rate of 8 
patients and minimal accrual in the first 6 months for ramp-up, we project the accrual for 
the trial may last approximately 7.4 years.  The rate of patients without evaluable biopsies 
will also be carefully monitored by the study team. If the rate is substantially different 
from the design assumptions, appropriate action plans, including protocol amendments 
may be made after discussions between NRG Oncology and NCI. 
 
15.6 
Secondary Endpoints and Statistical Analysis Plans 
15.6.1  Statistical Analysis Plan for Efficacy Endpoints 
The secondary efficacy endpoints include progression-free survival (PFS), duration of 
response (DOR), overall survival (OS), and intracranial objective response rate (ORR).  
They will be estimated for each mutation (or no mutation)/regimen combination. 
 
PFS is defined as the time from second step registration to the date of the first recorded 
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occurrence of disease progression or death from any cause (whichever occurs first), as 
determined by the investigator according to RECIST v1.1.   
 
OS is defined as the time from second step registration to the date of death from any 
cause.  
 
DOR is defined as the time from the first occurrence of a documented BOR of CR or PR 
to the first date of recorded disease progression or death from any cause (whichever 
occurs first), as determined by the investigator according to RECIST v1.1.  DOR will be 
derived for efficacy-evaluable patients (eligible patients with at least one cycle of ALK 
inhibitor) with a BOR of CR or PR. 
 
The Kaplan-Meier method will be used to estimate the distribution and median for PFS, 
OS, and DOR, with 95% confidence intervals constructed through use of the Brookmeyer 
and Crowley method. PFS and OS rates at specific time-points will also be estimated 
using the Kaplan-Meier method, with 95% confidence intervals calculated on the basis of 
Greenwood’s estimate for the variance.  
 
Intracranial objective response rate (ORR) is defined as the rate of CNS response among 
patients with known CNS metastasis but no prior CNS radiation therapy. Patients who 
required additional treatment (for their non-cranial systemic disease) will be considered 
as non-responders (if they have not previously had an intra-cranial response). The 
associated 95% confidence intervals (using Clapper-Pearson method) will also be 
reported. 
 
15.6.2 Statistical Analysis Plan for Safety Endpoints 
For each patient, the maximum severity of reported adverse events assessed using NCI 
Common Terminology Criteria for Adverse Events (CTCAE, v. 5.0) will be used in all 
summaries. Adverse events will be summarized regardless of relationship to protocol 
treatment as assessed by the investigator. All adverse events, adverse events leading to 
withdrawal, interruption or modification of protocol treatment, Grade ≥ 3 adverse events, 
and serious adverse events will be summarized. Deaths and cause of death will be 
summarized.  The rate of treatment-related adverse events will be reported with the 
frequency and severity (e.g., type, grade, and attribution). The safety analysis will be 
performed for cohorts if the respective stage 1 futility boundaries are not met.  
 
15.6.3 Statistical Analysis Plan for Correlative Sciences 
For each resistance mutation, the agreement of the biopsy result (present, absent, 
unavailable) and the cfDNA result (present, absent, unavailable) will be assessed at the 
end of the trial.  There will also be an interim assessment of these results after 200 
patients have been evaluated (accrual will not be suspended while awaiting these 
evaluations).  These interim results will be discussed with the FDA to determine whether 
the agreement is high enough so that cfDNA mutation results could be substituted for the 
biopsy results in the remainder of the trial.  
 
 
 
 
 
 
 
 
 
 
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APPENDIX I: ANALYSIS PLANS FOR CFDNA RESULTS    
 
Agreement of cfDNA and biopsy results will be considered separately for MET amplification 
and for the gene mutations.  Note that an eligibility requirement is that the patient have an 
evaluable biopsy results for MET amplification and the gene mutations, but not necessarily a 
evaluable cfDNA results.  Therefore, in the agreement tables that follow there is a category for 
unavailable cfDNA results but no such category for biopsy results.   As it is possible to obtain a 
tumor biopsy after an unavailable cfDNA result, the agreement estimated will be restricted to 
patients who have both evaluable biopsy and evaluable cfDNA results.  We will take the biopsy 
results as the reference standard.  However, it is possible that cfDNA results may in some cases 
be more reflective of the tumor’s biology than the biopsy results (because of tumor 
heterogeneity). 
 
These analysis plans will be reviewed with the FDA prior to examining any agreement results 
from this trial. 
 
Agreement for MET amplification results 
At the end of the trial, the following table will be completed. 
 
 
 
cfDNA result 
 
 
Present 
Absent 
Unavailable 
Total 
 
Biopsy result 
Present 
a 
b 
 
 
Absent 
c 
d 
 
 
total 
 
 
 
 
 
The sensitivity and specificity of the cfDNA results for the biopsy results are given by a/(a+b) 
and d/(c+d), respectively.  If the one-sided 95% lower confidence interval for the sensitivity is 
greater than or equal to 90%, and the one-sided 95% lower confidence interval for the specificity 
is greater than or equal to 90%, then the cfDNA MET amplification results will be deemed to 
agree sufficiently with the biopsy results to be used as a substitute.  (The score method will be 
used to form the confidence limits.) 
 
To get an idea of what observed agreement would be necessary to satisfy the above criterion, 
note the following: With approximately 600 patients with biopsy results, and assuming a 10% of 
the cfDNA results are unavailable and a biopsy MET amplification rate of 7.3% (Table 15.1), 
there would be 39 biopsy MET amplified patients and 501 biopsy non-MET amplified patients 
(with cfDNA results). 
 
Therefore, an observed sensitivity of greater than 98.0% and an observed specificity of greater 
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than 92.3% would be needed to declare the cfDNA results a reliable substitute for the biopsy 
results.   
 
Agreement for gene mutation results 
At the end of the trial, the following summary table for the gene mutation results will be 
completed (gene mutation considered G1202, C1156Y, I1171, L1196, V1180, F1174, and 
L1198F):   
 
 
 
cfDNA result 
 
 
Some mutations 
 
 
No mutations 
 
 
 
 
Same as 
biopsy 
results 
Some 
different 
than biopsy 
results 
 
Unavailable 
 
total 
 
Biopsy 
result 
Some 
mutations 
a 
b 
c 
 
 
No 
mutations 
N.A. 
d 
e 
 
 
Total 
 
 
 
 
 
 
 
N.A. = not applicable 
The sensitivity will be estimated by a/(a+b+c) and the specificity by e/(d+e). 
 
In addition, an agreement table will be completed for each gene mutation separately: G1202, 
C1156Y, I1171, L1196, V1180, F1174, and L1198F.   The table for G1202 is shown here: 
 
G1202  
 
cfDNA result 
 
 
Present 
Absent 
Unavailable 
Total 
 
Biopsy result 
Present 
a 
b 
 
 
Absent 
c 
d 
 
 
total 
 
 
 
 
For each gene mutation the sensitivity will be estimated by a/(a+b) and the specificity by 
d/(c+d). 
 
 
The cfDNA gene mutation results will be deemed to agree sufficiently with the biopsy results to 
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be used as a substitute if both of the following two conditions are met: 
 
(1) The one-sided lower 95% confidence limits for the overall sensitivity and specificity are 
greater than or equal to 90%. 
 
AND 
 
(2) For each mutation, the one-sided upper 99% confidence limits for the sensitivity and 
specificity are greater than or equal to 90%. 
 
 
The rationale behind this decision rule is that as the methods for identifying the different gene 
mutations are the same, one would expect a priori the agreement to be the same or similar for the 
different genes.  This justifies pooling the information and condition (1).  However, we would 
not want to use the cfDNA as a substitute for the biopsy results if there was very strong evidence 
that the agreement was not adequate for one or more of the mutations.  This justifies condition 
(2).  
 
 
To get an idea of what observed agreement would be necessary to satisfy condition 1, we note 
the following: With approximately 600 patients with biopsy results, and assuming a 10% of the 
cfDNA results are unavailable and a rate of 50.9% for one or mutations being present (Table 
15.1), an observed sensitivity of greater than 93.1% and an observed specificity of greater than 
93.1% would be needed to declare the cfDNA results a reliable substitute for the biopsy results.   
 
 
Interim Analysis of cfDNA results 
The interim assessment for assessing agreement will occur when the first 200 patients have had 
their cfDNA results evaluated.  We utilize the same decision rules given above to decide whether 
we could substitute cfDNA results for the remainder of the trial.  Because of the relatively small 
numbers, the observed agreement will need to be very high to satisfy condition 1:  For agreement 
concerning MET amplification, we would expect only about 13 patients to have biopsy MET 
amplification and evaluable cfDNA results.  This translates into a required observed sensitivity 
of >99%, which means all the patients with biopsy MET amplification would also need to have 
cfDNA MET amplification.  The observed specificity of the MET amplification would need to 
be greater than 93.9%.  
 
For the gene mutations, one would expect about 90 patients to have some mutation and 90 
patients to have no mutations, requiring an observed sensitivity and specificity of 95.3% to 
satisfy condition 1 above.  To be able to substitute cfDNA results for biopsy results for the rest 
of the trial, the criteria would need to be satisfied for MET amplification and the gene mutations. 
 
 
 
 
 
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APPENDIX II: TECHICAL SPECIFICATIONS FOR FOUNDATIONONE®CDX SOLID 
TUMOR ASSAY (20-MAY-2019) 
 
 
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APPENDIX III: SPECIMEN INSTRUCTIONS FOR FOUNDATIONONE®CDX SOLID 
TUMOR ASSAY (20-MAY-2019) 
 
 
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APPENDIX IV: TECHNICAL SPECIFICATIONS FOR FOUNDATIONONE®LIQUID  
BLOOD-BASED ASSAY (20-MAY-2019) 
 
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APPENDIX V: SPECIMEN INSTRUCTIONS FOR FOUNDATIONONE®LIQUID  
BLOOD-BASED ASSAY (20-MAY-2019) 
 
 
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APPENDIX VI: CTEP COLLABORATIVE AGREEMENTS LANGUAGE 
 
Protocols that involve agent(s) covered by a collaborative agreement with a biotech/pharma 
company(ies) must incorporate the NCI/ DCTD Collaborative Agreement Language shown 
below. 
 
 
The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to 
the NCI under a Collaborative Agreement (CRADA, CTA, CSA) between the 
Pharmaceutical Company(ies) (hereinafter referred to as “Collaborator(s)”) and the 
NCI Division of Cancer Treatment and Diagnosis.  Therefore, the following 
obligations/guidelines, in addition to the provisions in the “Intellectual Property 
Option to Collaborator” 
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm) contained 
within the terms of award, apply to the use of the Agent(s) in this study: 
 
1.   Agent(s) may not be used for any purpose outside the scope of this protocol, nor 
can Agent(s) be transferred or licensed to any party not participating in the 
clinical study.  Collaborator(s) data for Agent(s) are confidential and proprietary 
to Collaborator(s) and shall be maintained as such by the investigators. The 
protocol documents for studies utilizing Agents contain confidential information 
and should not be shared or distributed without the permission of the NCI.  If a 
copy of this protocol is requested by a patient or patient’s family member 
participating on the study, the individual should sign a confidentiality agreement. 
A suitable model agreement can be downloaded from: http://ctep.cancer.gov. 
 
2.   For a clinical protocol where there is an investigational Agent used in 
combination with (an)other Agent(s), each the subject of different Collaborative 
Agreements, the access to and use of data by each Collaborator shall be as follows 
(data pertaining to such combination use shall hereinafter be referred to as “Multi-
Party Data”): 
 
a.   NCI will provide all Collaborators with prior written notice regarding the 
existence and nature of any agreements governing their collaboration with 
NCI, the design of the proposed combination protocol, and the existence of 
any obligations that would tend to restrict NCI's participation in the proposed 
combination protocol. 
 
b.   Each Collaborator shall agree to permit use of the Multi-Party Data from the 
clinical trial by any other Collaborator solely to the extent necessary to allow 
said other Collaborator to develop, obtain regulatory approval or 
commercialize its own Agent. 
 
c.   Any Collaborator having the right to use the Multi-Party Data from these trials 
must agree in writing prior to the commencement of the trials that it will use 
the Multi-Party Data solely for development, regulatory approval, and 
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commercialization of its own Agent. 
 
3.   Clinical Trial Data and Results and Raw Data developed under a Collaborative 
Agreement will be made available to Collaborator(s), the NCI, and the FDA, as 
appropriate and unless additional disclosure is required by law or court order as 
described in the IP Option to Collaborator 
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm). 
Additionally, all Clinical Data and Results and Raw Data will be collected, used 
and disclosed consistent with all applicable federal statutes and regulations for the 
protection of human subjects, including, if applicable, the Standards for Privacy 
of Individually Identifiable Health Information set forth in 45 C.F.R. Part 164. 
 
4.   When a Collaborator wishes to initiate a data request, the request should first be 
sent to the NCI, who will then notify the appropriate investigators (Group Chair 
for Cooperative Group studies, or PI for other studies) of Collaborator's wish to 
contact them. 
 
5.   Any data provided to Collaborator(s) for Phase 3 studies must be in accordance 
with the guidelines and policies of the responsible Data Monitoring Committee 
(DMC), if there is a DMC for this clinical trial. 
 
6.   Any manuscripts reporting the results of this clinical trial must be provided to 
CTEP by the Group office for Cooperative Group studies or by the principal 
investigator for non-Cooperative Group studies for immediate delivery to 
Collaborator(s) for advisory review and comment prior to submission for 
publication.  Collaborator(s) will have 30 days from the date of receipt for review.  
Collaborator shall have the right to request that publication be delayed for up to 
an additional 30 days in order to ensure that Collaborator’s confidential and 
proprietary data, in addition to Collaborator(s)’s intellectual property rights, are 
protected.  Copies of abstracts must be provided to CTEP for forwarding to 
Collaborator(s) for courtesy review as soon as possible and preferably at least 
three (3) days prior to submission, but in any case, prior to presentation at the 
meeting or publication in the proceedings. Press releases and other media 
presentations must also be forwarded to CTEP prior to release. Copies of any 
manuscript, abstract and/or press release/ media presentation should be sent to: 
 
Email: ncicteppubs@mail.nih.gov  
 
The Regulatory Affairs Branch will then distribute them to Collaborator(s).  No 
publication, manuscript or other form of public disclosure shall contain any of 
Collaborator’s confidential/ proprietary information. 
 
 
 
 
 
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APPENDIX VII: NRG-LU003 PILL DIARY FOR ALECTINIB 
This pill diary is to be utilized for alectinib daily. 
 
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APPENDIX VIII: NRG-LU003 PILL DIARY FOR BRIGATINIB 
This pill diary is to be utilized for brigatnib only. 
 
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APPENDIX IX: NRG-LU003 PILL DIARY FOR CRIZOTINIB 
This pill diary is to be utilized for crizotinib only. 
 
 
 
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APPENDIX X: NRG-LU003 PILL DIARY FOR ENSARTINIB (21-JUNE-2019) 
This pill diary is to be utilized for ensartinib only. 
  
 
 
 
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APPENDIX XI: NRG-LU003 PILL DIARY FOR LDK378 (CERITINIB) (17-FEB-2020) 
This pill diary is to be utilized for LDK378 (ceritinib) only. 
 
 
 
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APPENDIX XII: NRG-LU003 PILL DIARY FOR LORLATINIB 
This pill diary is to be utilized for lorlatinib only. 
 
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APPENDIX XIII: PROHIBITED THERAPIES, HERBAL SUPPLEMENTS AND 
MEDICATIONS TO BE USED WITH CAUTION  
 
 
This is not an exhaustive list. Please consult a pharmacist for complete drug interactions. If a 
drug appears on more than one list, follow the most conservative rule. It is the investigator’s 
responsibility to ensure that any drugs under consideration have not been newly identified 
as CYP inhibitors. 
 
CYP3A 4,5 Inhibitors (Strong) 
CYP3A 4,5 Inhibitors 
(Moderate)  
CYP34A 4, 5 Inhibitors (Weak) 
Boceprevir 
ACT-178882 
Almorexant 
Clarithromycin 
Amprenavir 
Alprazolam 
Cobicistat (GS-9350) 
Aprepitant 
AMD070 
Conivaptan 
Atazanavir 
Amiodarone 
Danoprevir 
Casopitant 
Amlodipine 
Elvitegravir 
Ciprofloxacin 
Atorvastatin 
Fosamprenavir 
Crizotinib 
Azithromycin 
Idelalisib 
Darunavir 
Berberine 
Indinavir 
Diltiazem 
Bicalutamide 
Itraconazole 
Dronedarone 
Blueberry Juice 
Grapefruit Juice 
Elvitegravir 
Chlorzoxazone 
Ketoconazole 
Erythromycin 
Cilostazol 
LCL161 
FK1706 
Cimetidine 
Lopinavir 
Fluconazole 
Clotrimazole 
Mibefradil 
Fosamprenavir 
Cranberry Juice 
Nefazodone 
Imatinib 
Cyclosporine 
Nelfinavir 
Ledipasvir 
Daclatasvir 
Posaconazole 
Lomitapide  
Delavirdine 
Ritonavir 
Schisandra sphehanthera 
Everolimus 
Saquinavir 
Tipranavir/ritonavir 
Faldaprevir 
Telaprevir 
Tofisopam 
Fluvoxamine 
Telithromycin 
Verapamil 
Fosaprepitant 
Tipranavir 
 
Gingko 
Troleandomycin 
 
Goldenseal 
Voriconazole 
 
GSK1292263 
 
 
GSK2248761 
 
 
Isoniazid 
 
 
Ivacaftor 
 
 
Lacidipine 
 
 
Liagliptin 
 
 
Lomitapide 
 
 
M100240 
 
 
Nilotinib 
 
 
Oral Contraceptives 
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Pazopanib 
 
 
Peppermint Oil 
 
 
Propiverin 
 
 
Ranitidine 
 
 
Resveratrol 
 
 
Roxithromycin 
 
 
Seville Orange Juice 
 
 
Simeprevir 
 
 
Sitaxentan 
 
 
Suvorexant 
 
 
Tabimorelin 
 
 
Tacrolimus 
 
 
Teriflunomide 
 
 
Ticagrelor 
 
 
Tolvaptan 
 
 
Zileuton 
 
CYP3A 4,5 Inducers (Strong and Moderate) 
CYP3A 4,5 Inducers (Weak)  
Avasimibe 
Amprenavir 
Bosentan 
Aprepitant 
Carbamazepine 
Armodafinil 
Efavirenz 
AZD 7325 
Enzalutamide 
Bexarotene 
Etravirine 
Boceprevir 
Genistein 
Brivaracetam 
Lersivirine 
Clobazam 
Lopinavir 
Danshen 
Mitotane 
Dexamethasone 
Modafinil 
Echinacea 
Nafcillin 
Eslicarbazepine 
Phenobarbital 
Garlic 
Phenytoin 
Ginseng 
Pioglitazone 
Glycyrrhizin 
Rifabutin 
LCL161 
Rifampin 
Methylprednisolone 
Ritonavir 
Nevirapine 
Semagacestat 
Oritavancin 
St. John’s Wort 
Oxcarbazepine 
Thioridazine 
PA-824 
Tipranavir 
Pleconaril 
 
Prednisone 
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CYP2C8 Inhibitors 
(Strong)  
CYP2C8 Inhibitors 
(Moderate)  
CYP2C8 Inhibitors 
(Weak)  
CYP2C8 Inducers 
(Strong)  
Gemfibrozil 
Trimethoprim 
Fluvoxamine 
Rifampin 
 
Glitazones 
 
Ketoconazole 
 
Montelukast 
 
Quercetin 
 
CYP2C9 Inhibitors (Strong)  CYP2C9 Inhibitors (Moderate) CYP2C9 Inhibitors (Weak)  
fluconazole 
Amiodarone 
Diosmin 
 
Felbamate 
Disulfiram 
 
Fluconazole 
Fluvastatin  
 
Miconazole 
Fluvoxamine 
 
Piperine 
Voriconazole 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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APPENDIX XIV:  PATIENT DRUG INFORMATION HANDOUT AND WALLET CARD 
FOR ENSARTINIB (21-JUNE-2019) 
 
Information for Patients, Their Caregivers and Non-Study Healthcare Team on Possible 
Interactions with Other Drugs and Herbal Supplements  
 
The patient ____________________________ is enrolled on a clinical trial using the 
experimental study drug, ensartinib (X-396 HCl).  This clinical trial is sponsored by the 
National Cancer Institute.  This form is addressed to the patient but includes important 
information for others who care for this patient.  
 
These are the things that you as a healthcare provider need to know: 
  
Ensartinib may interact with certain specific enzymes in your liver.  
 
• The enzymes in question are CYP3A4 and 2C9. Ensartinib is broken down mainly by 
CYP 3A4 and may be affected by other drugs that inhibit or induce this enzyme.  
Ensartinib inhibits CYP 3A4 and 2C9 and may affect other drugs that are broken down by 
these enzymes.   
• Ensartinib is highly protein bound. Patients receiving other medications that are also highly 
protein bound may need to be monitored more frequently. 
 
To the patient: Take this paper with you to your medical appointments and keep the 
attached information card in your wallet.   
 
Ensartinib may interact with other drugs which can cause side effects. For this reason, it is very 
important to tell your study doctors of any medicines you are taking before you enroll onto this 
clinical trial.  It is also very important to tell your doctors if you stop taking any regular 
medicines, or if you start taking a new medicine while you take part in this study.  When you talk 
about your current medications with your doctors, include medicine you buy without a 
prescription (over-the-counter remedy), or any herbal supplements such as St. John’s Wort.  It is 
helpful to bring your medication bottles or an updated medication list with you. 
 
Many health care providers can write prescriptions.  You must tell all of your health care 
providers (doctors, physician assistants, nurse practitioners, pharmacists) you are taking part in a 
clinical trial.  
 
These are the things that you and they need to know:  
 
Ensartinib must be used very carefully with other medicines that use certain liver enzymes to be 
effective.  Before you enroll onto the clinical trial, your study doctor will work with your regular 
health care providers to review any medicines and herbal supplements that are considered strong 
inhibitors or inducers of CYP3A4 and substrates of CYP3A4 and 2C9. 
 
• Please be very careful!  Over-the-counter drugs (including herbal supplements) may 
contain ingredients that could interact with your study drug.  Speak to your doctors or 
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pharmacist to determine if there could be any side effects.  
• You may need to be monitored more frequently if you are receiving other medications 
that are also highly protein bound 
• Your regular health care provider should check a frequently updated medical reference or 
call your study doctor before prescribing any new medicine or discontinuing any 
medicine.  Your study doctor’s name is  
_____________________________________ and he or she can be contacted at  
 
_____________________________________. 
January 2017 
STUDY DRUG INFORMATION WALLET CARD   
You are enrolled on a clinical trial using the experimental 
study drug ensartinib (X-396 HCl).  This clinical trial is 
sponsored by the NCI.  Ensartinib may interact with drugs 
that are processed by your liver.  Because of this, it is very 
important to: 
➢ Tell your doctors if you stop taking any medicines or if you 
start taking any new medicines. 
➢ Tell all of your health care providers (doctors, physician 
assistants, nurse practitioners, or pharmacists) that you are 
taking part in a clinical trial. 
➢ Check with your doctor or pharmacist whenever you need 
to use an over-the-counter medicine or herbal supplement. 
➢ You may need to be monitored more frequently if you are 
receiving other medications that are also highly protein bound. 
Ensartinib interacts with specific liver enzymes called 
CYP3A4 and 2C9 and must be used very carefully with other 
medicines that interact with these enzymes.  
➢ Before you enroll onto the clinical trial, your study doctor 
will work with your regular health care providers to review 
any medicines and herbal supplements that are considered 
strong inhibitors or inducers of CYP 3A4 and substrates 
of CYP3A4 and 2C9. 
➢ Before prescribing new medicines, your regular health care 
providers should go to a frequently-updated medical 
reference for a list of drugs to avoid, or contact your study 
doctor.   
➢ Your study doctor’s name is 
_____________________________ and can be contacted 
t
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