A Phase 2 Single-Arm Study of M6620 in Combination With Irinotecan in Patients With Progressive TP53 Mutant Gastric and Gastro-Esophageal Junction Cancer
Phase: PHASE2
Conditions: Clinical Stage III Gastric Cancer AJCC v8, Clinical Stage III Gastroesophageal Junction Adenocarcinoma AJCC v8, Clinical Stage IV Gastric Cancer AJCC v8, Clinical Stage IV Gastroesophageal Junction Adenocarcinoma AJCC v8, Metastatic Gastric Adenocarcinoma, Metastatic Gastroesophageal Junction Adenocarcinoma, Unresectable Gastric Adenocarcinoma, Unresectable Gastroesophageal Junction Adenocarcinoma
Sponsor: National Cancer Institute (NCI)

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SUMMARY OF CHANGES – Protocol
For Protocol Amendment 9 to A Phase 2 Single-Arm Study of M6620 in Combination with 
Irinotecan in Patients with Progressive TP53 Mutant Gastric and Gastro-Esophageal 
Junction Cancer: This protocol is being amended:
x
The PI, Dr. Das, is leaving Vanderbilt. We are transferring the study to Dr. Jordan Berlin
x
We addressed all CTEP recommendations per review on September 14, 2022
NCI Protocol #: 10211
Local Protocol #: VICCNCIGI10211
NCI Version Date: December 2, 2022
Protocol Date: December 2, 2022
The changes reflect revisions from vAugust 17, 2022 v.December 2, 2022
#
Section
Page
Change
1.
TITLE
1
OLD TEXT:
Version Date: August 17, 2022
NEW TEXT:
Version Date: December 2, 2022
RATIONALE: Updated protocol header so document version date
2. TITLE
1
Updated PI contact information
3. 7.2.2
43
Please remove the newly created section titled: Change from M6620 
CAEPR version 1.4 (older) to version 2.0.  These changes only need to be 
listed in the summary of changes.
PI Response: Updated as requested.
4. 8.1.1
48
For M6620, please update the storage conditions to:
Storage: Store intact vials protected from light inside cardboard boxes at 
room temperature, below 25°C (77°F), do not freeze with excursions 
allowed between 15 and 30°C (59 and 86°F).
If a storage temperature excursion is identified, promptly return M6620 to 
between 15 and 30°C below 25°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.
PI Response: Updated as requested.

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NCI Protocol #:
10211
Local Protocol #:
VICCNCIGI10211
ClinicalTrials.gov Identifier: NCT03641313
TITLE: A Phase 2 Single-Arm Study of M6620 in Combination with Irinotecan in Patients 
with Progressive TP53 Mutant Gastric and Gastro-Esophageal Junction Cancer
Corresponding Organization:
LAO-CT018 / Yale University Cancer Center LAO
Principal Investigator:
Jordan D. Berlin, M.D.
Vanderbilt-Ingram Cancer Center
2220 Pierce Avenue
PRB 777
Nashville, TN, 37232, USA
Telephone: 615-936-8580
Fax: 615-343-7602
e-mail: Jordan.berlin@vumc.org
Participating Organizations 
LAO-11030 / University Health Network Princess Margaret Cancer Center LAO
LAO-CA043 / City of Hope Comprehensive Cancer Center LAO
LAO-CT018 / Yale University Cancer Center LAO
LAO-MA036 / Dana-Farber - Harvard Cancer Center LAO
LAO-MD017 / JHU Sidney Kimmel Comprehensive Cancer Center LAO
LAO-OH007 / Ohio State University Comprehensive Cancer Center LAO
LAO-PA015 / UPMC Hillman Cancer Center LAO
LAO-TX035 / University of Texas MD Anderson Cancer Center LAO
LAO-NCI / National Cancer Institute LAO
CATCHUP / Creating Access to Targeted Cancer Therapy for Underserved Populations
Statistician:
Gregory D. Ayers
Center for Quantitative Sciences
Vanderbilt University Medical Center
2220 Pierce Avenue
Suite 571
Nashville, TN 37232
Telephone: 615-343-9180
Fax: 615-936-2602

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e-mail: dan.ayers@vumc.org
Responsible Study Coordinator:
Jennifer Whisenant
Vanderbilt-Ingram Cancer Center
2220 Pierce Avenue, 691 PRB
Nashville, TN 37232
Telephone: 615-875-8630
e-mail address: j.whisenant@vumc.org
Responsible Research Nurse:
Jennifer Teller
VICC Clinical Trials Shared Resource
3322 West End Avenue
Nashville, TN 37203
Telephone: 615-875-9327
e-mail address: jennifer.l.teller@vumc.org
NCI-Supplied Agent:  M6620 (NSC 780162)
Other Agent(s):  Irinotecan, NSC 616348, Commercial
IND #:  140668
IND Sponsor: DCTD, NCI
Protocol Type / Version # / Version Date:
Original / Version 0.1 / Version Date: 1 March 2018
Amendment 1 / Version 1.0 / Version Date: 27 January 2020
Amendment 2 / Version 1.1 / Version Date: 24 July 2020
Amendment 3 / Version 1.2 / Version Date: 27 August 2020
Amendment 4 / Version 1.3 / Version Date: 15 February 2021
Amendment 5 / Version 1.4 / Version Date: 27 July 2021
Amendment 6 / Version 2.0 / Version Date: 29 October 2021
Amendment 7 / Version 2.1/  Version Date: 06 December 2021
Amendment 8/  Version 2.2/  Version Date: 20 December 2021
Amendment 9/ Version 2.3/ Version Date: 17 August 2022

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SCHEMA
This is a phase II single arm, multicenter study accessing the efficacy of M6620 in combination 
with irinotecan in patients with progressive metastatic or unresectable gastric or 
gastroesophageal junction (GEJ) adenocarcinoma harboring a TP53 mutation. Patients with 
TP53 mutations only in exons 2 and 4-11, will be eligible for the trial. Mutations conferring 
eligibility can be determined from any next generation sequencing (NGS) assay.
The trial will follow the Flow Schema as below (Figure 1):
Figure 1. Flow Schema 
The first 6 patients will be closely monitored for safety after being treated at a starting M6620 
dose of 270 mg/m2 in combination with irinotecan (180 mg/m2). The starting dose has been 
established as tolerable from NCI #9938. Dose limiting toxicities (DLTs) will be assessed in the 
28-day period following C1D1 of treatment in these patients. A DLT is defined as grade 4 
hematologic toxicity lasting ≥ 7 days, febrile neutropenia consisting of ≥ grade 2 fever and grade 
4 neutropenia, grade 4 diarrhea despite supportive measures, any other non-hematologic toxicity 
≥ grade 3 occurring in cycle 1 of treatment or the inability to meet C2 treatment parameters 
within 4 weeks of C1D15. No on-treatment tumor biopsies will be obtained in the patients

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enrolled in the safety lead-in and thus M6620 will not be omitted on C1D1 as it will for the 
subsequent 9 patients undergoing pharmacodynamic biomarker assessment. 
Irinotecan will be administered via intravenous infusion over 90 minutes, and M6620 will be 
administered via intravenous infusion over 60 minutes immediately following irinotecan on days 
1 and 15. Only on C1D1 will the treatment schedule deviate as M6620 will be omitted for the 
patients undergoing research biopsies. Treatment cycles repeat every 28 days. Patients will 
continue treatment in the absence of disease progression, unacceptable toxicity, death, 
withdrawal of consent, or study termination.
The primary endpoint of study is the objective response rate (ORR). Assuming a 10% type I 
error and 80% power, Simon’s minimax 2-stage design requires 16 efficacy-evaluable patients. If  
0 patients in the first 12 treated do not demonstrate a response, stop early for futility. If 3 or more 
patients experience an ORR among 16 efficacy-evaluable patients, declare the experimental
combination worthy of further study.
Secondary endpoints are duration of response (DOR), time to progression (TTP), progression-
survival (PFS), and overall survival (OS) in the whole cohort. Exploratory endpoints are ORR, 
DOR, TTP, PFS, and OS in sub-cohorts based on first-line platinum sensitivity and presence of 
other DNA damage response defects (DDRD). In patients undergoing research biopsies, tissue 
samples will be collected 24 hours (+/- 3 hours) post-irinotecan infusion on C1D2 and 24 hours
(+/- 3 hours) post-M6620 infusion on C2D2.

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TABLE OF CONTENTS
SCHEMA.........................................................................................................................................3 
1. 
OBJECTIVES......................................................................................................................8 
1.1 
Primary Objectives...................................................................................................8 
1.2 
Secondary Objectives...............................................................................................8 
1.3 
Exploratory Objectives ............................................................................................8 
2. 
BACKGROUND .................................................................................................................8 
2.1 
Study Disease...........................................................................................................8 
2.2 
CTEP IND Agent.....................................................................................................9 
2.3 
Irinotecan ...............................................................................................................15 
2.4 
Rationale ................................................................................................................16 
2.5 
Correlative Studies Background ............................................................................20 
3. 
PATIENT SELECTION....................................................................................................21 
3.1 
Eligibility Criteria..................................................................................................21 
3.2 
Exclusion Criteria ..................................................................................................23 
3.3 
Inclusion of Women and Minorities ......................................................................24 
4. 
REGISTRATION PROCEDURES ...................................................................................25 
4.1 
Investigator and Research Associate Registration with CTEP..............................25 
4.2 
Site Registration.....................................................................................................26 
4.3 
Patient Registration................................................................................................28 
4.4 
General Guidelines.................................................................................................29 
5. 
TREATMENT PLAN........................................................................................................29 
5.1 
Agent Administration.............................................................................................29 
5.2 
General Concomitant Medication and Supportive Care Guidelines......................32 
5.3 
Duration of Therapy...............................................................................................34 
5.4 
Duration of Follow Up...........................................................................................35 
6. 
DOSING DELAYS/DOSE MODIFICATIONS................................................................35 
7. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ............................40 
7.1 
Rave-CTEP-AERS Integration..............................................................................40 
7.2 
Comprehensive Adverse Events and Potential Risks List(s) (CAEPRs)...............41 
7.3 
Adverse Event Characteristics...............................................................................44 
7.4 
Routine Adverse Event Reporting .........................................................................46 
7.5 
Pregnancy...............................................................................................................47 
7.6 
Secondary Malignancy...........................................................................................47 
7.7 
Second Malignancy................................................................................................47 
8. 
PHARMACEUTICAL INFORMATION..........................................................................47 
8.1 
CTEP IND Agent(s)...............................................................................................48 
8.2 
Irinotecan ...............................................................................................................50 

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9. 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ........................................51 
9.1 
Integral Laboratory or Imaging Studies.................................................................54 
9.2 
Integrated Correlative Studies................................................................................54 
9.3 
Exploratory Correlative Studies.............................................................................55 
10. 
STUDY CALENDAR .......................................................................................................57 
11. 
MEASUREMENT OF EFFECT........................................................................................60 
11.1 
Antitumor Effect – Solid Tumors ..........................................................................60 
12. 
STUDY OVERSIGHT AND DATA REPORTING / REGULATORY 
REQUIREMENTS.............................................................................................................67 
12.1 
Study Oversight .....................................................................................................67 
12.2 
Data Reporting.......................................................................................................68 
12.3 
Data Quality Portal ................................................................................................70 
12.4 
CTEP Multicenter Guidelines................................................................................70 
12.5 
Collaborative Agreements Language.....................................................................70 
13. 
STATISTICAL CONSIDERATIONS...............................................................................72 
13.1 
Study Design/Endpoints.........................................................................................72 
13.2 
Sample Size/Accrual Rate......................................................................................73 
13.3 
Stratification Factors..............................................................................................74 
13.4 
Analysis of Secondary Endpoints..........................................................................74 
13.5 
Reporting and Exclusions ......................................................................................74 
REFERENCES ..............................................................................................................................75 
APPENDIX A: PERFORMANCE STATUS CRITERIA...............................................................1 
APPENDIX B: CTEP MULTICENTER GUIDELINES ................................................................2 
APPENDIX C: PATIENT DRUG INFORMATION HANDOUT AND WALLET 
CARD ..................................................................................................................................3 
14. 
TABLE OF CONTENTS ..................................................................................................7 
15. 
1.0 PURPOSE.........................................................................................................8 
16. 
2.0 SCOPE ..............................................................................................................8 
17. 
3.0 ABBREVIATIONS..........................................................................................8 
18. 
4.0 INTRODUCTION............................................................................................8 
5.0 
ROLES AND RESPONSIBILITIES....................................................................8 
6.0 
MATERIALS AND EQUIPMENT REQUIRED................................................9 
7.0 
OPERATING PROCEDURES...........................................................................10 
8.0 
SHIP TO FNLCR FOR ANALYSIS (OPTIONAL) .........................................12 
19. 
APPENDIX 1: BATCH RECORD.................................................................................14 
20. 
APPENDIX 2: PD SAMPLE SHIPPING MANIFEST ..................................................1 

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1. OBJECTIVES
1.1
Primary Objectives
x
Determine ORR superiority (target 25%) in TP53 mutant patients with progressive 
metastatic or unresectable gastric/GEJ cancer who receive M6620 and irinotecan 
compared to ORR (5%) in historical control patients treated with single agent irinotecan 
alone.
1.2
Secondary Objectives
x
Determine DOR, TTP, PFS, and OS superiority in TP53 mutant gastric/GEJ cancer 
patients who receive M6620 and irinotecan compared to these measures in historical 
control patients treated with irinotecan alone.
x
Perform the following correlative studies in 9 patients:
o
ℽ-H2AX, .AP1 p-Ser 824 andp-ATR analysis from biopsies collected at 24 
hours (+/- 3 hours) post-irinotecan infusion on C1D2 and at 24 hours (+/- 3 hours)
post-M6620 on C2D2.
1.3
Exploratory Objectives 
•
Determine ORR, DOR, TTP, PFS, and OS in patients with other concomitant DDRD, 
such as mutations in BRCA1, BRCA2, MRE11, RAD50, RAD51, RAD52, RAD54L, 
NBN, ATM, H2AX, PALB2, RPA, BRIP1, BARD1, ATR, ATRX, CHK1, CHK2, 
MDM2, MDM4, FANCA, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCL, 
treated with the experimental combination. 
•
Determine whether patients with first line platinum sensitivity (PFS > 3 months) 
demonstrate improved ORR, DOR, TTP, PFS, and OS compared to patients who were 
platinum insensitive (PFS < 3 months).
2. BACKGROUND
2.1
Study Disease
Gastric and gastro-esophageal junction (GEJ) cancer remains a major global health concern and 
is the third leading cause of annual cancer associated mortality (Torr et al., 2016). Unfortunately, 
many patients present with advanced disease where palliative systemic therapy (chemotherapy 
and more recently, immunotherapy) is the primary treatment option rather than curative surgery. 
5-year survival rates are <5% in these patients (SEER, database 2018) and naturally there 
remains a grave need to add new therapeutics for patients in this setting. One such avenue for 
drug development is targeting salvage DNA repair pathways in cancer cells. Cancer cells rely on 

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these pathways to retain functional genomic integrity in the face of faulty DNA replication and 
DDRD. This reliance creates therapeutic opportunities to combine cytotoxic chemotherapy with 
salvage repair pathway inhibitors.
DDRD have already been shown in gastric adenocarcinoma patients to predict sensitivity to 
DNA repair inhibitors such as PARP inhibitors. In a randomized phase II study of 124 
progressive adenocarcinoma patients treated with olaparib and paclitaxel versus paclitaxel alone, 
those with ATM serine/threonine kinase (ATM) deficits had a marked OS benefit from the 
combination compared to all treated patients (Bang et al., 2015). The tumor suppressor gene 
TP53 is a downstream effector of ATM and is the most frequently mutated gene across all 
human cancer. It is mutated in 30-70% of gastric and GEJ adenocarcinoma patients with most 
mutations falling within exon 2 and exons 4-11 (Bass et al., 2014). Cancer cells with mutations 
in TP53 tend to depend on ataxia telangiectasia and Rad3-related protein kinase (ATR) as a 
primary mediator of DNA damage.  ATR is normally activated by single strand interruptions 
associated with replication stress however its activity can also be triggered by pharmacologic 
stressors including topoisomerase (Top1) inhibitors, anti-metabolic agents or ionizing radiation. 
Upon activation, ATR activates Chk1, a cell cycle-kinase whose downstream effects lead to cell 
cycle arrest in S-phase or the G2-M checkpoint (Zeman et al., 2014). 
2.2
CTEP IND Agent
2.2.1
M6620
M6620 (VRT-0768079) is a highly potent and selective ATP-competitive inhibitor of ATR, 
 
(Investigator’s Brochure, 2017).  In comparison, 
M6620 was >100-fold weaker inhibitor of ATM (Ki=34 nM) and >1000-fold less effective 
against other closely related kinases, such as DNA-dependent protein kinase (DNA-PK) (Ki>4 
mcM), mTOR (Ki>1 mcM), and PI3K-gamma (Ki=0.22 mcM) (Fokas et al., 2012).  
The starting dose of M6620 will be 270 mg m-2 as determined from NCI #9938.
Effect of M6620 on DNA Damage Response (DDR) signaling and DNA damage
M6620 potentiated the activity of multiple DNA-damaging agents in numerous cancer cell lines
from a range of indicationsInvestigator’s Brochure, 2017). Concurrent treatment of cancer 
cell lines with M6620 and various DNA-damaging agents led to sustained M6620-dose-
dependent decreases in levels of chemotherapy-induced CHK1pS345, a major substrate of ATR 
(Fokas et al., 2012; Hall et al., 2014).  In the presence of DNA damage, primarily DSBs, histone 
H2AX is phosphorylated at serine 139 to produce γH2AX (H2AXpS139).  Although all three 
DDR regulatory kinases, ATM, ATR, and DNA-PK phosphorylate H2AX to γH2AX, they are 
variably activated during different DNA-damage repair mechanisms (e.g., HR repair, non-
homologous end joining [NHEJ] repair, base excision repair due induced by stalled replication 

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forks, etc.) (Kuo and Yang, 2008). In addition, for the efficient DNA-damage repair, the DDR 
regulatory kinases must be able to access damaged sites in the chromatin environment.  ATM has 
been shown to phosphorylate the heterochromatin protein KAP1 at serine 824 (KAP1pS824) in 
response to DNA damage (White et al., 2012).  Exposure of lung cancer cell lines as well as 
primary tumors to M6620 in combination with DNA-damaging agents enhanced levels of the 
DNA-damage markers, i.e., γH2AX and KAP1pS824, as compared to DNA-damaging agent alone 
(Hall et al., 2014).  Sequential treatment of cells with DNA-damaging agent followed 15 h later 
by M6620 resulted in an initial inhibition of phospho-CHK1 (for 1 to 2 h) (Investigator’s 
Brochure, 2017).  However, over time, phospho-CHK1 re-appeared despite continued exposure 
to M6620.  The rebound of phospho-CHK1 has been attributed to non-specific phosphorylation 
by an undefined kinase.  However, despite the transient inhibition of phospho-CHK1, the 
sustained accumulation of the DNA damage markers was observed.  Together these data suggest 
that disruption of ATR-mediated DDR signaling by M6620 leads to sustained accumulation of 
DNA damage in cancer cells exposed to DNA-damaging agents.  It has been suggested that the 
failure to repair chemotherapy-induced DNA damage in the presence of M6620 is the driver of 
enhanced cytotoxicity in cancer cells.  These data support using the DNA-damage markers as
pharmacodynamic markers of M6620 activity.  
M6620-mediated radiosensitivity of pancreatic ductal adenocarcinoma cells was associated with 
inhibition of HR repair (Fokas et al., 2012).  M6620 caused increased persistence of γH2AX 
levels both in vitro and in vivo.  Adding M6620 to gemcitabine and ionizing radiation (IR) 
dramatically enhanced antitumor effects, with early and late apoptosis and abrogation of IR-
induced G2 checkpoint in cell culture experiments.  It has been suggested that by promoting 
strong S-phase arrest, chemoradiation may further increase dependence of tumor cells on ATR-
mediated homologous recombination (HR) repair of DNA double strand breaks (DSBs) and for 
survival.  
Nonclinical studies
In vitro antitumor activity

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In addition, significant radiosensitization effects by M6620 were observed against two human 
pancreatic cancer cell lines with mutant KRAS and mutant p53 (MiaPaCa-2 and PSN1) 
(P<0.05), but not against non-cancerous fibroblast cell lines (Fokas et al., 2012).  In addition, 
M6620 profoundly sensitized pancreatic tumor cells to gemcitabine-based chemoradiation.
This suggests that the 
functional status of the ATM pathway is a contributing factor in the cellular response to the 
inhibition of ATR.
Of note, the response/TP53 status relationship was unclear in the panel of heterogeneous cancer 
cell lines exposed to M6620 + chemotherapy (Hall et al., 2014).  Although not significant, there 
was a trend of causality between response and p53 status (P=0.08) for M6620 combined with 
cisplatin.  Furthermore, no clear relationship between cellular response to M6620 + cisplatin and 
TP53 status was observed in seven primary lung tumors.  
In vivo antitumor activity
The in vivo activity of M6620 was tested in multiple mouse xenograft models derived from 
human lung cancer cell lines and primary human tumor cells (Hall et al., 2014; Investigator’s 
Brochure, 2017). M6620 potentiated antitumor effects of cisplatin, gemcitabine, irinotecan, and 
IR in a dose- and schedule-dependent manner.  Antitumor efficacy correlated with inhibition of 
phospho-CHK1 and an increase in DNA-damage markers.  This supports ATR inhibition as a 

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Clinical Efficacy
 
A summary of preliminary activity is as follows: 
x
M6620 + gemcitabine in advanced solid tumors:  Among 48 patients, 4 (one each 
NSCLC, head and neck cancer, breast cancer, and unknown primary cancer) had partial
response (PR) and 29 patients had stable disease (SD). In an additional cohort of 18 
patients with advanced NSCLC, 3 had PRs and 15 had SD.
x
M6620 + cisplatin in advanced solid tumors: Among 26 patients, 4 (1 each BRCA2+
ovarian cancer, epithelioid mesothelioma, TNBC, neuroendocrine prostate cancer) had 
PRs, and 15 patients had SD.  In an additional cohort of 18 patients with advanced 
TNBC, 7 had PR and 6 had SD.
x
M6620 + carboplatin in advanced solid tumors refractory to standard therapy:  Among 21 
evaluable patients, 1 had PR (ovarian cancer) and 14 had SD.  
x
M6620 + carboplatin or M6620 + cisplatin in platinum-resistant advanced SCLC:  There 
were no objective responses observed among nine evaluable patients and 4 had SD.
x
M6620 + gemcitabine + cisplatin in advanced solid tumors: Of 7 evaluable patients, 1 
had PR (CRC) and 4 had SD.
x
M6620 + carboplatin + paclitaxel in advanced solid tumors refractory to standard 
therapy:  Among 8 evaluable patients, 2 had PR (1 each adenosquamous carcinoma of the 
cervix and melanoma) 3 had SD.
Safety summary from studies with M6620 as single agent or in combination with cytotoxic 
therapy (Investigator’s Brochure, 2017)
Infusion-related reactions (local or systemic), nausea, and vomiting are considered adverse drug 
reactions (ADRs) for M6620, and myelosuppression events are considered ADRs for M6620 in
combination with carboplatin.  

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x
Nausea and vomiting have occurred commonly in patients receiving M6620
monotherapy. Many of the affected subjects experienced these events on the same day 
as M6620 was administered, and there was some suggestion of a dose response. 
x
Hematologic AEs in subjects who received M6620 in combination with carboplatin 
have included neutropenia, thrombocytopenia, and febrile neutropenia.
x
M6620 has not been assessed in developmental and reproductive toxicity studies at this 
stage of development.  However, M6620 inhibits DNA-damage repair and it will be 
administered in conjunction with cytotoxic chemotherapy; thus, the potential for 
teratogenicity should be M6620 considered high.  Patients on M6620 studies must take 
stringent measures to avoid fathering or bearing children while on study drug and for 6 
months after discontinuation of M6620.  Refer to the M6620 clinical study protocols 
for specific contraceptive requirements.
Guidance on prior and concomitant medications (Investigator’s Brochure, 2017)
Because the drug interaction profile of M6620 has not been fully characterized, caution should 
be used when co-administering medications with M6620.
 
2.3
Irinotecan
Top1 inhibitors, such as irinotecan, have long been cornerstones of therapy for gastrointestinal 
malignancies including colon, pancreatic, esophageal, gastric and GEJ cancer. Top1 is a key 
enzyme in the DNA repair process and stabilizes partially unwound double helixes during DNA 
replication. The enzyme generates single stranded breaks and creates unstable intermediate 
complexes known as Top1 Cleavage Complexes (Top1cc) (Zeman et al., 2014). Top1 inhibitors 
prevent the reversal of unstable Top1cc intermediates and DNA re-ligation. Persistence of these 
cleavage complexes results in replication fork collisions, interruption of transcription complexes, 
replication stress and ultimately double stranded breaks. 
Single agent irinotecan monotherapy is utilized largely in the third-line setting for gastric/GEJ 
adenocarcinoma patients and produces at best, an overall response rate (ORR) of 7% (Makiyama
et al. 2018). We realize using this ORR as a historical comparator for our experimental treatment
arm in TP53 mutant patients represents a generalization. However, as there are no prior studies 
which have determined ORR of later-line single agent irinotecan in TP53 mutant gastric/GEJ 

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patients, we do not have any other viable options with this study design. A meta-analysis from 
Xu et al. suggests TP53 mutant gastric cancer patients may have a more robust response to 
chemotherapy (in the first-line setting) with platinum agents or platinum plus irinotecan however
no trials assessing single agent irinotecan or later-line irinotecan were included in the analysis
(Xu et al., 2014). A colon cancer trial from Netter et al. found no differential benefit from 
FOLFIRI in TP53 mutant patients compared to TP53 WT patients, however this was again a 
first-line trial and a different patient population (Netter et al., 2015). We are combining 
irinotecan with the ATR inhibitor M6620 in progressive TP53 mutant gastric and GEJ 
adenocarcinoma patients on our trial. The combination of ATR inhibitors with other replication 
stress inducers, including other Top1 inhibitors, are being explored in several other early phase 
clinical trials (Thomas et al., 2017; O’Carrigan et al., 2016).  
2.4
Rationale
Preclinical activity of M6620 against ATR has been demonstrated in the esophageal cancer cell 
lines OE21, OE33 and FLO-1 (first two squamous, latter adenocarcinoma). OE21 cell lines were 
treated with M6620 and then exposed to hypoxic conditions to stimulate ATR activity. In 
response to hypoxia, phosphorylated Chk1 levels initially increased.  These levels decreased 
after exposure to M6620. Specificity of the inhibitor was demonstrated by treating OE21 cell 
lines with either M6620 or the ATM inhibitor KU-55933. M6620 decreased Chk1 dependent
phosphorylation of the site S473 on the down-steam KAP-1 protein but not phosphorylation of 
the site S824 which is predominantly phosphorylated by ATM. OE21 and FLO-1 cells were 
exposed to increasing dosage of cisplatin (.5 uM, 1 uM) and carboplatin (20 uM, 40 uM, 60 uM) 
plus M6620 versus a control DMSO solution. In each scenario, addition of the ATR inhibitor 
significantly reduced cell viability compared to chemotherapy alone (Leszcznyska et al., 2016). 
The combination of M6620 with SN-38 (active metabolite of irinotecan) was explored in 
colorectal cancer cell line studies with COLO205. In vitro experiments suggested synergism 
between the two agents at concentrations of M6620 as low as 80 nanomolar; M6620 increased 
the IC50 of SN-38 nearly eight-fold. This was then tested in xenograft colon cancer mice 
models. Mice were treated with intraperitoneal irinotecan, oral M6620, or the combination. 
While M6620 had no impact on tumor growth when dosed as a single agent at 60 mg/kg it 
demonstrated significant anti-tumor activity when dosed in combination with irinotecan at 20 
mg/day. The combination produced a greater and more sustained reduction in tumor volume than 
single-agent irinotecan at 40 mg/day (Figure 1). There was no signal for greater toxicity with the 
combination compared to the higher dose of irinotecan as a similar drop in body weight was 
noted in mice who received either treatment (Josse et al., 2014).

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Figure 1: Xenograft model where mice bearing COLO205 tumors were treated with vehicle, 
irinotecan, M6620 or the combination of M6620 and irinotecan. VX-970 is another name of 
M6620.
Additional pre-clinical data suggests cancer cell lines with deficits in the ATM and TP53
pathway are particularly sensitive to ATR inhibitors. Min et al. assessed response to the ATR 
inhibitor AZD 6738 in gastric cancer cell lines. In their experiments, SNU-601 and SNU-484
were chosen as the model cell lines of resistance and sensitivity, respectively. The authors 
explored why the two cells lines had such disparate sensitivity to AZD 6738 and found ATM-
Chk2 axis proteins downregulated in SNU-601 cells compared to levels in SNU-484 cells. 
Knocking down ATM expression in SNU-484 with siRNA or an ATM inhibitor resensitized the 
cells to ATR inhibition (Min et al., 2017). Kwok et al. looked at CLL cell lines in vitro and in 
vivo xenograft mice models and found ATM and TP53 deficient cell lines were markedly more 
sensitive than their wild-type counterparts to AZD 6738 (Figure 2). Further, AZD 6738 
sensitized these deficient cell lines to chemotherapy with agents such as fludarabine, 
bendamustine and chlorambucil (Kwok et al., 2016). Ma et al demonstrated this same principle 
in triple negative breast cancer (TNBC) mouse models. In their experiments three TNBC mouse 
model xenografts were generated: one wild-type (WU-BC3) and two TP53 mutants (WU-BC4 
and WU-BC5). These models were treated with irinotecan and a Chk1 inhibitor (UCN-01 or 
AZD7762) as single agents or in combination. The combination therapy induced apoptosis and 
tumor death in WU-BC4 and WU-BC5 models but not in WU-BC3. Knocking out TP53 
however, sensitized WU-BC3 tumors to the combination therapy (Ma et al., 2012). Manic et al. 
also demonstrated that TP53 deficient cell lines were particularly susceptible to ATR-Chk1 axis 
inhibition in RAS mutant colorectal cancer stem cells (CSCs). In their experiments, CSCs with 
siRNA induced TP53 knockdown were sensitive to the Chk1 inhibitor LY2606368 (Manic et al., 
2017).

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Figure 2: Assessing DNA damage by y-H2AX induction in WT CLL, WT CLL w/ATM 
inhibitor and Mec1 TP53 deficient CLL lines post addition of AZ6738.
As demonstrated by the preclinical data above, targeting the ATR axis in TP53 mutant patients 
represents a promising opportunity to enhance cancer cell death. There is an ongoing phase I trial 
NCT02595931 determining the optimal dose of M6620 in combination with irinotecan in 
refractory solid tumor patients. We will use the recommended phase II dose (RP2D) from this 
trial as the treatment dose for patients on our study. Thomas et al. recently reported the phase I 
results from M6620 and the Top1 inhibitor topotecan in advanced solid tumor patients and 
demonstrated safety at the MTD as well as signals of efficacy (Thomas et al., 2017). Our primary 
aim is to demonstrate that TP53 mutant patients will achieve an ORR of 20% with the 
experimental combination. Secondary aims include demonstrating duration of response (DOR),
time to progression (TTP) and overall survival (OS) benefit of the combination in patients on 
study compared to TTP and OS in historical controls treated with single agent irinotecan.
Exploratory aims include assessing the relationship of other DDRD gene mutations and 
sensitivity to first line platinum therapy with response to M6620 plus irinotecan.
In the 9 patients (median 3 prior lines of treatment) who have been treated thus far on study 
10211 with irinotecan plus M660, median PFS was 3.91 (95% CI 2.63 – NR) months and median 
OS has not yet been reached (95% CI 4.81 – NR) (10-month OS rate > 60%) (Figure 3). For 
context, in second-line prospective studies of irinotecan monotherapy in patients with gastric and 
GEJ adenocarcinoma, median PFS was 2-2.1 months and 10-month OS rates were 30% (Lee et 
al. 2019, Sym et al. 2013). Of the 9 patients, 3 patients have achieved disease control for more 
than 5 months (with 1 patient currently with stable disease for 11 months), with 1 patient 
achieving an objective response which was maintained for 7 months (Table 1). The median PFS 
observed thus far in patients treated with study 10211 approximates the PFS observed with 
ramucirumab plus paclitaxel (median PFS 4.4 months in RAINBOW trial) which currently 
represents the second-line treatment standard for patients with gastric and GEJ adenocarcinoma
(Wilke et al. 2014). Observing this level of activity in the third-line and beyond setting is unusual 
for patients with this disease and suggests the study combination may possess meaningful later-
line clinical activity in this disease population. If this study meets its primary endpoint, the 

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subsequent randomized phase II study would compare irinotecan plus M6620 versus either TAS-
102 or irinotecan in patients with third-line and beyond gastric and GEJ adenocarcinoma
(stratified by TP53 tumor status). TAS-102 represents the current third-line treatment standard 
for this patient population and garnered FDA approval based upon the results of the TAGS 
study; median PFS and OS in patients with gastric and GEJ adenocarcinoma treated with the 
drug were 2 months and 5.7 months, respectively (Shitara et al. 2018). 
Beyond the anti-tumor activity observed with irinotecan plus M6620, the study combination 
appears to be well tolerated. No DLTs were observed in the first 6 patients treated on the study
during the establishment of the safe dose. No grade 4 adverse events have occurred in patients in 
the interim analysis and the most common grade 3 adverse events include anemia (1 case), 
neutropenia (1 case), diarrhea (1 case), leukopenia (1 case) and vomiting (1 case). Most adverse 
events experienced by patients were grade 1/2 in nature and in line with the adverse event profile 
of irinotecan.
Figure 3: PFS and OS data from 9 patients in interim analysis of study 10211.
Abbreviations: NR, not reached; CI, confidence interval
Table 1: Response data from 9 patients in interim analysis of study 10211.

20
2.5
Correlative Studies Background
A: TP53 and DDRD Genes:
Mutations in TP53 (exons 2 and 4-11) are a prerequisite for enrollment onto the study and will 
be ascertained from archived tissue through any CLIA certified NGS assay. Although we will be 
illustrating how the FoundationOne/FoundationOne Cdx, the dominant NGS assay used at our 
institution, reports our mutations of interest, this applies to any CLIA certified NGS assay.
Results from the FoundationOne/FoundationOne Cdx assay are clearly presented in a 
synthesized report that specifies the codon (thus identifying the exon) a specific TP53 mutation 
falls within. Concomitant mutations in other DDRD genes are also reported in a similar manner. 
Some of these DDRD mutations we feel could improve the likelihood of response with the 
experimental therapy include BRCA1, BRCA2, MRE11, RAD50, RAD51, RAD52, RAD54L, 
NBN, ATM, H2AX, PALB2, RPA, BRIP1, BARD1, ATR, ATRX, CHK1, CHK2, MDM2, 
MDM4, FANCA, FANCC, FANCD2, FANCE, FANCF, FANCG, and FANCL. These genes 
have been validated across assays and play important roles in homologous recombination (from 
published literature in breast and ovarian cancer) and the ATR axis (from data cited in the pre-
clinical rationale above) (Walsh, 2015).
B: Tissue Based Biomarkers of DNA Damage and Inhibition of ATR Mediated Signaling:
ℽ-H2AX is phosphorylated histone which is a well validated marker of DNA damage. From a 
variety of pre-clinical studies (including Min et al. mentioned above), it has been shown to 
accumulate at sites of DNA double stranded breaks (Kuo et al., 2008; Ivashkevich et al., 2012).
P-ATR is a marker for direct ATR pathway activation and signaling. This has been demonstrated 
in cell line models from several laboratories including the Cortez laboratory at Vanderbilt (Nam 

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et al., 2011). KAP1 is a heterochomatin protein which is phosphorylated by ATM at the Ser 824 
residue following DNA damage. It often co-localizes with ℽ-H2AX at DNA damage foci 
however is not dependent on ATR for phosphorylation, carrying potential to serve as a marker of
generalized DNA damage in the setting of ATR inhibition (White at al., 2012). Changes in tissue 
levels of ℽ-H2AX, KAP1 p-Ser 824 and p-ATR will be measured in the initial nine patients 
enrolled on the first stage of the study. Because we do not know a priori what the baseline levels 
of ℽ-H2AX, KAP1 p-Ser 824 and p-ATR are in TP53 mutant patients with gastric and GEJ 
adenocarcinoma, we have sent tissue from 4 archived TP53 mutant gastric/GEJ patients (16 
slides) to PADIS for measurement of these levels. These baseline levels are currently being 
quantitated and will help us determine what degree of change in the markers-of-interest 
constitutes a significant change in study patients. Patients will undergo core biopsies 
(endoscopically of primary site or percutaneously of metastatic site) on C1D2 24 hours (+/- 3
hours) post-irinotecan infusion and on C2D2 at 24 hours (+/- 3 hours) post-M6620, for tissue 
ascertainment. Tissue will be prepared and sent to the PADIS laboratory for quantification and 
analysis. Our hypothesis is we will see a differential pattern of dynamic changes in levels of each
between responding and progressing patients. We believe responding patients will demonstrate 
significant declines in ℽ-H2AX (post-irinotecan, levels should peak while post-M6620, this 
signal should be knocked down) and p-ATR levels, and increases in KAP1 p-Ser 824 levels,
while progressing patients will demonstrate less robust changes. Multiplex immunofluorescence 
assays will be utilized to quantify levels of ℽ-H2AX, p-ATR and KAP1 p-Ser 824. Tumor biopsy 
specimens will be NBF fixed and paraffin embedded. Specimens will be loaded into the Bond-
Max processing module. The module will stain the slides in an automated fashion with a 
biotinylated ℽ-H2AX, p-ATR and KAP1 p-Ser 824 monoclonal antibodies as the recorder and 
streptavidin Alexa fluor 488 coated antibodies as the detector. The slides will then be stained 
with DAPI prior to image processing. Image capture will be performed through the software 
provided by the imaging system manufacturer. This same software will perform quantification of 
ℽ-H2AX, p-ATR and KAP1 p-Ser 824 (Redon et al., 2010; Kinders et al., 2010).
3. PATIENT SELECTION
3.1
Eligibility Criteria 
3.1.1
Patients must have histologically or cytologically confirmed progressive metastatic or 
unresectable gastric or GEJ adenocarcinoma 
3.1.2
Patients must have measurable disease, defined as at least one lesion that can be 
accurately measured in at least one dimension (longest diameter to be recorded for non-
nodal lesions and short axis for nodal lesions) as ≥20 mm (≥2 cm) by chest x-ray or as 
≥10 mm (≥1 cm) with CT scan, MRI, or calipers by clinical exam.  See Section 11 for the 
evaluation of measurable disease.

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3.1.3
Patients must have progressed after or been intolerant of at least two lines of systemic 
therapy. Patients with HER2 positive gastric and GEJ adenocarcinoma must have 
progressed on trastuzumab plus chemotherapy in the first line setting. Patients with 
microsatellite unstable (MSI-H) tumors must have received prior immunotherapy with 
pembrolizumab.
3.1.4
Age ≥18 years.  Because no dosing or adverse event data are currently available on the 
use of M6620 in combination with irinotecan in patients <18 years of age, children are 
excluded from this study, but will be eligible for future pediatric trials.
3.1.5
Both men and women of all races and ethnic groups are eligible for this trial.
3.1.6
ECOG performance status ≤1 (Karnofsky ≥60%, see Appendix A).
3.1.7
Patients must have normal organ and marrow function as defined below:

leukocytes 
≥3,000/mcL

absolute neutrophil count 
≥1,500/mcL

platelets 
≥100,000/mcL

hemoglobin
≥ 9 g/dL

total bilirubin
within normal institutional limits

AST(SGOT)/ALT(SGPT) 
≤2.5 × institutional upper limit of normal; if liver
involvement ≤ 5x ULN

creatinine clearance 
≥45 mL/min/1.73 m2 for patients with creatinine levels 
above institutional normal.
3.1.8
Patients must have a TP53 mutation (only those known hot-spot mutations that fall within 
exon 2 or exons 4-11 will be accepted) determined from available archived tumor tissue 
that has been subjected to NGS through FoundationOne/FoundationOneCDx or a similar
assay performed in a CLIA-certified laboratory. Investigators from other sites, who have 
potential patients who meet study eligibility, will send copies of NGS reports from these 
patients via Medidata Rave case reports to the Responsible Study Coordinator (contact 
information on Title Page). Our research team will review each report to ensure each 
patient possesses the mutations of interest. Similar review will happen for each patient we 
enroll on the study at our institution. Case reports from all screened patients will be 
centrally available on the Rave study database

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3.1.9
Nine patients must be willing to undergo endoscopic or CT guided tumor biopsies for 
mandatory correlative studies. If the biopsy is deemed not safe by the treating physician, 
the patient may still enroll given that the other eligibility criteria are met.
3.1.10 The effects of M6620 on the developing human fetus are unknown.  For this reason and 
because DNA-damage response (DDR) inhibitors, as well as irinotecan, are known to be 
teratogenic, women of child-bearing potential and men able to father children who have 
female partners of child-bearing potential must agree to use adequate contraception 
(hormonal or barrier method of birth control; abstinence) prior to study entry, for the 
duration of study participation, and for 6 months after trial participant’s final dose of 
M6620 or irinotecan (whichever agent is completed last).  Should a woman become 
pregnant or suspect she is pregnant while she or her partner is participating in this study, 
she should inform her treating physician immediately.
3.1.11 Ability to understand and the willingness to sign a written informed consent document.
3.2
Exclusion Criteria
3.2.1
Patients with early stage untreated or resectable gastric adenocarcinoma.
3.2.2
Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for 
nitrosoureas or mitomycin C) prior to entering the study.
3.2.3
Patients who have previously received irinotecan.
3.2.4
Patients who have not recovered from adverse events due to prior anti-cancer therapy 
(i.e., have residual toxicities > Grade 1, except alopecia) that was administered more than 
four weeks prior to starting study therapy.
3.2.5
Patients who are receiving any other investigational agents.
3.2.6
Patients with untreated or symptomatic brain metastases should be excluded from this 
clinical trial because of their poor prognosis and because they often develop progressive 
neurologic dysfunction that would confound the evaluation of neurologic and other 
adverse events.
3.2.7
History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to M6620 or irinotecan.

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3.2.8
and irinotecan and its active metabolite, 
SN-38, are metabolized by CYP3A4 and UGT1A1, respectively; therefore, concomitant 
administration with strong inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole, 
clarithromycin, ritonavir, indinavir, nelfinavir and saquinavir) or inducers of CYP3A4 
(e.g. rifampin, phenytoin, carbamazepine, phenobarbital, St. John’s Wort) should be 
avoided. Because the lists of these agents are constantly changing, it is important to 
regularly consult a frequently-updated medical reference for a list of drugs to avoid or 
minimize use of.  APPENDIX C (Patient Drug Information Handout and Wallet Card) 
should be provided to patients. As part of the enrollment/informed consent procedures, 
the patient will be counseled on the risk of interactions with other agents, and what to do 
if new medications need to be prescribed or if the patient is considering a new over-the-
counter medicine or herbal product.  
3.2.9
Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, 
symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or 
psychiatric illness/social situations that would limit compliance with study requirements.
3.2.10 Pregnant women are excluded from this study because M6620 as a DNA-damage 
response (DDR) inhibitor may have the potential for teratogenic or abortifacient effects.  
Because there is an unknown but potential risk for adverse events in nursing infants 
secondary to treatment of the mother with M6620, breastfeeding should be discontinued 
if the mother is treated with M6620.  These potential risks also apply to irinotecan.
3.2.11 HIV-positive patients are excluded unless they have an undetectable viral load and are 
able to use anti-viral agents that do not interact with CYP3A4 (or regimens with agents 
that are not major inhibitors of cytochrome P450 enzymes).
3.2.12 History of other malignancy within 36 months prior to enrollment. Patients with local 
cancers of any type, provided no recurrence over this timeframe, are eligible.
3.3
Inclusion of Women and Minorities
NIH policy requires that women and members of minority groups and their subpopulations be 
included in all NIH-supported biomedical and behavioral research projects involving NIH-
defined clinical research unless a clear and compelling rationale and justification establishes to 
the satisfaction of the funding Institute & Center (IC) Director that inclusion is inappropriate 
with respect to the health of the subjects or the purpose of the research. Exclusion under other 
circumstances must be designated by the Director, NIH, upon the recommendation of an IC
Director based on a compelling rationale and justification. Cost is not an acceptable reason for 
exclusion except when the study would duplicate data from other sources. Women of 
childbearing potential should not be routinely excluded from participation in clinical research. 
Please see http://grants.nih.gov/grants/funding/phs398/phs398.pdf.
This clinical trial will not exclude potential subjects from participating in this or any study solely 
on the basis of ethnic origin or socioeconomic status. Every attempt will be made to enter all 
eligible patients in this protocol to address the study objectives in a population representative of 

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x
Addition to a site roster,
x
Assign the treating, credit, consenting, or drug shipment (IVR only) tasks in OPEN,
x
Act as the site-protocol Principal Investigator (PI) on the IRB approval, and
x
Assign the Clinical Investigator (CI) role on the Delegation of Tasks Log (DTL). 
In addition, all investigators act as the Site-Protocol PI (Investigator listed on the IRB approval),
consenting/treating/drug shipment investigator in OPEN, or as the Clinical Investigator (CI) on
the DTL 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.
4.2
Site Registration
Sites participating with the NCI Central Institutional Review Board (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).
In addition, the Site-Protocol PI (i.e., the investigator on the IRB/REB approval) must meet the 
following five criteria to complete processing of the IRB/REB approval record:
x
Holds an Active CTEP status,
x
Rostered at the site on the IRB/REB approval (applies to US and Canadian sites only) and 
on at least one participating roster,
x
If using NCI CIRB, rostered on the NCI CIRB Signatory record,
x
Includes the IRB number of the IRB providing approval in the Form FDA 1572 in the 
RCR profile, and
x
Holds the appropriate CTEP registration type for the protocol. 
Additional Requirements
Additional requirements to obtain an approved site registration status include:
x
An active Federal wide Assurance (FWA) number,
x
An active roster affiliation with the Lead Protocol Organization (LPO) or a Participating 
Organization, and
x
Compliance with all protocol-specific requirements (PSRs).
4.2.1
Downloading Regulatory Documents

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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 PO on the protocol. One
way to search for a protocol is listed below.
x
Log on to the CTSU members’ website (https://www.ctsu.org) using your CTEP-IAM
username and password,
x
Click on Protocols in the upper left of your 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 LAO-CT018, and 
protocol number 10211,
x
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.) 
4.2.2
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.
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.
Delegation of Tasks Log (DTL)
Each site must complete a protocol-specific DTL using the DTL application in the Delegation 
Log section on the CTSU members’ website.  The Clinical Investigator (CI) is required to review 
and electronically sign the DTL prior to the site receiving an Approved site registration status 
and enrolling patients to the study.  To maintain an approved site registration status the CI must 
re-sign the DTL at least annually and when a new version of the DTL is released; and activate 
new task assignments requiring CI sign-off.  Any individual at the enrolling site on a 
participating roster may initiate the site DTL.  Once the DTL is submitted for CI approval, only 
the designated DTL Administrators or the CI may update the DTL.  Instructions on completing 
the DTL are available in the Help Topics button in the DTL application and include a Master 
Task List, which describes DTL task assignments, CI signature, and CTEP registration 
requirements.

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4.2.3
Checking Site Registration Status
Site’s registration status may be verified on the CTSU website. 
x
Click on Regulatory at the top of your screen
x
Click on Site Registration, and
x
Enter your 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.
4.3
Patient Registration
4.3.1
OPEN / IWRS
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 LPOs registration/randomization systems or Theradex Interactive Web Response 
System (IWRS) for retrieval of patient registration/randomization assignment.  OPEN or
IWRS will populate the patient enrollment data in NCI’s clinical data management 
system, Medidata Rave.
Requirements for OPEN access:  
x
A valid CTEP-IAM account.
x
To perform enrollments or request slot reservations:  Must be on an LPO roster, 
ETCTN Corresponding roster, or Participating Organization roster with the role of 
Registrar.  Registrars must hold a minimum of an AP registration type.
x
If a DTL is required for the study, the registrar(s) must hold the OPEN Registrar 
task on the DTL for the site.
x
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.  If a DTL is required for the study, the IVR or 
NPIVR must be assigned the appropriate OPEN-related tasks on the DTL.
Prior to accessing OPEN, site staff should verify the following:
x
Patient has met all eligibility criteria within the protocol stated timeframes, and 
x
All patients have signed an appropriate consent form and HIPAA 
authorization form (if applicable).

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Note: The OPEN system will provide the site with a printable confirmation of 
registration and treatment information. IWRS system also sends an email confirmation 
of the registration. 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.
4.4
General Guidelines
Following registration, patients should begin protocol treatment within 7 calendar days.  Issues 
that would cause treatment delays should be discussed with the Principal Investigator.  If a 
patient does not receive protocol therapy following registration, the patient’s registration on the 
study may be canceled.  The Study Coordinator should be notified of cancellations as soon as 
possible.
5. TREATMENT PLAN
5.1
Agent Administration
Treatment will be administered on an outpatient basis.  Reported adverse events and potential 
risks are described in Section 7.  Appropriate dose modifications are described in Section 6.  No 
investigational or commercial agents or therapies other than those described below may be 
administered with the intent to treat the patient's malignancy.
Regimen Description
Agent
Premedications; 
Precautions
Dose
Route
Schedule
Cycle 
Length
Irinotecan
Benztropine 1 mg PO, 
ondansetron 12 mg IV, 
Dexamethasone 8 mg IV 
30 minutes prior to chemo
180 mg/m2 in 
250 cc D5W
IV over 90
minutes
before
M6620
Day 1 
and 15
28 days 
(4 weeks)
M6620
No scheduled pre-
medications prior to 
M6620 unless there was
an infusion reaction with 
the first dose (see below).
270 mg/m2
IV over 60 
minutes, 
immediately
** after 
irinotecan
Day 1**
and 15

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**The exception to this is during C1 when M6620 is omitted on D1 only for those patients 
undergoing on-treatment biopsies for pharmacodynamic assessment.
The doses of irinotecan and M6620 administered will be determined by calculating the patient's 
body surface area (BSA) based on the patient’s weight in kilograms measured pre-dose on each 
day of dosing (and the patient’s height measured at baseline). 
If the patient’s weight on the day of dosing differs by > ±10% from the weight used to calculate 
the dose, then doses of irinotecan and M6620 must be recalculated prior to administration. 
Unless otherwise specified (e.g. by established institutional practice), all doses may be rounded 
up (or down) to the nearest milligram; and a ±5% variance in the calculated total dose will be 
allowed for ease of dose administration. 
Every effort should be made to target infusion timings to be as close to scheduled duration as 
possible.  But given the variability of infusion pumps, time windows of ± 10 minutes for the 
duration of scheduled infusions are permitted.  (Additionally, prolongation of infusion duration 
for the purpose of managing suspected or actual adverse event such as infusion reaction will not 
be considered a protocol deviation.)
5.1.1
M6620
Infuse over 60 minutes using an infusion set 
Systemic infusion-related reactions to M6620 may include signs or symptoms such as 
pruritus, flushing, chills/rigors, urticaria/rash, headache, bronchospasm/dyspnea, and 
hypotension or hypertension, among others. 
   
If any subject develops pruritus, flushing, or any other symptom suggestive of a systemic 
infusion reaction, standard measures may be employed to manage these symptoms (e.g., 
antihistamines and/or steroids not prohibited by the protocol).  The effectiveness of 
desensitizing measures to prevent either recurrence or first occurrence of systemic 

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infusion reactions to M6620 has not been shown; nonetheless, standard desensitizing 
measures prior to subsequent administrations of M6620 may be employed as long as they
are not prohibited by protocol, for example:
x
Premedication with 200 mg hydrocortisone approximately 60 minutes before 
infusion, and 10 mg of chlorpheniramine or equivalent antihistamine
approximately 30 minutes before infusion.
x
Alternative antihistamine and steroid combinations may be considered.
x
If standard measures to limit symptoms of an infusion reaction are insufficient, 
then the infusion time may be extended beyond 60 minutes but no longer than 90 
minutes.
Local infusion-related reactions to M6620, sometimes described as infusion site 
reactions, may include signs or symptoms such as infusion site erythema, swelling or 
pain.
The IV catheter through which M6620 is infused should be monitored for evidence of 
erythema, tenderness, or induration. An infusion site reaction may be non-serious, or it 
may be serious requiring immediate intervention, and should be managed according to 
standard of care.
To minimize the possibility of phlebitis, M6620 should be administered through a large-
bore catheter into a large-caliber peripheral vein. The IV infusion site should be 
monitored closely for the development of erythema, induration, purulence, tenderness, or 
warmth.  If any subject develops phlebitis, or signs or symptoms of inflammation that 
may progress to phlebitis or that the patient cannot tolerate, standard measures should be 
employed to ameliorate these symptoms (including removal of the infusion catheter and 
resumption of infusion through a different vein).
5.1.2
Irinotecan
Consistent with the irinotecan product label in combination with any overriding 
established institutional practice, it is recommended that patients receive premedication 
with antiemetic agents prior to administration of irinotecan: 
x
In clinical studies (of the weekly dosage schedule), the majority of patients 
received 10 mg of dexamethasone given in conjunction with another type of 
antiemetic agent, such as a 5-HT3 blocker (e.g., ondansetron or granisetron).
x
Antiemetic agents should be given on the day of treatment, starting at least 30 
minutes before administration of irinotecan. 
x
Physicians should also consider providing patients with an antiemetic regimen 
(e.g., prochlorperazine) for subsequent use as needed.
x
Unless contraindicated, prophylactic administration of 1 mg of oral benztropine 
should be given to all patients to prevent immediate severe cholinergic symptoms-

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32
such as rhinitis, increased salivation, miosis, lacrimation, diaphoresis, flushing, and 
intestinal hyperperistalsis that can cause abdominal cramping; bradycardia may 
also occur. If patients continue to experience symptoms, therapeutic administration 
of atropine (e.g. 0.25mg to 1mg intravenous or subcutaneous atropine) should be 
considered.
Both early (occurring during or shortly after irinotecan infusion) and late diarrhea 
(generally occurring >24 hours after administration of irinotecan) have been observed.  
Whereas early diarrhea is usually transient and infrequently severe, late diarrhea may be 
prolonged and can be life threatening.  Late diarrhea may lead to dehydration, electrolyte 
imbalance, or sepsis; and late diarrhea can be complicated by colitis, ulceration, bleeding, 
ileus, obstruction, and infection.  In clinical studies using weekly irinotecan dosing,
Grade 3-4 late diarrhea occurred in 23-31% of patients.  The median time to onset of late 
diarrhea was 11 days with weekly dosing, and 5 days with 3-week dosing (Prescribing 
Information, April, 2016).
Prior to initiation of irinotecan, patients should be informed that they may experience 
diarrhea and should have loperamide readily available to begin treatment for late 
diarrhea.  Patients should be counseled on loperamide use; for example, a loperamide 
regimen might include the following:
x
Begin loperamide at the first episode of poorly formed or loose stools or the 
earliest onset of bowel movements more frequent than normal.
x
Loperamide 4 mg at the first onset of diarrhea, followed by 2 mg with each loose 
motion until diarrhea-free for at least 12 hours (maximum dosage:  16 mg/24 
hours).
x
Loperamide is not recommended to be used for more than 48 consecutive hours at 
these doses, because of the risk of paralytic ileus. Hold loperamide if constipation 
develops.
x
During the night, the patient may take 4 mg of loperamide every 4 hours.
x
Adjunct anti-diarrheal therapy is permitted and should be recorded when used.
x
Diphenoxylate-atropine may be used in cases of loperamide resistance.
5.2
General Concomitant Medication and Supportive Care Guidelines
M6620 is contraindicated in patients with a known hypersensitivity to any component of the drug 
product.  
. Because there is a potential for interaction of M6620 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 

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33
interactions. The study team should check a frequently-updated medical reference for a list of 
drugs to avoid or minimize use of. Appendix C (Patient Drug Information Handout and Wallet 
Card) should be provided to patients.
Because the drug interaction profile of M6620 has not been fully characterized, caution should 
be used when coadministering medications with M6620.
Irinotecan is contraindicated in patients with a known hypersensitivity to the drug or its 
excipients.
Patients should be advised to avoid any foods known to aggravate diarrhea.  Avoid diuretics or 
laxatives in patients with diarrhea.
Monitor and replace fluid and electrolytes as clinically indicated.  Consider antibiotic support for 
ileus, fever, or severe neutropenia. 
Exposure to irinotecan or its active metabolite SN-38 is substantially reduced in patients 
concomitantly receiving the CYP3A4 enzyme-inducing anticonvulsants phenytoin, 
phenobarbital, carbamazepine, or St. John’s wort.  The appropriate starting dose for patients 
taking these or other strong inducers such as rifampin and rifabutin has not been defined.
x
Consider substituting non-enzyme inducing therapies at least 2 weeks prior to 
initiation of irinotecan therapy.  
x
Do not administer strong CYP3A4 inducers with irinotecan unless there are no 
therapeutic alternatives.

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Irinotecan and its active metabolite, SN-38, are metabolized via the human cytochrome P450 
3A4 isoenzyme (CYP3A4) and uridine diphosphate-glucuronosyl transferase 1A1 (UGT1A1), 
respectively.  Patients receiving concomitant ketoconazole, a CYP3A4 and UGT1A1 inhibitor, 
have increased exposure to irinotecan hydrochloride and its active metabolite SN-38.
Coadministration of irinotecan with other inhibitors of CYP3A4 (e.g., clarithromycin, indinavir, 
itraconazole, lopinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telaprevir, voriconazole) or 
UGT1A1 (e.g., atazanavir, gemfibrozil, indinavir) may increase systemic exposure to irinotecan 
or SN-38.
x
Discontinue strong CYP3A4 inhibitors at least 1 week prior to starting irinotecan 
therapy.  
x
Do not administer strong CYP3A4 or UGT1A1 inhibitors with irinotecan unless there 
are no therapeutic alternatives.
The irinotecan infusion site should be monitored for signs of inflammation; care should be taken 
to avoid extravasation.  Should extravasation occur, flushing the site with sterile water and 
applications of ice are recommended. 
Prophylactic use of hematopoietic growth factors is allowed per the treating physician’s 
discretion after cycle 1.
5.3
Duration of Therapy
In the absence of treatment delays due to adverse event(s), treatment may until one of the 
following criteria applies:
x
Disease progression
x
Intercurrent illness that prevents further administration of treatment
x
Unacceptable adverse event(s)
x
Patient decides to withdraw from the study
x
General or specific changes in the patient's condition render the patient unacceptable 
for further treatment in the judgment of the investigator
x
Clinical progression
x
Patient non-compliance
x
Pregnancy

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o
All women of child bearing potential should be instructed to contact the 
investigator immediately if they suspect they might be pregnant (e.g., missed 
or late menstrual period) at any time during study participation.
o
The investigator must immediately notify CTEP in the event of a confirmed 
pregnancy in a patient participating in the study.
x
Termination of the study by sponsor
x
The drug manufacturer can no longer provide the study agent
The reason(s) for protocol therapy discontinuation, the reason(s) for study removal, and the 
corresponding dates must be documented in the Case Report Form (CRF).
5.4
Duration of Follow Up
Patients will be in safety follow-up for a minimum of 30 days after final dose irinotecan or 
M6620 (whichever dose occurs last) or until death, whichever occurs first.  Patients removed 
from study for unacceptable adverse event(s) will be followed until resolution or stabilization of 
the adverse event.
Each patient will be followed for survival every 2 months (±14 days) after the patient’s final 
treatment with M6620 or irinotecan (whichever occurs last) until death, termination of the trial, 
patient withdraws consent, or for a maximum of 1 year after a patient’s final treatment with 
M6620/irinotecan – whichever comes first.  Survival contact may be made via clinic visit, chart 
review, obituary or similar observation (e.g. Social Security death index), or by telephone.
6. DOSING DELAYS/DOSE MODIFICATIONS
As needed for management of irinotecan-related toxicity, the dose reduction levels for irinotecan 
are as follows: 
Dose Level
Irinotecan Dose
Starting Dose
180 mg/m2
-1
150 mg/m2
-2
120 mg/m2
For patients known to be homozygous for the UGT1A1*28 allele, a reduction in the starting 
irinotecan dose by at least one dose level should be considered by the patient’s study physician.  
As needed for management of M6620-related toxicity, the dose reduction levels for M6620 are
as follows
Dose Level
M6620 Dose
Starting Dose
270 mg/m2
-1
240 mg/m2

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-2
210 mg/m2
Beginning with Cycle 2, Day 1:  On the day(s)† of treatment, the following criteria must be 
met before administering any cycle’s 1st dose of irinotecan or 1st dose of M6620 (both of 
which are intended for Day 1 of each cycle):
x
Absolute neutrophil count (ANC) ≥ 1,000/mcL.
x
Platelets ≥ 100,000/mcL.
x
Creatinine within normal institutional limits; or 
≥ 45 mL/min/1.73m2 for patients with creatinine level above institutional 
normal.
x
Total bilirubin within normal institutional limits.
x
AST (SGOT) and ALT (SGPT) ≤ 2.5 x institutional upper limit of normal 
(ULN); or 
if liver involvement, then ≤ 5 x ULN.
x
Treatment-related diarrhea is Grade 0 or Grade 1
x
Serum potassium within normal institutional limits (may be corrected with K 
repletion).
Within each cycle, the patient’s study physician may additionally elect to require 
any or all of these conditions in order to administer that cycle’s 2nd dose of 
irinotecan and/or M6620 (both of which are scheduled for Day 15 of each cycle).
† If a cycle’s 1st dose of irinotecan and the cycle’s 1st dose of M6620 occur on 
different days (e.g. in a setting of AE management, in which one agent is held, 
while the other agent is administered), then the above criteria and below dose 
modifications are separately applicable to the cycle’s 1st dose of the one agent on 
the earlier day, and then to cycle’s 1st dose of the other agent on the later day.
Beginning with Cycle 2, Day 1:  Dose modification according to the below tables and
clarifications will be performed on the day(s) of treatment prior to administering any
cycle’s 1st dose of irinotecan or 1st dose of M6620 (both of which are intended for Day 1 of 
each cycle):
x
Dose modification of irinotecan is based on the nadir toxicity observed in the interval 
between initiation of sequential doses of irinotecan.  Dose modification of M6620 is based 
on the nadir toxicity observed in the interval between initiation of sequential doses of 
M6620.
x
Dose modification (e.g. holds or reductions) of irinotecan will be based on toxicity 

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attributed by the patient’s study physician as possibly, probably, or definitely related to 
irinotecan.  (For events deemed by the patient’s study physician as unlikely or unrelated to 
irinotecan, dose modification of irinotecan is not required; but may be optionally elected.)
x
Dose modification (e.g. holds or reductions) of M6620 will be based on toxicity attributed
by the patient’s study physician as possibly, probably, or definitely related to M6620. (For 
events deemed by the patient’s study physician as unlikely or unrelated to M6620, dose 
modification of M6620 is not required; but may be optionally elected.) 
x
If dosing of either irinotecan or M6620 is individually held, tolerated treatment with the 
other agent may be administered as monotherapy – i.e. separable dosing is permitted.
x
Patients requiring a dose delay of >2 weeks beyond the date of intended dosing should
permanently discontinue the delayed agent.  (As treatment is intended for every two 
weeks, a dose delay of 2 weeks facilitates a total of 4 weeks between treatments.)
Regardless of the reason for holding study treatment, the maximum allowed duration of 
treatment interruption is 4 weeks.  If >28 days separates sequential doses of irinotecan or 
M6620, then the respective agent must be permanently discontinued.
x
If one agent (irinotecan or M6620) is permanently discontinued, tolerated treatment with 
the other agent may continue per protocol. 
x
If a patient experiences multiple adverse events and there are conflicting management 
recommendations, the study physician should use the recommended dose adjustment that 
reduces the dose to the lowest level.
x
Dose re-escalation is not allowed.
x
A minimum of 11 days must separate sequential doses of irinotecan.  A minimum of 11 
days must separate sequential doses of M6620.
x
For toxicities not mentioned below, especially laboratory abnormalities deemed not 
clinically significant by the patient’s study physician, dose reduction is not required and 
will be at the study physician’s discretion.
x
At any time, a more conservative course of dose modification may be elected (e.g. if a 
modification indicates holding until improvement to Grade 1, the study physician may 
instead elect to hold until resolution to Grade 0). 
x
Although these dose modifications are applicable to treatment(s) administered on Day 1 of 
each new cycle (i.e. beginning with and including Day 1 of Cycle 2), the patient’s study 
physician may optionally elect to also apply these modifications to the second dose within 
any existing cycle (e.g. Day 15 dosing during any cycle, including Cycle 1).
x
Dose modifications do not apply to the following toxicities, even if related: alopecia, 
anemia, alkaline phosphatase levels, electrolyte disturbances (if able to be corrected), and 
nausea /vomiting if antiemetics have not been maximized.
Nausea
Management of Irinotecan
Management of M6620
≤ Grade 1
No change in dose.
No change in dose.

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Nausea
Management of Irinotecan
Management of M6620
Grade 2
Hold* until ≤ Grade 1, then resume
at same dose level.
Hold* until ≤ Grade 1, then resume
at same dose level.
Grade 3
Hold* until < Grade 2, then resume
at one dose level lower, if 
indicated.**
Hold* until < Grade 2, then resume
at one dose level lower, if 
indicated.**
Grade 4
Hold* until < Grade 2, then resume 
at 2 dose levels lower.***
Hold* until < Grade 2, then resume 
at 2 dose levels lower.***
*Patients requiring a delay of >2 weeks should go off protocol therapy.
**Patients requiring > 2 dose reductions should go off protocol therapy.
***Patients requiring > 1 dose reduction should go off protocol therapy.
Recommended management:  Antiemetics.
Vomiting
Management of Irinotecan
Management of M6620
≤ Grade 1
No change in dose.
No change in dose.
Grade 2
Hold* until ≤ Grade 1, then resume 
at same dose level.
Hold* until ≤ Grade 1, then resume 
at same dose level.
Grade 3
Hold* until < Grade 2, then resume 
at one dose level lower, if 
indicated.**
Hold* until < Grade 2, then resume 
at one dose level lower, if 
indicated.**
Grade 4
Hold* until < Grade 2, then resume 
at 2 dose levels lower.***
Hold* until < Grade 2, then resume 
at 2 dose levels lower.***
*Patients requiring a delay of >2 weeks should go off protocol therapy.
**Patients requiring > 2 dose reductions should go off protocol therapy.
***Patients requiring > 1 dose reduction should go off protocol therapy.
Recommended management:  Antiemetics.
Diarrhea
Management of Irinotecan
Management of M6620
≤ Grade 1
No change in dose; alternatively, 
hold* until resolved to baseline, 
then resume at same dose level.
No change in dose; alternatively, 
hold* until resolved to baseline, 
then resume at same dose level.
Grade 2
Hold* until resolved to baseline, 
then resume at one dose level 
lower, if indicated.**
Hold* until resolved to baseline, 
then resume at one dose level 
lower, if indicated.**
Grade 3
Hold* until resolved to baseline, 
then resume at one dose level 
lower, if indicated.**
Hold* until resolved to baseline, 
then resume at one dose level 
lower, if indicated.**
Grade 4
Hold* until resolved to baseline, 
then resume at 2 dose levels
lower.***
Hold* until resolved to baseline, 
then resume at 2 dose levels 
lower.***
*Patients requiring a delay of >2 weeks should go off protocol therapy.
**Patients requiring > 2 dose reductions should go off protocol therapy.
***Patients requiring > 1 dose reduction should go off protocol therapy.

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Diarrhea
Management of Irinotecan
Management of M6620
Baseline defined as the most immediately known status prior to initiating study treatment on 
Cycle 1, Day 1.
Recommended management:  Loperamide antidiarrheal therapy.
Example loperamide dosage schedule:  4 mg at first onset, followed by 2 mg with each loose 
motion until diarrhea-free for at least 12 hours (maximum dosage:  16 mg/24 hours).
Adjunct anti-diarrheal therapy is permitted and should be recorded when used.
Neutropenia
(neutrophil 
count decreased)
Management of Irinotecan
Management of M6620
≤ Grade 1
No change in dose.
No change in dose.
Grade 2
Hold* until ≤ Grade 1, then resume 
with no change in dose.
Hold* until ≤ Grade 1, then resume 
with no change in dose.
Grade 3
Hold* until ≤Grade 1, then resume
at one dose level lower, if 
indicated.**
Hold* until ≤ Grade 1, then resume 
at one dose level lower, if 
indicated.**
Grade 4
Hold* until ≤Grade 1, then resume 
at 2 dose levels lower.***
Hold* until ≤ Grade 1, then resume 
at 2 dose levels lower.***
Febrile
Neutropenia****
Hold* until resolved, then resume 
at 2 dose levels lower.***
Hold* until resolved, then resume 
at 2 dose levels lower.***
*Patients requiring a delay of >2 weeks should go off protocol therapy.
**Patients requiring >2 dose reductions should go off protocol therapy.
***Patients requiring >1 dose reduction should go off protocol therapy.
**** Febrile neutropenia defined as an absolute neutrophil count (ANC) < 1000/mm3 with a 
single temperature of >38.3 degrees C (101 degrees F) or a sustained temperature of ≥ 38 
degrees C (100.4 degrees F) for more than one hour.
Thrombocytopenia
(platelet count 
decreased)
Management of Irinotecan
Management of M6620
≤ Grade 1
Hold* until platelets ≥ 100,000 
/mm3, then resume with no change 
in dose.
Hold* until platelets ≥ 100,000 
/mm3, then resume with no change 
in dose.
Grade 2
Hold* until platelets ≥ 100,000 
/mm3, then resume with no change 
in dose.
Hold* until platelets ≥ 100,000 
/mm3, then resume with no change 
in dose.
Grade 3
Hold* until platelets ≥ 100,000 
/mm3, then resume at one dose 
level lower, if indicated.**
Hold* until platelets ≥ 100,000 
/mm3, then resume at one dose 
level lower, if indicated.**

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Thrombocytopenia
(platelet count 
decreased)
Management of Irinotecan
Management of M6620
Grade 4
Hold* until platelets ≥ 100,000 
/mm3, then resume at 2 dose levels
lower.***
Hold* until platelets ≥ 100,000 
/mm3, then resume at 2 dose levels
lower.***
*Patients requiring a delay of >2 weeks should go off protocol therapy.
**Patients requiring >2 dose reductions should go off protocol therapy.
***Patients requiring >1 dose reduction should go off protocol therapy.
7. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The Rave
CTEP-AERS Integration will determine if the following list of AEs (Section 7.2) and the 
characteristics of an observed AE (Sections 7.3 and 7.4) will determine whether the event 
requires expedited reporting in addition to routine reporting.
7.1
Rave-CTEP-AERS Integration
The Rave Cancer Therapy Evaluation Program Adverse Event Reporting System (CTEP-
AERS) integration enables evaluation of post-baseline AEs 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 is used to 
collect AEs that start during the period or persist from the previous reporting period.  
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 Event 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:
x
The reporting period (course/cycle) is correct, and
x
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 

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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:
x
Study specific documents:  Protocols > Documents > Education and Promotion, 
and
x
Expedited Safety Reporting Rules Evaluation user guide:  Resources > CTSU 
Operations Information > User Guides & Help Topics.
NCI requirements for SAE reporting are available on the CTEP website: 
x
NCI Guidelines for Investigators:  Adverse Event Reporting Requirements is 
available at 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguid
elines.pdf.
7.2
Comprehensive Adverse Events and Potential Risks List(s) (CAEPRs)
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.
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses next to 
the AE in the SPEER.  If this CAEPR is part of a combination protocol using multiple 
investigational agents and has an AE listed on different SPEERs, use the lower of the grades to 
determine if expedited reporting is required.
7.2.1
CAEPRs for CTEP IND Agent(s)

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43
7.2.2
Adverse Event List(s) for Irinotecan
The irinotecan package insert contains a black box warning for the following:
x
Early and late forms of diarrhea can occur. Early diarrhea may be 
accompanied by cholinergic symptoms which may be prevented or ameliorated by 
atropine.  Late diarrhea can be life threatening and should be treated promptly 
with loperamide.  Monitor patients with diarrhea and give fluid and electrolytes as 

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needed.  Institute antibiotic therapy if patients develop ileus, fever, or severe 
neutropenia.  Interrupt irinotecan and reduce subsequent doses if severe diarrhea 
occurs. 
x
Severe myelosuppression may occur.
The package insert also includes a listing of adverse reactions:
x
Common adverse reactions (≥30%) observed in combination therapy clinical 
studies of irinotecan are:  nausea, vomiting, abdominal pain, diarrhea, constipation, 
anorexia, mucositis, neutropenia, leukopenia (including lymphocytopenia), 
anemia, thrombocytopenia, asthenia, pain, fever, infection, abnormal bilirubin, and
alopecia.
x
Common adverse reactions (≥30%) observed in single agent therapy clinical 
studies of irinotecan are:  nausea, vomiting, abdominal pain, diarrhea, constipation, 
anorexia, neutropenia, leukopenia (including lymphocytopenia), anemia, asthenia,
fever, body weight decreasing, and alopecia.
Please refer to the irinotecan package insert for the comprehensive list of adverse events.
7.3
Adverse Event Characteristics 
x
CTCAE term (AE description) and grade:  The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
5.0 (starting April 1, 2018) will be utilized for AE reporting.  All appropriate treatment 
areas should have access to a copy of the CTCAE version 5.0.  A copy of the CTCAE 
version 5.0 can be downloaded from the CTEP web site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.
x
Attribution of the AE:
-
Definite – The AE is clearly related to the study treatment.
-
Probable – The AE is likely related to the study treatment.
-
Possible – The AE may be related to the study treatment.
-
Unlikely – The AE is doubtfully related to the study treatment.
-
Unrelated – The AE is clearly NOT related to the study treatment.
7.3.1
Distribution of Adverse Event Reports
CTEP-AERS is programmed for automatic electronic distribution of reports to the 
following individuals:  Principal Investigator and Adverse Event Coordinator(s) (if
applicable) of the Corresponding Organization or Lead Organization, the local treating 
physician, and the Reporter and Submitter.  CTEP-AERS provides a copy feature for 
other e-mail recipients. 
7.3.2
Expedited Reporting Guidelines

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2For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive half-lives, 
rounded UP to the nearest whole day, after the agent/intervention was last administered.  Footnote “1” above 
applies after this reporting period.
Effective Date:  May 5, 2011
7.3.3
Additional Protocol-Specific Expedited Adverse Event Reporting Exclusions
For this protocol only, the AEs/grades listed below do not require expedited reporting via 
CTEP-AERS.  However, they still must be reported through the routine reporting 
mechanism (Section 7.4):
CTCAE 
System Organ 
Class (SOC)
Adverse Event
Grade
≥24h 
Hospitalizationa
Attributionb
to
Irinotecan
Comments
GI
Diarrhea
2
Regardless
Related
Expected with 
chemotherapy
Bone Marrow
Pancytopeniac
2
Regardless
Related
Expected with 
chemotherapy
GI
Nausea/Vomiting
2
Regardless
Related
Expected with 
chemotherapy
a Indicates that an adverse event required hospitalization for ≥24 hours or prolongation of 
hospitalization by ≥24 hours of a patient.
b Possibly, probably or definitely related to irinotecan.
c Including one or more of the following:  Neutropenia, leukopenia (including lymphocytopenia), 
anemia, and thrombocytopenia.
7.4
Routine Adverse Event Reporting
All Adverse Events must be reported in routine study data submissions.  AEs reported 
expeditiously through CTEP-AERS must also be reported in routine study data 
submissions.
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.  AEs are reported in a routine manner at scheduled times 
during the trial using Medidata Rave.  For this trial, the Adverse Event CRF is used for routine 
AE reporting in Rave.
Adverse events will also be reported to EMD Serono:
Fax: +1 (781) 681-2961 ͒or ͒E-mail: usdrugsafety@emdserono.com ͒

Specifying: 
x
Protocol Number and/or Title ͒
x
Subject Number ͒

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x
Site Number/PI Name ͒
x
SAE/Onset Date ͒Relevant follow-up information should be submitted to EMD Serono 
Drug Safety as soon as it becomes available. ͒
7.5
Pregnancy
Although not an adverse event in and of itself, pregnancy as well as its outcome must be 
documented via CTEP-AERS.  In addition, the Pregnancy Information Form included within 
the NCI Guidelines for Adverse Event Reporting Requirements must be completed and 
submitted to CTEP.  Any pregnancy occurring in a patient or patient’s partner from the time of 
consent to 90 days after the last dose of study drug must be reported and then followed for 
outcome.  Newborn infants should be followed until 30 days old.  Please see the “NCI 
Guidelines for Investigators: Adverse Event Reporting Requirements for DCTD (CTEP and CIP) 
and DCP INDs and IDEs” (at http://ctep.cancer.gov/protocolDevelopment/adverse_effects.htm)
for more details on how to report pregnancy and its outcome to CTEP. 
7.6
Secondary Malignancy
A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g.,
treatment with investigational agent/intervention, radiation or chemotherapy). A secondary 
malignancy is not considered a metastasis of the initial neoplasm.
CTEP requires all secondary malignancies that occur following treatment with an agent under an 
NCI IND/IDE be reported expeditiously via CTEP-AERS. Three options are available to 
describe the event: 
x
Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic leukemia 
[AML]) 
x
Myelodysplastic syndrome (MDS) 
x
Treatment-related secondary malignancy 
Any malignancy possibly related to cancer treatment (including AML/MDS) should also be 
reported via the routine reporting mechanisms outlined in each protocol. 
7.7
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.
8. PHARMACEUTICAL INFORMATION
A list of the adverse events and potential risks associated with the investigational or commercial 
agent administered in this study can be found in Section 7.1.

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8.1
CTEP IND Agent(s)
8.1.1
M6620 (NSC 780162)
Other Names: VRT-0768079, MSC2527093A, VX-970
Classification: ATR inhibitor
Molecular Formula: C24H25N5O3S                 M.W.: 463.55 Da
Mode of Action: Ataxia telangiectasia mutated and Rad3-related (ATR) kinase is an apical regulator 
of checkpoint pathways triggered by DNA damage.  The DNA damage response (DDR) is regulated 
by ATR kinase and ataxia telangiectasia mutated (ATM) kinase, which are recruited to distinct DNA 
damage structures.  M6620 disrupts ATR-mediated DNA damage response signaling and leads to 
sustained accumulation of DNA damage in cancer cells co-treated with DNA-damaging agents.
Description: The drug substance for M6620 is the free base.
How Supplied: M6620 is supplied by Merck KGaA/EMD Serono, Inc. 
  
  
  
  
Route of Administration: Intravenous (IV) infusion.

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Method of Administration: Prior to administration the solution should be given one hour at ambient 
temperature to warm up if stored refrigerated following preparation. Infuse over 60 minutes using an 
infusion set 
 The infusion time may be 
extended beyond 60 minutes (as tolerated) but no more than 90 minutes if standard procedures to 
limit symptoms of an infusion reaction are insufficient or if the total volume of the infusion exceeds 
600 mL.  To minimize the possibility of phlebitis, M6620 should be administered through a large 
bore catheter into a large caliber peripheral vein or central venous access.
Patient Care Implications: Monitor for infusion site reactions, irritation, and phlebitis for at 
least 30 minutes following infusion. M6620 absorbs in the UV-visible radiation spectrum and is 
widely distributed including skin, so patients receiving M6620 should take protective measures 
to minimize sun exposure. Women of childbearing potential and men should use appropriate 
contraception while on study drug and for 6 months after discontinuation of M6620. 
Potential Drug Interactions: M6620 is primarily metabolized by 
  
  
Availability
M6620 is provided to the NCI under a Collaborative Agreement between the Pharmaceutical 
Collaborator and the DCTD, NCI (see Section 12.4).
8.1.2
Agent Ordering and Agent Accountability
8.1.2.1 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 participating 
investigator at that institution.
In general, sites may order initial agent supplies when a subject is being screened for 
enrollment onto the study.

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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.
8.1.2.2 Agent Inventory Records – 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 ordering investigator on this protocol.
8.1.3
Investigator’s Brochure Availability
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.
8.1.4
Useful Links and Contacts
x
CTEP Forms, Templates, Documents:  http://ctep.cancer.gov/forms/
x
NCI CTEP Investigator Registration:  RCRHelpDesk@nih.gov
x
PMB policies and guidelines: 
http://ctep.cancer.gov/branches/pmb/agent management.htm
x
Online Agent Order Processing (OAOP) application
https://ctepcore.nci.nih.gov/OAOP
x
CTEP Identity and Access Management (IAM) account: 
https://ctepcore.nci.nih.gov/iam/
x
CTEP and IAM account help:  ctepreghelp@ctep.nci.nih.gov
x
IB Coordinator:  IBCoordinator@mail.nih.gov
x
PMB email:  PMBAfterHours@mail.nih.gov
x
PMB phone and hours of service: (240) 276-6575 Monday through Friday 
between 8:30 am and 4:30 pm (ET)
8.2
Irinotecan
Product description: Irinotecan (CAMPTOSAR) is a topoisomerase inhibitor.  Irinotecan is a 
derivative of camptothecin. Camptothecins interact specifically with the enzyme topoisomerase 
I, which relieves torsional strain during DNA replication by inducing reversible single-strand
breaks.  Irinotecan and its active metabolite SN-38 bind to the topoisomerase I-DNA complex 
and prevent re-ligation of these single-strand breaks.
Irinotecan is typically available in three single-dose sizes:  2, 5 and 15 mL-fill vials, respectively 
containing 40, 100 and 300 mg irinotecan hydrochloride.

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Irinotecan vials should be stored consistent with the product label at controlled room temperature 
15° to 30°C (59° to 86°F).  Protect from light.  Keep the vial in the carton until time of until time 
of use.
Solution preparation: Irinotecan will be prepared consistent with established local procedures 
and the package insert:
x
Inspect vial contents for particulate matter and discoloration and repeat inspection 
when drug product is withdrawn from vial into syringe.
x
Irinotecan injection is intended for single use only and any unused portion should 
be discarded.
x
Irinotecan injection must be diluted prior to infusion.  Irinotecan should be diluted 
in 5% Dextrose Injection, USP, (preferred) or 0.9% Sodium Chloride Injection, 
USP, to a final concentration range of 0.12 mg/mL to 2.8 mg/mL.  Other drugs 
should not be added to the infusion solution.
x
The solution is physically and chemically stable for up to 24 hours at room 
temperature and in ambient fluorescent lighting.  Solutions diluted in 5% Dextrose 
Injection, USP, and stored at refrigerated temperatures (approximately 2° to 8°C, 
36° to 46°F), and protected from light are physically and chemically stable for 48 
hours.  Refrigeration of admixtures using 0.9% Sodium Chloride Injection, USP, is 
not recommended due to a low and sporadic incidence of visible particulates.  
Freezing irinotecan and admixtures of irinotecan may result in precipitation of the 
drug and should be avoided.
Route of administration: All patients are scheduled to receive irinotecan as a 90 minute 
intravenous infusion on Day 1 and Day 15 of each 28-day cycle.  Irinotecan will be administered 
consistent with established local procedures and the package insert:
x
The irinotecan Injection solution should be used immediately after reconstitution 
as it contains no antibacterial preservative.  Because of possible microbial 
contamination during dilution, it is advisable to use the admixture prepared with 
5% Dextrose Injection, USP, within 24 hours if refrigerated (2° to 8°C, 36° to 
46°F).  In the case of admixtures prepared with 5% Dextrose Injection, USP, or 
Sodium Chloride Injection, USP, the solutions should be used within 4 hours if 
kept at room temperature.  If reconstitution and dilution are performed under strict 
aseptic conditions (e.g., on Laminar Air Flow bench), irinotecan injection solution 
should be used (infusion completed) within 12 hours at room temperature or 24 
hours if refrigerated (2° to 8°C, 36° to 46°F).
Agent Ordering: Each site will obtain irinotecan from commercial supply.
9.
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES
Several biomarker correlative studies will be performed on this study:

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x
Archival tumor must be assayed for TP53 mutations prior to enrollment in the 
study using any NGS CLIA certified assay.
x
Archival tumor will also be assessed for additional mutations in DNA Damage 
Response Deficiency (DDRD) genes (see below) via the NGS CLIA certified 
assay used to determine TP53 mutational status.
x
Paired tumor biopsies (from 9 patients) will be collected at 24 hours (+/- 3 hours)
post-irinotecan on C1D2 and at 24 hours (+/- 3 hours) post-M6620 on C2D2 to 
quantify DNA damage and validate on-target inhibition. Expression levels of ℽ-
H2AX, KAP1 p-Ser 824 and p-ATR will be quantified. 
The biomarker table is listed below:
Biomarker Namea
AND Lead PI and 
Site
Assay
(CLIA: 
Y/N)
Use (Integral, Integrated, 
or Exploratory) AND 
Purpose b
Tissue/Body 
Fluid Tested
and Timing of 
Assay
M/O Funding 
Source(s) 
c
TP53 Mutation (exons 2 
and 4-11)
Any CLIA certified NGS 
assay
NGS
CLIA: Yes
Integral
To identify candidates eligible for 
the trial. 
Tissue (Archival)
M
Insurance 
DDRD
(BRCA1, BRCA2, 
MRE11, RAD50, RAD51, 
RAD52, RAD54L, NBN, 
ATM, H2AX, PALB2, 
RPA, BRIP1, BARD1, 
ATR, ATRX, CHK1, 
CHK2, MDM2, MDM4, 
FANCA, FANCC, 
FANCD2, FANCE, 
FANCF, FANCG, 
FANCL)
Any CLIA certified NGS 
assay
NGS
CLIA: Yes
Exploratory 
To identify patient sub-group who 
may derive further benefit from 
the experimental therapy. List of 
genes generated from well 
validated homologous 
recombination genes (from ovarian 
literature) and ATR axis 
mutations. 
Tissue (Archival). 
M
Insurance

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9.1
Integral Laboratory or Imaging Studies
9.1.1
TP53 Mutation
Mutations in TP53 are a prerequisite for enrollment onto the study and will be ascertained via
any CLIA certified NGS assay. Only mutations in exons 2 and 4-11 will be accepted given the 
possible disparate prognosis of non-hotspot TP53 mutant gastric cancer patients compared to 
those with hotspot mutations (Tahara et al., Oncotarget 2016).
9.1.1.1
Collection of Specimen(s)
Collection of tissue (whether fresh or archival) should follow your institutional procedures and 
policies. 
Acceptable samples for testing:
x
Formalin-fixed paraffin embedded (FFPE) specimens including core-needle biopsies
only.
9.1.1.2
Handling of Specimens(s)
x
Use standard fixation methods to preserve nucleic acid integrity. 10% neutral-buffered 
formalin for 6–72 hours is industry standard. DO NOT use other fixatives (e.g., Bouins, 
B5, AZF, Holland’s).
x
Do not decalcify. When decalcification is required, EDTA is recommended. Do not use 
strong acids (e.g., hydrochloric acid, sulfuric acid, picric acid).
9.2
Integrated Correlative Studies
9.2.1
ℽ-H2AX
ℽ-H2AX is a well validated marker of DNA damage. We will be assessing it to look at the on-
target effect of M6620. The biomarker should peak after administration of irinotecan on C1D1. 
When we check levels at 24 hours post-M6620 infusion on C2D2 this signal should be effaced 
given the inhibition of ℽ-H2AX phosphorylation by the ATR inhibitor. We believe responding 
patients will demonstrate a greater decline in phosphorylated ℽ-H2AX levels than patients who 
do not respond to the combination. 
9.2.2.1
Collection of Specimen(s)
In 9 patients, mandatory tumor biopsies (core biopsy only) will be collected at the following time 
points:
•
C1D2 at 24 hours (+/- 3 hours) post-irinotecan
•
C2D2 at 24 hours (+/- 3 hours) post-M6620 infusion
Multiplexed immunofluorescence assays (IFA) will be performed on the biopsies in collaboration 
with the PADIS, Frederick National Laboratory for Cancer Research (FNLCR) and NCLN PD 
Assay Laboratory at MD Anderson.  This panel includes ɣH2AX and pNBS1 biomarkers with 

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βCATN segmentation. Additional biomarker such as KAP1 p-Ser 824 and p-ATR could be 
evaluated depending on the results of ɣH2AX, pNBS1 IFA with βCATN segmentation assay. We 
will test the hypothesis that declines in ℽ-H2AX from post-irinotecan levels are a measure of the 
on-target effect of M6620. 
9.2.2.2
Handling of Specimens(s)
In accordance with SOP340507, biopsy specimens are collected into pre-chilled 1.5mL Sarstedt, 
O-ring screw cap tubes (VWR, Cat#: 83009-010) and then flash frozen in liquid nitrogen or a dry 
ice/ethanol bath. It is imperative that biopsies are flash frozen within 2 minutes of collection in 
order to preserve key pharmacodynamic biomarkers.
Biopsies for PD analyses will be shipped on dry ice to the PADIS laboratory after both the pre-
dose and the post-dose timepoints have been collected. Store all frozen biopsies at -80ºC or lower 
until shipment.
9.2.2.3
Shipping of Specimen(s)
Frozen biopsy samples from participating sites are shipped and delivered to FNLCR PD Central 
Receiving using the following delivery address: 
Attention: Dan Danner NCI-F/FNLCR 
1073 Beasley Street, Building 1073 
Fort Detrick Frederick, MD 21701 
Phone: 301 846-5748 
Please Note: Do not ship frozen biopsy specimens on Fridays and one day prior to any 
Federal holiday, FNLCR receiving is closed and unable to receive samples weekends and on all Federal 
holidays. This prevents the risk of dry ice sublimation and loss of sample integrity.
Email the NCI-F PADIS group at NCI_PD_Support@mail.nih.gov prior to shipping with 
expected arrival date, protocol number, specimen IDs, histologic classification of the primary 
tumor, tracking information, and site information. PADIS needs to be notified as soon as 
possible of all protocol deviations or issues, prior to shipment of specimens(s), and these must be 
noted on the sample shipping manifest (Appendix 2) and batch record (Appendix 1). One batch 
record is completed per patient’s biopsy specimens with all required information noted. If 
shipping multiple patient biopsies, one shipping manifest can be completed including all patient 
specimens within the shipment.
Please contact Amy Pantella at 301-846-6747 or Rachel Andrews at 301-846-1951 (email: 
NCI_PD_Support@mail.nih.gov) for any shipping or protocol inquiries.
9.2.2.4
Site(s) Performing Correlative Study  
The ɣH2AX, pNBS1 IFA with βCATN segmentation assay will be performed at the NCLN PD 
Assay Laboratory at MD Anderson. 
9.3
Exploratory Correlative Studies
9.3.1
DDRD Mutations

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DDRD Mutations will be ascertained from the CLIA certified NGS assays used to determine 
eligibility for the study based on TP53 mutational status. 
Concomitant mutations in other DDRD genes which we feel could improve the likelihood of 
response with the experimental therapy include BRCA1, BRCA2, MRE11, RAD50, RAD51, 
RAD52, RAD54L, NBN, ATM, H2AX, PALB2, RPA, BRIP1, BARD1, ATR, ATRX, CHK1, 
CHK2, MDM2, MDM4, FANCA, FANCC, FANCD2, FANCE, FANCF, FANCG, and FANCL. 
These genes have been validated across assays to play important roles in homologous 
recombination (from published literature in breast and ovarian cancer) and the ATR axis (from 
data cited in the pre-clinical rationale above) (Walsh, 2015).
Collection and handling as per specifications listed for TP53 under 9.1.1.1 and 9.1.1.2
9.3.1.1
Assessment of KAP1 p-Ser 824 and p-ATR
P-ATR is a marker for direct ATR pathway activation and signaling. This has been demonstrated 
in cell line models from several laboratories including the Cortez laboratory at Vanderbilt (Nam 
et al., 2011). KAP1 p-Ser 824 is an ATR independent marker of DNA damage which co-
localizes with ℽ-H2AX at DNA damage foci. Changes in tissue levels of p-ATR and KAP1 p-Ser
824 will be measured in the initial nine patients enrolled on the first stage of the study. We 
anticipate seeing differential patterns of dynamic changes in these levels between responding and 
progressing patients. We believe responding patients will demonstrate greater levels of rise in 
KAP1 p-Ser 824 and greater levels of decline in p-ATR in tumor tissue than progressing patients. 
9.3.1.2
Collection of Specimen(s)
In 9 patients, mandatory tumor biopsies will be collected at the following time points:
• C1D2 at 24 hours (+/- 3 hours) post-irinotecan
• C2D2 at 24 hours (+/- 3 hours) post-M6620 infusion
Depending on the results of ɣH2AX, pNBS1 IFA with βCATN segmentation assay, multiplexed
immunofluorescence assays (IFA) could be performed on biopsies in collaboration with the PADIS, 
Frederick National Laboratory for Cancer Research (FNLCR)Laboratories. As noted above, this 
panel includes KAP1 p-Ser 824 and p-ATR.
9.3.1.3
Handling of Specimens(s)
In accordance with SOP340507, biopsy specimens are collected into pre-chilled 1.5mL Sarstedt, O-
ring screw cap tubes (VWR, Cat#: 83009-010) and then flash frozen in liquid nitrogen or a dry 
ice/ethanol bath. It is imperative that biopsies are flash frozen within 2 minutes of collection in order 
to preserve key pharmacodynamic biomarkers.
Biopsies for PD analyses will be shipped on dry ice to the PADIS laboratory after both the pre-dose 
and the post-dose timepoints have been collected. Store all frozen biopsies at -80ºC or lower until 
shipment.
9.3.1.4
Shipping of Specimen(s)
Frozen biopsy samples from participating sites are shipped and delivered to FNLCR PD Central 

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Receiving using the following delivery address: 
Attention: Dan Danner NCI-F/FNLCR 
1073 Beasley Street, Building 1073 
Fort Detrick Frederick, MD 21701 
Phone: 301 846-5748
Please Note: Do not ship frozen biopsy specimens on Fridays and one day prior to any Federal 
holiday, FNLCR receiving is closed and unable to receive samples weekends and on all Federal 
holidays. This prevents the risk of dry ice sublimation and loss of sample integrity.
Email the NCI-F PADIS group at NCI_PD_Support@mail.nih.gov prior to shipping with 
expected arrival date, protocol number, specimen IDs, histologic classification of the primary 
tumor, tracking information, and site information. PADIS needs to be notified as soon as possible 
of all protocol deviations or issues, prior to shipment of specimens(s), and these must be noted on 
the sample shipping manifest (Appendix 2) and batch record (Appendix 1). One batch record is 
completed per patient’s biopsy specimens with all required information noted. If shipping 
multiple patient biopsies, one shipping manifest can be completed including all patient specimens 
within the shipment.
Please contact Amy Pantella at 301-846-6747 or Rachel Andrews at 301-846-1951 (email: 
NCI_PD_Support@mail.nih.gov) for any shipping or protocol inquiries.
9.3.1.5
Site(s) Performing Correlative Study  
Multiplexed immunofluorescence assays (IFA) for KAP1 p-Ser 824 and p-ATR will be 
performed at PADIS, Frederick National Laboratory for Cancer Research (FNLCR).  
10. STUDY CALENDAR
Pre-
Study
Cycle 1
Cycles2+
Off 
Study5
Wk
1
Wk
2
Wk
3
Wk
4
Wk
1
Wk
2
Wk
3
Wk
4
Irinotecan
A
A
A
A
M6620
B9
B
B
B
Informed consent
X
Demographics
X
Medical history
X
Concurrent meds
X
X--------------------------------------------------------------X
Physical exam
X
X
X
X
X
X
Vital signs1
X
X
X
X
X
X
Height
X
Weight
X
X
X
X
X
X
Performance status
X
X
X
X
X
X

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CBC w/diff, plts
X
X
X
X
X
X
Serum chemistry2
X
X
X
X
X
X
EKG3
X
Adverse event evaluation
X--------------------------------------------------------------X
X
Tumor measurements
X
Tumor measurements repeated every 8 weeks.  
Documentation (radiologic) must be provided for patients 
removed from study for progressive disease.
X
Radiologic evaluation
X
Radiologic measurements performed every 8 weeks.  
Confirmatory scans obtained no sooner than 4 weeks after 
initial documentation of an objective response.
X6
B-HCG
X4
X
Endoscopic or CT-guided Tissue 
Biopsy7
X
X
TP53 Tumor Mutation8
X
A:
Irinotecan:  Dose as assigned; 90 minute IV every 2 weeks.
B:
M6620:  Dose as assigned; 60 minute IV every 2 weeks (immediately after irinotecan). Monitor patients at least 30 
minutes post M6620 for infusion-related reactions and other potentially life-threatening adverse events.
1:
Vital signs including heart rate (HR), blood pressure (BP) and temperature (oral or tympanic); done at least once on
days of treatment prior to dosing (before initiation of any pre-medication).  Additional vitals and post-treatment 
monitoring as clinically indicated.
2:
Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, potassium, 
total protein, SGOT [AST], SGPT [ALT], sodium; LDH and phosphorous.
3:
Single EKG tracing at baseline; additionally as clinically indicated.
4:
Serum pregnancy test (women of childbearing potential) performed day 1 of every cycle.
5:
Off-study evaluation 30 to 37 days after final dose of irinotecan or M6620 (whichever dose occurs last).
6:
Only if previous radiologic evaluation was done >28 days prior to discontinuing study treatment.
7:
Fresh biopsy of primary lesion amenable to a safe endoscopic approach or percutaneous biopsy from metastatic site 
on C1D2 (at 24 hours (+/- 3 hours) post-irinotecan) and on C2D2 (at 24 hours (+/- 3 hours) post-completion of 
M6620). The same lesion will be biopsied during these two time points. Only 9 patients will undergo these 
biopsies. The first 6 patients enrolled on the study will not undergo tumor biopsies.
8:
Documentation of TP53 (p53) tumor mutation within 42 days prior to Cycle 1, Day 1 from NGS sequencing of 
available archival tissue. Sponsor must review and confirm documentation within 42 days of Cycle 1, Day 1. This 
time window does not refer to collection and assay of tissue.
9: 
Only for patients undergoing pharmacodynamic research biopsies, M6620 is omitted on Cycle 1 Day 1.
Baseline evaluations are to be conducted within 14 days (2 weeks) prior to start of protocol 
therapy, unless otherwise indicated.  Scans and x-rays must be done within 28 days (4 weeks) 
prior to the start of therapy.
Time windows: 
x
On Cycle 1, Day 1:  Physical Exam, Performance Status, CBC, and Serum 
Chemistry need not be repeated if already resulted ≤ 3 days prior to first dose of 
protocol therapy. On subsequent cycles, Physical Exam, Performance Status, CBC, 
and Serum Chemistry can be performed ≤ 2 days prior to dose administration.
x
In the absence of delayed dosing (e.g. due to an AE), every reasonable effort 
should be made to remain on a consistent dosing interval of 14 days between 
infusions of irinotecan/M6620.  However, for purpose of accommodating holidays, 
weekends, bad weather, scheduling limitations, etc., Day 15 treatment days 
beginning with and including Cycle 1, Day 15 may occur up to every 14 ±3 days.  
(A minimum of 11 days must separate sequential doses of irinotecan.  A minimum 
of 11 days must separate sequential doses of M6620.)

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x
Similarly, in the absence of delayed dosing (e.g. due to an AE), every reasonable 
effort should be made to remain on a consistent schedule of 4-Week (28-day) 
cycles; but for purpose of accommodating holidays, weekends, bad weather, 
scheduling limitations, etc., subsequent cycles (i.e. Cycles 2+) may occur up to 
every 28 days (4 weeks) plus 1-7 days.
x
Baseline evaluation of disease status by radiologic evaluation ≤ 28 days prior to 
initiating protocol treatment on Cycle 1, Day 1.  Re-scanning to occur every 
8 weeks (minus 1-6 days) after initiating protocol treatment on Cycle 1, Day 1. 
(The minus 1-6 day scan window is intended for flexibility in scheduling re-scans 
during Week 4 of every Even cycle – i.e. between Days 22-28 of Even cycles –
prior to initiation of scheduled treatment on Day 1 of every Odd cycle.) 
Scanning on the same day as Day 1 of an Odd cycle is discouraged but allowed, provided scan 
results receive appropriate RECIST review prior to initiating the new Odd cycle of study 
treatment (e.g. first re-scan is discouraged, but permitted on Cycle 3, Day 1, prior to 
irinotecan/M6620 treatment scheduled for later that same day).  Additional disease evaluations 
or increased scan frequency may be performed according to the medical judgment of the 
patient’s study physician, in accordance with the following:  In the event of suspected 
Progressive Disease (PD), a radiologic evaluation is to be performed as soon as possible; and in 
the event of a Complete or Partial Response (CR/PR), confirmatory imaging is to be performed 
no earlier than 28 days after the first assessment of CR/PR.
Prior to initiating study treatment, all patients must have metastatic or unresectable gastric/GEJ 
cancer with demonstrated evidence from a recognized laboratory, indicating that a primary lesion 
or metastatic site contains mutation of TP53 (p53). Only those mutations falling within exon 2 or 
exons 4-11, will confer eligibility. The NGS report for all potential patients will be sent via a 
case report form through Medidata Rave to the Responsible Study Coordinator who will ensure 
these reports are stored centrally in the study database (on Rave). Our research team will review 
each case report to ensure a patient meets eligibility based on the presence of an eligibility-
conferring TP53 mutation in his/her NGS panel. The first 9 patients will also undergo repeat
tumor biopsies on C1D1 post-irinotecan infusion and C2D2 within 24 hours post-M6620 
infusion; the same lesion will be biopsied during these two time points.
Subsequent to informed consent, an expanded screening window of up to 42 days (six weeks) 
prior to Cycle 1, Day 1 is applicable for any TP53 testing necessary to obtain standard-of-care 
results (e.g. FoundationOne).
Prior to initiating treatment, the screening team must have documentation that available archival 
specimens or fresh specimen [paraffin block(s) or unstained slides from paraffin block(s)] from 
the primary tumor and/or a metastatic site have both been requested from a local or outside 
facility.  Physical possession, however, of requested tissue or waiting for histological analysis or 
confirmation that an acquired specimen contains tumor tissue sufficient for analysis is not 
initially a requirement prior to starting study treatment.  However, as the study enrolls, if 
insufficient collective tissue from all patients ultimately becomes an anticipated risk to the study-

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wide analysis, the sponsor-investigator may require the confirmed presence of sufficient baseline 
tissue prior to initiating study treatment.
Note:  If a patient has a fresh biopsy done within 6 weeks for baseline TP53 eligibility testing, 
additional tissue for correlative research will need to be collected from the consenting patient 
(given he or she is among first 9) during a later procedure (i.e we will still require patient to get 
biopsies at 24 hours (+/- 3 hours) post-irinotecan infusion on C1D2 and at 24 hours (+/- 3 hours)
post-M6620 on C2D2). 
If a patient consents to a fresh baseline biopsy, but the patient’s lesion is deemed inaccessible to 
safe biopsy, the patient may still be allowed to enroll if otherwise eligible, subsequent to 
discussion with and advance written permission from the sponsor-investigator. 
At any time during the study (i.e. after signing consent, and until initiation of survival follow-
up), if additional biopsy is performed as standard-of-care, then a sample of the tissue, if 
available, may be requested for research purposes.
A woman of childbearing potential is defined as any female who has experienced menarche who 
has not undergone surgical sterilization (hysterectomy or bilateral oophorectomy) or is not 
postmenopausal.  Menopause is defined clinically as ≥12 months of spontaneous amenorrhea in a 
woman over 45 years of age in the absence of alternative biological or physiological cause. 
If the patient’s postmenopausal status is considered for childbearing potential with respect to 
study-required contraception, then postmenopausal status in females <62 years of age must be 
confirmed with a serum follicle-stimulating hormone (FSH) level >40 mIU/mL (or within local 
laboratory reference range for postmenopausal women). 
If a patient discontinues the study for reason other than progressive disease confirmed by 
radiologic evaluation (e.g. adverse event), then imaging involving sites of known or suspected 
disease should be continued every 8 weeks (± 7 days) for 6 months and then approximately every 
10 weeks (± 4 weeks) thereafter, relative to date(s) of prior scanning, until disease progression is 
confirmed by imaging.  (Note:  If the patient initiates treatment in another clinical trial, then any 
continuing scans done for this trial may terminate.) 
11. MEASUREMENT OF EFFECT
11.1
Antitumor Effect – Solid Tumors
For the purposes of this study, patients should be re-evaluated for response every 8 weeks,
regardless of any dosing delays or interruptions.  In addition to a baseline scan, confirmatory
scans should also be obtained 8 weeks following initial documentation of objective response.
Response and progression will be evaluated in this study using the new international criteria 
proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline 
(version 1.1) [Eur J Ca 45:228-247, 2009].  Changes in the largest diameter (unidimensional 

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measurement) of the tumor lesions and the shortest diameter in the case of malignant lymph 
nodes are used in the RECIST criteria.
11.1.1 Definitions
Evaluable for toxicity.  All patients will be evaluable for toxicity from the time of their 
first treatment with M6620 and irinotecan.
Evaluable for objective response. Only those patients who have measurable disease 
present at baseline, have received at least one cycle of therapy, and have had their disease 
re-evaluated will be considered evaluable for response.  These patients will have their 
response classified according to the definitions stated below (Note: Patients who exhibit 
objective disease progression prior to the end of cycle 1 will also be considered 
evaluable.)
Evaluable Non-Target Disease Response.  Patients who have lesions present at baseline 
that are evaluable but do not meet the definitions of measurable disease, have received at 
least one cycle of therapy, and have had their disease re-evaluated will be considered 
evaluable for non-target disease.  The response assessment is based on the presence, 
absence, or unequivocal progression of the lesions. 
11.1.2 Disease Parameters
Measurable disease.  Measurable lesions are defined as those that can be accurately 
measured in at least one dimension (longest diameter to be recorded) as ≥20 mm (≥2 cm) 
by chest x-ray or as ≥10 mm (≥1 cm) with CT scan, MRI, or calipers by clinical exam.  
All tumor measurements must be recorded in millimeters (or decimal fractions of 
centimeters).
Note:  Tumor lesions that are situated in a previously irradiated area might or might not 
be considered measurable.  If the investigator thinks it appropriate to include them, the 
conditions under which such lesions should be considered must be defined in the 
protocol.
Malignant lymph nodes. To be considered pathologically enlarged and measurable, a 
lymph node must be ≥15 mm (≥1.5 cm) in short axis when assessed by CT scan (CT scan 
slice thickness recommended to be no greater than 5 mm [0.5 cm]).  At baseline and in 
follow-up, only the short axis will be measured and followed.
Non-measurable disease.  All other lesions (or sites of disease), including small lesions 
(longest diameter <10 mm [<1 cm] or pathological lymph nodes with ≥10 to <15 mm [≥1 
to <1.5 cm] short axis), are considered non-measurable disease.  Bone lesions, 
leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis 
cutis/pulmonitis, inflammatory breast disease, and abdominal masses (not followed by 
CT or MRI), are considered as non-measurable.

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Note:  Cystic lesions that meet the criteria for radiographically defined simple cysts 
should not be considered as malignant lesions (neither measurable nor non-measurable) 
since they are, by definition, simple cysts.
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if non-
cystic lesions are present in the same patient, these are preferred for selection as target 
lesions.
Target lesions. All measurable lesions up to a maximum of 2 lesions per organ and 5 
lesions in total, representative of all involved organs, should be identified as target 
lesions and recorded and measured at baseline.  Target lesions should be selected on the 
basis of their size (lesions with the longest diameter), be representative of all involved 
organs, but in addition should be those that lend themselves to reproducible repeated
measurements.  It may be the case that, on occasion, the largest lesion does not lend itself 
to reproducible measurement in which circumstance the next largest lesion which can be 
measured reproducibly should be selected.  A sum of the diameters (longest for non-
nodal lesions, short axis for nodal lesions) for all target lesions will be calculated and 
reported as the baseline sum diameters.  If lymph nodes are to be included in the sum, 
then only the short axis is added into the sum.  The baseline sum diameters will be used 
as reference to further characterize any objective tumor regression in the measurable 
dimension of the disease.
Non-target lesions.  All other lesions (or sites of disease) including any measurable 
lesions over and above the 5 target lesions should be identified as non-target lesions and 
should also be recorded at baseline.  Measurements of these lesions are not required, but 
the presence, absence, or in rare cases unequivocal progression of each should be noted 
throughout follow-up.
11.1.3 Methods for Evaluation of Measurable Disease
All measurements should be taken and recorded in metric notation using a ruler or 
calipers.  All baseline evaluations should be performed as closely as possible to the 
beginning of treatment and never more than 4 weeks before the beginning of the 
treatment.
The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up. Imaging-based
evaluation is 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 (≥1 cm) 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. 

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Chest x-ray Lesions on chest x-ray are acceptable as measurable lesions when they are 
clearly defined and surrounded by aerated lung.  However, CT is preferable. 
Conventional CT and MRI This guideline has defined measurability of lesions on CT 
scan based on the assumption that CT slice thickness is 5 mm (0.5 cm) or less.  If CT 
scans have slice thickness greater than 5 mm (0.5 cm), the minimum size for a 
measurable lesion should be twice the slice thickness.  MRI is also acceptable in certain 
situations (e.g. for body scans).  
Use of MRI remains a complex issue.  MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which 
greatly impact image quality, lesion conspicuity, and measurement.  Furthermore, the 
availability of MRI is variable globally.  As with CT, if an MRI is performed, the 
technical specifications of the scanning sequences used should be optimized for the 
evaluation of the type and site of disease.  Furthermore, as with CT, the modality used at 
follow-up should be the same as was used at baseline and the lesions should be 
measured/assessed on the same pulse sequence.  It is beyond the scope of the RECIST 
guidelines to prescribe specific MRI pulse sequence parameters for all scanners, body 
parts, and diseases.  Ideally, the same type of scanner should be used and the image 
acquisition protocol should be followed as closely as possible to prior scans.  Body scans 
should be performed with breath-hold scanning techniques, if possible.
PET-CT At present, the low dose or attenuation correction CT portion of a combined 
PET-CT is not always of optimal diagnostic CT quality for use with RECIST 
measurements.  However, if the site can document that the CT performed as part of a 
PET-CT is of identical diagnostic quality to a diagnostic CT (with IV and oral contrast), 
then the CT portion of the PET-CT can be used for RECIST measurements and can be 
used interchangeably with conventional CT in accurately measuring cancer lesions over 
time.  Note, however, that the PET portion of the CT introduces additional data which 
may bias an investigator if it is not routinely or serially performed.  
Ultrasound Ultrasound is not useful in assessment of lesion size and should not be used 
as a method of measurement.  Ultrasound examinations cannot be reproduced in their 
entirety for independent review at a later date and, because they are operator dependent, it 
cannot be guaranteed that the same technique and measurements will be taken from one 
assessment to the next.  If new lesions are identified by ultrasound in the course of the 
study, confirmation by CT or MRI is advised.  If there is concern about radiation
exposure at CT, MRI may be used instead of CT in selected instances.
Endoscopy, Laparoscopy The utilization of these techniques for objective tumor 
evaluation is not advised.  However, such techniques may be useful to confirm complete 
pathological response when biopsies are obtained or to determine relapse in trials where 
recurrence following complete response (CR) or surgical resection is an endpoint.

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Tumor markers Tumor markers alone cannot be used to assess response.  If markers are 
initially above the upper normal limit, they must normalize for a patient to be considered 
in complete clinical response.  Specific guidelines for both CA-125 response (in recurrent 
ovarian cancer) and PSA response (in recurrent prostate cancer) have been published 
[JNCI 96:487-488, 2004; J Clin Oncol 17, 3461-3467, 1999; J Clin Oncol 26:1148-1159, 
2008].  In addition, the Gynecologic Cancer Intergroup has developed CA-125
progression criteria which are to be integrated with objective tumor assessment for use in 
first-line trials in ovarian cancer [JNCI 92:1534-1535, 2000].
Cytology, Histology These techniques can be used to differentiate between partial 
responses (PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor 
types, such as germ cell tumors, where known residual benign tumors can remain).
The cytological confirmation of the neoplastic origin of any effusion that appears or 
worsens during treatment when the measurable tumor has met criteria for response or 
stable disease is mandatory to differentiate between response or stable disease (an 
effusion may be a side effect of the treatment) and progressive disease.
FDG-PET While FDG-PET response assessments need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in 
assessment of progression (particularly possible 'new' disease).  New lesions on the basis 
of FDG-PET imaging can be identified according to the following algorithm: 
a.
Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of 
PD based on a new lesion.
b. No FDG-PET at baseline and a positive FDG-PET at follow-up:  If the positive FDG-
PET at follow-up corresponds to a new site of disease confirmed by CT, this is PD.  If 
the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, 
additional follow-up CT scans are needed to determine if there is truly progression 
occurring at that site (if so, the date of PD will be the date of the initial abnormal 
FDG-PET scan).  If the positive FDG-PET at follow-up corresponds to a pre-existing 
site of disease on CT that is not progressing on the basis of the anatomic images, this 
is not PD.
c.
FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy 
in cases where a residual radiographic abnormality is thought to represent fibrosis or 
scarring.  The use of FDG-PET in this circumstance should be prospectively 
described in the protocol and supported by disease-specific medical literature for the 
indication.  However, it must be acknowledged that both approaches may lead to false 
positive CR due to limitations of FDG-PET and biopsy resolution/sensitivity.
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.
11.1.4 Response Criteria
11.1.4.1
Evaluation of Target Lesions

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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 (<1 cm).
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 (0.5 cm).
(Note:  the appearance of one or more new lesions is also considered progressions).
Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum diameters while on 
study.
11.1.4.2
Evaluation of Non-Target Lesions
Complete Response (CR):  Disappearance of all non-target lesions and normalization 
of tumor marker level.  All lymph nodes must be non-pathological in size (<10 mm
[<1 cm] short axis).
Note:  If tumor markers are initially above the upper normal limit, they must 
normalize for a patient to be considered in complete clinical response.
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal limits.
Progressive Disease (PD):  Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target lesions.  Unequivocal progression
should not normally trump target lesion status.  It must be representative of overall 
disease status change, not a single lesion increase.
Although a clear progression of “non-target” lesions only is exceptional, the opinion 
of the treating physician should prevail in such circumstances, and the progression 
status should be confirmed at a later time by the review panel (or Principal 
Investigator).
11.1.4.3
Evaluation of Best Overall Response
The best overall response is the best response recorded from the start of the treatment 
until disease progression/recurrence (taking as reference for progressive disease the 
smallest measurements recorded since the treatment started).  The patient's best 

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response assignment will depend on the achievement of both measurement and 
confirmation criteria.
For Patients with Measurable Disease (i.e., Target Disease)
Target
Lesions
Non-Target
Lesions
New 
Lesions
Overall 
Response
Best Overall Response when 
Confirmation is Required*
CR
CR
No
CR
≥4 wks. Confirmation**
CR
Non-CR/Non-
PD
No
PR
≥4 wks. Confirmation**
CR
Not evaluated
No
PR
PR
Non-CR/Non-
PD/not 
evaluated
No
PR
SD
Non-CR/Non-
PD/not 
evaluated
No
SD
Documented at least once ≥4
wks. from baseline**
PD
Any
Yes or No
PD
no prior SD, PR or CR
Any
PD***
Yes or No
PD
Any
Any
Yes
PD

See RECIST 1.1 manuscript for further details on what is evidence of a new lesion.
**
Only for non-randomized trials with response as primary endpoint.
***  In exceptional circumstances, unequivocal progression in non-target lesions may be
accepted as disease progression.
Note:  Patients with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be 
reported as “symptomatic deterioration.” Every effort should be made to document the 
objective progression even after discontinuation of treatment.
For Patients with Non-Measurable Disease (i.e., Non-Target Disease)
Non-Target Lesions
New Lesions
Overall Response
CR
No
CR
Non-CR/non-PD
No
Non-CR/non-PD*
Not all evaluated
No
not evaluated
Unequivocal PD
Yes or No
PD
Any
Yes
PD

‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is 
increasingly used as an endpoint for assessment of efficacy in some trials so to assign this 
category when no lesions can be measured is not advised
11.1.5 Duration of Response

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Duration of overall response:  The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first 
date that recurrent or progressive disease is objectively documented (taking as reference 
for progressive disease the smallest measurements recorded since the treatment started).
The duration of overall CR is measured from the time measurement criteria are first met 
for CR until the first date that progressive disease is objectively documented.
Duration of stable disease:  Stable disease is measured from the start of the treatment 
until the criteria for progression are met, taking as reference the smallest measurements 
recorded since the treatment started, including the baseline measurements. 
11.1.6 Progression-Free Survival
PFS is defined as the duration of time from start of treatment to time of progression or 
death from any cause, whichever occurs first. Time to progression is defined as the 
duration of time from start of treatment to time of progression or death from progression.
12. STUDY OVERSIGHT AND DATA REPORTING / REGULATORY 
REQUIREMENTS
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7.0 
(Adverse Events: List and Reporting Requirements).
12.1
Study Oversight
This protocol is monitored at several levels, as described in this section.  The Protocol Principal 
Investigator is responsible for monitoring the conduct and progress of the clinical trial, including 
the ongoing review of accrual, patient-specific clinical and laboratory data, and routine and 
serious adverse events; reporting of expedited adverse events; and accumulation of reported 
adverse events from other trials testing the same drug(s).  The Protocol Principal Investigator and 
statistician have access to the data at all times through the CTMS web-based reporting portal.  
For the duration of this study, the Protocol Principal Investigator will have, at a minimum, 
quarterly conference calls with the Study Investigators and the CTEP Medical Officer(s) to
review accrual, progress, and pharmacovigilance.  Decisions to proceed to the second stage of a 
Phase 2 trial will require sign-off by the Protocol Principal Investigator and the Protocol 
Statistician.
All Study Investigators at participating sites who register/enroll patients on a given protocol are 
responsible for timely submission of data via Medidata Rave and timely reporting of adverse 
events for that particular study.  This includes timely review of data collected on the electronic 
CRFs submitted via Medidata Rave.

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All studies are also reviewed in accordance with the enrolling institution’s data safety monitoring 
plan.
12.2
Data Reporting
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:
x
A valid account, and 
x
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:
o
Rave CRA or Rave CRA (Lab Admin) role, must have a minimum of an 
Associate Plus (AP) registration type,
o
Rave Investigator role, must be registered as an Non-Physician Investigator 
(NPIVR) or Investigator (IVR), and
o
Rave Read Only role, site staff must have at a minimum an Associates (A) 
registration type.
x
Refer to https://ctep.cancer.gov/investigatorResources/default.htm for registration types 
and documentation required.
If the study has a DTL, individuals requiring write access to Rave must also be assigned the 
appropriate Rave tasks on the DTL.
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 Rave 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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12.2.1 Method
This study will be monitored by the Clinical Trials Monitoring Service (CTMS).  Data 
will be submitted to CTMS at least once every two weeks via Medidata Rave (or other 
modality if approved by CTEP).  Information on CTMS reporting is available at:  
http://www.theradex.com/clinicalTechnologies/?National-Cancer-Institute-NCI-11.  On-
site audits will be conducted on an 18-36 month basis as part of routine cancer center site 
visits. More frequent audits may be conducted if warranted by accrual or due to concerns 
regarding data quality or timely submission.  For CTMS monitored studies, after users 
have activated their accounts, please contact the Theradex Help Desk at (609) 619-7862
or by email at CTMSSupport@theradex.com for additional support with Rave and 
completion of CRFs.
12.2.2 Responsibility for Data Submission
For ETCTN trials, it is the responsibility of the PI(s) at the site to ensure that all 
investigators at the ETCTN Sites understand the procedures for data submission for each 
ETCTN protocol and that protocol specified data are submitted accurately and in a timely 
manner to the CTMS via the electronic data capture system, Medidata Rave.  
Data are to be submitted via Medidata Rave to CTMS on a real-time basis, but no less 
than once every 2 weeks.  The timeliness of data submissions and timeliness in resolving 
data queries will be tracked by CTMS.  Metrics for timeliness will be followed and
assessed on a quarterly basis.  For the purpose of Institutional Performance Monitoring, 
data will be considered delinquent if it is greater than 4 weeks past due.
Data from Medidata Rave and CTEP-AERS is reviewed by the CTMS on an ongoing 
basis as data is received.  Queries will be issued by CTMS directly within Rave.  The 
queries will appear on the Task Summary Tab within Rave for the CRA at the ETCTN to 
resolve.  Monthly web-based reports are posted for review by the Drug Monitors in the 
IDB, CTEP.  Onsite audits will be conducted by the CTMS to ensure compliance with 
regulatory requirements, GCP, and NCI policies and procedures with the overarching 
goal of ensuring the integrity of data generated from NCI-sponsored clinical trials, as 
described in the ETCTN Program Guidelines, which may be found on the CTEP 
(http://ctep.cancer.gov/protocolDevelopment/electronic applications/adverse events.htm
) and CTSU websites.
CTMS will utilize a core set of eCRFs that are Cancer Data Standards Registry and 
Repository (caDSR) compliant (http://cbiit.nci.nih.gov/ncip/biomedical-informatics-
resources/interoperability-and-semantics/metadata-and-models).  Customized eCRFs will 
be included when appropriate to meet unique study requirements.  The PI is encouraged 
to review the eCRFs, working closely with CTMS to ensure prospectively that all 
required items are appropriately captured in the eCRFs prior to study activation.  CTMS 
will prepare the eCRFs with built-in edit checks to the extent possible to promote data 
integrity.

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CDUS data submissions for ETCTN trials activated after March 1, 2014, will be carried 
out by the CTMS contractor, Theradex.  CDUS submissions are performed by Theradex 
on a monthly basis.  The trial’s lead institution is responsible for timely submission to 
CTMS via Rave, as above.
Further information on data submission procedures can be found in the ETCTN Program 
Guidelines 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.htm
).
12.3
Data Quality Portal
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 (LPO) 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. 
12.4
CTEP Multicenter Guidelines
N/A
12.5
Collaborative Agreements Language
The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the NCI 
under a Collaborative Agreement (CRADA, CTA, CSA) between the Pharmaceutical 
Company(ies) (hereinafter referred to as “Collaborator(s)”) and the NCI Division of Cancer

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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 
another Agent, each the subject of different Collaborative Agreements, the access to and use 
of data by each Collaborator shall be as follows (data pertaining to such combination use 
shall hereinafter be referred to as "Multi-Party Data”):
a.
NCI will provide all Collaborators with prior written notice regarding the existence and 
nature of any agreements governing their collaboration with NCI, the design of the 
proposed combination protocol, and the existence of any obligations that would tend to 
restrict NCI's participation in the proposed combination protocol.
b. Each Collaborator shall agree to permit use of the Multi-Party Data from the clinical trial 
by any other Collaborator solely to the extent necessary to allow said other Collaborator 
to develop, obtain regulatory approval or commercialize its own Agent.
c.
Any Collaborator having the right to use the Multi-Party Data from these trials must 
agree in writing prior to the commencement of the trials that it will use the Multi-Party
Data solely for development, regulatory approval, and commercialization of its own
Agent.
3. Clinical Trial Data and Results and Raw Data developed under a Collaborative Agreement 
will be made available to Collaborator(s), the NCI, and the FDA, as appropriate and unless 
additional disclosure is required by law or court order as described in the IP Option to 
Collaborator (http://ctep.cancer.gov/industryCollaborations2/intellectual property.htm).
Additionally, all Clinical Data and Results and Raw Data will be collected, used and 
disclosed consistent with all applicable federal statutes and regulations for the protection of 
human subjects, including, if applicable, the Standards for Privacy of Individually 
Identifiable Health Information set forth in 45 C.F.R. Part 164.
4. When a Collaborator wishes to initiate a data request, the request should first be sent to the 
NCI, who will then notify the appropriate investigators (Group Chair for Cooperative Group 
studies, or PI for other studies) of Collaborator's wish to contact them.

NCI Protocol #: 10211
Version Date: December 2, 2022
72
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.
13. STATISTICAL CONSIDERATIONS
13.1
Study Design/Endpoints
This is a single arm, two-stage phase II clinical trial to test the efficacy, with respect to the 
objective response rate, of M6620 plus Irinotecan compared to an historical objective response 
rate estimated from patients treated with Irinotecan alone.
13.1.1 Endpoints
Primary Endpoint.  The primary endpoint for the phase II clinical trial is the objective 
response rate (ORR) according to RECIST 1.1 response criteria.
Secondary Endpoints: PFS is defined as the time from study enrollment to disease 
progression or death for any reason. OS is defined as the time from study enrollment to 
death for any reason. DOR is the period-of-time from when patients achieve their best 
response (CR or PR) to when they progress or die for any reason. All patients will be 
followed for survival for up to 1 year. Patients lost-to-follow-up or alive and progression-
free at the end of the follow-up period will be censored for PFS. Patients lost-to follow-
up or alive at the end of the follow-up period will be censored for OS.
13.1.2 Patient population
Efficacy: All patients enrolled who receive any dose of M6620 or Irinotecan.

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75
insufficient data) [Note: By arbitrary convention, category 9 usually designates the 
“unknown” status of any type of data in a clinical database].
All of the patients who met the eligibility criteria at study enrollment, received at least 
one dose of study medication, and have at least one follow-up response evaluation will be
included in the primary analysis of the response rate.  Treatment will be considered to 
have failed in patients in response categories 4-9 (disease progression).  Thus, an 
incorrect treatment schedule or drug administration does not result in exclusion from the 
analysis of the response rate.  Precise definitions for categories 4-9 will be protocol 
specific. Patients who do not have a follow-up response evaluation will be replaced.
All conclusions should be based on all eligible patients. Subanalyses may then be 
performed on the basis of a subset of patients, excluding those for whom major protocol 
deviations have been identified (e.g., early death due to other reasons, early 
discontinuation of treatment, major protocol violations, etc.).  However, these 
subanalyses will not serve as the basis for drawing conclusions concerning treatment 
efficacy, and the reasons for excluding patients from the analysis will be clearly reported.  
The 95% confidence intervals should also be provided. 
REFERENCES
Bass A, Thorsson V, Shmulevich I et al. (2014). Comprehensive molecular characterization of 
gastric adenocarcinoma. Nature. 513(7517):202-209.
CAMPTOSAR (irinotecan) [Prescribing Information].  Pharmacia and Upjohn Company LLC;
April 2016. 
Dickson, M.A. and G.K. Schwartz.  (2009).  Development of cell-cycle inhibitors for cancer 
therapy.  Curr Oncol.  16:36-43.
Fokas, E., R. Prevo, J.R. Pollard et al. (2012).  Targeting ATR in vivo using the novel inhibitor 
VE-822 results in selective sensitization of pancreatic tumors to radiation.  Cell Death Dis.
3:e441.
Fokas, E., R. Prevo, E.M. Hammond et al.  (2014).  Targeting ATR in DNA damage response 
and cancer therapeutics.  Cancer Treat Rev.  40:109-117.
Hall, A.B., D. Newsome, Y. Wang et al.  (2014).  Potentiation of tumor responses to DNA 
damaging therapy by the selective ATR inhibitor M6620.
Hedegaard J, Thorsen K, Lund M et al. (2014). Next-Generation Sequencing of RNA and DNA 
Isolated from Paired Fresh-Frozen and Formalin-Fixed Paraffin-Embedded Samples of Human 
Cancer and Normal Tissue. PLoS One. 9(5):e98187.

NCI Protocol #: 10211
Version Date: December 2, 2022
76
Investigator’s Brochure (2017). M6620.  Vertex Pharmaceuticals, Inc., Boston, MA. Version 7.0
(June 21, 2017).
Ivashkevich A, Redon C, Nakamura A et al. (2012). USE OF THE γ-H2AX ASSAY TO 
MONITOR DNA DAMAGE AND REPAIR IN TRANSLATIONAL CANCER RESEARCH. 
Cancer Lett. 327(1-2):123-133.
Josse R, Martin S, Guha R et al. (2014). ATR inhibitors VE-821 and M6620 sensitize cancer 
cells to topoisomerase I inhibitors by disabling DNA replication initiation and fork elongation 
responses. Cancer Res. 74(23):6968–6979.
Kapa Biosystems [Technical Data Sheet]. Human Genomic DNA Quantification and QC Kit. 
https://www.n-
genetics.com/file/KAPA_hgDNA_Quantification_and_QC_Kit_TDS_KR0454_v2.16.pdf
Kinders RJ, Hollingshead M, Lawrence S et al. (2010). Development of a validated 
immunofluorescence assay for γH2AX as a pharmacodynamic marker of topoisomerase I 
inhibitor activity. Clin Cancer Res. 16(22):5447-57.
Kwok M, Davies M, Agathanggelou A et al. (2016). ATR inhibition induces synthetic lethality 
and overcomes chemoresistance in TP53- or ATM-defective chronic lymphocytic leukemia cells. 
Blood. 127(5):582-95.
Kuo, L.J. and L.-X. Yang.  (2008).  γ-H2AX - a novel biomarker for DNA double-strand breaks.  
In Vivo.  22:305-309.
Lee K, Maeng C, Kim T et al. (2019). A Phase III Study to Compare the Efficacy and Safety of 
Paclitaxel Versus Irinotecan in Patients with Metastatic or Recurrent Gastric Cancer Who Failed 
in First-line Therapy (KCSG ST10-01). The Oncologist. 24(1):18-e24.
Leszcznyska Katarzyna, Dobrynin G, Leslie R et al. (2016). Preclinical testing of an Atr 
inhibitor demonstrates improved response to standard therapies for esophageal cancer. Radiother 
Oncol. 121(2): 232–238.
Ma C, Cai S, Li S et al. (2012). Targeting Chk1 in p53-deficient triple-negative breast cancer is 
therapeutically beneficial in human-in-mouse tumor models.J Clin Invest. A22(4):1541-52.
Makiyama A, Arimizu K, Hirano G et al. (2018). Irinotecan monotherapy as third-line or later 
treatment in advanced gastric cancer. Gastric Cancer. 21(3):464-472.
Manic G, Signore M, Sistugu A et al. (2017). CHK1-targeted therapy to deplete DNA 
replication-stressed, p53-deficient, hyperdiploid colorectal cancer stem cells. Gut.  gutjnl-2016-
312623 (Epub).

NCI Protocol #: 10211
Version Date: December 2, 2022
77
Min A, Im SA, Jang H et al. (2017). AZD6738, A Novel Oral Inhibitor of ATR, Induces 
Synthetic Lethality with ATM Deficiency in Gastric Cancer Cells. Mol Cancer Ther.
2017;16(4):566-57.
Nam E, Zhao R, Glick G et al. (2011). Thr-1989 Phosphorylation Is a Marker of Active Ataxia 
Telangiectasia-mutated and Rad3-related (ATR) Kinase. J Biol Chem. 286(33):28707-28714.
Netter J, Lehmann-Che J, Lambert J et al. (2015). Functional TP53 mutations have no impact on 
response to cytotoxic agents in metastatic colon cancer. Bulletin Du Cancer. 102(2):117-125.
O’Carrigan B, Jose de Miguel Luken M, Papadatos-Pastos D et al. (2016). Phase I trial of a first-
in-class ATR inhibitor M6620 as monotherapy (mono) or in combination (combo) with 
carboplatin (CP) incorporating pharmacodynamics (PD) studies. J Clin Oncol. 34(15):S2504.
Pitts, T.M., S.L. Davis, S.G. Eckhardt, et al.  (2014).  Targeting nuclear kinases in cancer: 
development of cell cycle kinase inhibitors.  Pharmacol Ther.  142:258-269.
Reaper, P.M., M.R. Griffiths, J.M. Long, et al. (2011).  Selective killing of ATM- or p53-
deficient cancer cells through inhibition of ATR.  Nat Chem Biol.  7:428-430.
Redon CE, Nakamura AJ, Zhang YW et al. (2010). Histone gammaH2AX and poly(ADP-
ribose) as clinical pharmacodynamic biomarkers.  Clin Cancer Res. 16(18):4532-4
SEER database. https://seer.cancer.gov/statfacts/html/stomach.html
Sym S, Hong J, Park J et al. (2013). A randomized phase II study of biweekly irinotecan 
monotherapy or a combination of irinotecan plus 5-fluorouracil/leucovorin (mFOLFIRI) in 
patients with metastatic gastric adenocarcinoma refractory to or progressive after first-line 
chemotherapy. Cancer Chemother Pharmacol. 71:481-488.
Shitara K, Doi T, Dvorkin M et al. (2018). Trifluridine/tipiracil versus placebo in patients with 
heavily pretreated metastatic gastric cancer (TAGS): a randomised, double-blind, placebo-
controlled, phase 3 trial. Lancet Oncol. 19(11):1437-1448.
Tahara T, Shibata T, Okamoto Y et al. (2016). Mutation spectrum of TP53 gene predicts 
clinicopathological features and survival of gastric cancer. Oncotarget. 7(27):42252–42260.
Thomas A, Redon C, Sciuto L et al. (2017). Phase I Study of ATR Inhibitor M6620 in 
Combination With Topotecan in Patients With Advanced Solid Tumors. J Clin Oncol. 
Epublication prior to print: http://ascopubs.org/doi/full/10.1200/JCO.2017.76.6915.  
Torre L, Siegel R, Ward E et al. (2016). Global Cancer Incidence and Mortality Rates and 
Trends—An Update. Cancer Epidemiology Biomarkers and Prevention. 25(1):16-27.
Walsh, CS. (2015).  Two decades beyond BRCA1/2: Homologous recombination, hereditary 
cancer risk and a target for ovarian cancer therapy. Gynecol Oncol. 137(2):343-350.

NCI Protocol #: 10211
Version Date: December 2, 2022
78
Weber, A.M. and A.J. Ryan. (2015).  ATM and ATR as therapeutic targets in cancer.  
Pharmacol Therap.  Epub (ahead of print).
White, D., I.U. Rafalska-Metcalf, A.V. Ivanov et al.  (2012).  The ATM substrate KAP1 controls 
DNA repair in heterochromatin: regulation by HP1 proteins and serine 473/824 phosphorylation.  
Mol Cancer Res.  10:401-414.
Wilke H, Muro K, Van Cutsem E, et al. Ramucirumab plus paclitaxel versus placebo plus 
paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction 
adenocarcinoma (RAINBOW): a double-blind, randomised phase 3 trial. Lancet Oncol.
2014;15(11):1224-1235.
Xu HY, Xu WL, Wang LQ et al. (2014). Relationship between P53 Status and Response to 
Chemotherapy in Patients with Gastric Cancer: A Meta-Analysis. PLOS One. Epublication 
(https://doi.org/10.1371/journal.pone.0095371).
Yan, S., M. Sorrell, and Z. Berman.  (2014).  Functional interplay between ATM/ATR-mediated 
DNA damage response and DNA repair pathways in oxidative stress.  Cell Mol Life Sci.
71:3951-3967.
Zeman, M.K. and K.A. Cimprich.  (2014).  Causes and consequences of replication stress.  Nat
Cell Biol.  16:2-9.

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

DCTD Standard Operating Procedures
APPENDIX B: CTEP MULTICENTER GUIDELINES
Not applicable.

DCTD Standard Operating Procedures
APPENDIX C: PATIENT DRUG INFORMATION HANDOUT AND WALLET CARD
Information for Patients, Their Caregivers and Non-Study Healthcare Team on Possible Interactions with Other Drugs 
and Herbal Supplements 
Patient 
Name:
Diagnosis: 
Trial #:
10211
Study 
Doctor:
Study Doctor 
Phone #:
Study 
Drug(s):
M6620
Please show this paper to all your healthcare providers (doctors, physician assistants, nurse practitioners, pharmacists), and tell 
them you are taking part in a clinical trial sponsored by the National Cancer Institute. 
x Please be very careful!  Over-the-counter drugs (including herbal supplements) may contain ingredients that could interact 
with your study drug.  Speak to your doctors or pharmacist to determine if there could be any side effects. 
x Make sure your doctor knows to avoid certain prescription medications. 
x Your regular health care provider should check a frequently updated medical reference or call your study doctor before 
prescribing any new medicine or discontinuing any medicine.  
Version Feb/2019
(Next page: Patient Drug Interaction Wallet Card)
PATIENT DRUG INTERACTION WALLET CARD 

DCTD Standard Operating Procedures
http://dctd.cancer.gov/ResearchResources/ResearchResources-biomarkers.htm and be sure to use the 
current version.

DCTD Standard Operating Procedures
BATCH
INITIALS:
DATE: