Randomized Phase II Trial of Topotecan Plus M6620 (VX-970, Berzosertib) Vs. Topotecan Alone in Patients With Relapsed Small-Cell Lung Cancer
Phase: PHASE2
Conditions: Extensive Stage Lung Small Cell Carcinoma, Extrapulmonary Small Cell Neuroendocrine Carcinoma, Limited Stage Lung Small Cell Carcinoma, Platinum-Resistant Lung Small Cell Carcinoma, Platinum-Sensitive Lung Small Cell Carcinoma, Recurrent Lung Small Cell Carcinoma
Sponsor: National Cancer Institute (NCI)

i
TO:
Cancer Therapy Evaluation Program
FROM: Anish Thomas, MBBS, M.D., Principal Investigator,
Developmental Therapeutics Branch, NCI, CCR
DATE: 10/21/2022
RE:
Amendment version date: 10/21/2022 for Protocol 20-C-0009 (#10268):
“Randomized Phase II Trial of Topotecan plus M6620 (VX-970) vs. Topotecan 
alone in Patients with Relapsed Small-Cell Lung Cancer”
The purpose of this amendment is to expand the assessment of circulating free DNA beyond 
exome and panel sequencing to include cfDNA fragmentomics and the application of spatial 
transcriptomics, both as exploratory studies. 
Briefly, in the last 4-5 years since the clinical trial development started and patients were 
enrolled, the understanding of SCLC heterogeneity has undergone a major shift. Rather than 
mutations, heterogeneity of SCLC is now thought to be driven by the expression of distinct 
transcription factors [1-4]. SCLC consist of tumor cells with neuroendocrine (NE) and non-
neuroendocrine (non-NE) features [1-6], further defined by differential expression of the three 
lineage-defining transcription factors (TFs) ASCL1, NEUROD1, and POU2F3. A fourth 
subgroup has been variously characterized by YAP1 expression [1-4] or low expression of all 
three transcription factors accompanied by an inflamed gene signature [5]. SCLC heterogeneity 
increases over the course of treatment, with expansion of the non-NE cell population associated 
with chemo-resistance [5-7]. These TFs cannot be inferred from cfDNA assays proposed in the 
current version of the protocol. 
Dying cells in the human body release their content into the bloodstream. Genomic DNA that is 
bound by nucleosomes and TFs escapes endogenous nucleases and so remains protected in 
plasma [8]. Regular turnover of lymphoid and myeloid cells in the human body is the major 
contributor to the pool of cell-free DNA (cfDNA) in plasma. However, in cancer, a detectable 
fraction of cfDNA arises from tumors. This suggests that cfDNA has the potential to map the 
tumor transcriptome and therefore can help uncover the regulatory landscape of cancer from 
plasma. Fragmentomics seeks to uncover the tissue of origin of cfDNA using the information on 
cfDNA fragment length. We will apply a genome-wide approach for analysis of cfDNA 
fragmentation profiles called DELFI (DNA evaluation of fragments for early interception) [9]. 
This approach provides a view of cfDNA “fragmentomes”, permitting evaluation in any 
individual of the size distribution and frequency of millions of occurring cfDNA fragments 
across the genome. In a proof of principle study, genome-wide fragmentation profiles could non-
invasively distinguish between NSCLC and SCLC. Specifically, consistent decrease in aggregate 
fragment coverage at regions containing the ASCL1 binding sites (±200 bp) was observed in 
patients with SCLC compared to non-cancer individuals or those with other cancer types.  In 
contrast, at distances further from ASCL1 binding sites (>2000 bp), the fragment coverage for 
patients with SCLC and other patients were similar. As cfDNA fragmentomes can 
comprehensively represent both genomic and chromatin characteristics, it has the potential to 
identify the determinants of response and resistance to topotecan and topotecan plus M6620.

ii
Although our understanding of cell-extrinsic influences on SCLC plasticity is rudimentary, a key 
role of these non-genetic mechanisms is suggested by two important observations: (i) 
transcriptional subtypes of human SCLC are not strongly associated with specific mutational 
patterns [1] and (ii) differences in neuroendocrine gene expression programs between human 
tumors and patient-derived xenografts [6]. We hypothesize that the dynamic interactions between 
tumor microenvironment (TME) and the cancer cells shape SCLC cell states. The sequencing 
approaches proposed in the current protocol such as bulk RNA-seq does not provide a context of 
the spatial interactions between cells and TME in tissue. As seen in Figure 1, cancer associated 
fibroblast (CAF) and tumor associated macrophage (TAM) molecular signatures may be higher 
around non-NE SCLC when analyzed using bulk sequencing data. However, sequencing data 
from TME regions (spatial transcriptomic approach using Nanostring GeoMx digital spatial 
profiling) shows an opposite trend, proven by immunohistochemistry (IHC), showing higher 
enrichment of CAFs and TAMs around high NE tumors, highlighting the utility of the spatial 
transcriptomic approach.
Spatial transcriptomics is a novel approach allowing measurement and mapping of gene activity 
to the resolution of single to few cells keeping the position information intact [7,10-11]. Mapping 
the cell-intrinsic and -extrinsic factors that impact SCLC tumor cell states in their positional 
context could yield important insights into the biologic basis of response and resistance to 
topotecan and topotecan plus M6620.

iii
Figure 1. Discordance of stromal features derived from bulk and spatial transcriptome data. 
Correlation of (A) CAF (B) TAM gene expression signatures with tumor NE scores from bulk RNA-seq 
data. IMPOWER 133 trial data of treatment-naïve advanced SCLC patients Correlation of (C) CAF and 
(D) TAM gene expression signatures with tumor NE scores specifically in the tumor regions of interest. 
Preliminary data from 10 SCLC patient tumors profiled as transcriptome-wide spatial RNA profiling using 
GeoMX Whole Transcriptome Atlas platform Correlation of (E) CAF and (F) TAM gene expression 
signatures with tumor NE scores specifically in the TME regions of interest. Preliminary Data as above (G) 
Multiplex IHC showing high TAMs and CAFs in stroma around high NE tumor compared with low NE 
tumor (CAF marker, ACTA2 in green; TAM marker CD163 in red; Blue/DAPI labels DNA/nuclei showing 
SCLC tumor clusters). 
References:
1. Rudin CM, Poirier JT, Byers LA, et al. Molecular subtypes of small cell lung cancer: a 
synthesis of human and mouse model data. Nat Rev Cancer. 2019;19(5):289-297.
2. Gazdar, A.F., et al., Characterization of Variant Subclasses of Cell-Lines Derived from 
Small Cell Lung-Cancer Having Distinctive Biochemical, Morphological, and Growth-
Properties. Cancer Research, 1985. 45(6): p. 2924-2930.

iv
3. Zhang, W., et al., Small cell lung cancer tumors and preclinical models display 
heterogeneity of neuroendocrine phenotypes. Translational Lung Cancer Research, 2018. 
7(1): p. 32-+.
4. Calbo, J., et al., A Functional Role for Tumor Cell Heterogeneity in a Mouse Model of 
Small Cell Lung Cancer. Cancer Cell, 2011. 19(2): p. 244-256.
5. Lissa D, Takahashi N, Desai P, et al. Heterogeneity of neuroendocrine transcriptional 
states in metastatic small cell lung cancers and patient-derived models. Nat Commun. 
2022;13(1):2023.
6. Thomas A, Takahashi N, Rajapakse VN, et al. Therapeutic targeting of ATR yields 
durable regressions in small cell lung cancers with high replication stress. Cancer Cell. 
2021;39(4):566-579 e567.
7. Roper N, Velez MJ, Chiappori A, et al. Notch signaling and efficacy of PD-1/PD-L1 
blockade in relapsed small cell lung cancer. Nat Commun. 2021;12(1):3880.
8. Snyder MW, Kircher M, Hill AJ, Daza RM, Shendure J. Cell-free DNA Comprises an In 
Vivo Nucleosome Footprint that Informs Its Tissues-Of-Origin. Cell. 2016 Jan 14;164(1-
2):57-68. doi: 10.1016/j.cell.2015.11.050. PMID: 26771485; PMCID: PMC4715266.
9. Mathios, D., Johansen, J.S., Cristiano, S. et al. Detection and characterization of lung 
cancer using cell-free DNA fragmentomes. Nat Commun 12, 5060 (2021).
https://doi.org/10.1038/s41467-021-24994-w
10. Gavriel F, Nobuyoki T, Israa S, et al. Subtyping of Small Cell Lung Cancer using plasma 
cell-free nucleosomes. bioRxiv 2022; doi: https://doi.org/10.1101/2022.06.24.497386
11. Lissa D, Takahashi N, Desai P, et al. Integrated genomic and transcriptomic analysis of 
small cell lung cancer reveals inter- and intratumoral heterogeneity. Nat Communs. 2022:
In press.
SUMMARY OF CHANGES
I.
COMMENTS REQUIRING A RESPONSE (AMENDMENT 17) –
ADMINISTRATIVE & EDITORIAL ISSUES:
#
Section
Comments
1.
5.7
In the Biomarker Plan Table, update the laboratory information in the 
Laboratory Performing Assay Column for each biomarker being performed by the 
MoCha laboratory to the following:  
NCLN Genomics Laboratory or MoCha, Frederick National Laboratory for Cancer 
Research (FNLCR) 
Dr. Mickey Williams
mickey.williams@nih.gov
PI Response: Biomarker plan table has been update as requested.

v
#
Section
Comments
2.
5.7
In the Biomarker Plan Table, please separate cfDNA into two rows as two separate 
assays are being performed by two different laboratories.  See below.  Renumber 
the subsequent biomarkers accordingly.
3
cfDNA -
Fragmentomics
Fragmentomics 
Exploratory
To determine 
prognostic 
and 
predictive 
role, and 
their 
usefulness to 
track tumor 
evolution and 
heterogeneity 
in response 
to treatment
O
Blood
Baseline,
Cycle 1 
Day 5 †, 
Cycle 2 
Day 1 †, 
Cycle 3 
Day 1, 
and at 
progression.
Delfi Diagnostics, Baltimore, 
MD
Lorenzo Rinaldi 
rinaldi@delfidiagnostics.com
4
Circulating 
Tumor DNA 
(ctDNA) 
TSO500
Exploratory
To determine 
prognostic 
and 
predictive 
role, and 
their 
usefulness to 
track tumor 
evolution and 
heterogeneity 
in response 
to treatment
O
Blood
Baseline,
Cycle 1 
Day 5 †, 
Cycle 2 
Day 1 †, 
Cycle 3 
Day 1, 
and at 
progression.
NCLN Genomics Laboratory 
or MoCha, Frederick 
National Laboratory for 
Cancer Research (FNLCR) 
Dr. Mickey Williams
mickey.williams@nih.gov
PI Response: cfDNA have been separated into two rows as two separate assays 
are being performed by two different laboratories. subsequent biomarkers 
accordingly
3.
5.8.1.2
Replace current section 5.8.1.2 with the following:
5.8.1.2 Site Performing Correlative Study
RNA-Seq will be performed on baseline tumor samples at The NCLN Genomics 
Laboratory or MoCha, Frederick National Laboratory for Cancer Research 
(FNLCR).

vi
#
Section
Comments
5.8.1.3 Shipment of Specimens from the EET Biobank to Site Performing 
Correlative Study 
Specimens will be shipped from the EET Biobank to one of the laboratories 
designated in Section 5.8.1.2.
5.8.1.4   Contact Information for Notification of Specimen Shipment
Thomas Forbes (NCLNGenomicsReceiving@nih.gov)
PI Response: Section 5.8.1.2 has been updated as requested.
4.
5.8.2.2
Replace current section 5.8.2.2 with the following:
5.8.2.2 Site Performing Correlative Study
RNA-Seq will be performed on baseline tumor samples at The NCLN Genomics 
Laboratory or MoCha, Frederick National Laboratory for Cancer Research 
(FNLCR).
5.8.2.3 Shipment of Specimens from the EET Biobank to Site Performing 
Correlative Study 
Specimens will be shipped from the EET Biobank to one of the laboratories 
designated in Section 5.8.2.2.
5.8.2.4   Contact Information for Notification of Specimen Shipment
Thomas Forbes (NCLNGenomicsReceiving@nih.gov)
PI Response: Section 5.8.2.2 has been updated as requested.
5.
5.8.3.2
Replace current section 5.8.3.2 with the following:
5.8.3.2 Site Performing Correlative Study
RNA-Seq will be performed on baseline tumor samples at The NCLN Genomics 
Laboratory or MoCha, Frederick National Laboratory for Cancer Research 
(FNLCR).

vii
#
Section
Comments
5.8.3.3 Shipment of Specimens from the EET Biobank to Site Performing 
Correlative Study 
Specimens will be shipped from the EET Biobank to one of the laboratories 
designated in Section 5.8.3.2.
5.8.3.4   Contact Information for Notification of Specimen Shipment
Thomas Forbes (NCLNGenomicsReceiving@nih.gov)
PI Response: Section 5.8.3.2 has been updated as requested.
6.
5.8.4
Add the follow new Sections to 5.8.4 following current Section 5.8.4.2
5.8.4.3 Shipment of Specimens from the EET Biobank to Site Performing 
Correlative Study 
Specimens will be shipped from the EET Biobank to:
Please add shipping address for NCI DTB Laboratory
5.8.4.4 Contact Information for Notification of Specimen Shipment
Please add contact email for notification of specimen shipment for this assay
PI Response: Section 5.8.4 has been updated as requested.
7.
5.9.2
Please create separate sections for cfDNA - Fragmentomics and Circulating Tumor 
DNA as follows.  Renumber subsequent sections accordingly :
5.9.2 cfDNA - Fragmentomics
Characterization of plasma cfDNA can potentially provide rapid, noninvasive 
improved monitoring of disease burden, depth of responses to treatment, and 
timely warning of disease relapse in patients with SCLC [1].  Peripheral blood will 
be collected to assess cfDNA for genetic mutations specific to SCLC.
5.9.2.1 Specimen Receipt and Processing at the EET Biobank
Whole blood collected in Streck tubes will be centrifuged to separate buffy coat 
and plasma and will be stored in a -80°C freezer. 

viii
#
Section
Comments
The nucleic acids will be analyzed to determine concentration and quality.  
Aliquots of DNA and RNA will be shipped for analysis.
5.9.2.2 Site Performing Correlative Study
This study will be performed by Delfi Diagnostics.
5.9.2.3 Shipment of Specimens from the EET Biobank to Site Performing 
Correlative Study 
Specimens will be shipped from the EET Biobank to:
Please add shipping address for Delfi Diagnostics
5.9.2.4 Contact Information for Notification of Specimen Shipment
Please add contact email for notification of specimen shipment for this assay
5.9.3
Circulating Tumor DNA (ctDNA)
Characterization of plasma cfDNA can potentially provide rapid, noninvasive 
improved monitoring of disease burden, depth of responses to treatment, and 
timely warning of disease relapse in patients with SCLC [46].  Peripheral blood 
will be collected to assess cfDNA for genetic mutations specific to SCLC.
5.9.3.1
Specimen Receipt and Processing at the EET Biobank
Whole blood collected in Streck tubes will be centrifuged to separate buffy coat 
and plasma and will be stored in a -80°C freezer. 
The nucleic acids will be analyzed to determine concentration and quality.  
Aliquots of DNA and RNA will be shipped for analysis.
5.9.3.2 Site Performing Correlative Study
ctDNA will be performed at The NCLN Genomics Laboratory or MoCha, 
Frederick National Laboratory for Cancer Research (FNLCR).

ix
#
Section
Comments
5.9.3.3 Shipment of Specimens from the EET Biobank to Site Performing 
Correlative Study 
Specimens will be shipped from the EET Biobank to one of the laboratories 
designated in Section 5.9.3.2.
5.9.3.4   Contact Information for Notification of Specimen Shipment
Thomas Forbes (NCLNGenomicsReceiving@nih.gov)
PI Response: Section 5.9.2 has been updated as requested.
8.
5.9.4
Add the following new Sections to current Section 5.9.3 SLFN11, cMYC, and 
ATM (now 5.9.4).
5.9.4.3 Shipment of Specimens from the EET Biobank to Site Performing 
Correlative Study 
Specimens will be shipped from the EET Biobank to:
Please add shipping address for NCI DTB Laboratory
5.9.4.4 Contact Information for Notification of Specimen Shipment
Please add contact email for notification of specimen shipment for this assay
PI Response: Section 5.9.4 has been updated as requested.
9.
5.9.5.2
In the Section for WES, replace current Section 5.9.4.2 (now 5.9.5.2) with the 
following:
5.9.5.2 Site Performing Correlative Study
WES will be performed on baseline tumor samples at The NCLN Genomics 
Laboratory or MoCha, Frederick National Laboratory for Cancer Research 
(FNLCR).
5.9.5.3 Shipment of Specimens from the EET Biobank to Site Performing 
Correlative Study 
Specimens will be shipped from the EET Biobank to one of the laboratories 
designated in Section 5.9.5.2.

x
#
Section
Comments
5.9.5.4   Contact Information for Notification of Specimen Shipment
Thomas Forbes (NCLNGenomicsReceiving@nih.gov)
PI Response: Section 5.9.5.2 has been updated as requested.
II.
RECOMMENDATIONS (AMENDMENT 17):
#
Section
Comments
10.
Title 
Page
Please note that “Hillman” was omitted during the revision of LAO-PA015 / UPMC 
Cancer Center Institute LAO. Please update and add Hillman to this participating org.
PI Response: “Hillman” has been added to the org name.
11.
4.1
Please replace the first paragraph with the updated language below:
Food and Drug Administration (FDA) regulations require sponsors to select 
qualified investigators. National Cancer Institute (NCI) policy requires all 
individuals contributing to NCI-sponsored trials to register with their qualifications 
and credentials and to renew their registration annually. To register, all 
individuals must obtain a Cancer Therapy Evaluation Program (CTEP) Identity 
and Access Management (IAM) account at https://ctepcore.nci.nih.gov/iam. In 
addition, persons with a registration type of Investigator (IVR), Non-Physician 
Investigator (NPIVR), or Associate Plus (AP) must complete their annual 
registration using CTEP’s web-based Registration and Credential Repository 
(RCR) at https://ctepcore.nci.nih.gov/rcr.  
PI Response: First paragraph in section 4.1 has been updated as requested.
III.
CTEP RECOMMENDATIONS FOLLOWING AMENDMENT 15 REVIEW
#
Sectio
n
Comments
1
Cover 
Page
Please revise the following Participating Organization as indicated.
LAO-PA015 / UPMC Hillman University of Pittsburgh Cancer Center Institute
LAO
PI Response: Change has been made.

xi
2
4.2
Please revise the excerpt below as specified.
Sites participating with the NCI Central Institutional Review Board (NCI CIRB) 
must submit the Study Specific Worksheet (SSW) for Local Context (SSW) to the 
CIRB using IRBManager to indicate their intent to open the study locally.  
Please revise the excerpt below as specified.
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 to be completed:
x
Holds an active CTEP status,
Active status at the site(s) on the IRB/REB approval (applies to US and 
Canadian sites only) on at least one participating organization’s roster,
x
If using NCI CIRB, active on the NCI CIRB roster under the applicable 
CIRB Signatory Institution(s) record,
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
Lists all sites on the IRB/REB approval as Practice Sites in the Form FDA 
1572 in the RCR profile; and
x
Holds the appropriate CTEP registration type for the protocol. 
Additional Requirements
Additional site requirements to obtain an approved site registration status include:
x
An active Federalwide Assurance (FWA) number,
x
An active roster affiliation with the Lead Protocol Organization (LPO) or a 
Participating Organization (PO), and
x
An active roster affiliation with the NCI CIRB roster under at least one 
CIRB Signatory Institution (US sites only); and
x
Compliance with all protocol-specific requirements (PSRs).
PI Response: Change has been made.
3
4.2.1
Please revise the excerpt below as specified.

xii
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 to institutions 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. on a participating roster. To view/download site 
registration forms:
Please revise the excerpt below as specified.
x
Click on Documents, Protocol Related Documents, and use the Document 
Type filter and select Site Registration, and to download and complete the 
forms provided.  (Note:  For sites under the CIRB, IRB data will load 
automatically to the CTSU.) 
PI Response: Change has been made.
4
4.2.3
Please revise this subsection as indicated.
Submit required forms and documents to the CTSU Regulatory Office using the 
Regulatory Submission Portal on the CTSU members’ 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
by phone or email: 1-866-651-CTSU (2878), or CTSURegHelp@coccg.org in 
order to receive further instruction and support.
PI Response: Change has been made.
5
4.3.1
Please revise the excerpt below as specified.
x
To perform enrollments or request slot reservations:  Must be Be on an 
LPO roster, ETCTN Corresponding roster, or PO Participating 
Organization roster with the role of Registrar.  Registrars must hold a 
minimum of an Associate Plus (AP) AP registration type.

xiii
Please revise the excerpt below as specified.
x
All patients have signed an appropriate consent form and Health Insurance 
Portability and Accountability Act (HIPAA) HIPAA authorization form (if 
applicable).
PI Response: Change has been made.
6
4.3.4
Please revise the Theradex Helpdesk number as indicated.
This link to the Theradex website is also on the CTSU website OPEN tab. For 
questions about the use of IWRS for slot reservations, contact the Theradex 
Helpdesk at 855-828-6113 609-619-7862 or Theradex main number 609-799-
7580; CTMSSupport@theradex.com.
PI Response: Change has been made.
7
10.3.1
Please delete the language within this subsection and replace with the following 
language.
10.3.1
Rave-CTEP-AERS Integration
The Rave Cancer Therapy Evaluation Program Adverse Event Reporting 
System (CTEP-AERS) integration enables evaluation of Adverse Events 
(AEs) entered in Rave to determine whether they require expedited 
reporting and facilitates entry in CTEP-AERS for those AEs requiring 
expedited reporting.  Sites must initiate all AEs for this study in Medidata 
Rave.
Include the following (highlighted) paragraphs about pre-treatment AEs 
only if the study requires reporting of pre-treatment AEs. Pre-existing 
medical conditions are not considered adverse events and therefore 
should not be reported on an Adverse Event form.
Pre-treatment AEs:  AEs that occur after informed consent is signed and 
prior to start of treatment are collected in Medidata Rave using the Pre-
treatment Adverse Event form. 
Pre-existing medical conditions (formerly referred to as baseline AEs) 
identified during baseline assessment are not considered AEs and therefore 

xiv
should not be reported on the Pre-treatment Adverse Event form. If these 
pre-existing conditions worsen in severity, the investigator must reassess 
the event to determine if an expedited report is required. Whether or not an 
expedited report is required, the worsened event should be reported as a 
routine AE.
Treatment-emergent AEs:  All AEs that occur after start of treatment are 
collected in Medidata Rave using the Adverse Event form, which is 
available for entry at each treatment course or reporting period and is used 
to collect AEs that start during the period or persist from the previous 
reporting period.  AEs that occur 30 Days after the Last Administration of 
the Investigational Agent/Intervention are collected using the Late 
Adverse Event form.
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 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.  Contact the CTSU Help Desk at 1-888-823-5923 or by email at 
ctsucontact@westat.com if you have any issues submitting an expedited 
report in CTEP-AERS.
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 

xv
from Medidata Rave.
Additional information about the CTEP-AERS integration is available on 
the CTSU members’ website:
x
Study specific documents:   Protocols > Documents> Protocol 
Related Documents> Adverse Event Reporting, and  
x
Additional resources: Resources > CTSU Operations Information> 
User Guides & Help Topics.
NCI requirements for SAE reporting are available on the CTEP website: 
NCI Guidelines for Investigators:  Adverse Event Reporting Requirements is 
available at 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguid
elines.pdf.
PI Response: Change has been made.
8
13.2
Please replace the paragraph below with the provided language.
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 email from iMedidata. To accept the invitation, site staff must 
either click on the link in the email or log in to iMedidata via the CTSU members’ 
website  under Data Management > Rave Home and click to accept the invitation 
in the Tasks pane located in the upper right-corner of the iMedidata screen. 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 eLearning link in 
the Tasks pane located in the upper right corner of the iMedidata screen.  If an 
eLearning is required for a study and has not yet been taken, the link to the 
eLearning will appear under the study name in the Studies pane located in the 
center of the iMedidata screen; 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 replace the eLearning link under the study name. 
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 

xvi
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. 
PI Response: Change has been made.
9
13.3
Please revise this subsection as indicated.
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, DQP Form Status and the DQP Reports modules 
are available to access details and reports of unanswered queries, 
delinquent forms, forms with current status 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, DQP Form 
Status, and DQP Reports 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 

xvii
regarding questions about Rave Calendaring functionality. 
Include the following paragraph only if study is not using the Calendaring 
functionality in Rave; otherwise, delete.
This study does not use the Rave Calendaring functionality and therefore 
the DQP Delinquent Forms module will not include details for this study, 
and the DQP Summary table on the Rave Home page will display N/A for 
the Total Delinquencies summary count.
PI Response: Change has been made.
IV.
RESPONSE TO RA FROM CTEP (10/6/2022):
1. The following changes have been made to the participation organizations table:
a.
Added:  Early Drug Development Opportunity Program (EDDOP) 
b. Deleted:  Create Access to Targeted Cancer Therapy for Underserved 
Populations (CATCH-UP) 
V.
PI REQUESTED CHANGES:
1. Title page:
a.
Version date has been updated in all headers and in the title page.
b. Data managers have been updated as previous ones are no longer part of the 
study.
2. Section 2.5.4.1, cfDNA Fragmentomics and Spatial Transcriptomics: Rationale for 
the expansion of circulating free DNA assessment to include fragmentomics and the 
application of spatial transcriptomics has been added.
3. Section 5.7, Biomarker Plan: Spatial transcriptomics, fragmentomics and TSO500 have 
been added as assays used for the analysis of tumor tissue and/or blood samples.
Corresponding labs performing the analysis have also been updated.
4. Section 5.8.4, Spatial Transcriptomics: Processing of samples for this new integrated 
analysis has been added.
5. Section 5.9.2, cfDNA: Delfi Diagnostics has been added as laboratory evaluating cfDNA 
in blood samples, per the added exploratory analysis.

NCI Protocol #:  10268 
Version Date:  October 21, 2022 
 
1 
 
NCI Protocol #: 
10268 
 
Local Protocol #: 
20-C-0009 
 
ClinicalTrials.gov Identifier:  NCT03896503 
 
TITLE:  Randomized Phase II Trial of Topotecan plus M6620 (VX-970, Berzosertib) vs. 
Topotecan alone in Patients with Relapsed Small-Cell Lung Cancer 
 
Corresponding Organization: LAO-NCI/ National Cancer Institute LAO 
 
 
Principal Investigator: 
Anish Thomas, MBBS, M.D.  
 
Developmental Therapeutics Branch (DTB) 
 
Center for Cancer Research 
 
National Cancer Institute 
 
10 Center Drive, Room 4-5330 
 
Bethesda, MD 20892 
 
Phone: 240-614-6467 
 
E-mail: anish.thomas@nih.gov 
 
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 
Early Drug Development Opportunity Program (EDDOP) 
 
Statistician: 
Seth M. Steinberg, Ph.D. 
Head, Biostatistics and Data Management Section 
9609 Medical Center Drive, Room 2W334 
Rockville, MD-20852 
Office: 240.276.5563 
Email: steinbes@mail.nih.gov 
Study Coordinator: 
Rasa Vilimas, RN, BSN 
Research Nurse Specialist 
Thoracic and Gastrointestinal Oncology Branch 
9000 Rockville Pike 
Building 10, Room 8D44 
Bethesda, MD 20892 
Office: 240-858-3158 
Email: rasa.vilimas@nih.gov 
 
Responsible Research Nurse: 
Rasa Vilimas, RN, BSN 
Research Nurse Specialist 
Responsible Data Manager: 
Jessie McGlone 
Office of The Clinical Director (NCI Contractor) 

NCI Protocol #:  10268 
Version Date:  October 21, 2022 
 
2 
 
Thoracic and Gastrointestinal Oncology Branch 
9000 Rockville Pike 
Building 10, Room 8D44 
Bethesda, MD 20892 
Office: 240-858-3158 
Email: rasa.vilimas@nih.gov 
 
Back-up Data Manager: 
Sonali Chibb 
Office of The Clinical Director (NCI Contractor) 
Bldg 82 Room 101 
9030 Old Georgetown Rd. 
Bethesda, MD 20892 
Office: 240-858-7454 
Email: sonali.chibb@nih.gov 
 
  
Bldg 82 Room 100 
9030 Old Georgetown Rd. 
Bethesda, MD 20892 
Office: 240-760-7565 
Email: jessie.mcglone@nih.gov 
 
 
 
 
NCI-Supplied Agent: M6620 (VX-970, berzosertib), NSC 780162 
Other Agent(s): Topotecan, NSC 609699, Commercial 
 
IND#:  
IND Sponsor: DCTD, NCI 
 
Protocol Type/Version #/Version Date: Original / September 14, 2018 
 
Revision 1 / December 4, 2018 
 
Revision 2 / January 17, 2019 
Revision 3 / February 25, 2019 
Revision 4a / April 22, 2019 
Revision 5 / May 17, 2019 
Amendment 1 / September 18, 2019 (Disapproved) 
Amendment 2 / October 8, 2019 
 
Amendment 3 / December 12, 2019 
 
Amendment 4 / February 10, 2020 
 
Amendment 5 / June 4, 2020 
 
Amendment 6/ August 11, 2020 (Disapproved) 
 
Amendment 7/ September 2, 2020 (Disapproved) 
 
Amendment 8/ October 6, 2020 (Disapproved) 
 
Amendment 9/ October 26, 2020 
Amendment 10/ January 05, 2021 (Disapproved) 
Amendment 11/ April 07, 2021 
Amendment 12/ May 19, 2021 
Amendment 13/ January 07, 2022 (Disapproved) 
Amendment 14/ February 01, 2022 (Disapproved) 
Amendment 15/ March 23, 2022 
Amendment 16/ August 10, 2022 
Amendment 17/ September 26, 2022 (Disapproved) 
Amendment 18/ October 21, 2022 

NCI Protocol #:  10268 
Version Date:  October 21, 2022 
 
3 
 
SCHEMA 
 
This study is a randomized Phase 2 study of patients with relapsed SCLC.  SCLC patients who 
have failed prior therapy will be randomized 2:1 to receive either topotecan in combination with 
M6620 or topotecan alone.  Patients will be stratified at the time of randomization for being 
sensitive or resistant/refractory to prior therapy.  Patients who progress while on topotecan alone 
will be eligible to cross-over and receive topotecan with M6620 combination treatment.  A 
separate cohort of patients with extrapulmonary small cell cancer will be accrued while the 
primary cohort is accruing and will receive the combination of M6620 and topotecan. 

NCI Protocol #:  10268
Version Date:  October 21, 2022
4
TABLE OF CONTENTS
SUMMARY OF CHANGES......................................................................................................... iv
SCHEMA
3
TABLE OF CONTENTS.................................................................................................................4
OBJECTIVES8
Primary Objective......................................................................................................8
Secondary Objectives................................................................................................8
Exploratory Objectives..............................................................................................8
BACKGROUND .................................................................................................................9
Study Disease ............................................................................................................9
Rationale..................................................................................................................10
M6620 (VX-970, Berzosertib) ................................................................................12
Mechanism of Action.............................................................................................12
Nonclinical Pharmacokinetics ...............................................................................12
Clinical Pharmacokinetics .....................................................................................12
Safety summary from studies with M6620 as single agent or in 
combination with cytotoxic therapy.......................................................................12
Clinical Efficacy ....................................................................................................13
Topotecan ................................................................................................................20
Correlative Studies Background..............................................................................20
SLFN11 expression................................................................................................20
ATM expression.....................................................................................................22
MYC amplification................................................................................................22
Circulating cell-free DNA and circulating tumor cells (CTCs).............................22
Whole exome sequencing (WES)..........................................................................25
PATIENT SELECTION....................................................................................................25
Eligibility Criteria....................................................................................................26
Inclusion Criteria ...................................................................................................26
Exclusion Criteria ..................................................................................................27
Inclusion of Women and Minorities........................................................................28
REGISTRATION PROCEDURES ...................................................................................29
Investigator and Research Associate Registration with CTEP ...............................29
Site Registration ......................................................................................................30
Downloading Regulatory Documents....................................................................31
Protocol Specific Requirements for NCI Protocol 10268 Site Registration..........32
Submitting Regulatory Documents........................................................................32
Checking Site Registration Status..........................................................................32
Patient Registration .................................................................................................33
OPEN / IWRS........................................................................................................33
Special Instructions for Patient Enrollment...........................................................34

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Two Step Registration Process ..............................................................................35
OPEN/IWRS Questions? .......................................................................................35
General Guidelines..................................................................................................35
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ........................................35
Summary Table for Specimen Collection ...............................................................35
Specimen Procurement Kits and Scheduling ..........................................................37
EET Biobank..........................................................................................................37
PADIS Laboratory .................................................................................................38
Specimen Collection................................................................................................39
Biopsy Collection Procedure .................................................................................39
Blood Collection....................................................................................................40
Specimen Tracking System Instructions .................................................................42
Specimen Tracking System Overview and Enrollment Instructions.....................42
EET Biobank Specimen Labeling..........................................................................42
Overview of Process at Treating Site.....................................................................44
Shipping Specimens from Clinical Site to the EET Biobank..................................46
Specimen Shipping Instructions ............................................................................46
Shipping Address...................................................................................................48
Contact Information for Assistance .......................................................................48
Shipping of Specimens from Clinical Site to PADIS laboratory ............................49
Specimen Shipping Instructions ............................................................................49
Shipping Address...................................................................................................50
Contact Information for Assistance .......................................................................51
Biomarker Plan........................................................................................................52
Integrated Correlative Studies.................................................................................55
SLFN11..................................................................................................................55
ATM.......................................................................................................................55
cMYC amplification ..............................................................................................56
Spatial Transcriptomics .........................................................................................57
Exploratory/Ancillary Correlative Studies..............................................................58
Circulating tumor cells...........................................................................................58
cfDNA - Fragmentomics........................................................................................58
Circulating Tumor DNA (ctDNA).........................................................................59
SLFN11, cMYC, and ATM ...................................................................................59
Whole Exome Sequencing.....................................................................................60
TREATMENT PLAN........................................................................................................60
Agent Administration..............................................................................................60
M6620....................................................................................................................62
Topotecan...............................................................................................................63
General Concomitant Medication and Supportive Care Guidelines .......................63
Duration of Therapy ................................................................................................64
Duration of Follow-Up............................................................................................65
DOSING DELAYS/DOSE MODIFICATIONS................................................................65

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M6620 dose modification........................................................................................65
Topotecan dose modification ..................................................................................66
PHARMACEUTICAL INFORMATION..........................................................................67
CTEP IND Agent ....................................................................................................67
M6620 (VX-970, Berzosertib) (NSC 780162) ......................................................67
Agent Ordering and Agent Accountability............................................................69
Investigator Brochure Availability ........................................................................70
Useful Links and Contacts.....................................................................................70
Commercial Agent ..................................................................................................70
Topotecan...............................................................................................................70
STATISTICAL CONSIDERATIONS...............................................................................72
Study Design/Endpoints..........................................................................................72
Sample Size/Accrual Rate.......................................................................................75
Analysis of Secondary Endpoints............................................................................76
Reporting and Exclusions........................................................................................77
Evaluation of Toxicity ...........................................................................................77
Evaluation of Response..........................................................................................77
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ............................77
Comprehensive Adverse Events and Potential Risks List (CAEPR)......................78
CAEPRs for CTEP IND Agent..............................................................................78
Adverse Event List for Topotecan.........................................................................80
Adverse Event Characteristics.................................................................................80
Expedited Adverse Event Reporting .......................................................................81
Rave-CTEP-AERS Integration..............................................................................81
Distribution of Adverse Event Reports..................................................................82
Expedited Reporting Guidelines............................................................................82
Routine Adverse Event Reporting...........................................................................84
Pregnancy ................................................................................................................84
Secondary Malignancy............................................................................................84
STUDY CALENDAR .......................................................................................................85
MEASUREMENT OF EFFECT........................................................................................88
Antitumor Effect – Solid Tumors............................................................................88
Definitions
88
Disease Parameters ................................................................................................88
Methods for Evaluation of Measurable Disease ....................................................89
Response Criteria...................................................................................................91
Duration of Response.............................................................................................93
Progression-Free Survival......................................................................................93
Response Review...................................................................................................93
STUDY OVERSIGHT AND DATA REPORTING / REGULATORY 
REQUIREMENTS.............................................................................................................93

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Study Oversight.......................................................................................................93
Data Reporting ........................................................................................................94
Method
95
Responsibility for Data Submission.......................................................................95
Data Quality Portal..................................................................................................96
CTEP Multicenter Guidelines .................................................................................97
Collaborative Agreements Language ......................................................................97
REFERENCES ..................................................................................................................99
APPENDICES .................................................................................................................103
APPENDIX A: Performance Status Criteria.........................................................103
APPENDIX B: Formula to Estimate Renal Function Using Serum 
Creatinine ..............................................................................................................104
APPENDIX C: Patient Drug Interactions Handout and Wallet Card ...................105
APPENDIX D: PD  SPECIMENSUBMISSIONFORMANDCHAINOF
CUSTODY ............................................................................................................107
APPENDIX E: TISSUE BIOPSY VERIFICATION.........................................109

NCI Protocol #:  10268
Version Date:  October 21, 2022
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OBJECTIVES
Primary Objective
To determine if the combination of M6620 with topotecan will result in an improvement in 
progression-free survival (PFS) compared to topotecan alone in patients with relapsed small cell 
lung cancer (SCLC).
Secondary Objectives
To determine the objective response rate (ORR) and overall survival (OS) with the 
combination of M6220 and topotecan in patients with relapsed SCLC and extrapulmonary 
small cell cancers.
Exploratory Objectives
x
To perform molecular profiling assays on malignant and normal tissues, including, but not 
limited to RNA sequencing (RNA-Seq):
o
To assess expression of genes Schlafen family member 11 (SLFN11), MYC,
and Ataxia-Telangiesctasia mutated (ATM) among others. 
o
To identify potential predictive biomarkers of response to a combination of 
M6620 with topotecan.
o
Identify mechanisms of drug sensitivity and resistance using DNA- and RNA-
based assessment platforms. 
x
To contribute genetic analysis data from de-identified biospecimens to Genomic Data 
Commons (GDC), a well annotated cancer molecular and clinical data repository, for 
current and future research; specimens will be annotated with key clinical data, including 
presentation, diagnosis, staging, summary treatment, and if possible, outcome.
x
To bank formalin-fixed, paraffin-embedded (FFPE) tissue, blood (for cell-free DNA 
analysis), and nucleic acids obtained from patients at the EET Biobank at Nationwide 
Children's Hospital.
x
To characterize circulating cell-free DNA (cfDNA) and circulating tumor cells in patients 
with relapsed SCLC and extrapulmonary small cell cancers.
x
To identify potential predictive biomarkers of response to a combination of M6620 with 
topotecan in patients with extrapulmonary small cell cancers.

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9
BACKGROUND
Study Disease
SCLC is the most aggressive and lethal form of lung cancer.  It represents 15% of all lung 
cancers, with an annual incidence of over 34,000 cases in the United States alone.  SCLC is 
characterized by rapid doubling time, high growth fraction and early and widespread metastatic 
involvement [2].  Response rates to first-line chemotherapy are exceptionally high, in the order 
of 60% to 70%.  Unfortunately, these responses are also disappointingly transient, with median 
PFS of <5 months [3, 4] and nearly all patients relapse within one year.  Extensive-stage SCLC 
is generally unresponsive to chemotherapy at relapse, and fewer than 5% of patients survive for
two years [2].  Treatment of SCLC as well as survival after a diagnosis of SCLC have not 
changed substantially in the past 30 years [5].  Due to an urgent need for effective interventions 
in this disease, SCLC was singled out by the NCI as a designated “recalcitrant” cancer based on 
incidence rate, exceptionally high lethality, and the lack of substantial therapeutic progress made 
over several decades [6, 7]. 
At the time of diagnosis with SCLC, most patients (60-70%) will have extensive-stage (ES) 
disease, defined as cancer that has spread beyond the ipsilateral lung and regional lymph nodes 
and cannot be included in a single radiation field [2].  The primary treatment modality for 
patients with ES-SCLC is systemic chemotherapy consisting of platinum and etoposide followed 
by prophylactic cranial irradiation in patients with a response [8].  Topotecan is Food and Drug 
Administration (FDA)-approved for patients with SCLC with chemotherapy-sensitive disease 
after failure of first-line chemotherapy (Hycamtin® Package Insert, 2015).  Topotecan inhibits re-
ligation of topoisomerase I-mediated single-strand DNA breaks leading to lethal double-strand 
DNA breaks (DSB) (Hycamtin® Package Insert, 2015).  Sensitivity to first-line chemotherapy 
has been considered as the main driver of second-line therapy outcome in SCLC.  For this 
reason, relapsed SCLC has been traditionally classified into sensitive and resistant disease 
according to the type of response to first-line therapy and to treatment-free interval (treatment-
free interval longer or shorter than 60–90 days) [9].  Although this definition was designed many 
years ago and based on a small patient series [10], first-line chemotherapy sensitivity has since 
been confirmed to be a prognostic factor to predict response to second line and further therapy in 
meta-analyses [11] and randomized studies [12, 13]. 
Diagnosis of small cell cancers (including SCLC) is based on morphologic features and do not 
rely on immunohistochemical staining [14, 15]. Small cell cancer cells are defined by the 
following morphologic features: nuclear appearance, which includes finely granular chromatin, 
lack of prominent nucleoli; and marked nuclear fragility and malleability; scant cytoplasm and 
indistinct cell borders. High mitotic rate, apoptotic bodies, and large areas of geographic 
necrosis are typical. Tumor cells are usually positive for one or more of chromogranin or 
synaptophysin, although around 10 percent may be unreactive for neuroendocrine markers.
Extrapulmonary small cell carcinoma is a distinct clinicopathologic entity that can arise in a wide 
range of extrapulmonary sites. These tumors have been described most frequently in the urinary 
bladder, prostate, esophagus, stomach, colon and rectum, gallbladder, larynx, salivary glands, 
cervix, and skin. They are extremely rare and management of systemic disease with 
chemotherapy is patterned after the approach used in SCLC [16].

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Rationale
Because of frequent chromosomal alterations, dysregulation of genes that promote replication 
origin firing (e.g., MYC) and the high expression of DNA damage repair proteins, we have 
postulated that SCLC has high levels of endogenous replicative stress- defined by collapse of 
DNA replication forks due to various perturbations that interfere with replication[17] (Figure 1).  
Cellular responses to replicative stress-referred to as the DNA damage response (DDR)-is critical 
for repair of the damage and normal cell cycle progression.  Ataxia telangiectasia and Rad3-
related (ATR) is a key DDR regulator.  By using a synthetic lethal short interfering RNA screen, 
we identified depletion of ATR as a top candidate for topoisomerase 1 (TOP1) inhibitor synthetic 
lethality [18]. 
Figure 1: Replicative Stress in SCLC: Causes, Consequences and Therapeutic Opportunities: The hallmarks of 
SCLC include sustained proliferation, resistance to apoptosis, unlimited replicative potential, genomic instability, 
and evasion of growth suppressors (genes that are up-regulated are indicated in blue and those that are down-
regulated in red).  All of these hallmarks except resistance to apoptosis have been directly linked to replicative 
stress.  Therapeutic approaches that further exacerbate replication stress by inhibiting the target proteins shown in 
the figure could selectively kill SCLC by replicative damage [17].
Inhibition of ATR may represent an effective strategy to overcome the rewiring of homologous 
recombination (HR) and related DNA repair pathways, which may underlie drug resistance in 
platinum-refractory SCLC cells.  A recent study showed that ATR inhibition disrupted the 
rewired HR and replication fork protection pathways in breast cancer 1 gene (BRCA1)-deficient 
cancer cells that acquired poly (ADP-ribose) polymerase (PARP) inhibitor resistance [4].  Doerr 

NCI Protocol #:  10268 
Version Date:  October 21, 2022 
 
11 
 
et al. (2017) have demonstrated an actionable dependence on ATR/checkpoint kinase 1 (CHK1)-
mediated cell cycle checkpoints for SCLC [19].  In these studies, ATR inhibitors induced 
genotoxic damage and apoptosis in human and murine SCLC cell lines and murine SCLC tumors 
were highly sensitive to ATR inhibitors.  
 
We showed that inhibition of ATR by short interfering RNA or VE-821 and its clinical 
derivative M6620 sensitizes tumor cells to TOP1 inhibitors.  M6620, enhanced the in vivo tumor 
response to irinotecan without additional toxicity (Figure 2).  ATR inhibition abrogated the S-
phase replication elongation checkpoint and the replication origin-firing checkpoint induced by 
TOP1 cleavage complexes [18].  We found that a combination of an ATR inhibitor and 
topotecan can be safely combined and that heightening replicative stress in this manner can yield 
durable responses in small cell cancers and initiated a Phase 1/2 trial of the combination [20].  
 
In this current study, we hypothesize that the combination of M6620 and topotecan can improve 
PFS compared to topotecan alone in patients with relapsed SCLC. 
 
 
Figure 2: The clinical ATR inhibitor M6620 potentiates the efficacy of irinotecan in the colorectal cancer 
COLO205 mouse xenograft model.  Mice bearing COLO205 tumors (volume ~250 mm3) were treated with 
vehicle, irinotecan (20 mg/kg or 40 mg/kg administered by intraperitoneal bolus injection on day 0 of each 4-day 
cycle), M6620 (60 mg/kg administered by oral gavage on days 0, 1, and 2 of each 4-day cycle), or the combination 
of both drugs (using the schedule for administration of each compound alone).  Treatment was continued for 4 
cycles.  Each group consisted of 8 mice.  Animals receiving irinotecan or the combination of irinotecan and M6620 
were allowed to recover after treatment to assess tumor regrowth.  Tumor size was assessed twice a week [18].  
 
Extrapulmonary small cell cancers of various tissues of origin may arise by different 
mechanisms.  In case of prostate small cell, it arises in the setting of therapeutic resistance to 
highly potent AR-targeting therapy whereas in EGFR mutated cancers it arises in the setting of 
potent EGFR-targeting. But in general, extrapulmonary small cell cancers have in common 
signatures of RB1 loss [21-23] which in turn drives replication stress.  A recent paper has shown 
that AR transcriptional activity was lower in small cell prostate cancers compared to 
adenocarcinoma [22].  Accordingly, in clinical practice small cell prostate cancer patients are 
continued on androgen suppression while they are on small cell-directed therapy.  Taken 
together, it appears that although extrapulmonary small cell cancers (including prostate small 

NCI Protocol #:  10268
Version Date:  October 21, 2022
12
cell) can arise by different mechanisms but have in common high replication stress and may be 
susceptible to ATR inhibition, supporting their inclusion in this trial. 
M6620 (VX-970, Berzosertib)
Mechanism of Action
M6620 (VX-970, berzosertib) is an ATP-competitive, highly potent, tightly binding inhibitor of 
ATR.  M6620 blocks ATR with a concentration associated with 50% inhibition (IC50) of 20 nM
[24]. 
Nonclinical Pharmacokinetics
In all nonclinical species (the mouse, rat, dog, and monkey), M6620 exhibited a high volume of 
distribution (Vd); tissue exposure, including tumor, was high [24].  In rats, no accumulation or 
retention was observed in tissues, and the elimination half-lives (t1/2) were similar across all 
tissues and whole blood.  The whole blood t1/2 was 11.6 h in rats and 9.8 h in dogs.  M6620 was 
extensively bound to plasma proteins; the free fraction of M6620 was only 2.1% in human blood.
M6620 is primarily eliminated by oxidative metabolism, with the cytochrome 450 (CYP) 3A4 
isoform being the principle isoform responsible [24].  Strong inducers or inhibitors of CYP3A4 
may alter M6620 kinetics and blood levels.  Based on its minimal inhibition or induction effects 
on CYPs, M6620 is expected to have a low potential for drug-drug interactions.  M6620
metabolites are excreted in the urine and bile.  All metabolites observed in human hepatocyte 
incubations were also observed in either rat or dog hepatocyte incubations and in the blood, bile, 
or urine from rats or dogs.  The systemic clearance of M6620 following IV administration was 
26 and 13 mL/min/kg in the rat and dog, respectively.
Clinical Pharmacokinetics  
Clinical pharmacokinetics (PK) have been evaluated both in whole blood and plasma [24].  
Mean exposure, area under the curve (AUC) profiles were similar in whole blood and plasma.  
Overall, the maximum observed concentration (Cmax) was 1.3-fold greater in whole blood than in 
plasma.  The results suggest that plasma is an appropriate matrix to characterize the M6620 PK.  
The terminal elimination half-life (t1/2) was approximately 17 h across all doses.  In the M6620
single dose studies, M6620 exposures (Cmax and AUC0-∞) increased in a dose-proportional 
manner.  Collectively, the data suggest that co-administration of gemcitabine, cisplatin, or 
carboplatin 24 hours before M6620 administration did not appear to affect the PK of M6620.
Safety summary from studies with M6620 as single agent or in combination with 
cytotoxic therapy 
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
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.
x
Some systemic infusion-related reactions to M6620 have been serious, including those 
described as acute hypersensitivity reactions.  In almost all cases, these reactions 
occurred within minutes of the second exposure to M6620 and they included 
hypotension and mental status changes.  All subjects fully recovered with standard care 
procedures.
x
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.  To minimize the possibility of phlebitis, M6620 should be administered through a 
large-bore catheter into large-caliber peripheral vein.  
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 adverse events (AEs) in subjects who received M6620 in combination 
with carboplatin have included anemia, neutropenia, thrombocytopenia, and febrile 
neutropenia.
x
M6620 (VX-970, berzosertib) 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. 
Clinical Efficacy
In a Phase 1 clinical trial of patients with advanced cancers, M6620 monotherapy was well 
tolerated with no dose-limiting toxicities (DLTs) at doses up to 480 mg/m2 administered weekly 
[25].  We conducted a Phase 1/2 clinical trial of M6620 combined with topotecan, a highly 
selective inhibitor of Top1.  The Phase 1 part of the trial enrolled patients with advanced solid 
tumors with progressive disease (PD) and was recently reported [20].  Phase 2 recently 
completed enrolment and the results are summarized below.  The primary objective of Phase 1
was to determine the recommended Phase 2 dose (RP2D) by evaluating the feasibility, safety, 
AEs, DLT, and the maximum tolerated dose (MTD).  Secondary objectives were to characterize 
the pharmacodynamics and to assess preliminary antitumor activity.  Paired hair follicles and 
tumor biopsies obtained post-topotecan and post-M6620/topotecan at time points established for 
quantifying phosphorylation of the histone H2AX (γH2AX) were used to confirm DNA damage. 
Between September 2016 and February 2017, 21 patients enrolled in the Phase 1 study.  The 
combination was well tolerated, which allowed for dose escalation to the highest planned dose 
level (topotecan 1.25 mg/m2, days 1 to 5; M6620 210 mg/m2, days 2 and 5).  One of six patients 
at this dose level experienced grade 4 thrombocytopenia that required transfusion, a DLT.  Most 
common treatment-related grade 3 or 4 toxicities were anemia, leukopenia, and neutropenia 
(~40-50%% each); lymphopenia (14%); and thrombocytopenia (25%).  The most common 
toxicities across all dose levels (DLs) (N = 21) were anemia and lymphopenia (100% each), 

NCI Protocol #:  10268 
Version Date:  October 21, 2022 
 
14 
 
leukopenia (90%), neutropenia (81%), thrombocytopenia (76%), and nausea (62%).  The most 
common grade 3 and 4 toxicities were anemia, leukopenia, and neutropenia (19% each); 
lymphopenia (14%); and thrombocytopenia (10%).  Pegfilgrastim was not routinely administered 
during the first cycle but was used from cycle 2 onward in eight patients and cycle 4 onward in 
one patient.  
 
Two partial responses (PR) (≥18 months, ≥7 months) and seven stable disease (SD) responses ≥3 
months (median, 9 months; range, 3 to 12 months) were seen.  Of five patients with SCLC in 
Phase 1, all of whom had platinum-refractory disease, three derived durable clinical benefit (one 
PR and two prolonged SD; ≥ 6, ≥ 7, and 10 months; Figure 3).  All three were diagnosed with 
extensive-stage SCLC, had received four cycles of platinum and etoposide, and were found to 
have SD or near-complete responses (CR) to first-line therapy but had PD soon after first-line 
chemotherapy.  The median PFS of patients with SCLC (n = 5) was 10.2 months (95% CI, 1.4 to 
10.2 months), and 6-month PFS probability was 60.0% (95% CI, 12.6% to 88.2%). 
 
 
Figure 3: Response to topotecan plus M6620 in a Phase 1 trial.  The waterfall plot shows responses in evaluable 
patients (n = 19) [26].  
 
In summary, the Phase 1 trial established tolerable doses of M6620 in combination with 
topotecan and showed preliminary pharmacodynamic evidence of ATR inhibition and enhanced 
DSBs.  The toxicity profile of the combination largely mirrored that of topotecan, which as 
monotherapy is associated with a high frequency of myelosuppression.  The most common 
reason for dose reduction was neutropenia, which did not recur with pegfilgrastim prophylaxis.  
The lack of additive toxicities with ATR inhibition is possibly related to the differentiating 
features of rapidly dividing cancer cells, including higher replicative stress and increased DNA 
damage [27]. Although the number of patients with SCLC treated in the Phase 1 study was small, 
an important clinical activity signal was noted.   
We recently completed enrolment on the Phase 2 trial  evaluating the efficacy of topotecan and 
M6620 in previously treated subjects with SCLC.  Both platinum-sensitive and refractory 
patients were eligible.  The primary endpoint was ORR..  Response had to be confirmed by the 
investigator at least four weeks later. The trial was conducted using Simon two-stage Minimax 
design to rule out an unacceptably low 10% response rate (p0=0.10) in favor of targeted response 

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rate of 30% (p1=0.30), considered clinically meaningful based on outcomes with topotecan alone 
in relapsed SCLC [9].   
 
Between June 2017 and April 2019, a total of 26 patients were enrolled, all of whom had 
evidence of disease progression before study participation. As of data cut-off on 3/18/2020, all 
patients completed at least one cycle (median: 5.5 cycles; range: 1–33) of treatment. Twenty-five 
patients were evaluable for the primary endpoint. Patient median age was 63 years (range: 51–
78), and 17 patients (65.4%) were women. Most patients had extensive-stage at diagnosis (18/26, 
69.2%). Notably, most patients had platinum-resistant disease (21/26, 80.8%). Seven of 16 
(43.8%) patients had confirmed partial responses (PRs) in the first stage, allowing continued 
enrollment onto the second stage. In the overall study, nine of 25 patients (36.0%, 95% 
confidence interval, CI: 18.0–57.5) achieved a confirmed PR, meeting the primary endpoint for 
response (Figure 4, Table 2). One patient had an unconfirmed response at first imaging (39.7% 
tumor reduction) but disease progression soon after. Most patients (17/25 patients; 68.0%) 
experienced tumor regressions. After a median potential follow up of 20.7 months, the median 
progression-free survival (PFS) was 4.8 months (95% CI: 2.8–7.4). The PFS at 4 months and 6 
months were 60.0% (38.4-76.1) and 36.0% (18.2–54.2), respectively. The median overall 
survival (OS) was 8.5 months (5.6-13.6). OS at 6 months and 12 months were 68.0% (46.1–82.5) 
and 32.0% (15.2–50.2) respectively. 
 
Responses were observed in patients with both platinum-sensitive and platinum resistant disease 
(ORR 60.0% [3/5 patients; 95% CI: 14.7–94.7] and 30.0% [6/20; 95% CI: 11.9–54.3] 
respectively; p = 0.31 by Fisher’s exact test) (Figure 4). The median (95% CI) duration of 
response (DOR) was 6.4 months (1.1–14.3). Durable responses among patients with platinum-
resistant disease were notable given that these tumors rarely respond to topotecan monotherapy, 
and are typically fatal within weeks of relapse [28, 29]. Four of six (66.7%) responders with 
platinum-resistant SCLC had DOR more than 6 months. Two of the platinum-resistant 
responders (33.3%; patient # 33 and 50) remain without disease progression and on treatment at 
data cut-off, 24 and 13 months respectively after starting treatment. The DOR, PFS and OS were 
not significantly different between patients with platinum-sensitive and resistant disease, and 
patients who were previously treated with PD-1/PD-L1 inhibitors and those treated without.  
 
Table 1. Treatment efficacy of M6620 and topotecan in SCLC 
patients 
Evaluable patients 
(n = 25) Ɨ 
    ORR (95% CI) 
9 (36.0%, 18.0–57.5) 
 Best response 
  
        PR (confirmed) 
9 (36.0%) 
        PR (unconfirmed)ƗƗ 
1 (4.0%) 
        SD 
11 (44.0%) 
        PD 
4 (16.0%) 
Median DOR (months, 
95%CI) 
6.4 (1.1–14.3) 

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Ongoing treatment
2 (8.0%)
PFS
     Median (months, 95%CI)
4.8 (2.8–7.4)
     At 4 months (95%CI)
60.0% (38.4–76.1%)
     At 6 months (95%CI)
36.0% (18.2–54.2%)
OS
     Median (months, 95%CI)
8.5 (5.6–13.6)
     At 6 months (95%CI)
68.0% (46.1–82.5%)
     At 12 months (95%CI)
32.0% (15.2–50.2%)
Data were presented as n (%). Tumor response was evaluated by RECIST 
version 1.1. 
Ɨ: one patient was not evaluable due not to show 1st restaging scan. 
ƗƗ : One had PR initially but PD 19 days after. ORR: objective response 
rate; PR: partial response; SD: stable disease, PD: progressive disease; 
DOR: duration of response; CI: confidence interval; PFS: progression free 
survival; OS: overall survival.
Table 2. Duration of response among responding platinum-resistant patients 

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Figure 4: Efficacy of topotecan and M6620 in relapsed SCLC. A) Efficacy of the combination of M6620 and 
topotecan in SCLC patients based on duration of response. B) Tumor responses to the combination of M6620 and 
topotecan in SCLC patients based on maximum change in tumor dimensions from baseline. Each bar represents a 
patient’s tumor response.
A
B

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The toxicity profile of the combination in SCLC patients mirrored that of the phase I population 
of patients with solid tumors. The most common treatment-related AEs (n, %) were anemia (25, 
96.2%), lymphopenia (25, 96.2%), thrombocytopenia (24, 92.3%), and neutropenia (13, 50.0%) 
followed by gastrointestinal symptoms such as nausea (13, 50.0%) and vomiting (11, 42.3%). 
Treatment-related serious AEs were infrequent and observed in 4/26 (15.4%) patients, and 
included grade 4 febrile neutropenia, grade 3 anemia, grade 4 thrombocytopenia, grade 3 vomiting, 
and grade 2 nausea. Most AEs were attributable to topotecan, which as monotherapy is associated 
with a high frequency of myelosuppression[9]. The differentiating features of rapidly dividing 
cancer cells, including higher replicative stress and increased DNA damage that render them more 
susceptible to ATR inhibition may explain the absence of major overlapping toxicities with this 
combination.  
 
Table 3. Treatment-Related Adverse Events (maximum grade, all cycles) 
Adverse Event (N=26) 
All 
≥Grade 3 
 
Anemia 
25 (96.2%) 
14 (53.8%) 
 
Lymphopenia 
25 (96.2%) 
18 (69.2%) 
 
Thrombocytopenia 
24(92.3%) 
15 (57.7%) 
 
White blood cell decreased 
20 (76.9%) 
8 (30.8%) 
 
Neutropenia 
13 (50.0%) 
4 (15.4%) 
 
Febrile neutropenia 
1 (3.8%) 
1 (3.8%) 
 
Nausea 
13 (50.0%) 
1 (3.8%) 
 
Fatigue 
12 (46.2%) 
0 (0%) 
 
Vomiting 
11 (42.3%) 
1 (3.8%) 
 
Anorexia 
8 (30.8%) 
2 (7.7%) 
 
Diarrhea 
3 (11.5%) 
0 (0%) 
 
Constipation 
1 (3.8%) 
0 (0%) 
 
Total bilirubin increased 
2 (7.7%) 
0 (0%) 
 
ALT increased 
2 (7.7%) 
0 (0%) 
AST increased 
1 (3.8%) 
0 (0%) 
Hypophosphatemia 
11 (42.3%) 
3 (11.5%) 
Hypomagnesemia 
2 (7.7%) 
0 (0%) 
Alopecia 
4 (15.4%) 
0 (0%) 
Infusion related reaction 
2 (7.7%) 
0 (0%) 
Abdominal pain 
1 (3.8%) 
1 (3.8%) 
Bruising 
1 (3.8%) 
0 (0%) 
Chills 
1 (3.8%) 
0 (0%) 
Creatinine increased 
1 (3.8%) 
0 (0%) 
Dyspepsia 
1 (3.8%) 
0 (0%) 
Gastroesophageal reflux disease 
1 (3.8%) 
0 (0%) 
Generalized muscle weakness 
1 (3.8%) 
0 (0%) 
Hiccups 
1 (3.8%) 
0 (0%) 
Malaise 
1 (3.8%) 
0 (0%) 
Peripheral motor neuropathy 
1 (3.8%) 
0 (0%) 

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Adverse Event (N=26) 
All 
≥Grade 3 
Peripheral sensory neuropathy 
1 (3.8%) 
0 (0%) 
Sinus tachycardia 
1 (3.8%) 
0 (0%) 
Skin and subcutaneous tissue 
disorders 
1 (3.8%) 
0 (0%) 
Skin hypopigmentation 
1 (3.8%) 
0 (0%) 
Adverse events were evaluated according to Common Terminology Criteria for Adverse Events version 4.0. 
AST: aspartate aminotransferase; ALT: alanine aminotransferase. 
 
Given that SCLCs share a common molecular phenotype with extrapulmonary small cell 
cancers, we reasoned that these cancers – independent of their tissue of origin – may also be 
responsive to combined ATR and TOP1 inhibition. To address this hypothesis, we amended the 
clinical trial of M6620 and topotecan and enrolled 10 patients with extrapulmonary small cell 
cancers and tumor progression after at least one previous systemic chemotherapy. All ten 
patients were treated with at least one cycle (range: 1–10) and were evaluable for treatment 
efficacy. Treatment with M6620 and topotecan resulted in two confirmed PRs and an 
unconfirmed PR, yielding ORR of 20.0% (Figure 5). Notably, deep and durable responses were 
observed in tumors refractory to prior TOP1 inhibitor treatments. Two of five patients who 
achieved PR or SD had tumor progression previously on TOP1 inhibitors. This included a patient 
with treatment refractory breast SCNC who had a major tumor regression lasting 8.5 months.  
 
Figure 5: Efficacy of M6620 and topotecan in SCNCs regardless of tissue of origin. A) Responses to the 
combination of M6620 and topotecan in EP-SCNCs based on change in tumor dimensions from baseline. Each bar 
represents a patient’s tumor response. B) Efficacy of the combination of M6620 and topotecan in EP-SCNCs based 
on duration of response. C) CT scans of the abdomen showing tumor regression in a patient with breast SCNC with 

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liver metastases (patient #57). The patient had undergone extensive previous treatments including topotecan. REC, 
rectal; BLD, bladder; TRL, transformed lung cancer; BRE: breast; CVX, cervix; GBL, gall bladder; PRO, prostate; 
OVA, ovarian.
Topotecan
Topotecan has been approved by the FDA for the treatment of 1) metastatic carcinoma of the 
ovary after disease progression on or after initial or subsequent chemotherapy, 2) SCLC
platinum-sensitive disease in patients who progressed after first-line chemotherapy, and 3) as a 
combination therapy with cisplatin for Stage IV-B, recurrent, or persistent carcinoma of the 
cervix which is not amenable to curative treatment (Hycamtin® Package Insert, 2015).  
Topotecan is a semi-synthetic derivative of camptothecin and is an anti-tumor drug with 
topoisomerase I-inhibitory activity.  Topotecan binds to the topoisomerase I-DNA complex and 
prevents religation of these single-strand breaks.  The cytotoxicity of topotecan is thought to be 
due to double-strand DNA damage produced during DNA synthesis, when replication enzymes 
interact with the ternary complex formed by topotecan, topoisomerase I, and DNA.  Mammalian 
cells cannot efficiently repair these DSBs.  Bone marrow suppression (primarily neutropenia) is 
the dose-limiting toxicity of topotecan at the approved doses (Hycamtin® Package Insert, 2015). 
The FDA approved dose of topotecan for treating SCLC is 1.5 mg/m2. However, lower doses at 
1.25 mg/m2 appear to be as effective as the approved dose, but with reduced toxicity [30].
Correlative Studies Background
Several genomic alterations can drive responses to topotecan plus ATR inhibition [31, 32].  
These include 1) low expression of SLFN11; 2) overexpression of replicative stress-inducing 
oncogenes such as MYC, Cyclin E1 (CCNE1), Apolipoprotein B mRNA editing enzyme, 
catalytic polypeptide-like 3A (APOBEC3A), apolipoprotein B mRNA editing catalytic 
polypeptide-like 3B (APOBEC3B), others; 3) reduced expression of DDR/cell cycle checkpoint 
genes Excision Repair Cross-Complementation Group 1 (ERCC1), X-Ray Repair Cross 
Complementing 1 (XRCC1), Cell Division Cycle 25A (CDC25A), ATM, others; and 4) processes 
beyond DDR e.g., loss of tumor suppressor proteins of the switch/sucrose nonfermentable 
chromatin remodeling complex including AT-rich interactive domain-containing protein 1A 
(ARID1A).  Given the broad range of potential biomarkers to ATR inhibition, RNA-seq will be 
performed on fresh pre-treatment biopsies to allow simultaneous evaluation of multiple 
biomarkers, with a specific focus on expression of 3 genes – SLFN11, MYC, and ATM (see 
below). Additionally, archival tissue and tissue remaining after RNA-seq will be used for 
SLFN11, MYC, and ATM immunohistochemistry (IHC) and for whole exome sequencing (WES). 
SLFN11 Expression 
SLFN11 is frequently inactivated in cancer cell lines and has been shown to sensitize cancer 
cells to anticancer drugs.  In particular, elevated SLFN11 expression is associated with 
sensitivity to DNA-damaging agents which concurrently promote replication fork stalling and 
cell cycle checkpoint activation, and induce replication stress [33]. 
SLFN11 is highly expressed in SCLC as compared with other histologies [34]. In contrast, 
SLFN11 expression is low to nearly absent in lung squamous cell carcinoma and 

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adenocarcinoma (Figure 6A) [35].  SLFN11 expression has a bimodal distribution in SCLC and 
may provide meaningful stratification as a predictive biomarker in clinical studies of SCLC.  
SLFN11 gene expression by RNA-Seq is concordant with SLFN11 protein expression by 
quantitative western blot (Figure 6B).  
 
SCLC cells with high SLFN11 expression are more sensitive to DNA-damaging chemotherapy, 
and SLFN11 inactivation confers resistance to these agents [34].  Patients with SLFN11-positive 
tumors treated with a combination of temozolomide and veliparib had a significantly prolonged 
PFS and OS compared with patients with SLFN11-negative tumors.  Consistent with its role in 
determining chemosensitivity, SLFN11 expression is higher in tumors from SCLC patients who 
respond to DNA-damaging therapy versus those who do not and is higher in tumors from 
treatment-naive SCLC patients than in recurrent/relapsed SCLC [35].  Recent studies have 
shown that SLFN11 suppression by epigenetic silencing could be causal to acquired resistance to 
DNA-damaging chemotherapy in SCLC [35-37].   
 
Studies from the National Cancer Institute (NCI) Developmental Therapeutics Branch (DTB) 
group demonstrated that SLFN11 blocks replication independently of ATR and that SLFN11-
negative cells dominantly rely on ATR under replication stress [38].  Consistently, in terms of 
cytotoxicity, the effect of ATR inhibition under camptothecin is highly prominent in SLFN11-
deleted cells but is limited in parental cells (Figure 6C).  ATR inhibition overcomes resistance to 
topoisomerase 1 inhibitors in SLFN11-negative cancer cells.  
 
Based on the above considerations, we hypothesize that relapsed SCLC tumors with low 
SLFN11 expression (and resistant to topotecan) would be rendered sensitive to topotecan by 
ATR inhibition.  
 
 
Figure 6: (A) SLFN11 expression in primary SCLC samples plotted with TCGA datasets [34].  (B) Concordance 
between SLFN11 gene expression by RNA-seq and SLFN11 protein expression by quantitative western blot [35] 

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(C) Viability curves for camptothecin alone (circles) and with ATRi (triangles) in isogenic DU145 prostate cancer 
cell lines [39]
ATM Expression 
ATR inhibition could be synthetically lethal in ATM deficient tumors potentially due to the 
overlapping and cooperating roles of these pathways in coordinating cell cycle progression with 
DNA repair.  One explanation for this is that the ATM-dependent DDR is necessary to cope with 
the DSBs that arise at stalled replication forks that collapse upon ATR inhibition.  Accordingly, 
ATR inhibition has single-agent anti-tumor activity in ATM-deficient, but not ATM-proficient 
xenograft models [40].  Therefore, ATR inhibition could be more effective in ATM deficient 
SCLC.
MYC Amplification
Genomic amplifications in MYC have been identified in 6%-25% of primary human SCLC [41]
and in 30%-50% of SCLC cell lines [42, 43] and has been associated with poor outcome, tumor 
progression, and treatment resistance [44].  Although the mechanisms underlying SCLC 
resistance are not very well elucidated, in vivo MYC-driven SCLC rapidly relapse following 
chemotherapy [45].  MYC amplification is thought to increase replicative stress and dependence 
on ATR signaling.  In mice, reduced levels of ATR (found in a mouse model of the ATR-Seckel 
syndrome) completely prevented the development of MYC-induced lymphomas or pancreatic 
tumors, indicating a synthetic lethality between MYC and ATR in vivo [46]. 
Based on the above considerations, we hypothesize that MYC amplified SCLC tumors would 
respond better to topotecan plus M6620 compared to topotecan alone. 
Circulating Cell-Free DNA and Circulating Tumor Cells (CTCs)
The molecular landscape of cancer is just beginning to be defined.  However, we do not know 
enough about the genomic and molecular landscape of tumors from patients who enter early 
phase clinical trials.  With this study, we will attempt to learn more about specific molecular 
features of cancers from this patient subgroup.  It is particularly important to learn, as early as 
possible, if there are molecular features that can inform about potential response or resistance to 
treatments.
cfDNA is a promising biomarker that is being investigated in multiple tumor types.  Changes in 
the levels of cfDNA can be used to monitor disease course, treatment responses, and recurrences.  
Lack of recurrent hotspot mutations- for example epidermal growth factor receptor (EGFR) exon 
19 deletion or T790M, for which there are FDA approved tests, makes it challenging to use this 
approach in SCLC.  Recent studies have shown feasibility of using a SCLC-specific panel to 
monitor disease burden, depth of response to treatment, and timely warning of disease relapse in 
patients with this disease [1].
Similar to cfDNA, molecular characterization of circulating tumor cells (CTCs) is emerging as 
an exciting opportunity in SCLC, given the limitations of tissue availability particularly at 

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relapse. A recent study demonstrated the high fraction of CTCs in SCLC and showed that CTCs 
reflect the tumor characteristics [47]. 
cfDNA Fragmentomics and Spatial Transcriptomics
In the last 4-5 years since the clinical trial development started and patients were enrolled, the 
understanding of SCLC heterogeneity has undergone a major shift. Rather than mutations, 
heterogeneity of SCLC is now thought to be driven by the expression of distinct transcription 
factors[48-51]. SCLC consist of tumor cells with neuroendocrine (NE) and non-neuroendocrine 
(non-NE) features[49, 50, 52-55], further defined by differential expression of the three lineage-
defining transcription factors (TFs) ASCL1, NEUROD1, and POU2F3. A fourth subgroup has 
been variously characterized by YAP1 expression[49, 56-58] or low expression of all three 
transcription factors accompanied by an inflamed gene signature[59]. SCLC heterogeneity 
increases over the course of treatment, with expansion of the non-NE cell population associated 
with chemo-resistance[59-61]. These TFs cannot be inferred from cfDNA assays proposed in the 
version of the protocol prior to 10/21/2022. 
Dying cells in the human body release their content into the bloodstream. Genomic DNA that is 
bound by nucleosomes and TFs escapes endogenous nucleases and so remains protected in 
plasma[62]. Regular turnover of lymphoid and myeloid cells in the human body is the major 
contributor to the pool of cell-free DNA (cfDNA) in plasma. However, in cancer, a detectable 
fraction of cfDNA arises from tumors. This suggests that cfDNA has the potential to map the 
tumor transcriptome and therefore can help uncover the regulatory landscape of cancer from 
plasma. Fragmentomics seeks to uncover the tissue of origin of cfDNA using the information on
cfDNA fragment length. We will apply a genome-wide approach for analysis of cfDNA 
fragmentation profiles called DELFI (DNA evaluation of fragments for early interception) [63]. 
This approach provides a view of cfDNA “fragmentomes”, permitting evaluation in any 
individual of the size distribution and frequency of millions of occurring cfDNA fragments 
across the genome. In a proof of principle study, genome-wide fragmentation profiles could non-
invasively distinguish between NSCLC and SCLC. Specifically, consistent decrease in aggregate 
fragment coverage at regions containing the ASCL1 binding sites (±200 bp) was observed in 
patients with SCLC compared to non-cancer individuals or those with other cancer types.  In 
contrast, at distances further from ASCL1 binding sites (>2000 bp), the fragment coverage for 
patients with SCLC and other patients were similar. As cfDNA fragmentomes can 
comprehensively represent both genomic and chromatin characteristics, it has the potential to 
identify the determinants of response and resistance to topotecan and topotecan plus M6620.
Although our understanding of cell-extrinsic influences on SCLC plasticity is rudimentary, a key 
role of these non-genetic mechanisms is suggested by two important observations: (i) 
transcriptional subtypes of human SCLC are not strongly associated with specific mutational 
patterns [48] and (ii) differences in neuroendocrine gene expression programs between human 
tumors and patient-derived xenografts [64]. We hypothesize that the dynamic interactions 
between tumor microenvironment (TME) and the cancer cells shape SCLC cell states. The 
sequencing approaches proposed in the current protocol such as bulk RNA-seq does not provide 
a context of the spatial interactions between cells and TME in tissue. 

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Figure 7: Discordance of stromal features derived from bulk and spatial transcriptome data. Correlation of (A) CAF 
(B) TAM gene expression signatures with tumor NE scores from bulk RNA-seq data. IMPOWER 133 trial data of 
treatment-naïve advanced SCLC patients Correlation of (C) CAF and (D) TAM gene expression signatures with 
tumor NE scores specifically in the tumor regions of interest. Preliminary data from 10 SCLC patient tumors 
profiled as transcriptome-wide spatial RNA profiling using GeoMX Whole Transcriptome Atlas platform 
Correlation of (E) CAF and (F) TAM gene expression signatures with tumor NE scores specifically in the TME 
regions of interest. Preliminary Data as above (G) Multiplex IHC showing high TAMs and CAFs in stroma around 

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high NE tumor compared with low NE tumor (CAF marker, ACTA2 in green; TAM marker CD163 in red; 
Blue/DAPI labels DNA/nuclei showing SCLC tumor clusters). 
As seen in Figure 7, cancer associated fibroblast (CAF) and tumor associated macrophage 
(TAM) molecular signatures may be higher around non-NE SCLC when analyzed using bulk 
sequencing data. However, sequencing data from TME regions (spatial transcriptomic approach 
using Nanostring GeoMx digital spatial profiling) shows an opposite trend, proven by 
immunohistochemistry (IHC), showing higher enrichment of CAFs and TAMs around high NE 
tumors, highlighting the utility of the spatial transcriptomic approach.
Spatial transcriptomics is a novel approach allowing measurement and mapping of gene activity 
to the resolution of single to few cells keeping the position information intact [65-67]. Mapping 
the cell-intrinsic and -extrinsic factors that impact SCLC tumor cell states in their positional 
context could yield important insights into the biologic basis of response and resistance to 
topotecan and topotecan plus M6620.  
Whole Exome Sequencing (WES)
Although a deadly and common cancer, SCLC was not included in The Cancer Genome Atlas 
(TCGA) due to challenges of tissue acquisition.  Only a limited number of SCLC exomes-
around 200 or so- have been published [41, 68]. The vast majority of published exomes of 
SCLC (>95% cases), are from primary tumors. The mutational landscape of relapsed SCLC as 
well as its relation to therapies is not known.  Tissue collection on this trial provides an 
opportunity to explore the relapsed SCLC exome.  Tissue remaining from studies outlined in 
Sections 2.5.1, 2.5.2 and 2.5.3 will be archived for future WES.  In addition, a tube of blood will 
be collected from each patient at baseline for germline DNA. 
PATIENT SELECTION
In order to determine eligibility, subjects will be screened per the STUDY CALENDAR once 
the subject has signed the appropriate consent.  In addition, the following minimal risk activities 
may be performed prior to obtaining subject consent: 
x
Email, written, in person or telephone communications with prospective subjects 
x
Review of existing medical records to include H&P, laboratory studies, etc. 
x
Review of existing MRI, x-ray, or CT images
x
Review of existing photographs or videos
x
Review of existing pathology specimens/reports from a specimen obtained for diagnostic 
purposes 

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Eligibility Criteria
Inclusion Criteria
Patients enrolled to the primary cohort must have limited- or extensive-disease SCLC at 
diagnosis, with relapse at study entry with measurable disease at random assignment per 
RECIST 1.1.  See Section 12 for the evaluation of measurable disease.  Both platinum-
sensitive and platinum-resistant patients will be included.
Patients with extrapulmonary small cell cancers (cancers with small cell morphology 
and arising outside the lung, such as small cell prostate, bladder, etc.; see Sections 2.1
and 2.2 for disease description and rationale.) will be eligible for the exploratory cohort.
Patients must be ≥18 years of age because no dosing or adverse event data are currently 
available on the use of M6620 in combination with topotecan in patients <18 years of 
age. 
ECOG performance status ≤2 (Karnofsky ≥60%, see APPENDIX A:Performance 
Status Criteria
Patients must have adequate organ and marrow function as defined below:

Hemoglobin 
≥9.0 g/dL - patients may receive transfusion to 
meet the Hb eligibility.

Absolute Neutrophil Count (ANC)
≥1,500/mcL

Platelets
≥100,000/mcL

Total Bilirubin
≤2 mg/dL

AST(SGOT)/ALT(SGPT)
≤3.0 × institutional ULN

Creatinine
≤ institutional ULN
OR

Glomerular Filtration Rate (GFR)
≥60 mL/min/1.73 m2 unless data exists 
supporting safe use at lower kidney function 
values, no lower than 30 mL/min/1.73m2 (See
APPENDIX B:
Formula to Estimate Renal 
Function Using Serum Creatinine –
Cockcroft-Gault Equation)
Human immunodeficiency virus (HIV)-positive subjects on combination antiretroviral 
therapy are eligible as long as they are on effective anti-retroviral therapy with 
undetectable viral load within 6 months and there is no drug-drug interaction with 
M6220. 
For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral 
load must be undetectable on suppressive therapy, if indicated.

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Patients with a history of hepatitis C virus (HCV) infection must have been treated and 
cured.  For patients with HCV infection who are currently on treatment, they are 
eligible if they have an undetectable HCV viral load.
The effects of M6620 on the developing human fetus are unknown.  For this reason and 
because DNA-damage response (DDR) inhibitors as well as other therapeutic agents 
used in this trial are known to be teratogenic, women 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 completion of M6620 administration.  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.  Men treated or enrolled on this protocol 
must also agree to use adequate contraception prior to the study, for the duration of 
study participation, and for 6 months after completion of M6620 administration.
Patients with treated brain metastases are eligible if they are symptomatically stable
while off steroid therapy for a minimum of 21 days.  
Patients with a prior or concurrent malignancy whose natural history or treatment does 
not have the potential to interfere with the safety or efficacy assessment of the 
investigational regimen are eligible for this trial.
Patients with known history or current symptoms of cardiac disease, or history of 
treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac 
function using the New York Heart Association Functional Classification.  To be 
eligible for this trial, patients should be class 2B or better.
Ability to understand and the willingness to sign a written informed consent document.
Exclusion Criteria
Patients with symptomatic brain metastasis are not eligible due to their extremely poor 
prognosis and since it is unclear whether the investigational agent penetrates the blood-
brain barrier.  However, subjects who have had treatment for their brain metastasis and 
are symptomatically stable while off steroid therapy for a minimum of 21 days may be 
enrolled. 
Patients who have received prior topotecan therapy.
Patients who have had chemotherapy or radiotherapy within 3 weeks prior to enrolment. 
Note: Patients who have had palliative radiotherapy may be included as long as they 
have recovered from any radiotherapy related adverse events (allow at least a week 
between radiotherapy completion and study treatment). 

NCI Protocol #:  10268
Version Date:  October 21, 2022
28
Patients who have not recovered from adverse events due to prior anti-cancer therapy 
except hair loss and peripheral neuropathy (i.e., have residual toxicities > Grade 1).  
Patients who are receiving any other investigational agents.
History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to M6620 or topotecan used in study.
M6620 is primarily metabolized by CYP3A4; therefore, concomitant administration 
with strong inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole, clarithromycin, 
HCV and HIV protease inhibitors, nefazodone, posaconazole, telithromycin, 
voriconazole) or inducers of CYP3A4 (e.g., rifampin, phenytoin, carbamazepine, 
phenobarbital, St. John’s Wort) should be avoided.  Patients requiring any medications 
or substances that are strong inhibitors or inducers of CYP3A during the course of the 
study are ineligible.  (Refer to APPENDIX C: Patient Drug Interactions Handout 
and Wallet Card).  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 of which to minimize use.  The Patient Drug Interactions Handout and 
Wallet Card should be provided to patients (APPENDIX C:
Patient Drug 
Interactions Handout and Wallet Card).  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.  
Patients with uncontrolled intercurrent illness.
Pregnant women are excluded from this study because M6620 as a 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 may also apply to topotecan used in this study.
Patients with high grade neuroendocrine cancers, but with no small cell morphology 
will not be eligible.
Patients with psychiatric illness/social situations that would limit compliance with study 
requirements.
Patients with Li-Fraumeni syndrome will not be eligible.
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 

NCI Protocol #:  10268
Version Date:  October 21, 2022
29
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.
REGISTRATION PROCEDURES
Investigator and Research Associate Registration with CTEP
Food and Drug Administration (FDA) regulations require sponsors to select qualified 
investigators. National Cancer Institute (NCI) policy requires all individuals contributing to NCI-
sponsored trials to register with their qualifications and credentials and to renew their registration 
annually. To register, all individuals must obtain a Cancer Therapy Evaluation Program (CTEP) 
Identity and Access Management (IAM) account at https://ctepcore.nci.nih.gov/iam. In addition, 
persons with a registration type of Investigator (IVR), Non-Physician Investigator (NPIVR), or 
Associate Plus (AP) must complete their annual registration using CTEP’s web-based 
Registration and Credential Repository (RCR) at https://ctepcore.nci.nih.gov/rcr.  
RCR utilizes five person registration types.
x
IVR:  MD, DO, or international equivalent,
x
NPIVR:  advanced practice providers (e.g., NP or PA) or graduate level researchers (e.g., 
PhD),
x
AP:  clinical site staff (e.g., RN or CRA) with data entry access to CTSU applications 
such as the Roster Update Management System (RUMS), OPEN, Rave, acting as a 
primary site contact, or with consenting privileges,
x
Associate (A):  other clinical site staff involved in the conduct of NCI-sponsored trials, 
and
x
Associate Basic (AB):  individuals (e.g., pharmaceutical company employees) with 
limited access to NCI-supported systems.
RCR requires the following registration documents:
Documentation Required
IVR
NPIVR
AP
A
AB
FDA Form 1572
✔
✔
Financial Disclosure Form
✔
✔
✔
NCI Biosketch (education, training, employment, 
license, and certification)
✔
✔
✔

NCI Protocol #:  10268
Version Date:  October 21, 2022
30
Documentation Required
IVR
NPIVR
AP
A
AB
GCP training
✔
✔
✔
Agent Shipment Form (if applicable)
✔
CV (optional)
✔
✔
✔
An active CTEP-IAM user account and appropriate RCR registration is required to access all 
CTEP and Cancer Trials Support Unit (CTSU) websites and applications.  In addition, IVRs and 
NPIVRs must list all clinical practice sites and Institutional Review Boards (IRBs) covering their 
practice sites on the FDA Form 1572 in RCR to allow the following:
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
In addition, all investigators acting 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.
Site Registration
This study is supported by the NCI Cancer Trials Support Unit (CTSU).
IRB Approval  
Sites participating with the NCI Central Institutional Review Board (NCI CIRB) must submit the 
Study Specific Worksheet (SSW) for Local Context to the CIRB using IRB Manager 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).

NCI Protocol #:  10268
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31
Sites using their local IRB or REB must submit their approval to the CTSU Regulatory Office 
using the Regulatory Submission Portal located in the Regulatory section of the CTSU website.  
Acceptable documentation of local IRB/REB approval includes:
x
Local IRB documentation,
x
IRB-signed CTSU IRB Certification Form, and/or
x
Protocol of Human Subjects Assurance Identification/IRB Certification/Declaration of 
Exemption Form.
In addition, the Site-Protocol PI (i.e., the investigator on the IRB/REB approval) must meet the 
following criteria to complete processing of the IRB/REB approval record to be completed:
x
Holds an Active CTEP status,
x
Active status at the site(s) on the IRB/REB approval (applies to US and Canadian sites 
only) on at least one participating organization’s roster,
x
If using NCI CIRB, active on the NCI CIRB roster under the applicable CIRB Signatory 
Institution(s) record,
x
Includes the IRB number of the IRB providing approval in the Form FDA 1572 in the 
RCR profile, 
x
Lists all sites on the IRB/REB approval as Practice Sites in the Form FDA 1572 in the 
RCR profile; and
x
Holds the appropriate CTEP registration type for the protocol. 
Additional Requirements
Additional site requirements to obtain an approved site registration status include:
x
An active Federalwide Assurance (FWA) number,
x
An active roster affiliation with the Lead Protocol Organization (LPO) or a Participating 
Organization, 
x
An active roster affiliation with the NCI CIRB roster under at least one CIRB Signatory 
Institution (US sites only); and
x
Compliance with all protocol-specific requirements (PSRs).
Downloading Regulatory Documents
Download the site registration forms from the protocol-specific page located on the CTSU 
members’ website.  Permission to view and download this protocol and its supporting documents 
is restricted to institutions and its associated investigators and staff on a participating roster. To 
view/download site registration forms:
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-NCI, and 
protocol number 10268,

NCI Protocol #:  10268
Version Date:  October 21, 2022
32
x
Click on Documents, Protocol Related Documents, and use the Document Type filter 
select Site Registration, to download and complete the forms provided.  (Note:  For sites 
under the CIRB initiative, IRB data will load automatically to the CTSU.) 
Protocol Specific Requirements for NCI Protocol 10268 Site Registration
x
Specimen Tracking System Training Requirement:
o
All data entry users (Clinical Research Associate role) at each participating site will 
need to complete the Theradex-led training.
o
Theradex will provide a certificate of completion, which will need to be submitted to 
the CTSU through the Regulatory Submission Portal.
o
The training is a one-time only requirement per individual.   If an individual has 
previously completed the training for another ETCTN study, the training does not 
need to be completed again nor does the certificate of completion need to be 
resubmitted to the CTSU.  However, new versions of the Specimen Tracking system 
may require new training.
o
This training will need to be completed before the first patient enrollment at a given 
site.
o
Please contact STS Support at Theradex for the training 
(STS.Support@theradex.com, Theradex phone: 609-799-7580). 
x
Requirement for LPO approval of participating site’s local informed consent
o
Each participating site will need to provide the local informed consent prior to 
enrolling their first patient. 
o
All amendments will require participating sites to receive approval of their local 
informed consent from LPO unless amendment specific PSRs are different.
o
The Local informed consent document will need to be submitted via CTSU per 4.2.3.
Submitting Regulatory Documents
Submit required forms and documents to the CTSU Regulatory Office using the Regulatory 
Submission Portal on the CTSU members’ 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 by phone or email: 1-866-651-CTSU (2878), or 
CTSURegHelp@coccg.org in order to receive further instruction and support.
Checking Site Registration Status
Site’s registration status may be verified on the CTSU website. 

NCI Protocol #:  10268
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33
x
Click on Regulatory at the top of the screen,
x
Click on Site Registration, and
x
Enter the site’s 5-character CTEP Institution Code and click on Go.
o
Additional filters are available to sort by Protocol, Registration Status, Protocol 
Status, and/or IRB Type.
Note:  The status shown only reflects institutional compliance with site registration requirements 
as outlined within the protocol.  It does not reflect compliance with protocol requirements for 
individuals participating on the protocol or the enrolling investigator’s status with NCI or their 
affiliated networks.
Patient Registration
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 Lead 
Protocol Organization (LPOs) registration/randomization systems or Theradex Interactive Web 
Response System (IWRS) for retrieval of patient registration/randomization assignment.  OPEN 
will populate the patient enrollment data in NCI’s clinical data management system, Medidata 
Rave.
Requirements for OPEN access:  
x
A valid CTEP-IAM account.
x
To perform enrollments or request slot reservations:  Must be on an LPO roster, ETCTN 
Corresponding roster, or PO roster with the role of Registrar.  Registrars must hold a 
minimum of an Associate Plus (AP) registration type.
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.  
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 Health Insurance Portability 
and Accountability Act (HIPAA) authorization form (if applicable).
Note: The OPEN system will provide the site with a printable confirmation of registration and 
treatment information. Please print this confirmation for your records.

NCI Protocol #:  10268
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34
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.
Patient enrollment for this study will be facilitated using the Slot Reservation System in 
conjunction with the registration system in OPEN.  Prior to discussing protocol entry with the 
patient, all site staff must use the CTSU OPEN Slot Reservation System to ensure that a slot on 
the protocol is available to the patient.  Once a slot reservation confirmation is obtained, site staff 
may then proceed to enroll the patient to this study. 
Special Instructions for Patient Enrollment
Slot reservation:
Sites must submit the following documentation/information to the study team before their slot 
request will be approved and they are able to enroll the patient in OPEN:
Patient initials
Date of birth (month/year)
Diagnosis
Projected consent date/Screening start date
Projected date of enrollment
History and physical
Laboratory results
Pathology report
This Study will use the ETCTN Specimen Tracking System (STS). 
x
All biospecimens collected for this trial must be submitted using the ETCTN Specimen 
Tracking System (STS) unless otherwise noted.  
x
The system is accessed through Rave user roles: “Rave CRA” and “Rave CRA 
(Labadmin)” for data entry at the treating institutions and “Biorepository” for users 
receiving the specimens for processing and storage at reference labs and the 
Biorepository.  
x
Please refer to the Medidata Account Activation and Study Invitation Acceptance link on 
the CTSU website in the Data Management section under the Rave Home tab and then 
under Rave Resource Materials.
x
Important:  Failure to complete required fields in STS may result in a delay in 
sample processing.  Any case reimbursements associated with sample submissions will 
not be credited if samples requiring STS submission are not logged into STS.
Detailed instructions on use of the STS can be found in Section 5.4.

NCI Protocol #:  10268
Version Date:  October 21, 2022
35
Two Step Registration Process
The study will utilize a two-step registration process in OPEN. Subjects who sign an informed 
consent form and meet the pre-registration eligibility criteria should be pre-registered to the 
study by completing the initial registration step, Step #1, in OPEN. This will generate a subject 
ID with which to label the pre-registration tissue specimen. The second registration step, Step #2, 
should be completed in order to register and randomize subjects to the treatment phase of the 
study or to record a screen failure. 
OPEN/IWRS Questions?
Further instructional information on OPEN is provided on the OPEN tab of the CTSU website at 
https://www.ctsu.org or at https://open.ctsu.org.  For any additional questions contact the CTSU 
Help Desk at 1-888-823-5923 or ctsucontact@westat.com.
Theradex has developed a Slot Reservations and Cohort Management User Guide, which is 
available on the Theradex website:  http://www.theradex.com/clinicalTechnologies/?National-
Cancer-Institute-NCI-11. This link to the Theradex website is also on the CTSU website OPEN 
tab. For questions about the use of IWRS for slot reservations, contact the Theradex Helpdesk at
855-828-6113 or Theradex main number 609-799-7580; CTMSSupport@theradex.com.
General Guidelines
Following registration, patients should begin protocol treatment within 14 days. Issues that 
would cause treatment delays should be discussed with the PI. 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.
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES
Summary Table for Specimen Collection
Time Point
Specimen and Quantity
Send Specimens To:
Archival
x Formalin-fixed paraffin-embedded 
(FFPE) tumor tissue block (preferred)1
If a block is not available, then submit:
x
1 H&E stained slide
x
30-502 unstained, charged, unbaked
slides
EET Biobank
Baseline

NCI Protocol #:  10268 
Version Date:  October 21, 2022 
 
36 
 
Time Point 
Specimen and Quantity 
Send Specimens To: 
 
x Tumor needle biopsy3  
o 2 tumor cores frozen  
o 3 tumor cores in formalin  
 
x 20 mL blood in cfDNA Streck tubes 
(2 x 10 mL) 
 
x 10 mL blood in EDTA tube (1 x 10 
mL) 
EET Biobank  
 
x 10 mL blood in Streck tube (1 x 10 
mL) 
PADIS Laboratory 
Cycle 1, Day 2 (4 hours +/- 60 minutes after end of infusion) 
 
x 10 mL blood in Streck tube (1 x 10 
mL) 
 
PADIS Laboratory 
Cycle 1, Day 4 (Pre-treatment) 
 
x 10 mL blood in Streck tube (1 x 10 
mL) 
 
 PADIS Laboratory 
Cycle 1, Day 5 (Pre-treatment) 
 
x 20 mL blood in cfDNA Streck tubes 
(2 x 10 mL) 
 
EET Biobank 
Cycle 2, Day 1 (Pre-treatment) 
 
x 10 mL blood in Streck tube (1 x 10 
mL) 
 
PADIS Laboratory 
 
x 20 mL blood in cfDNA Streck tubes 
(2 x 10 mL) 
 
EET Biobank 
Cycle 3, Day 1 (Pre-treatment) 
 
x 10 mL blood in Streck tube (1 x 10 
mL) 
PADIS Laboratory 
 
x 20 mL blood in cfDNA Streck tubes 
(2 x 10 mL) 
 
EET Biobank 
Progression 
 
x 10 mL blood in Streck tube (1 x 10 
mL) 
 
PADIS Laboratory 
 
x 20 mL blood in cfDNA Streck tubes 
(2 x 10 mL) 
 
EET Biobank 

NCI Protocol #:  10268
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37
Time Point
Specimen and Quantity
Send Specimens To:
1For archival tissue, a copy of the corresponding anatomic pathology report must be sent with the 
tissue and uploaded to Rave.
2 Should obtaining 30-50 slides not be feasible, collect as much as possible taking into account 
local policies. The reason the required quantity is not available should be noted.
3 For new biopsies, the Tissue Biopsy Verification Form (APPENDIX E), a copy of the 
radiology and/or operative reports from the tissue removal procedure and the diagnostic 
anatomic pathology report must be sent with the tissue to the EET Biobank.  When completed, 
upload the corresponding pathology report to Rave and send a copy to the EET Biobank. 
Specimen Procurement Kits and Scheduling 
EET Biobank
Specimen Shipping Kits 
Kits for the collection and shipment of specimens to the EET Biobank can be ordered online via the 
Kit Management system: (https://ricapps.nationwidechildrens.org/KitManagement). 
Users at the clinical sites will need to set up an account in the Kit Management system and select 
a specific clinical trial protocol to request a kit. Please note that protocol may include more than 
one type of kit. Each user may order two kit types per protocol per day (daily max = 6 kits).  Kits 
are shipped ground, so please allow 5-7 days for receipt.  A complete list of kit contents for each 
kit type is located on the Kit Management system website.
Note: Kits or supplies are only provided for specimens shipped to the Biorepository.  Institutional 
supplies must be used for all other specimen collection and processing.
Scheduling of Specimen Collections
Please adhere to the following guidelines when scheduling procedures to collect tissue: 
x
Tumor tissue specimens collected during biopsy procedures and fixed in formalin 
must be shipped on the same day of collection. 
x
Tissue can be collected Monday through Wednesday and shipped overnight for 
arrival on Tuesday through Thursday at the EET Biobank at Nationwide Children’s 
Hospital.  
Specimens submitted frozen (i.e., tumor biopsy tissue) can be collected on any day but 
must be stored frozen and shipped to the EET Biobank on Monday through Thursday.  In 
the event that frozen specimens cannot be shipped immediately, they must be maintained 
at -80 °C.
Fresh blood specimens may be collected and shipped Monday through Friday.

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38
PADIS Laboratory
Materials and Equipment Required 
1. Blood shipment container provided by National Cancer Institute at Frederick (NCI-F) –
store at room temperature

Controlled room temperature (CRT) gel packs

Styrofoam box

Shipping cardboard box (red/white)
2. Specimen collection kits provided by NCI-F – store at room temperature

Streck Cell-Free DNA Preservative Tubes, 10.0-mL draw capacity (Streck, Cat#:
218962). Do not use Streck tubes after expiration date.

50-mL Falcon tube containing absorbent paper (secondary holding tube)

Zip lock bag – to protect Specimen Submission Form (APPENDIX D) upon return

FedEx Priority Overnight return label; pre-addressed with NCI account information
Ordering Shipping Kits and Blood tubes
Important: Blood shipment containers and specimen collection kits are shipped separately.
1. Blood shipment containers can be requested by e-mail to
NCI_PD_Support@mail.nih.gov.  Specify the number of shipment containers you will 
need.

Allow at least six business days for receipt of the blood shipment containers.

A confirmation e-mail with the expected shipping date will be sent.
2. Specimen collection kits can be requested by e-mail to NCI_PD_Support@mail.nih.gov.  
Specify the number of specimen collection kits you will need.

Allow at least six business days for receipt of the specimen collection kits.

A confirmation e-mail with the expected shipping date will be sent.
Preparation
1. Store the blood shipment containers and the specimen collection kits at 18°C to 25°C 
(RT).
2. Do not use Streck tubes after their expiration date.
3. Print specimen labels for the Streck tubes to be collected including the Patient/Sample 
ID, CTEP/clinical protocol number, and collection date and time.
4. Patient/Sample IDs for blood samples collected at the NCI include the CTEP number 
followed by a unique patient identifier and a sequential specimen ID; NCI blood samples 
for CTC PD sampling are series 400 (see example label).

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39
Scheduling of Specimen Collections
All samples MUST be shipped within 24 hours of collection to ensure quality results.
Blood for CTC analysis will be shipped at room temperature to the PADIS laboratory on the day 
it is collected. Note: the collected blood samples are stable for up to 48 hours at room 
temperature (15˚C to 30˚C) prior to processing (per PADIS laboratory standards).  Avoid 
collecting specimens on Fridays, as PADIS laboratory is closed on Saturdays and Sundays.  Also 
avoid shipping on the day before a federal holiday.
Specimen Collection 
Biopsy Collection Procedure
Baseline tumor biopsy is mandatory for patients with small cell lung cancer. Pre-treatment 
biopsies will be optional for the cohort of extrapulmonary small cell patients.  For the collection 
of biopsy specimens, core needle biopsy is the preferred technique. It is preferred that at least
five core biopsies 16-18 gauge in diameter and at least 1 cm in length, are obtained; three in 
formalin and two frozen. Samples will be shipped on the same day as collection to the EET 
Biobank (see Section 5.5 below). Specimens should be placed immediately into buffered 
formalin (provided in the kit) in the provided specimen collection container.
Core needle biopsy (CNB) tumor tissues will be collected for molecular profiling.  Core biopsies 
at least 1 cm in length will be obtained through Interventional Radiology by a percutaneous 
approach using a 16-18-gauge needle. Only percutaneous biopsies will be performed on patients 
with solid tumors. However, excisional biopsy or endoscopic biopsy is allowed if medically 
indicated and can be used for analysis. Biopsies will be sent for analyses as defined in the 
protocol. Two core biopsies will be immediately flash-frozen using a dry ice/alcohol slurry as 
flash-frozen tissue for biobanking, and three core biopsies will be fixed in formalin. 
Formalin-Fixed Tumor Biopsies 
1. Label formalin-filled containers according to instructions in Section 5.4.2.2.
2. Obtain three 16-gauge or 18-gauge core needle biopsy specimens, and place one core in 
each cassette. 
3. Snap the cassette lids closed and place cassettes into a formalin-filled pre-labeled 
container as soon as possible after collection to prevent air drying. Up to two cassettes 
may be placed in one formalin jar.

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40
4. Secure the container lids and place the containers into the shipping kit. Keep tissue in 
formalin jars at room temperature until shipment to the EET Biobank. 
Collection of Flash-Frozen Biopsy
1. Tissue should be frozen as soon as possible.  Optimally, freeze within 30 minutes from 
resection.
2. Label two cryovials (with the core number) according to instructions in Section 5.4.2.2. 
3. Each core sample should be placed directly into a separate prelabeled and pre-chilled 
cryovial.
Pre-chilling the cryovials helps to keep the tissue from sticking to the sides of the vial, 
making accessioning and banking by the EET Biobank easier.
4. Each specimen contained in its cryovial should be flash frozen using a dry ice/alcohol 
slurry. 
5. Frozen specimens should be shipped (the day of collection) Priority Overnight on dry ice 
in an insulated shipper or a dual temperature-chambered kit (provided by Biorepository).
Archival Formalin-Fixed Paraffin-Embedded (FFPE) Tumor Specimen 
The following criteria must be met for previously-collected FFPE tissue:
x
Formalin-fixed paraffin-embedded tumor tissue block(s) must be submitted.  The optimal 
block is at least 70% tumor.  Specimen size requirement is as follows:
o
Surface area:  25 mm2 is optimal.  Minimum is 5 mm2.
o
Volume:  1 mm3 optimal.  Minimum volume is 0.2 mm3, however the success of 
DNA extraction decreases at suboptimal tissue volume.
Archival FFPE tissue from diagnosis or an earlier relapse will be collected. If an existing block 
cannot be submitted, the following are requested:
x
One (1) H&E slide,
x
Thirty to fifty (30 – 50)unstained, charged, unbaked slides. Note: fewer slides may be 
collected per section 5.1.
See Section 5.4.2.2 for labeling instructions.
Blood Collection 
Collection of Blood in Streck Tube
Important: If blood samples are collected by a second party (nursing staff, phlebotomist, etc.), 
remove all clinical and personal identifiers from tube when received and replace with the pre-
printed specimen label. Do not just place specimen label on top of clinical label. 
1. Place a pre-printed specimen label on the Streck tube. 
2. Collect whole blood aseptically by venipuncture or from a venous port into a Streck tube. 

NCI Protocol #:  10268
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41
3. Fill the Streck tube with a minimum of 8-mL volume for a 10-mL capacity tube until 
the blood flow stops to ensure the correct ratio of sample to anticoagulant and 
preservative. If < 8-mL blood volume is collected, make a note on the Specimen 
Submission Form (APPENDIX D) for that sample so the processing laboratory is aware 
of the deviation. 
4. Immediately mix the specimen tube by gently inverting the tube 8-10 times; tube 
inversion prevents clotting. Do no shake the tube, vigorous mixing can cause hemolysis. 
Inadequate or delayed mixing may result in inaccurate test results. 
5. Do not refrigerate or freeze specimens; keep tubes at 18 °C to 25 °C (RT).
x
Important: Do not place sample(s) on ice. If the clinical staff placed the Streck tube 
on ice, make a notation on the Specimen Submission Form (APPENDIX D) and 
bring the tube to 18 °C to 25 °C (RT) before proceeding with sample processing. 
6. Label each tube with Patient/Sample ID, collection date and time, and clinical trial time 
point (i.e., cycle, day, hour: C1D1-2h). 
7. Blood specimens should be shipped within 24 h of collection, preferably on the day of 
collection to ensure quality results. Packaging and shipping instructions are in SOP 
Section 9.0. 
x
Blood specimens may be stored or transported in Streck Tubes for up to 96 h at 18 °C 
to 25 °C (RT) prior to processing, but processing must begin within 96 h of 
collection. 
Important:
x
Processing limitations: a minimum volume of 8.0 mL of blood in the Streck tube is 
needed for processing.
x
Blood specimens MUST be stored, transported, and processed at 18 °C to 25 °C.
x
All samples MUST be shipped within 24 hours of collection to ensure quality results.
Collection of Blood in cfDNA Streck Tube
1. Label two 10 mL cfDNA Streck tubes according to the instructions in Section 5.4.2.1.
2. Collect blood in two pre-labeled cfDNA Streck tubes (10 mL), Cat No. 218992 and 
gently invert to mix. Note: blood must be thoroughly mixed to ensure preservation 
of specimen.
3. After collection, blood in cfDNA Streck tubes should never be refrigerated, as 
this will compromise the specimen.  Blood collected in cfDNA Streck tubes is stable 
at room temperature. These tubes will be shipped to the EET Biobank for further 
processing. Upon receipt at the EET Biobank, blood in cfDNA Streck tubes will be 
processed for plasma and DNA.
Collection of Blood in EDTA Tubes
1. Label EDTA tubes according to the instructions in section 5.4.2.1.
2. Collect 10 mL blood in EDTA tube(s) and gently invert tube to mix.
3. Sample should be maintained and shipped at room temperature.  
4. Ship on day of collection (whenever possible) according to instructions below.

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5. If blood cannot be shipped on the day of collection (e.g., a late scheduled collection), 
then refrigerate until shipment.
Specimen Tracking System Instructions
Specimen Tracking System Overview and Enrollment Instructions
For the ETCTN STS, the following information will be requested:
x
Protocol Number
x
Investigator Identification 
o
Institution and affiliate name
o
Investigator’s name
x
Eligibility Verification:  Patients must meet all the eligibility requirements listed in 
Section 3.
x
Additional Requirements:
o
Patients must provide a signed and dated, written informed consent form.
Upon enrolling a patient, IWRS will communicate with OPEN, assigning two separate and 
unique identification numbers to the patient, a Universal patient ID (UPID) and a Treatment 
patient ID.  The UPID is associated with the patient and used each and every time the patient 
engages with the portion of this or any other protocol that uses the ETCTN Specimen Tracking 
System.  The UPID contains no information or link to the treatment protocol.  IWRS will 
maintain an association between the UPID for ETCTN biobanking and molecular 
characterization and any treatment protocols the patient participates in, thereby allowing analysis 
of the molecular characterization results with the clinical data.  
Immediately following enrollment, the institutional anatomical pathology report for the diagnosis 
under which the patient is being enrolled must be uploaded into Rave.  The report must include 
the surgical pathology ID (SPID), collection date, block number, and the IWRS-assigned UPID 
and patient study ID for this trial.  For newly acquired biopsies, the radiology and operative 
report(s) must also be uploaded into Rave.  Important:  Remove any personally identifying 
information, including, but not limited to, the patient’s name, date of birth, initials, medical 
record number, and patient contact information from the institutional pathology report 
prior to submission.
Additionally, please note that the STS software creates pop-up windows when reports are 
generated, so you will need to enable pop-ups within your web browser while using the software.  
For questions regarding the Specimen Tracking System, please contact the STS Support at
STS.Support@theradex.com.
The Shipping List report must be included with all sample submissions.
EET Biobank Specimen Labeling

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Blood Specimen Labels
Include the following on blood specimens (including whole blood and frozen, processed blood 
products – like serum and plasma):
x
Patient Study ID
x
Universal Patient ID (UPID)
x
Specimen ID (automatically generated by Rave)
x
Time point
x
Specimen type (e.g., blood)
x
Collection date and time (to be added by hand)
Tissue Specimen Labels
Include the following on all tissue specimens or containers (e.g., formalin jar): 
x
Patient Study ID
x
Universal Patient ID (UPID)
x
Specimen ID (automatically generated by Rave)
x
Time point
x
Specimen type (e.g., FFPE Block, Formalin Fixed Tissue, Fresh Tissue in Media, etc.)
x
Tissue type (P for primary, M for metastatic or N for normal)
x
Surgical pathology ID (SPID) number  
x
Block number from the corresponding pathology report (archival only)
x
Collection date and time (to be added by hand)
Example of Specimen Label Generated by STS 
STS includes a label printing facility, accessed via the Print Label CRF in the All Specimens 
folder. A generated PDF is emailed to the user as a result of saving that form. 
The following image is an example of a tissue specimen label printed on a label that is 0.5” high 
and 1.28” wide.
The QR code in the above example is for the Specimen ID shown on the second line.  

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Labels may be printed on a special purpose label printer, one label at a time, or on a standard 
laser printer, multiple labels per page. Theradex recommends the use of these low temperature 
waterproof labels for standard laser printers: https://www.labtag.com/shop/product/cryo-laser-
labels-1-28-x-0-5-cl-23-colors-available/
The last line item on the label includes the following data points joined together:
1. Tissue only: Primary (P), Metastatic (M), Normal (N) tissue indicated at the 
beginning of the specimen ID; this field is blank if not relevant (e.g., for blood)
2. Block ID or blank if not relevant
3. SPID (Surgical Pathology ID) or blank if none
4. An optional alpha-numeric code that is protocol specific and is only included if the 
protocol requires an additional special code classification
Space is provided at the bottom of the label for the handwritten date and optional time.  
The last line on the example label is for the handwritten date and optional time.
Overview of Process at Treating Site
OPEN Registration
All registrations will be performed using the OPEN system. OPEN communicates automatically 
with the IWRS which handles identifier assignments, any study randomization and any 
prescribed slot assignments. If specimen analysis is required to determine eligibility, the 
protocol will be setup with multi-step registration.
Registration without eligibility specimen analysis: 
1. Site enters registration data into OPEN during one or more steps.
2. IWRS receives data from OPEN, generates the Patient Study ID and the Universal Patient 
ID, both of which are sent back to OPEN.
3. IWRS sends all applicable registration data directly to Rave at the end of the final 
registration step.
Any data entry errors made during enrollment should be corrected in Rave.
Rave Specimen Tracking Process Steps
Step 0: Log into Rave via your CTEP-IAM account, then navigate to the appropriate participant.
Step 1: Complete the Histology and Disease form (but do not upload reports until a specimen 
label can be applied to them) and the Baseline forms regarding Prior Therapies. Enter the 
initial clinical specimen data: 

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45 
 
x Specimen Tracking Enrollment CRF:  Enter Time Point, Specimen Category, 
Specimen Type, Block number, Tissue type, Surgical Path ID, number of labels needed 
(include extra labels to apply to reports to be uploaded).  CRF generates unique Specimen 
ID.  
 
Step 2:  Print labels using the Print Labels CRF located in the All Specimens folder, then 
collect specimen. 
x Label specimen containers and write collection date and time on each label. 
x After collection, store labeled specimens as described in Section 5.3.2. 
x Apply an extra specimen label to each report before scanning. Return to the Histology 
and Disease form to upload any initial Pathology, Radiology, Molecular Reports (up to 
4), Surgical (or Operative) reports and Tissue Biopsy Verification form (when 
applicable).  Return to Specimen Tracking Enrollment CRF to upload any molecular 
report (one per specimen) and/or specimen specific pathology or related report (one per 
specimen).  Uploaded reports should have protected health information (PHI) data like 
name, date of birth, mailing address, medical record number or social security number 
(SSN) redacted.  Do not redact SPID, block number, diagnosis or relevant dates, and 
include the UPID and patient Study ID on each document.  
 
Step 3:  Complete specimen data entry. 
x Specimen Transmittal Form: Enter Collection date and time and other required 
specimen details. 
 
Step 4:  When ready to ship, enter shipment information. 
x Shipping Status CRF:  Enter tracking number, your contact information, recipient, 
number of sample containers and ship date once for the 1st specimen in a shipment. 
x Copy Shipping CRF:  In the specimen folders for additional specimens (if any) that will 
be shipped with the initial specimen, please use the Copy Shipping form to derive 
common data into additional Shipping Status forms. A few unique fields will still need 
to be entered in Shipping Status. 
 
Step 5:  Print shipping list report and prepare to ship.  
x Shipping List report is available at the site level. 
x Print two copies of the shipping list, one to provide in the box, the other for your own 
records. 
x Print pathology or other required reports to include in the box. Be sure the printed copy 
includes the specimen label. 
 
Step 6:  Send email notification.  
x For only one of the specimens in the shipment, click “Send Email Alert” checkbox on the 
Shipping Status CRF to email recipient. 
 
Step 7:  Ship the specimen(s). 
 

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Step 8: Monitor the Receiving Status form located in each specimen folder for acknowledgment   
of receipt and adequacy.
Shipping Specimens from Clinical Site to the EET Biobank
Core biopsies that are fixed in formalin and fresh blood should be shipped as one shipment at 
ambient temperature, whenever possible. The same box sent with kit contents should be used to 
ship specimens to the EET Biobank. In winter months, please include extra insulation, such as 
bubble wrap, inside the shipping container.
For all archival tissue, the corresponding anatomical clinical pathology report is required both in 
the package and uploaded in the ETCTN specimen tracking system. If this is not available at the 
time of shipment, then it must be uploaded to the ETCTN specimen tracking system, or the 
specimen will not be processed. The pathology report must state the disease diagnosis made by 
the reviewing pathologist.
For formalin-fixed and frozen biopsies, if the corresponding anatomical pathology report is not 
available at the time of shipment, then the surgical and/or radiology report from the tissue 
removal procedure and the anatomic pathology report from diagnosis must be uploaded to the 
ETCTN specimen tracking system and included in the package, or the specimen will not be 
processed.  When completed, upload the corresponding pathology reports in RAVE.
Specimen Shipping Instructions
Tissue in formalin must be shipped on the day of collection.  Collect and ship on Monday 
through Wednesday.
Frozen specimens may be shipped on Monday through Thursday. 
Fresh blood may be shipped on Monday through Friday.  Please select “Saturday Delivery” 
when shipping fresh blood on a Friday. 
Shipping Blood in an Ambient Shipper
1. Before packaging specimens, verify that each specimen is labeled according to the 
instructions above and that the lids of all primary receptacles containing liquid are tightly 
sealed.
2. Prepare the SAF-T-TEMP Gel Pak for shipment.  Note:  If contents of the Pak are 
crunchy, place Pak in a warm water bath until gel is smooth.  Do not refrigerate, freeze, 
or microwave.
3. Place the SAF-T-TEMP Pak in bottom of insulated chest.  Note:  The insulated chest 
must be shipped inside the provided cardboard box(es).
4. Place the blood collection tubes in zip-lock bags.
5. Next, place blood into a biohazard envelope with absorbent material.  Expel as much air 
as possible and seal the envelope securely.

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6. Place the biohazard envelope into a Tyvek envelope.  Expel as much air as possible and 
seal securely.
7. Place packaged blood collection tube(s) and a copy of the shipping manifest from the 
Sample Tracking System on top of the SAF-T-TEMP Pak.
8. Place the lid on the insulated chest.
9. Close the outer flaps of the shipping box and tape shut.
10. Attach a shipping label to the top of the shipping container.
11. Attach an Exempt Human Specimen sticker to the side of the box.
12. Ship specimens via overnight courier to the address listed below.  FedEx Priority 
Overnight is strongly recommended to prevent delays in package receipt.
Shipping Frozen and Ambient Specimens in a Dual-Chamber Kit
The Dual Chambered Specimen Procurement Kit is constructed to allow the shipment of frozen 
(on dry ice) and ambient (room temperature) specimens in the same container.  Dry ice may be 
placed in either compartment of the kit but should not be put in both.  The dual chambered 
kit is only used for shipments that contain both frozen and ambient specimens.  If formalin-fixed 
tissue is shipped separately (not in the same shipment as frozen specimens), then it must be 
shipped using institutional shipping supplies.
x
Frozen specimens may be shipped on Monday through Thursday.  Ensure that 
sufficient dry ice is included to completely encase the specimens to maintain 
specimen integrity during shipment.  
x
Formalin-fixed tissue may only be shipped on Monday through Wednesday.
1. Before packaging specimens, verify that each specimen is labeled according to the 
instructions above and that lids of all primary receptacles containing liquid are tightly 
sealed. 
2. Pre-fill one of the kit chambers about 1/3 with dry ice.
3. Prepare the frozen specimens for shipment:
a.
Place the specimens into zip-lock bags. 
b. Place the zip-lock bags into a biohazard envelope containing absorbent material. 
Expel as much air as possible before sealing the biohazard envelope.
c.
Put each biohazard envelope into a Tyvek envelope. Expel as much air as possible 
and then seal the Tyvek envelope.
4. Quickly place the Tyvek envelope containing frozen specimens in the kit 
compartment that is pre-filled with dry ice.  Place the Tyvek envelope on top of the 
dry ice.  Cover the specimens with additional dry ice until the compartment is almost 
completely full.  
5. Place the Styrofoam lid on top to secure specimens during shipment.  Do not tape the 
inner chamber shut.

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6. Prepare the ambient specimens for shipment:
a.
Seal the lids of the formalin jars with parafilm. Place absorbent material around 
the primary container of each liquid specimen. Place the specimens into zip-lock 
bags.
b. Place specimens inside the secondary pressure vessel with bubble wrap. 
c.
Secure the lid on the secondary pressure vessel and set it inside the kit chamber.
7. Insert a copy of the required forms in the kit chamber with the ambient specimens.
8. Place the Styrofoam lid on top of the kit compartment to secure specimens during 
shipment.  Do not tape the inner chamber shut.
9. Close the outer lid of the Specimen Procurement Kit and tape it shut with durable 
sealing tape.  Do not completely seal the container.
10. Complete a FedEx air bill and attach to top of shipping container.
11. Complete a dry ice label.
12. Attach the dry ice label and an Exempt Human Specimen sticker to the side of the 
shipping container.
13. Ship specimens via overnight courier to the address below.  FedEx Priority Overnight 
is strongly recommended to prevent delays in package receipt.
Shipping Address
Ship to the address below. Ship formalin-fixed, frozen, and fresh blood specimens the same day 
of specimen collection.  Do not ship specimens the day before a holiday.
EET Biobank The Research Institute at Nationwide Children's Hospital
700 Children's Drive, WA1340
Columbus, Ohio 43205
PH: (614) 722-2865
FAX: (614) 722-2897
Email: BPCBank@nationwidechildrens.org
FedEx Priority Overnight service is very strongly preferred.  
NOTE: The EET Biobank FedEx Account will not be provided to submitting institutions.
Contact Information for Assistance
For all queries, please use the contact information below:
EET Biobank
Toll-free Phone: (800) 347-2486
E-mail:  BPCBank@nationwidechildrens.org

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Shipping of Specimens from Clinical Site to PADIS laboratory
Specimen Shipping Instructions
Samples will be shipped on the same day of blood draw directly to the PADIS Laboratory.  This 
assay is currently being optimized.
Important:
All samples MUST be shipped within 24 h of collection to ensure quality results.
1. Complete a Specimen Submission Form (APPENDIX D) for all samples in the shipment.
2. For each sample record the Patient/Sample ID, Clinical Protocol/CTEP number, 
collection date and time, clinical trial time point, and clinical diagnosis if known.
Inclusion of the clinical diagnosis allows the specimen processing laboratory to more 
efficiently enrich CTCs from the blood sample.
3. In the comments field, record any deviations during blood collection (e.g., < 8.0-mL 
blood).
Packaging Instructions
1. Store CRT packs at 18 °C to 25 °C (RT). DO NOTrefrigerate or freeze CRT packs.
2. Place an 18 °C to 25 °C (RT) CRT pack in the bottom of a Styrofoam shipping container.
3. Wrap absorbent paper around the specimen-filled Streck tube and place in a 50-mL
Falcon centrifuge tube or blood shipping tube.

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4. Place the tube in the Styrofoam box on top of the CRT pack, put a second 18 °C to
25 °C (RT) CRT pack on top of the tube, and insert the completed Specimen
Submission Form (APPENDIX D) into a Zip lock bag and place on top of the CRT gel 
pack.
5. Close the Styrofoam box and place it inside a cardboard shipping box.
6. Seal the cardboard box and attach the return shipping label to the outside of the box; do
not cover the UN3373 (Biological substance, Category B) sticker with the shipping label.
Shipping Address
Specimens should be shipped to:
Attention: Dan Danner
NCI-F/FNLCR
1073 Beasley Street, Building 1073
Fort Detrick
Frederick, MD 21701
Phone: 301 846-5748
Send an e-mail on the day of shipment to NCI_PD_Support @mail.nih.gov to ensure timely
receipt and processing of the samples.  The subject line should state: “PD Clinical Shipment
Notification”
For each specimen being shipped include the following information:
x
Patient/Sample ID (s)
x
FedEx Tracking Number (s)

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x
Your Site Name
Contact Information for Assistance
For any other issues or questions regarding specimen collection and shipment for the PADIS
laboratory, contact Amy Pantella at 301-846-6747 or Rachel Andrews at 301-846-1951 (Email: 
NCI_PD_Support@mail.nih.gov).

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Biomarker Plan
List of Biomarker Assays in Order of Priority
Priority
Biomarker 
Name
Biomarker Assay
Biomarker Type 
and Purpose
M/O
Specimen(s) and 
Time Point(s) 
Laboratory Performing Assay
1
SLFN11
RNA-Seq
Integrated
Correlate level of 
expression with 
outcome
M*
Tumor needle 
biopsy**
Baseline
NCLN Genomics Laboratory or MoCha, Frederick 
National Laboratory for Cancer Research (FNLCR)
Dr. Mickey Williams
mickey.williams@nih.gov
Spatial 
transcriptomics
Spatial transcriptomics
Integrated
Correlate level of 
expression with 
outcome
M*
Tumor needle 
biopsy**
Baseline
NCI DTB 
Anish Thomas
anish.thomas@nih.gov
cMYC 
(amplification)
RNA-Seq
Integrated
Correlate level of 
expression with 
outcome
M*
Tumor needle 
biopsy**
Baseline
NCLN Genomics Laboratory or MoCha, Frederick 
National Laboratory for Cancer Research (FNLCR)
Dr. Mickey Williams
mickey.williams@nih.gov
ATM
RNA-Seq
Integrated
Correlate level of 
expression with 
outcome
M*
Tumor needle 
biopsy**
Baseline
NCLN Genomics Laboratory or MoCha, Frederick 
National Laboratory for Cancer Research (FNLCR)
Dr. Mickey Williams
mickey.williams@nih.gov
2
CTC 
phospho-ATR and 
γH2AX 
Exploratory
To determine 
prognostic and 
predictive role, and 
their usefulness to 
track tumor 
evolution and 
heterogeneity in 
response to 
treatment
O
Blood
Baseline, 
Cycle 1 Day 2#, Cycle 
1 Day4†, Cycle 2 Day 
1†, Cycle 3 Day 1, and 
at progression.
PADIS Dr. Ralph Parchment
parchmentr@mail.nih.gov

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53 
 
Priority 
Biomarker 
Name 
Biomarker Assay 
Biomarker Type 
and Purpose 
M/O 
Specimen(s) and 
Time Point(s)  
Laboratory Performing Assay 
3 
cfDNA - 
Fragmentomics 
 
Fragmentomics  
Exploratory 
 
To determine 
prognostic and 
predictive role, and 
their usefulness to 
track tumor 
evolution and 
heterogeneity in 
response to 
treatment 
O 
Blood 
Baseline, 
Cycle 1 Day 5 †,  
Cycle 2 Day 1 †, 
Cycle 3 Day 1,  
and at progression. 
 
Delfi Diagnostics, Baltimore, MD 
 
 
Lorenzo Rinaldi  
rinaldi@delfidiagnostics.com 
4 
Circulating 
Tumor DNA 
(ctDNA) 
TSO500 
Exploratory 
 
To determine 
prognostic and 
predictive role, and 
their usefulness to 
track tumor 
evolution and 
heterogeneity in 
response to 
treatment 
O 
Blood 
Baseline, 
Cycle 1 Day 5 †,  
Cycle 2 Day 1 †, 
Cycle 3 Day 1,  
and at progression. 
 
NCLN Genomics Laboratory or MoCha, Frederick 
National Laboratory for Cancer Research (FNLCR) 
 
Dr. Mickey Williams 
mickey.williams@nih.gov 
5 
SLFN11, ATM, 
cMYC  
Immunohistochemistry 
Exploratory 
 
O 
Tumor needle 
biopsy** 
Baseline 
NCI DTB  
 
Anish Thomas 
anish.thomas@nih.gov 
6 
WES 
Whole Exome 
Sequencing 
Exploratory 
O 
Tumor needle biopsy 
and blood (1x10mL, 
EDTA)** 
Baseline 
NCLN Genomics Laboratory or MoCha, Frederick 
National Laboratory for Cancer Research (FNLCR) 
 
Dr. Mickey Williams 
mickey.williams@nih.gov 
 
* Pre-treatment biopsies will be optional for the extrapulmonary cohort. The same panel of biomarker assays will be performed on samples from patients in the 
extrapulmonary cohort when biopsy is available.  
** Archival tissue will be collected to use to supplement sampling from fresh biopsy.   
ATM = Ataxia-Telangiectasia Mutated gene; cfDNA= circulating cell-free DNA; CTC = Circulating Tumor Cells; IHC = Immunohistochemistry; MoCha = 
Molecular Characterization Laboratory; MYC = family of regulator genes and proto-oncogenes that code for transcription factors; PADIS = Pharmacodynamic 
Assay Development; SLFN11 = Schlafen family member 11; TBD = To Be Determined; WES = Whole Exome Sequencing 

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54 
 
† Blood samples should be collected prior to drug administration. 
# Blood Samples for CTC at C1D2 should be collected 4 hours (+/- 60 minutes) after end of infusion.  
 

55
Integrated Correlative Studies
SLFN11
Studies from the NCI, DTB group demonstrated that SLFN11 blocks replication independently 
of ATR and that SLFN11-negative cells dominantly rely on ATR under replication stress [38].  
ATR inhibition overcomes resistance to topoisomerase 1 inhibitors in SLFN11-negative cancer 
cells. 
SLFN11 expression characterized by RNA-seq of a baseline tumor biopsy in this study may 
demonstrate a correlation with topotecan sensitivity mediated by ATR inhibition.  
Specimens Receipt and Processing at the EET Biobank
Tumor tissue received in formalin will be paraffin-embedded.  All FFPE blocks will be sectioned 
to generate an initial hematoxylin and eosin (H&E)-stained slide, and for nucleic acid 
extractions, additional RNase-free slides.
DNA and RNA will be co-extracted from tumor tissue.  The nucleic acids will be analyzed to 
determine concentration and quality. Aliquots of DNA and RNA will be shipped to the central 
sequencing laboratory for analysis.
Site Performing Correlative Study
RNA-Seq will be performed on baseline tumor samples at The NCLN Genomics 
Laboratory or MoCha, Frederick National Laboratory for Cancer Research 
(FNLCR).Shipment of Specimens from the EET Biobank to Site Performing 
Correlative Study 
Specimens will be shipped from the EET Biobank to one of the laboratories designated in 
Section 5.8.1.2.
Contact Information for Notification of Specimen Shipment
Thomas Forbes (NCLNGenomicsReceiving@nih.gov)
ATM
ATR inhibition may be more effective in patients with ATM-deficient tumors [40]. ATM 
deficiency characterized by RNA-sequencing of a baseline tumor may demonstrate a correlation 
with topotecan sensitivity mediated by ATR inhibition.   
Specimen Receipt and Processing at the EET Biobank

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Tumor tissue received in formalin will be paraffin embedded.  All FFPE blocks will be sectioned 
to generate an initial hematoxylin and eosin (H&E)-stained slide, and for nucleic acid 
extractions, additional RNase-free slides.
DNA and RNA will be co-extracted from tumor tissue. The nucleic acids will be analyzed to 
determine concentration and quality. Aliquots of DNA and RNA will be shipped to the central 
sequencing laboratory for analysis.
Site Performing Correlative Study
RNA-Seq will be performed on baseline tumor samples at The NCLN Genomics Laboratory or 
MoCha, Frederick National Laboratory for Cancer Research (FNLCR).
Shipment of Specimens from the EET Biobank to Site Performing Correlative Study 
Specimens will be shipped from the EET Biobank to one of the laboratories designated in 
Section 5.8.2.2.
Contact Information for Notification of Specimen Shipment
Thomas Forbes (NCLNGenomicsReceiving@nih.gov)
cMYC amplification
Genomic amplifications in MYC may increase replicative stress and dependence on ATR 
signaling [46]. MYC amplification characterized by RNA-sequencing of a baseline tumor 
biopsy in this study may demonstrate a correlation with topotecan sensitivity mediated by ATR 
inhibition.
Specimens Receipt and Processing at the EET Biobank
Tumor tissue received in formalin will be paraffin-embedded.  All FFPE blocks will be sectioned 
to generate an initial hematoxylin and eosin (H&E)-stained slide, and for nucleic acid 
extractions, additional RNase-free slides.
DNA and RNA will be co-extracted from tumor tissue.  The nucleic acids will be analyzed to 
determine concentration and quality. Aliquots of DNA and RNA will be shipped to the central 
sequencing laboratory for analysis.
Site Performing Correlative Study
RNA-Seq will be performed on baseline tumor samples at The NCLN Genomics Laboratory or 
MoCha, Frederick National Laboratory for Cancer Research (FNLCR).

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Shipment of Specimens from the EET Biobank to Site Performing Correlative Study 
Specimens will be shipped from the EET Biobank to one of the laboratories designated in 
Section 5.8.3.2.
Contact Information for Notification of Specimen Shipment
Thomas Forbes (NCLNGenomicsReceiving@nih.gov)
Spatial Transcriptomics
Spatial transcriptomics is a novel approach allowing measurement and mapping of gene activity 
to the resolution of single to few cells keeping the position information intact [65-67]. Mapping 
the cell-intrinsic and -extrinsic factors that impact SCLC tumor cell states in their positional 
context could yield important insights into the biologic basis of response and resistance to 
topotecan and topotecan plus M6620.
Specimens Receipt and Processing at the EET Biobank
As this analysis is being added following completion of the study accrual, available tumor tissue 
will be used for this analysis. Tissue processing concerns will be addressed between the EET 
biobank and study team by various methods as needed
Site Performing Correlative Study
Analysis will be performed by the NCI Developmental Therapeutics Branch Laboratory.
Shipment of Specimens from the EET Biobank to Site Performing Correlative Study 
Specimens will be shipped from the EET Biobank to:
Anish Thomas 
Center for Cancer Research
National Cancer Institute
Building 10 Room 4-5330
Bethesda, MD 20892
Contact Information for Notification of Specimen Shipment
Anish Thomas (anish.thomas@nih.gov)

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Exploratory/Ancillary Correlative Studies
Circulating tumor cells
Patients with SCLC have demonstrated a high amount of CTC compared with patients with other 
solid tumor malignancies.  CTCs (“liquid biopsies”) may reflect the changing burden of disease 
over course of treatments.  Peripheral blood will be collected to assess CTC and characterize 
disease [47].
Specimen Receipt and Processing at the PADIS Laboratory
Samples will be shipped on the same day of blood draw directly to the PADIS Laboratory.  This 
assay is currently being optimized.
Site Performing Correlative Study
This study will be performed by the PADIS Laboratory.
cfDNA - Fragmentomics
Characterization of plasma cfDNA can potentially provide rapid, noninvasive improved 
monitoring of disease burden, depth of responses to treatment, and timely warning of disease 
relapse in patients with SCLC [1].  Peripheral blood will be collected to assess cfDNA for 
genetic mutations specific to SCLC.
Specimen Receipt and Processing at the EET Biobank
Whole blood collected in Streck tubes will be centrifuged to separate buffy coat and plasma and 
will be stored in a -80°C freezer. 
The nucleic acids will be analyzed to determine concentration and quality.  Aliquots of DNA and 
RNA will be shipped for analysis.
Site Performing Correlative Study
This study will be performed by Delfi Diagnostics.
Shipment of Specimens from the EET Biobank to Site Performing Correlative Study 
Specimens will be shipped from the EET Biobank to:
Lorenzo Rinaldi 
2809 Boston St, Suite 503
Baltimore MD 21224

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Contact Information for Notification of Specimen Shipment
Lorenzo Rinaldi (rinaldi@delfidiagnostics.com)
Circulating Tumor DNA (ctDNA)
Characterization of plasma cfDNA can potentially provide rapid, noninvasive improved 
monitoring of disease burden, depth of responses to treatment, and timely warning of disease 
relapse in patients with SCLC [1].  Peripheral blood will be collected to assess cfDNA for 
genetic mutations specific to SCLC.
Specimen Receipt and Processing at the EET Biobank
Whole blood collected in Streck tubes will be centrifuged to separate buffy coat and plasma and 
will be stored in a -80°C freezer. 
The nucleic acids will be analyzed to determine concentration and quality.  Aliquots of DNA and 
RNA will be shipped for analysis.
Site Performing Correlative Study
ctDNA will be performed at The NCLN Genomics Laboratory or MoCha, Frederick National 
Laboratory for Cancer Research (FNLCR).
Shipment of Specimens from the EET Biobank to Site Performing Correlative Study 
Specimens will be shipped from the EET Biobank to one of the laboratories designated in 
Section 5.9.3.2.
Contact Information for Notification of Specimen Shipment
Thomas Forbes (NCLNGenomicsReceiving@nih.gov)
SLFN11, cMYC, and ATM
Specimens Receipt and Processing at the EET Biobank
Tumor tissue received in formalin will be paraffin-embedded. All FFPE blocks will be sectioned 
to generate an initial hematoxylin and eosin (H&E)-stained slide.
Site Performing Correlative Study
Immunohistochemistry (IHC) will be performed on baseline tumor samples by NCI DTB.  

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Shipment of Specimens from the EET Biobank to Site Performing Correlative Study 
Specimens will be shipped from the EET Biobank to:
Anish Thomas, MD 
Center for Cancer Research
National Cancer Institute
Building 10 Room 4-5330
Bethesda, MD 20892
Contact Information for Notification of Specimen Shipment
Anish Thomas (anish.thomas@nih.gov)
Whole Exome Sequencing
Specimens Receipt and Processing at the EET Biobank
Tumor tissue received in formalin will be paraffin-embedded. All FFPE blocks will be sectioned 
to generate an initial hematoxylin and eosin (H&E)-stained slide, and for nucleic acid 
extractions, additional RNase-free slides.
DNA and RNA will be co-extracted from tumor tissue. DNA will be extracted from the whole 
blood collected in the EDTA tube.  The nucleic acids will be analyzed to determine 
concentration and quality. Aliquots of DNA and RNA will be shipped to the central sequencing 
laboratory for analysis.
Site Performing Correlative Study 
WES will be performed on baseline tumor samples at The NCLN Genomics Laboratory or 
MoCha, Frederick National Laboratory for Cancer Research (FNLCR).
Shipment of Specimens from the EET Biobank to Site Performing Correlative Study 
Specimens will be shipped from the EET Biobank to one of the laboratories designated in 
Section 5.9.5.2.
Contact Information for Notification of Specimen Shipment
Thomas Forbes (NCLNGenomicsReceiving@nih.gov)
TREATMENT PLAN
Agent Administration

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61 
Treatment will be administered in general on an outpatient basis unless a patient needs to be 
admitted for logistical reasons.  Reported AEs and potential risks are described in Section 10.  
Appropriate dose modifications are described in Section 7.  No investigational or commercial 
agents or therapies other than those described below may be administered with the intent to treat 
the patient's malignancy. 
 
Participants meeting inclusion and exclusion criteria will receive either monotherapy with 
topotecan 1.25 mg/m2 IV Days 1-5 or combination therapy consisting of topotecan 1.25 mg/m2 
IV Days 1-5 with M6620 210 mg/m2 IV Days 2 and 5 administered each 21-day cycle until 
disease progression or development of intolerable side effects. Pegfilgrastim will be administered 
at least 24 hours after the last dose of topotecan, starting with the first cycle. Acceptable 
alternatives include filgrastim administered daily or pegfilgrastim administered via on-body 
injector. Concomitant administration of granulocyte stimulating factor (G-CSF) pegfilgrastim 
and topotecan can prolong the duration of neutropenia.  Patients on the topotecan monotherapy 
arm will be eligible to receive the combination treatment at progression.  On days 2 and 5, the 
drugs will be administered sequentially, with topotecan followed by M6620. M6620 should be 
administered within 15 minutes after topotecan administration is completed.  
 
For cardiac safety measures, an EKG will be performed at pre-study and as clinically indicated. 
 
Subjects will be monitored weekly during the first cycle by basic labs (complete blood count 
[CBC] with differential and chemistries [acute panel, hepatic panel, and mineral panel] on days 8 
and 15) and if clinically indicated in subsequent cycles. 

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Regimen Description
Agent
Premedications; 
Precautions
Dose
Route
Schedule
Cycle 
Length
M6620
Premedicate if 
subject develops 
infusion reactions 
(Section 6.1.1); 
refer to Section
6.2 for 
restrictions
210 
mg/m2 in 
D5W to a 
final 
concentra
-tion 
between 
0.075 
mg/mL to 
1 mg/mL
IV over 60 
minutes (+/- 10 
minutes) 
(within 15 
minutes after 
completion of 
topotecan 
administration)
Days 2 and 
5
21 days
Topotecan
Antiemetic 
prophylaxis is 
recommended. 
For example, 
ondansetron 16 
mg PO or IV 30 
minutes prior to 
topotecan; 
Additionally, 
take home 
antiemetics are 
recommended as 
needed. For 
example, 
ondansetron 8 mg 
PO q6 prn. 
1.25 
mg/m2
IV over 30 
minutes 
Days 1-5
IV = intravenously; PO = by mouth; q6 prn = every 6 hours as needed
M6620
M6620 will be supplied as a 20 mg/mL solution. M6620 must be diluted with 5% dextrose in 
water solution before intravenous infusion as detailed in Section 8.1.1.
An appropriate volume of concentrated drug product solution is diluted before use, according to 
the dose indicated in the table above. Total dose of M6620 is not to exceed 800 mg/dose. 
The dose of M6620 in dextrose in water solution will be infused IV over 60 minutes (±10 
minutes).
Infuse using an infusion set containing low-sorption or non-PVC, DEHP-free tubing and an in-
line 0.2 micron filter. 5% dextrose in water solution must be used for IV line priming and 
flushing. M6620 should not come in contact with 0.9% Sodium Chloride due to incompatibility.

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If any subject develops phlebitis or signs or symptoms of inflammation that may progress to 
phlebitis or which the subject 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. If any subject develops pruritus or evidence of allergic 
reaction, standard measures may be employed to ameliorate these symptoms or to prevent 
recurrence of these symptoms (e.g., premedication with acetaminophen 325 mg, PO 
approximately 30 minutes before the infusion, 200 mg hydrocortisone intravenously 
approximately 60 minutes before infusion, and 25 mg diphenhydramine intravenously
approximately 30 minutes before infusion; alternative antihistamine and steroid combinations 
may be considered, as long as not prohibited by protocol). If standard procedures to limit 
symptoms of injection site reaction or pruritus are insufficient, then the infusion time may be 
extended beyond 60 minutes, but no more than 90 minutes.
Topotecan
Topotecan is a cytotoxic anticancer drug. Prepare topotecan under a vertical laminar flow hood 
while wearing gloves and protective clothing. If topotecan solution contacts the skin, wash the 
skin immediately and thoroughly with soap and water. If topotecan contacts mucous 
membranes, flush thoroughly with water. Use procedures for proper handling and disposal of 
anticancer drugs. 
Each 4-mg powder for injection vial of topotecan is reconstituted with 4 mL Sterile Water for 
Injection. Then the appropriate volume of the reconstituted solution or solution for injection is
diluted in 5% Dextrose or 0.9% Sodium Chloride IV Infusion prior to administration. Topotecan 
will be administered as an intravenous infusion over 30 minutes.
General Concomitant Medication and Supportive Care Guidelines
Patients should receive general concomitant and supportive care medications (including 
antibiotics, nutritional support, growth factor support, correction of metabolic disorders, optimal 
symptom control, and pain management, etc.) based on best medical practice.  Supportive care 
can include palliative radiation therapy, including bone-directed radiation therapy for pain 
control in subjects deriving clinical benefit from treatment.  Study medications can be held per 
investigator discretion during this period.
Because there is a potential for interaction of M6620 with other concomitantly administered 
drugs, the case report form (CRF) must capture the concurrent use of all other drugs, over-the-
counter medications, or alternative therapies. The PI should be alerted if the patient is taking any 
agent known to affect or with the potential for drug interactions. For example, M6620 is 
metabolized by CYP 3A4 isoenzyme (CYP3A4); exposure to M6620 may be affected by 
concomitantly administered drugs that are strong inhibitors or inducers of CYP3A4. Sensitive 
substrates of CYP3A4 should be used with caution.
M6620 (VX-970, berzosertib) is a weak/moderate inhibitor of UGT1A1, UGT1A14, UGT1A9, 
UGT2B15, and UGT2B17.  UGT2B7, UGT1A3, and UGT1A6 were weakly or not inhibited.  
M6620 (VX-970, berzosertib) is predicted to not inhibit significantly the metabolic clearance of 

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SN-38 (active metabolite of irinotecan) at therapeutic exposures.  M6620 (VX-970, berzosertib) 
is a moderate inhibitor of P-gp and BCRP.  It is a P-gp substrate but not BCRP.  Based on in 
vitro data, there is low risk of drug-drug interaction with OATP1B3 and BCRP. Use caution 
when administered with sensitive substrates of OATP1B3 and BCRP.
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 Interactions Handout and Wallet 
Card should be provided to patients if available. 
Prior and concomitant medication/food restrictions are provided in the table below.
Medications taken from 28 days before the first dose of study drug will be documented as a prior 
medication. Medications taken after the first dose of study drug through the end of the study will 
be documented as concomitant medications. All medications must be recorded with indication, 
route of administration, and start and stop dates of administration. All subjects will be 
questioned about concomitant medication at each clinic visit. 
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.  
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.  The intravenous infusion 
site should be monitored closely for the development of erythema, induration, purulence, 
tenderness, or warmth.
Duration of Therapy
In the absence of treatment delays due to AE(s), treatment may continue 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

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x
General or specific changes in the patient's condition that render the patient unacceptable 
for further treatment in the judgment of the investigator
x
Clinical progression
x
Patient non-compliance
x
Pregnancy
o
All women of childbearing 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
*For patients who initially received monotherapy and cross over to the combination arm at 
progression, treatment will be stopped when disease progression occurs after combination 
therapy.
The reason(s) for protocol therapy discontinuation, the reason(s) for study removal, and the 
corresponding dates must be documented in the CRF.
Duration of Follow-Up
Patients will be followed every three months after removal from study treatment until study closure 
or death, whichever occurs first. Patients without radiographic PD/death will also be followed for 
response at least every 12 weeks until PD/death or until 6 months after the last patient completes 
study treatment (whichever occurs first). Patients removed from study for unacceptable adverse 
event(s) will also be followed until resolution or stabilization of the adverse event.  Study accrual 
will be completed approximately 2 years from study initiation.
DOSING DELAYS/DOSE MODIFICATIONS
M6620 dose modification
No dose modifications of M6620 may be made during Cycle 1.
The dose of M6620 may be reduced for the first occurrence of drug-related toxicity (except 
during cycle 1) using the following toxicity-dependent guidelines:
1. For Grade 4 hematologic toxicity: The dose of M6620 will be reduced by 25%.
2. For Grade 3 non-hematologic toxicity (except disease related hyponatremia for which 
dose reduction will only be made for grade 4): The dose of M6620 will be reduced by 
25%.
3. For Grade 4 non-hematologic toxicity: The dose of M6620 will be reduced by 50%.

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Based on the criteria above, a maximum of 2 dose reductions will be permitted. If a grade 4 non-
hematologic toxicity were to recur, treatment will be discontinued. 
Dose modifications for Grade 4 hematologic and Grade 3 non-hematologic drug-related AE
Starting dose 
210 mg/m2
First dose reduction 
158 mg/m2
Second dose reduction 
105 mg/m2
Dose modifications for Grade 4 non-hematologic drug-related AE
Starting dose 
210 mg/m2
First dose reduction 
105 mg/m2
In addition, in case of Grade 3 or higher toxicity during any cycle beyond Cycle 1, treatment may 
be interrupted and may be resumed when all toxicities have returned to Grade 2 or less, at the 
discretion of the investigator. Treatment interruptions may occur for a maximum of 21 days. 
Topotecan dose modification
No dose modifications of topotecan may be made during cycle 1. 
The dose of topotecan may be reduced for drug-related toxicity (except during cycle 1) using the 
toxicity-dependent guidelines in the table below. Topotecan dose reductions will be accomplished 
by decreasing the dose of topotecan for each of the 5 days.
To initiate subsequent cycles of topotecan, the day 1 ANC should be >1500/mm3 and platelets 
>100,000/mm3. Treatment interruptions may occur for a maximum of 21 days.
Based on the below criteria, a maximum of 2 dose reductions will be permitted. 
A. Dose adjustments for renal functions (to be made 
regardless of whether the decrease in renal function is drug 
related or not)
Creatinine clearance 
(Cockcroft-Gault formula)
Topotecan 1st Dose Reduction 
(mg/m2)
>60
no adjustment
40-59
1
20-39
0.75
<20
Discontinue
B. Dose adjustments for non-hematologic toxicities
Non-hematologic toxicity
Topotecan 1st Dose Reduction 
(mg/m2)
Topotecan 2nd Dose 
Reduction (mg/m2)
Grades 1 and 2
no adjustment
Grades 3 and 4 (except grade 3 
nausea)
1
0.75

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67
C. Dose adjustments for hematologic toxicities
Hematologic toxicity
Topotecan 1st Dose Reduction 
(mg/m2)
Topotecan 2nd Dose 
Reduction (mg/m2)
Grades 1 and 2
no adjustment
Grade 3 neutropenia persisting 
after day 21
1
0.75 
Grade 4 thrombocytopenia or 
Grade 4 neutropenia with fever 
or infection or of duration ≥ 7 
days
1
0.75
In addition, in case of Grade 3 or higher toxicity during any cycle beyond Cycle 1, treatment 
may be interrupted and may be resumed when all toxicities have returned to Grade 2 or less, at 
the discretion of the investigator. 
Subjects assigned to both agents who develop intolerance to topotecan, but who may be 
benefiting from therapy, may continue on single agent M6620, administered weekly (on days 2 
and 5 of 21-day cycle) at the same dose they have received in combination therapy, until disease 
progression.
PHARMACEUTICAL INFORMATION
A list of the adverse events and potential risks associated with the investigational and 
commercial agents administered in this study can be found in Section 10.1.
CTEP IND Agent
M6620 (VX-970, Berzosertib) (NSC 780162)
Other Names: VRT-0768079, MSC2527093A, VX-970
Chemical Name: 5-(4-(isopropylsulfonyl)phenyl)-3-(3-(4-
((methylamino)methyl)phenyl)isoxazol-5-yl)pyrazin-2- amine
Classification: ATR inhibitor
CAS Registry Number: 1232416-25-9
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 (VX-970, berzosertib) disrupts ATR-mediated DNA damage response 
signaling and leads to sustained accumulation of DNA damage in cancer cells co-treated with DNA-
damaging agents.

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Description: The drug substance for M6620 (VX-970, berzosertib) is the free base. 
 
How Supplied: M6620 (VX-970, berzosertib) is supplied by Merck KGaA/EMD Serono, Inc. and 
distributed by the Pharmaceutical Management Branch, CTEP/DCTD/NCI as single-use 200 mg 
vials containing a sterile solution (20 mg/mL).  M6620 (VX-970, berzosertib) solution for injection 
is a yellow liquid formulated in 20% betadex sulfobutyl ether sodium (w/v) and 86 mM acetate 
buffer, 10 mL total volume, supplied in clear glass vials in cardboard boxes with foam inserts. 
 
Preparation: M6620 (VX-970, berzosertib) solution for injection must be diluted with 5% dextrose 
in water solution prior to administration.  Do not use 0.9% Sodium Chloride due to incompatibility 
with M6620 (VX-970, berzosertib).  To prepare the infusion solution add the dose volume of M6620 
(VX-970, berzosertib) to a non-polyvinyl chloride (non-PVC), di(2-ethylhexyl) phthalate (DEHP)-
free EVA infusion bag containing 5% dextrose in water. Gently invert the IV bag 5-10 times to 
mix the solution.  Confirm the solution is clear and free of precipitates and/or particulates.  The 
final concentration must be between 0.075 mg/mL to 1 mg/mL.  Place the IV bag into an opaque 
cover to protect from light.   
 
Storage: Store intact vials protected from light inside cardboard boxes at room temperature, below 
25°C (77°F). Do not freeze.    
 
If a storage temperature excursion is identified, promptly return M6620 (VX-970, berzosertib) 
to 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. 
 
Stability: Stability testing of the intact vials is on-going.  Prepared solutions must be protected from 
light and used within 4 hours from time of preparation if stored at room temperature or 24 hours if 
stored refrigerated (2-8°C).  
 
Route of Administration: Intravenous (IV) infusion. 
 
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 containing low-sorption or non-PVC, DEHP-free tubing and an in-line 0.2 micron filter.  
5% dextrose in water solution must be used for IV line priming and flushing.  M6620 (VX-970, 
berzosertib) should not come in contact with 0.9% Sodium Chloride due to incompatibility. 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 (VX-970, 
berzosertib) 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. M6620 
(VX 970, berzosertib) absorbs in the UV-visible radiation spectrum and is widely distributed 
including skin, so patients receiving M6620 (VX-970, berzosertib) should take protective 
measures to minimize sun exposure. 

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Women of childbearing potential and men should use appropriate contraception while on study 
drug and for 6 months after discontinuation of M6620 (VX-970, berzosertib).
Potential Drug Interactions: M6620 (VX-970, berzosertib) is primarily metabolized by 
CYP3A4.  M6620 (VX-970, berzosertib) has a low potential to inhibit CYP1A2, 2B6, 2C8, 2C9, 
2C19, 2D6, and 3A4, and a moderate potential to reversibly inhibit CYP2E1.  The potential for 
M6620 (VX-970, berzosertib) to induce CYP450 enzymes CYP1A2, 2B6, and 3A4 at 
concentrations up to 6 μM is low.  Concomitant administration with strong inhibitors or inducers 
of CYP3A4 should be avoided.  Sensitive substrates of CYP3A4 should be used with caution.
M6620 (VX-970, berzosertib) is a weak/moderate inhibitor of UGT1A1, UGT1A14, UGT1A9, 
UGT2B15, and UGT2B17.  UGT2B7, UGT1A3, and UGT1A6 were weakly or not inhibited.  
M6620 (VX-970, berzosertib) is predicted to not inhibit significantly the metabolic clearance of 
SN-38 (active metabolite of irinotecan) at therapeutic exposures.
M6620 (VX-970, berzosertib) is a moderate inhibitor of P-gp and BCRP.  It is a P-gp substrate but 
not BCRP.  Based on in vitro data, there is low risk of drug-drug interaction with OATP1B3 and 
BCRP. Use caution when administered with sensitive substrates of OATP1B3 and BCRP 
transporters.
Availability:  M6620 is an investigational agent supplied to investigators by the Division of 
Cancer Treatment and Diagnosis (DCTD), NCI.
M6620 is provided to the NCI under a Collaborative Agreement between the Pharmaceutical 
Collaborator and the DCTD, NCI (see Section 13.5).
Agent Ordering and Agent Accountability
NCI-supplied agents may be requested by eligible participating Investigators (or their authorized 
designee) at each participating institution. The CTEP-assigned protocol number must be used 
for ordering all CTEP-supplied investigational agents. The eligible participating investigators at 
each participating institution must be registered with CTEP, DCTD through an annual 
submission of FDA Form 1572 (Statement of Investigator), NCI Biosketch, Agent Shipment 
Form, and Financial Disclosure Form (FDF).  If there are several participating investigators at 
one institution, CTEP-supplied investigational agents for the study should be ordered under the 
name of one lead participating investigator at that institution.
Drug orders of M6620 should be placed after enrollment onto the study and randomization. 
Provide the patient ID number in the comment box when submitting an order request.
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, 

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call or email PMB any time. Refer to the PMB’s website for specific policies and guidelines 
related to agent management.  
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.
Investigator Brochure Availability
The current versions of the IBs for the agent will be accessible to site investigators and research 
staff through the PMB OAOP application. Access to OAOP requires the establishment of a 
CTEP IAM account and the maintenance of an “active” account status, a “current” password and 
active person registration status.  Questions about IB access may be directed to the PMB IB 
Coordinator via email.
Useful Links and Contacts
CTEP Forms, Templates, Documents:  http://ctep.cancer.gov/forms/
NCI CTEP Investigator Registration:  RCRHelpDesk@nih.gov
PMB policies and guidelines: 
http://ctep.cancer.gov/branches/pmb/agent_management.htm
PMB OAOP application: https://ctepcore.nci.nih.gov/OAOP
CTEP IAM account: https://ctepcore.nci.nih.gov/iam/
CTEP IAM account help:  ctepreghelp@ctep.nci.nih.gov
IB Coordinator:  IBCoordinator@mail.nih.gov
PMB email:  PMBAfterHours@mail.nih.gov
PMB phone and hours of service: (240) 276-6575 Monday through Friday between 8:30 
am and 4:30 pm (ET)
Commercial Agent 
Topotecan
For additional information see the Topotecan Package Insert.
Chemical Name: (S)-10-[(dimethylamino)methyl]-4-ethyl-4,9-dihydroxy-1Hpyrano[3’,4’:6,7] 
indolizino [1,2-b]quinoline-3,14-(4H ,12H)-dione monohydrochloride
Other Names:  HYCAMTIN®
Classification:  Anti-tumor Topoisomerase Inhibitor

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71 
CAS Registry Number:  123948-87-8 
 
Molecular Formula:  C23H23N3O5 
MW:  421.45 Da 
 
Mode of Action:  Topotecan is a semi-synthetic derivative of camptothecin and is an anti-tumor 
drug with topoisomerase I-inhibitory activity.  Topoisomerase I relieves torsional strain in DNA 
by inducing reversible single-strand breaks.  Topotecan binds to the topoisomerase I-DNA 
complex and prevents re-ligation of these single-strand breaks.  The cytotoxicity of topotecan is 
thought to be due to double-strand DNA damage produced during DNA synthesis, when 
replication enzymes interact with the ternary complex formed by topotecan, topoisomerase I, and 
DNA.  Mammalian cells cannot efficiently repair these double-strand breaks. 
 
How Supplied:  
 
Powder for Injection (4 mg) 
Topotecan powder for injection is supplied as a sterile, lyophilized, buffered, light yellow to 
greenish powder for reconstitution available in single-dose vials.  Each vial contains topotecan 
hydrochloride equivalent to 4 mg of topotecan as free base.  The reconstituted solution ranges in 
color from yellow to yellow-green and is intended for administration by intravenous infusion. 
 
Solution for Injection (4 mg/4 mL) 
Topotecan Injection is supplied as a clear yellow to yellow-green solution in single use vial for 
intravenous infusion only following dilution.  Each mL contains topotecan hydrochloride 
equivalent to 1 mg of topotecan free base.  
 
Preparation:  
Topotecan Injection is a cytotoxic anticancer drug.  Prepare topotecan hydrochloride injection 
under a vertical laminar flow hood while wearing gloves and protective clothing.  If Topotecan 
Injection solution contacts the skin, wash the skin immediately and thoroughly with soap and 
water.  If Topotecan Injection contacts mucous membranes, flush thoroughly with water.  Handle 
and dispose of topotecan for injection consistent with recommendations for the handling and 
disposal of hazardous drugs. 
 
Powder for Injection (4 mg) 
Reconstitute each 4-mg vial of topotecan with 4 mL Sterile Water for Injection, USP.   
 
Powder for Injection (4 mg) and Solution for injection (4 mg/mL) 
Dilute the appropriate volume of the solution in a minimum of 50 mL of 5% Dextrose in Water 
Injection or 0.9% Sodium Chloride, USP prior to administration. 
 
Storage:   
 
Powder for Injection (4 mg) 
Store at controlled room temperature between 20°C and 25°C (68°F and 77°F) [see USP].  
Protect from light in original carton.  
 

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Solution for Injection (4 mg/mL)
Unopened vials of Topotecan Injection are stable until the date indicated on the package when 
stored at 2°C to 8°C (36°F and 46°F) and protected from light in the original package. 
Stability:  Unopened vials of topotecan powder for injection are stable until the date indicated 
on the package when stored between 20°C and 25°C (68°F and 77°F) [see USP] and protected 
from light in the original carton. Because the vials contain no preservative, contents should be 
used immediately after reconstitution. Topotecan diluted for infusion is stable at approximately 
20°C to 25°C (68°F to 77°F) and ambient lighting conditions for 24 hours.
Route of Administration:  Topotecan Injection is administered by intravenous infusion over 30 
minutes. 
Method of Administration:  Verify dose using body surface area prior to dispensing.  
Recommended dosage should generally not exceed 4 mg intravenously.
Agent Ordering:  Topotecan is commercially available.  
STATISTICAL CONSIDERATIONS
Study Design/Endpoints
This study is an open label, randomized Phase 2 study of patients with relapsed SCLC. SCLC 
patients who have failed prior therapy will be randomized 2:1 to receive either topotecan in 
combination with M6620 or topotecan alone. The rationale for 2:1 randomization is to obtain 
more clinical and molecular data from patients who receive combination of M6620 and 
topotecan. Patients will be stratified at the time of randomization for being sensitive or 
resistant/refractory to prior therapy.  Patients on the topotecan monotherapy arm will be eligible 
to cross-over to receive the topotecan with M6620 combination treatment at progression. A 
separate cohort of patients with extrapulmonary small cell cancer will be accrued while the 
primary cohort is accruing and will only receive the combination therapy (see Section 9.3 for 
secondary endpoints).
Cohorts
Number
Name
Description
1
Primary Cohort
Patients with measurable SCLC.
2
Exploratory Cohort
Patients with extrapulmonary small cell cancer.
Arms
Number
Name
Description
1
Arm 1*-monotherapy
Topotecan
2
Arm 2 -combination 
Topotecan + M6620

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73 
treatment 
*Arm 1 patients (on the topotecan monotherapy) will be eligible to cross-over to Arm 2 at progression to receive the 
combination treatment. 
 
Stratifications 
 
Number 
Name 
Description 
1 
Platinum response-sensitive 
First-line chemotherapy sensitivity response 
treatment-free interval ≥ 90 days 
2 
Platinum response-resistant 
First-line chemotherapy sensitivity response 
treatment-free interval < 90 days 
 
The primary objective of the trial is to determine if the combination of M6620 with topotecan 
will result in an improvement in PFS compared to topotecan alone in patients with relapsed 
SCLC. 
 
Published results suggest that the median PFS for single agent therapy for previously treated 
patients which included a combination of sensitive and resistant /refractory patients was 
approximately 3 months (median 3.0-4.3 months for sensitive and 1.5-2.6 months for refractory; 
[9, 12, 13, 69, 70] (refer to the Selected randomized studies of cytotoxic agents for SCLC Table 
below).  It would be desirable to improve the PFS to be as high as 6 months by use of a 
combination therapy. More recent data suggest that PFS of single-agent DNA targeted therapies 
in previously treated SCLC patients which included a combination of sensitive and resistant 
/refractory patients may be lower- closer to 2 months than 3 months [15].   
 

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74 
Selected randomized studies of cytotoxic agents for SCLC 
No.  
Patients  
Treatments 
Primary 
endpoint 
Median 
PFS- 
topotecan 
Median 
OS- 
topotecan 
Reference 
1 
Sensitive 
SCLC 
Topotecan 
vs. CAV  
ORR 
3.3 months 
(sensitive) 
6.3 months 
(sensitive) 
[9] 
 
2 
Refractory or 
sensitive 
SCLC; 2nd 
line 
Topotecan 
vs. 
amrubicin 
OS 
4.3 months 
(sensitive) 
 
2.6 months 
(refractory)  
 
 
9.9 months 
(sensitive) 
 
5.7 months 
(refractory) 
[13] 
3 
Sensitive 
SCLC  
2:1 
Topotecan 
vs. 
amrubicin 
ORR 
3.3 months 
(sensitive) 
7.6 months 
(sensitive) 
[70] 
4 
Refractory or 
sensitive 
SCLC 
Topotecan 
vs. 
amrubicin 
ORR 
3.0 months 
(sensitive) 
 
1.5 months 
(refractory)  
NA  
[12] 
5 
Sensitive 
SCLC; 2nd 
line 
PO vs. IV 
topotecan  
ORR 
3.7 months 
(sensitive) 
 
8.7 months 
(sensitive) 
[69] 
CAV = combination therapy of cyclophosphamide, doxorubicin, and vincristine; ORR = 
objective response rate; OS = overall survival; PO = by mouth; IV = intravenously 
 
Kaplan-Meier curves and a one-tailed log-rank test will be the primary analysis methods.   PFS 
assessment will be determined once 48 patients have progressed or died without progression.  
Assuming exponential PFS curves, the hazard rate for topotecan alone associated with a 3-month 
median PFS is 0.2310, or approximately a 23% hazard of progressing per month.  If we assume 
that the addition of M6620 could increase the median PFS to 6 months, the corresponding hazard 
rate is 0.1155 and the resulting hazard ratio for the comparison of the two overall actuarial 
curves would be 2.00.  Following the principles of a Phase 2 trial, to have 85% power to 
compare these curves and detect a difference with a one-tailed 0.10 significance level log-rank 
test, simulations demonstrate that a total of 18 evaluable patients randomized to the topotecan 
alone arm and 36 evaluable patients randomized to the topotecan and M6620 arm will need to be 
randomized over a 2-year period and followed for up to an additional 12 months; power will be 
reduced to 79% if follow-up ends after the 2-year enrollment period.  If the comparison were 
between 2.5 and 5 months, the power remains at 85%. As indicated above, the final evaluation 
for PFS will take place after 48 patients have progressed or died without progression; thus, the 
actual time of the evaluation cannot be determined until these events have been noted. 
  
 

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An interim evaluation for futility will take place during accrual after 24 patients on both arms 
combined have progressed. If any unusual patterns are detected at this time or the efficacy signal 
strongly favors the topotecan arm, this may warrant an early study closure.
If patients are enrolled on the topotecan single agent and they have progressed, they will be 
eligible to receive the topotecan plus M6620 combination treatment at that time; they will be 
considered to have progressed at their initial time as their primary outcome. The small number 
of patients who could potentially cross-over (up to 18 patients) will be evaluated for their second 
PFS and response rate in an exploratory manner. 
After the trial has completed accrual, the overall results will be reported as well as separately by 
sensitive vs. resistant/refractory patients. The overall results and results by stratum will be 
reported along with two-sided 80% and 95% confidence intervals at the median time.
Sample Size/Accrual Rate
It is expected that approximately 25-30 patients per year (about 2-3 patients per month) will be 
enrolled, and thus accrual will be completed in approximately 2 years. 
We expect to enroll 18 evaluable patients randomized to the topotecan alone arm and 56 
evaluable patients in the topotecan and M6620 arm (36 randomized evaluable SCLC patients and 
up to 20 patients with extrapulmonary small cell cancer). 
To allow for inevaluable patients, the accrual ceiling will be set at 100 total patients.
DOMESTIC PLANNED ENROLLMENT REPORT
Racial Categories
Ethnic Categories
Total
Not Hispanic or Latino
Hispanic or Latino
Female
Male
Female
Male
American Indian/ Alaska 
Native
3
3
2
2
10
Asian
4
3
2
2
11
Native Hawaiian or 
Other Pacific Islander
1
2
1
1
5
Black or African 
American
10
11
1
1
23
White
9
12
3
6
30

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76
Racial Categories
Ethnic Categories
Total
Not Hispanic or Latino
Hispanic or Latino
Female
Male
Female
Male
More Than One Race
1
1
2
3
7
Total
28
32
11
15
86
PHS 398 / PHS 2590 (Rev. 08/12 Approved Through 8/31/2015)
OMB No. 0925-0001/0002
INTERNATIONAL PLANNED ENROLLMENT REPORT
Racial Categories
Ethnic Categories
Total
Not Hispanic or Latino
Hispanic or Latino
Female
Male
Female
Male
American Indian/ Alaska 
Native
0
0
0
0
0
Asian
0
1
0
0
1
Native Hawaiian or 
Other Pacific Islander
0
0
0
0
0
Black or African 
American
0
1
0
0
1
White
2
3
2
1
8
More Than One Race
1
1
0
0
2
Total
3
6
2
1
12
PHS 398 / PHS 2590 (Rev. 08/12 Approved Through 8/31/2015)
OMB No. 0925-0001/0002
Analysis of Secondary Endpoints
Secondary evaluations will include objective response rate and overall survival in both patients 
with relapsed SCLC and extrapulmonary small cell cancer. 
In addition, a small cohort of patients with extrapulmonary small cell cancer patients will be 
included based on preliminary evidence of efficacy in these patients in the ongoing Phase 2
study. Up to 20 patients with extrapulmonary small cell cancer will receive the combination of 

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77
M6620 and topotecan; this cohort will only accrue while the SCLC patients are accruing, and 
accrual will be terminated at the end of the accrual to the randomized SCLC trial. There are 
currently no benchmarks of ORR for relapsed extra-pulmonary small cell cancers.  In many 
types of relapsed cancers, an ORR of 30% or greater would be considered clinically meaningful.  
As such we would use the same threshold here for the extra-pulmonary small cell cancer cohort.  
These results will be considered hypothesis generating and an ORR of 30% or greater will be 
interesting and may lead to consideration of more definitive future trials in this population. 
Reporting and Exclusions
Evaluation of Toxicity
All patients will be evaluable for toxicity from the time of their first treatment with M6620.
Evaluation of Response
All patients included in the study must be assessed for response to treatment, even if there are 
major protocol treatment deviations or if they are ineligible. Each patient will be assigned one of 
the following categories:  1) complete response, 2) partial response, 3) stable disease, 4) 
progressive disease, 5) early death from malignant disease, 6) early death from toxicity, 7) early 
death because of other cause, or 9) unknown (not assessable, insufficient data). [Note: By 
arbitrary convention, category 9 usually designates the “unknown” status of any type of data in a 
clinical database.]
All patients who met the eligibility criteria (with the possible exception of those who received no 
study medication) should be included in the main analysis of the response rate. Patients in 
response categories 4-9 should be considered to have a treatment failure (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. 
All conclusions should be based on all eligible patients.  Sub analyses 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 may not serve as the basis for drawing 
conclusions concerning treatment efficacy, and the reasons for excluding patients from the 
analysis should be clearly reported. The 95% confidence intervals should also be provided.
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS 
AE monitoring and reporting is a routine part of every clinical trial.  The following list of AEs 
(Section 10.1) and the characteristics of an observed AE (Sections 10.2 and 10.3) will determine 
whether the event requires expedited reporting via the CTEP Adverse Event Reporting System 
(CTEP-AERS) in addition to routine reporting.

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Comprehensive Adverse Events and Potential Risks List (CAEPR)
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single list of 
reported and/or potential 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.
CAEPRs for CTEP IND Agent
CAEPR for M6620
Comprehensive Adverse Events and Potential Risks list (CAEPR)
for 
M6620 (VX-970, berzosertib, NSC 780162)
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single list of reported 
and/or potential adverse events (AE) associated with an agent using a uniform presentation of events by 
body system. In addition to the comprehensive list, a subset, the Specific Protocol Exceptions to 
Expedited Reporting (SPEER), appears in a separate column and is identified with bold and italicized 
text. This subset of AEs (SPEER) is a list of events that are protocol specific exceptions to expedited 
reporting to NCI (except as noted below).  Refer to the 'CTEP, NCI Guidelines: Adverse Event Reporting 
Requirements'  http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf
for further clarification. Frequency is provided based on 323 patients. Below is the CAEPR for M6620 
(VX-970, berzosertib).
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses next to 
the AE in the SPEER.  If this CAEPR is part of a combination protocol using multiple 
investigational agents and has an AE listed on different SPEERs, use the lower of the grades to 
determine if expedited reporting is required.

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79 
Version 2.0, July 13, 20221 
 
 Adverse Events with Possible  
 Relationship to M6620 (VX-970, berzosertib) 
 (CTCAE 5.0 Term) 
[n= 323] 
 
 
 Specific Protocol 
Exceptions to 
Expedited Reporting 
(SPEER)  
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
  
Anemia 
 
 
 Anemia (Gr 3) 
GASTROINTESTINAL DISORDERS 
  
 
Constipation 
 
  
Diarrhea 
 
 
 Diarrhea (Gr 2) 
Nausea 
 
 
 Nausea (Gr 2) 
Vomiting 
 
 
 Vomiting (Gr 2) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
Fatigue 
 
 
 Fatigue (Gr 2) 
 
Fever 
 
  
 
Flu like symptoms 
 
  
INJURY, POISONING AND PROCEDURAL COMPLICATIONS 
  
 
Infusion related reaction 
 
 Infusion related reaction 
(Gr 2) 
INVESTIGATIONS 
  
 
Alanine aminotransferase 
increased 
 
 Alanine aminotransferase 
increased (Gr 2) 
 
Aspartate aminotransferase 
increased 
 
 Aspartate 
aminotransferase 
increased (Gr 2) 
 
Lymphocyte count 
decreased 
 
 Lymphocyte count 
decreased (Gr 2) 
Neutrophil count decreased  
 
 Neutrophil count 
decreased (Gr 2) 
Platelet count decreased 
 
 
 Platelet count decreased 
(Gr 2) 
METABOLISM AND NUTRITION DISORDERS 
  
 
Anorexia 
 
 Anorexia (Gr 2) 
NERVOUS SYSTEM DISORDERS 
  
 
Dizziness 
 
  
 
Headache 
 
 Headache (Gr 2) 
VASCULAR DISORDERS 
  
 
Flushing 
 
  
 
1This table will be updated as the toxicity profile of the agent is revised.  Updates will be distributed to all 
Principal Investigators at the time of revision.  The current version can be obtained by contacting 
PIO@CTEP.NCI.NIH.GOV.  Your name, the name of the investigator, the protocol and the agent should 
be included in the e-mail. 
 
Adverse events reported on M6620 (VX-970, berzosertib) trials, but for which there is insufficient 
evidence to suggest that there was a reasonable possibility that M6620 (VX-970, berzosertib) 
caused the adverse event: 
 
CARDIAC DISORDERS - Cardiac arrest; Palpitations 
EAR AND LABYRINTH DISORDERS - Tinnitus 
GASTROINTESTINAL DISORDERS - Abdominal pain; Ascites; Colonic obstruction; Dyspepsia; 
Mucositis oral 

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GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Edema limbs
IMMUNE SYSTEM DISORDERS - Allergic reaction; Anaphylaxis
INFECTIONS AND INFESTATIONS - Infections and infestations - Other (lower respiratory tract infection); 
Otitis externa; Sepsis; Soft tissue infection; Urinary tract infection
INVESTIGATIONS - Alkaline phosphatase increased; Blood bilirubin increased; Creatinine increased; 
GGT increased; Hemoglobin increased; Weight loss; White blood cell decreased
METABOLISM AND NUTRITION DISORDERS - Dehydration; Hyperglycemia; Hypokalemia; 
Hypophosphatemia
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthralgia; Back pain; Generalized 
muscle weakness; Myalgia
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - Neoplasms 
benign, malignant and unspecified (incl cysts and polyps) - Other (malignant neoplasm progression); 
Tumor pain
NERVOUS SYSTEM DISORDERS - Lethargy; Spinal cord compression; Syncope
PSYCHIATRIC DISORDERS - Confusion
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Atelectasis; Cough; Dyspnea; 
Respiratory, thoracic and mediastinal disorders - Other (hemotypsis)
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Pruritus; Rash maculo-papular
VASCULAR DISORDERS - Hypertension; Hypotension; Thromboembolic event; Vascular disorders -
Other (hypovolemic shock)
Note: M6620 (VX-970, berzosertib) in combination with other agents could cause an exacerbation of any 
adverse event currently known to be caused by the other agent, or the combination may result in events 
never previously associated with either agent.
Adverse Event List for Topotecan
The most common hematological grade 3/4 adverse reactions (≥5%) experienced by SCLC 
patients were neutropenia, anemia, thrombocytopenia and febrile neutropenia.  The most 
common non-hematological grade 3/4 adverse reactions (≥5%) experienced by SCLC patients 
were sepsis, dyspnea, pneumonia, abdominal pain, nausea, fatigue, asthenia, and pain.  See the 
topotecan package insert for more information
Adverse Event Characteristics 
CTCAE term (AE description) and grade:  The descriptions and grading scales found in the 
revised NCI CTCAE version 5.0 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 website
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.
For expedited reporting purposes only:  
AEs for the agent that are bold and italicized in the CAEPR (i.e., those listed in the SPEER 
column, Section 10.1) should be reported through CTEP-AERS only if the grade is above the 
grade provided in the SPEER.
Attribution of the AE:
-
Definite – The AE is clearly related to the study treatment.
-
Probable – The AE is likely related to the study treatment.

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-
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.
Expedited Adverse Event Reporting
Rave-CTEP-AERS Integration
Pre-treatment AEs:  AEs that occur after informed consent is signed and prior to start of 
treatment are collected in Medidata Rave using the Pre-treatment Adverse Event form. 
Pre-existing medical conditions (formerly referred to as baseline AEs) identified during 
baseline assessment are not considered AEs and therefore should not be reported on the 
Pre-treatment Adverse Event form. If these pre-existing conditions worsen in severity, 
the investigator must reassess the event to determine if an expedited report is required. 
Whether or not an expedited report is required, the worsened event should be reported as 
a routine AE.
Treatment-emergent AEs:  All AEs that occur after start of treatment are collected in 
Medidata Rave using the Adverse Event form, which is available for entry at each 
treatment course or reporting period and is used to collect AEs that start during the period 
or persist from the previous reporting period.  AEs that occur 30 Days after the Last 
Administration of the Investigational Agent/Intervention are collected using the Late 
Adverse Event form.
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
The CRA reports AEs in Rave at the time the Investigator learns of the event.  If the CRA 
modifies an AE, it must be re-submitted for rules evaluation.
Upon completion of AE entry in Medidata Rave, the CRA submits the AE for rules 
evaluation by completing the Expedited Reporting Evaluation form.  Both NCI and 
protocol-specific reporting rules evaluate the AEs submitted for expedited reporting.  A 
report is initiated in CTEP-AERS using information entered in Medidata Rave for AEs 
that meet reporting requirements.  The CRA completes the report by accessing CTEP-
AERS via a direct link on the Medidata Rave Expedited Reporting Evaluation form.  
Contact the CTSU Help Desk at 1-888-823-5923 or by email at ctsucontact@westat.com 
if you have any issues submitting an expedited report in CTEP-AERS.
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 

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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 
members’ website:
x
Study specific documents:   Protocols > Documents> Protocol Related 
Documents> Adverse Event Reporting, and  
x
Additional resources: Resources > CTSU Operations Information> User Guides
& Help Topics.
NCI requirements for SAE reporting are available on the CTEP website: 
NCI Guidelines for Investigators:  Adverse Event Reporting Requirements is available at 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf.
Distribution of Adverse Event Reports
CTEP-AERS is programmed for automatic electronic distribution of reports to the following 
individuals: PI and AE 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. 
Expedited Reporting Guidelines
Use the NCI protocol number and the protocol-specific patient ID assigned during trial 
registration on all reports.
Note:  A death on study requires both routine and expedited reporting, regardless of 
causality.  Attribution to treatment or other cause must be provided.
Death due to progressive disease should be reported as Grade 5 “Disease progression” in the 
system organ class (SOC) “General disorders and administration site conditions.” Evidence that 
the death was a manifestation of underlying disease (e.g., radiological changes suggesting tumor 
growth or progression: clinical deterioration associated with a disease process) should be 
submitted. 

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83 
Phase 1 and Early Phase 2 Studies: Expedited Reporting Requirements for Adverse Events 
that Occur on Studies under an IND/IDE within 30 Days of the Last Administration of the 
Investigational Agent/Intervention 1, 2 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, whether or not 
they are considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
An adverse event is considered serious if it results in ANY of the following outcomes:   
1) 
Death 
2) 
A life-threatening adverse event  
3) 
An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 
hours  
4) 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions  
5) 
A congenital anomaly/birth defect.  
6) 
Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization 
may be considered serious when, based upon medical judgment, they may jeopardize the patient or 
subject and may require medical or surgical intervention to prevent one of the outcomes listed in this 
definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI via electronic 
submission within the timeframes detailed in the table below. 
Hospitalization 
Grade 1 and Grade 2 Timeframes 
Grade 3-5 
Timeframes 
Resulting in 
Hospitalization  
≥ 24 hrs 
10 Calendar Days 
24-Hour 5 Calendar 
Days 
Not resulting in 
Hospitalization  
≥ 24 hrs 
Not required 
NOTE:  Protocol specific exceptions to expedited reporting of serious adverse events are found in the Specific 
Protocol Exceptions to Expedited Reporting (SPEER) portion of the CAEPR. 
Expedited AE reporting timelines are defined as: 
“24-Hour; 5 Calendar Days” - The AE must initially be submitted electronically within 
24 hours of learning of the AE, followed by a complete expedited report within 5 
calendar days of the initial 24-hour report. 
“10 Calendar Days” - A complete expedited report on the AE must be submitted 
electronically within 10 calendar days of learning of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as follows:  
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
x 
All Grade 3, 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
x 
Grade 2 AEs resulting in hospitalization or prolongation of hospitalization 
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 
 

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Routine Adverse Event Reporting
All AEs must be reported in routine study data submissions. AEs reported expeditiously 
through CTEP-AERS must also be reported in routine study data submissions.
AE 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.
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 AE 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 6 months
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: 
AE 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. 
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. 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.
CTEP requires all secondary malignancies that occur following treatment with an agent under an 
NCI IND/IDE be reported expeditiously via Medidata Rave. 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 the protocol. 

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STUDY CALENDAR
Patients may be hospitalized for convenience and logistical reasons for drug administration 
and/or research blood draws.  After registration, patients should begin protocol therapy within 14 
days.

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86 
Procedure 
Pre- 
Stud
y# 
Baseline 
Cycle = 21 days a 
End of 
Treatment/ 
Disease 
Progression b 
Post 
Therapy 
Follow-up c 
Cycle 1 
Cycle 2+ 
Day 
1@ 
Day 
2 
Day 
3 
Day 
4 
Day 
5 
Day 
8* 
Day 
15* 
Day 
1@ 
Day 
2 
Day 
3 
Day 
4 
Day 
5 
Day 
8 
Day 
15 
M6620 (VX-970, berzosertib)  
 
 
 
A 
 
 
A 
 
 
 
A 
 
 
A 
 
 
 
 
Topotecan 
 
 
B 
B 
B 
B 
B 
 
 
B 
B 
B 
B 
B 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concurrent Meds 
  X----------------------------------------------------------------------------------------------------------------------------------------------X 
 
Physical exam d 
X 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
Vital signs p 
X 
 
X 
X 
X 
X 
X 
 
 
X p 
X 
X 
X 
X 
 
 
X 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
Performance status 
X 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
PT, PTT 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
CBC w/diff, plts e, f 
X 
 
X 
 
 
 
 
X 
X 
X 
 
 
 
 
 
 
X 
 
Acute Care Panel g, f 
X 
 
X 
 
 
 
 
X 
X 
X 
 
 
 
 
 
 
X 
 
Hepatic Panel h, f 
X 
 
X 
 
 
 
 
X 
X 
X 
 
 
 
 
 
 
X 
 
Mineral Panel i, f 
X 
 
X 
 
 
 
 
X 
X 
X 
 
 
 
 
 
 
X 
 
EKG m 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum Pregnancy Test j 
X 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
Clinical Disease Assessment 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
Adverse Event Evaluation 
 
 
X----------------------------------------------------------------------------------------------------------X 
 
 
CT Scan 
X 
 
Tumor measurements are repeated every 6 weeks.  Documentation (radiologic) must be 
provided for patients removed from study for progressive disease.  
X 
 
Correlative Studies – 
Mandatory Biopsy k   
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Correlative Study – CTC 
blood sample 
 
X n  
 
X q 
 
X n 
 
 
 
X l, n 
 
 
 
 
 
 
X 
 
Correlative Study – cfDNA 
blood sample 
 
X n 
 
 
 
 
X n 
 
 
X l, n 
 
 
 
 
 
 
X 
 
Correlative Study – WES 
blood sample 
 
X n 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

NCI Protocol #:  10268 
Version Date:  October 21, 2022 
 
87 
Procedure 
Pre- 
Stud
y# 
Baseline 
Cycle = 21 days a 
End of 
Treatment/ 
Disease 
Progression b 
Post 
Therapy 
Follow-up c 
Cycle 1 
Cycle 2+ 
Day 
1@ 
Day 
2 
Day 
3 
Day 
4 
Day 
5 
Day 
8* 
Day 
15* 
Day 
1@ 
Day 
2 
Day 
3 
Day 
4 
Day 
5 
Day 
8 
Day 
15 
Follow-up phone call 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xo 
# 
Pre-study assessments may be performed within 21 days prior to registration. After registration, patients should begin protocol therapy within 14 days. Patient 
may undergo the pre-study assessments while in the washout period from a previous treatment. 
@ 
Exams, labs and pregnancy tests can be performed up to 2 business days prior to day 1 of each cycle. 
* 
C1D8 and C1D15 laboratory assessments can be performed in a +/- 3 days window 
A: 
M6620 (VX-970, berzosertib):  210 mg/m2 IV (over 60 minutes (+/- 10 minutes) (within 15 minutes after completion of topotecan administration) day 2 and day 
5, every 21 days 
B: 
Topotecan:  1.25 mg/m2 IV (over 30 minutes) day 1 to day 5, every 21 days  
 
a. 
 Number of cycles depends on disease progression and development of intolerable side effects.  On-study assessments can be performed within ±5 days of the 
specified time, unless otherwise indicated.  Next cycle treatment may be delayed up to 7 days to accommodate scheduling conflicts. 
b. 
Approximately 4 weeks after treatment discontinuation 
c. 
Follow-up for survival will be carried out every 3 months. Patients without radiographic PD/death will also be followed for response at least every 12 weeks until 
PD/death or until 6 months after the last patient completes study therapy (whichever occurs first). 
d. 
Symptom-directed physical examinations will be performed as clinically indicated in the investigator’s judgment 
e. 
 Includes neutrophils, lymphocytes, monocytes, eosinophils, basophils, WBC, RBC, hemoglobin, hematocrit, RBC indices, MCV, RDW, and platelets  
f. 
Only done in cycle1 and if clinically indicated in subsequent cycles 
g. 
Includes sodium (NA), potassium (K), chloride (CL) total CO2 (bicarbonate), creatinine, glucose, urea nitrogen, eGFR 
h. 
Includes alkaline phosphatase, ALT/GPT, AST/GOT, total bilirubin, direct bilirubin 
i. 
Includes albumin, calcium, magnesium (Mg), phosphorus 
j. 
Only for women of child-bearing potential 
k. 
All biopsies will be optional for all patients with extrapulmonary small cell cancer.  Archival tissue will be collected to supplement sampling from fresh biopsy. 
Biopsy needs to be done after registration and before C1D1 dosing. Biopsy can be done up to 7 days prior to C1D1 dosing. 
l. 
Only done on Day 1 of Cycles 2 and 3 (and not in subsequent cycles) and at progression.  
m. 
An EKG as clinically indicated at the after pre-study.  
n. 
Blood draw may be collected on the day of biopsy at baseline and before administration of study drugs at other timepoints (Cycle 1 Day 4, 5; Cycle 2 Day 1; 
Cycle 3 Day 1; at progression). 
o. 
Every 3 months. 
p. 
Vital signs are to be performed on days 1 through 5 before drug administration on each day and as clinically indicated.  
q. 
C1D2 CTC blood draw should be collected 4 hours (+/-60 min) after end of infusion.  
r. 
Patients who cross over will get CTC and cfDNA sampling similar to the primary arm (CTC on cycle day 2 and day 4; cfDNA on day 5; cycle 2 day 1). 

NCI Protocol #:  10268
Version Date:  October 21, 2022
88
MEASUREMENT OF EFFECT
Antitumor Effect – Solid Tumors
For the purposes of this study, patients should be re-evaluated for response every 6 weeks. In 
addition to a baseline scan, confirmatory scans should also be obtained 6 weeks following initial 
documentation of OR.
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 
measurement) of the tumor lesions and the shortest diameter in the case of malignant lymph 
nodes are used in the RECIST criteria.
Definitions
Evaluable for toxicity. All patients will be evaluable for toxicity from the time of their first 
treatment with M6620.
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. 
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 a computed tomography (CT) scan, magnetic resonance imaging (MRI) 
scan, 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 would be considered 
measurable if the lesion is increasing in size.  
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 

NCI Protocol #:  10268
Version Date:  October 21, 2022
89
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 magnetic resonance imaging (MRI)), are 
considered as non-measurable.
Note: Cystic lesions that meet the criteria for radiographically defined simple cysts should not 
be considered as malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts.
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable lesions, 
if they meet the definition of measurability described above.  However, if non-cystic lesions are 
present in the same 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. 
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.

NCI Protocol #:  10268 
Version Date:  October 21, 2022 
 
90 
 
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.  
 
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. 
 
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 
CR or surgical resection is an endpoint. 
 
Tumor markers:  Tumor markers alone cannot be used to assess response.  If markers are initially 
above the upper normal limit, they must normalize for a patient to be considered in complete 
clinical response.  Specific guidelines for both CA-125 response (in recurrent ovarian cancer) 
and Prostate-Specific Antigen (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 

NCI Protocol #:  10268
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91
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 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.
Response Criteria
Evaluation of Target Lesions
Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to <10 mm (<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.
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.

NCI Protocol #:  10268
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92
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 PI).
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 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
CR = Complete Response; PR = Partial Response; PD = Progressive Disease; SD = Stable 
Disease
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

NCI Protocol #:  10268
Version Date:  October 21, 2022
93
Non-CR/non-PD
No
Non-CR/non-PD*
Not all evaluated
No
not evaluated
Unequivocal PD
Yes or No
PD
Any
Yes
PD
CR = Complete Response; PD = Progressive Disease;
‘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
Duration of Response
Duration of overall response: The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first date that 
recurrent or progressive disease is objectively documented (taking as reference for progressive 
disease the smallest measurements recorded since the treatment started).
The duration of overall CR is measured from the time measurement criteria are first met for CR 
until the first date that progressive disease is objectively documented.
Duration of stable disease: Stable disease is measured from the start of the treatment until the 
criteria for progression are met, taking as reference the smallest measurements recorded since the 
treatment started, including the baseline measurements. 
Progression-Free Survival
PFS is defined as the duration of time from start of treatment to time of progression or death, 
whichever occurs first.
Response Review
Responses will not be reviewed independently in this study.
STUDY OVERSIGHT AND DATA REPORTING / REGULATORY 
REQUIREMENTS
AE lists, guidelines, and instructions for AE reporting can be found in Section 10 (Adverse 
Events: List and Reporting Requirements).
Study Oversight
This protocol is monitored at several levels, as described in this section. The Protocol PI is 
responsible for monitoring the conduct and progress of the clinical trial, including the ongoing 

NCI Protocol #:  10268
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94
review of accrual, patient-specific clinical and laboratory data, and routine and serious AEs;
reporting of AEs; and accumulation of reported adverse events from other trials testing the same 
drug(s). The Protocol PI and statistician have access to the data at all times through the CTMS 
web-based reporting portal.  
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. There will be an interim evaluation for futility after 24 patients on both arms 
combined have progressed. 
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.
All studies are also reviewed in accordance with the enrolling institution’s data safety monitoring 
plan.
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 a 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.

NCI Protocol #:  10268
Version Date:  October 21, 2022
95
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 email 
from iMedidata. To accept the invitation, site staff must either click on the link in the email or 
log in to iMedidata via the CTSU members’ website  under Data Management > Rave Home and 
click to accept the invitation in the Tasks pane located in the upper right-corner of the iMedidata 
screen. 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 eLearning link in the Tasks pane located in 
the upper right corner of the iMedidata screen.  If an eLearning is required for a study and has 
not yet been taken, the link to the eLearning will appear under the study name in the Studies pane 
located in the center of the iMedidata screen; 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 replace 
the eLearning link 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 receive a separate invitation from iMedidata 
to activate their account. Account activation instructions are located on the CTSU website in the 
Data Management section under the Rave resource materials (Medidata Account Activation and 
Study Invitation Acceptance).  Additional information on iMedidata/Rave is available on the 
CTSU members’ website in the Data Management > Rave section at www.ctsu.org/RAVE/ or by 
contacting the CTSU Help Desk at 1-888-823-5923 or by e-mail at ctsucontact@westat.com.  
Method
For studies assigned for CTMS Routine Monitoring:
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.
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. 

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96
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.
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).
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.

NCI Protocol #:  10268
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97
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, DQP Delinquent Forms, DQP Form Status, and DQP Reports 
modules.
CTEP Multicenter Guidelines
N/A
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 
Treatment and Diagnosis. Therefore, the following obligations/guidelines, in addition to the 
provisions in the “Intellectual Property Option to Collaborator” 
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm) contained within the 
terms of award, apply to the use of the Agent(s) in this study:
1. Agent(s) may not be used for any purpose outside the scope of this protocol, nor can 
Agent(s) be transferred or licensed to any party not participating in the clinical study. 
Collaborator(s) data for Agent(s) are confidential and proprietary to Collaborator(s) and shall 
be maintained as such by the investigators. The protocol documents for studies utilizing 
Agents contain confidential information and should not be shared or distributed without the 
permission of the NCI. If a copy of this protocol is requested by a patient or patient’s family 
member participating on the study, the individual should sign a confidentiality agreement. A 
suitable model agreement can be downloaded from: http://ctep.cancer.gov.
2. For a clinical protocol where there is an investigational Agent used in combination with 
(an)other Agent(s), each the subject of different Collaborative Agreements, the access to and 
use of data by each Collaborator shall be as follows (data pertaining to such combination use 
shall hereinafter be referred to as "Multi-Party Data”):
a.
NCI will provide all Collaborators with prior written notice regarding the existence and 
nature of any agreements governing their collaboration with NCI, the design of the 
proposed combination protocol, and the existence of any obligations that would tend to 
restrict NCI's participation in the proposed combination protocol.
b. Each Collaborator shall agree to permit use of the Multi-Party Data from the clinical trial 
by any other Collaborator solely to the extent necessary to allow said other Collaborator 
to develop, obtain regulatory approval or commercialize its own Agent.

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98 
 
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. 
 
5. Any data provided to Collaborator(s) for Phase 3 studies must be in accordance with the 
guidelines and policies of the responsible Data Monitoring Committee (DMC), if there is a 
DMC for this clinical trial. 
 
6. Any manuscripts reporting the results of this clinical trial must be provided to CTEP by the 
Group office for Cooperative Group studies or by the principal investigator for non-
Cooperative Group studies for immediate delivery to Collaborator(s) for advisory review and 
comment prior to submission for publication.  Collaborator(s) will have 30 days from the 
date of receipt for review.  Collaborator shall have the right to request that publication be 
delayed for up to an additional 30 days in order to ensure that Collaborator’s confidential and 
proprietary data, in addition to Collaborator(s)’s intellectual property rights, are protected.  
Copies of abstracts must be provided to CTEP for forwarding to Collaborator(s) for courtesy 
review as soon as possible and preferably at least three (3) days prior to submission, but in 
any case, prior to presentation at the meeting or publication in the proceedings.   Press 
releases and other media presentations must also be forwarded to CTEP prior to release.  
Copies of any manuscript, abstract and/or press release/ media presentation should be sent to: 
 
Email:  ncicteppubs@mail.nih.gov 
 
The Regulatory Affairs Branch will then distribute them to Collaborator(s).  No publication, 
manuscript or other form of public disclosure shall contain any of Collaborator’s confidential/ 
proprietary information. 
 
 

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99
REFERENCES
1.
Almodovar, K., et al., Longitudinal Cell-Free DNA Analysis in Patients with Small Cell 
Lung Cancer Reveals Dynamic Insights into Treatment Efficacy and Disease Relapse. J 
Thorac Oncol, 2018. 13(1): p. 112-123.
2.
Byers, L.A. and C.M. Rudin, Small cell lung cancer: where do we go from here? Cancer, 
2015. 121(5): p. 664-72.
3.
Belani, C.P., et al., Vismodegib or cixutumumab in combination with standard 
chemotherapy for patients with extensive-stage small cell lung cancer: A trial of the 
ECOG-ACRIN Cancer Research Group (E1508). Cancer, 2016. 122(15): p. 2371-8.
4.
Yazinski, S.A., et al., ATR inhibition disrupts rewired homologous recombination and 
fork protection pathways in PARP inhibitor-resistant BRCA-deficient cancer cells. Genes 
Dev, 2017. 31(3): p. 318-332.
5.
Gazdar, A.F., P.A. Bunn, and J.D. Minna, Small-cell lung cancer: what we know, what 
we need to know and the path forward. Nat Rev Cancer, 2017. 17(12): p. 725-737.
6.
Congress, U., Recalcitrant Cancer Research Act of 2012. 2012.
7.
Institute, N.C., Scientific Framework for Small Cell Lung Cancer (SCLC). 2014.
8.
van Meerbeeck, J.P., D.A. Fennell, and D.K. De Ruysscher, Small-cell lung cancer.
Lancet, 2011. 378(9804): p. 1741-55.
9.
von Pawel, J., et al., Topotecan versus cyclophosphamide, doxorubicin, and vincristine 
for the treatment of recurrent small-cell lung cancer. J Clin Oncol, 1999. 17(2): p. 658-
67.
10.
Giaccone, G., et al., Teniposide in the treatment of small-cell lung cancer: the influence 
of prior chemotherapy. J Clin Oncol, 1988. 6(8): p. 1264-70.
11.
Ardizzoni, A., M. Tiseo, and L. Boni, Validation of standard definition of sensitive versus 
refractory relapsed small cell lung cancer: a pooled analysis of topotecan second-line 
trials. Eur J Cancer, 2014. 50(13): p. 2211-8.
12.
Inoue, A., et al., Randomized phase II trial comparing amrubicin with topotecan in 
patients with previously treated small-cell lung cancer: North Japan Lung Cancer Study 
Group Trial 0402. J Clin Oncol, 2008. 26(33): p. 5401-6.
13.
von Pawel, J., et al., Randomized phase III trial of amrubicin versus topotecan as second-
line treatment for patients with small-cell lung cancer. J Clin Oncol, 2014. 32(35): p. 
4012-9.
14.
Rekhtman, N., Neuroendocrine tumors of the lung: an update. Arch Pathol Lab Med, 
2010. 134(11): p. 1628-38.
15.
Pietanza, M.C., et al., Randomized, Double-Blind, Phase II Study of Temozolomide in 
Combination With Either Veliparib or Placebo in Patients With Relapsed-Sensitive or 
Refractory Small-Cell Lung Cancer. J Clin Oncol, 2018. 36(23): p. 2386-2394.
16.
Brennan, S.M., et al., Should extrapulmonary small cell cancer be managed like small 
cell lung cancer? Cancer, 2010. 116(4): p. 888-95.
17.
Thomas, A. and Y. Pommier, Small cell lung cancer: Time to revisit DNA-damaging 
chemotherapy. Sci Transl Med, 2016. 8(346): p. 346fs12.
18.
Josse, R., et al., ATR inhibitors VE-821 and VX-970 sensitize cancer cells to 
topoisomerase i inhibitors by disabling DNA replication initiation and fork elongation 
responses. Cancer Res, 2014. 74(23): p. 6968-79.

NCI Protocol #:  10268 
Version Date:  October 21, 2022 
 
100 
19. 
Doerr, F., et al., Targeting a non-oncogene addiction to the ATR/CHK1 axis for the 
treatment of small cell lung cancer. Sci Rep, 2017. 7(1): p. 15511. 
20. 
Thomas, A., et al., Phase I Study of ATR Inhibitor M6620 in Combination With 
Topotecan in Patients With Advanced Solid Tumors. J Clin Oncol, 2017: p. 
JCO2017766915. 
21. 
Chang, M.T., et al., Small-Cell Carcinomas of the Bladder and Lung Are Characterized 
by a Convergent but Distinct Pathogenesis. Clin Cancer Res, 2018. 24(8): p. 1965-1973. 
22. 
Aggarwal, R., et al., Clinical and Genomic Characterization of Treatment-Emergent 
Small-Cell Neuroendocrine Prostate Cancer: A Multi-institutional Prospective Study. J 
Clin Oncol, 2018. 36(24): p. 2492-2503. 
23. 
Niederst, M.J., et al., RB loss in resistant EGFR mutant lung adenocarcinomas that 
transform to small-cell lung cancer. Nat Commun, 2015. 6: p. 6377. 
24. 
Vertex, VX-970 Investigator Brochure, Version 7.0. 2017. 
25. 
O'Carrigan, B., et al., Phase I trial of a first-in-class ATR inhibitor VX-970 as 
monotherapy (mono) or in combination (combo) with carboplatin (CP) incorporating 
pharmacodynamics (PD) studies. Journal of Clinical Oncology, 2016. 34(15). 
26. 
Thomas, A., et al., Phase I Study of ATR Inhibitor M6620 in Combination With 
Topotecan in Patients With Advanced Solid Tumors. J Clin Oncol, 2018. 36(16): p. 1594-
1602. 
27. 
Techer, H., et al., The impact of replication stress on replication dynamics and DNA 
damage in vertebrate cells. Nat Rev Genet, 2017. 18(9): p. 535-550. 
28. 
Horita, N., et al., Topotecan for Relapsed Small-cell Lung Cancer: Systematic Review 
and Meta-Analysis of 1347 Patients. Sci Rep, 2015. 5: p. 15437. 
29. 
O'Brien, M.E., et al., Phase III trial comparing supportive care alone with supportive 
care with oral topotecan in patients with relapsed small-cell lung cancer. J Clin Oncol, 
2006. 24(34): p. 5441-7. 
30. 
Huber, R.M., et al., Efficacy of a toxicity-adjusted topotecan therapy in recurrent small 
cell lung cancer. Eur Respir J, 2006. 27(6): p. 1183-9. 
31. 
Weber, A.M. and A.J. Ryan, ATM and ATR as therapeutic targets in cancer. 
Pharmacology & Therapeutics, 2015. 149: p. 124-138. 
32. 
Lecona, E. and O. Fernandez-Capetillo, Targeting ATR in cancer. Nat Rev Cancer, 2018. 
33. 
Zoppoli, G., et al., Putative DNA/RNA helicase Schlafen-11 (SLFN11) sensitizes cancer 
cells to DNA-damaging agents. Proc Natl Acad Sci U S A, 2012. 109(37): p. 15030-5. 
34. 
Lok, B.H., et al., PARP Inhibitor Activity Correlates with SLFN11 Expression and 
Demonstrates Synergy with Temozolomide in Small Cell Lung Cancer. Clin Cancer Res, 
2017. 23(2): p. 523-535. 
35. 
Gardner, E.E., et al., Chemosensitive Relapse in Small Cell Lung Cancer Proceeds 
through an EZH2-SLFN11 Axis. Cancer Cell, 2017. 31(2): p. 286-299. 
36. 
Nogales, V., et al., Epigenetic inactivation of the putative DNA/RNA helicase SLFN11 in 
human cancer confers resistance to platinum drugs. Oncotarget, 2016. 7(3): p. 3084-
3097. 
37. 
Tang, S.W., et al., Overcoming Resistance to DNA-Targeted Agents by Epigenetic 
Activation of Schlafen 11 (SLFN11) Expression with Class I Histone Deacetylase 
Inhibitors. Clinical Cancer Research, 2018. 24(8): p. 1944-1953. 
38. 
Murai, J., et al., SLFN11 Blocks Stressed Replication Forks Independently of ATR. 
Molecular Cell, 2018. 69(3): p. 371-+. 

NCI Protocol #:  10268 
Version Date:  October 21, 2022 
 
101 
39. 
Murai, J., et al., SLFN11 Blocks Stressed Replication Forks Independently of ATR. Mol 
Cell, 2018. 69(3): p. 371-384 e6. 
40. 
Min, A., et al., AZD6738, A Novel Oral Inhibitor of ATR, Induces Synthetic Lethality with 
ATM Deficiency in Gastric Cancer Cells. Mol Cancer Ther, 2017. 16(4): p. 566-577. 
41. 
George, J., et al., Comprehensive genomic profiles of small cell lung cancer. Nature, 
2015. 524(7563): p. 47-53. 
42. 
Johnson, B.E., et al., myc family DNA amplification in tumors and tumor cell lines from 
patients with small-cell lung cancer. J Natl Cancer Inst Monogr, 1992(13): p. 39-43. 
43. 
Sos, M.L., et al., A framework for identification of actionable cancer genome 
dependencies in small cell lung cancer. Proc Natl Acad Sci U S A, 2012. 109(42): p. 
17034-9. 
44. 
Brennan, J., et al., myc family DNA amplification in 107 tumors and tumor cell lines from 
patients with small cell lung cancer treated with different combination chemotherapy 
regimens. Cancer Res, 1991. 51(6): p. 1708-12. 
45. 
Mollaoglu, G., et al., MYC Drives Progression of Small Cell Lung Cancer to a Variant 
Neuroendocrine Subtype with Vulnerability to Aurora Kinase Inhibition. Cancer Cell, 
2017. 31(2): p. 270-285. 
46. 
Murga, M., et al., Exploiting oncogene-induced replicative stress for the selective killing 
of Myc-driven tumors. Nat Struct Mol Biol, 2011. 18(12): p. 1331-1335. 
47. 
Drapkin, B.J., et al., Genomic and Functional Fidelity of Small Cell Lung Cancer 
Patient-Derived Xenografts. Cancer Discov, 2018. 8(5): p. 600-615. 
48. 
Rudin, C.M., et al., Molecular subtypes of small cell lung cancer: a synthesis of human 
and mouse model data. Nat Rev Cancer, 2019. 19(5): p. 289-297. 
49. 
Lissa, D., et al., Heterogeneity of neuroendocrine transcriptional states in metastatic 
small cell lung cancers and patient-derived models. Nat Commun, 2022. 13(1): p. 2023. 
50. 
Thomas, A., et al., Therapeutic targeting of ATR yields durable regressions in small cell 
lung cancers with high replication stress. Cancer Cell, 2021. 39(4): p. 566-579 e7. 
51. 
Roper, N., et al., Notch signaling and efficacy of PD-1/PD-L1 blockade in relapsed small 
cell lung cancer. Nat Commun, 2021. 12(1): p. 3880. 
52. 
Gazdar, A.F., et al., Characterization of Variant Subclasses of Cell-Lines Derived from 
Small Cell Lung-Cancer Having Distinctive Biochemical, Morphological, and Growth-
Properties. Cancer Research, 1985. 45(6): p. 2924-2930. 
53. 
Zhang, W., et al., Small cell lung cancer tumors and preclinical models display 
heterogeneity of neuroendocrine phenotypes. Translational Lung Cancer Research, 2018. 
7(1): p. 32-+. 
54. 
Calbo, J., et al., A Functional Role for Tumor Cell Heterogeneity in a Mouse Model of 
Small Cell Lung Cancer. Cancer Cell, 2011. 19(2): p. 244-256. 
55. 
Roper, N., et al., Notch signaling and efficacy of PD-1/PD-L1 blockade in relapsed small 
cell lung cancer. Nature Communications, 2021. 12(1). 
56. 
McColl, K., et al., Reciprocal expression of INSM1 and YAP1 defines subgroups in small 
cell lung cancer. Oncotarget, 2017. 8(43): p. 73745-73756. 
57. 
Qu, S., et al., Molecular Subtypes of Primary SCLC Tumors and Their Associations With 
Neuroendocrine and Therapeutic Markers. Journal of Thoracic Oncology, 2022. 17(1): p. 
141-153. 
58. 
Owonikoko, T.K., et al., YAP1 Expression in SCLC Defines a Distinct Subtype With T-
cell-Inflamed Phenotype. J Thorac Oncol, 2021. 16(3): p. 464-476. 

NCI Protocol #:  10268 
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59. 
Gay, C.M., et al., Patterns of transcription factor programs and immune pathway 
activation define four major subtypes of SCLC with distinct therapeutic vulnerabilities. 
Cancer Cell, 2021. 39(3): p. 346-+. 
60. 
Stewart, C.A., et al., Single-cell analyses reveal increased intratumoral heterogeneity 
after the onset of therapy resistance in small-cell lung cancer. Nat Cancer, 2020. 1: p. 
423-436. 
61. 
Wagner, A.H., et al., Recurrent WNT pathway alterations are frequent in relapsed small 
cell lung cancer. Nature Communications, 2018. 9. 
62. 
Snyder, M.W., et al., Cell-free DNA Comprises an In Vivo Nucleosome Footprint that 
Informs Its Tissues-Of-Origin. Cell, 2016. 164(1-2): p. 57-68. 
63. 
Mathios, D., et al., Detection and characterization of lung cancer using cell-free DNA 
fragmentomes. Nature Communications, 2021. 12(1): p. 5060. 
64. 
Lissa, D., et al., Integrated genomic and transcriptomic analysis of small cell lung cancer 
reveals inter- and intratumoral heterogeneity. Nat Communs, 2022: p. In press. 
65. 
Stahl, P.L., et al., Visualization and analysis of gene expression in tissue sections by 
spatial transcriptomics. Science, 2016. 353(6294): p. 78-82. 
66. 
Ravi, V.M., et al., Spatiotemporal heterogeneity of glioblastoma is dictated by 
microenvironmental interference. bioRxiv, 2021: p. 2021.02.16.431475. 
67. 
Brady, L., et al., Inter- and intra-tumor heterogeneity of metastatic prostate cancer 
determined by digital spatial gene expression profiling. Nat Commun, 2021. 12(1): p. 
1426. 
68. 
Rudin, C.M., et al., Comprehensive genomic analysis identifies SOX2 as a frequently 
amplified gene in small-cell lung cancer. Nat Genet, 2012. 44(10): p. 1111-6. 
69. 
Eckardt, J.R., et al., Phase III study of oral compared with intravenous topotecan as 
second-line therapy in small-cell lung cancer. J Clin Oncol, 2007. 25(15): p. 2086-92. 
70. 
Jotte, R., et al., Randomized phase II trial of single-agent amrubicin or topotecan as 
second-line treatment in patients with small-cell lung cancer sensitive to first-line 
platinum-based chemotherapy. J Clin Oncol, 2011. 29(3): p. 287-93. 
 
 
 
 
 

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APPENDICES
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.

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APPENDIX B: Formula to Estimate Renal Function Using Serum Creatinine
Estimated creatinine clearance (Clcr) by the Cockcroft-Gault (C-G) equation (Cockcroft and Gault, 1976).
Followed by conversion to a value normalized to 1.73m2 with the patient’s body surface area (BSA).
References
1. Levey, A.S., L.A. Stevens, C.H. Schmid, et al.  (2009).  A new equation to estimate glomerular filtration rate.  Ann Inter Med.  
150:604-612.
2. Levey, A.S., J. Coresh, T. Greene, et al.  (2006).  Using standardized serum creatinine values in the modification of diet in renal 
disease study equation for estimating glomerular filtration rate.  Ann Intern Med.  145:247-254.
3. Cockcroft, D.W. and M.H. Gault.  (1976).  Prediction of creatinine clearance from serum creatinine.  Nephron.  16:31-41.

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APPENDIX C:Patient Drug Interactions 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 #:
Study 
Doctor:
Study Doctor 
Phone #:
Study 
Drug(s):
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. 
These are the things that your healthcare providers need to know:
M6620 (VX-970, berzosertib) interacts with specific enzymes in the liver or other tissues like the gut and 
certain transport proteins that help move drugs in and out of the cell.
Explanation
CYP 
isoenzymes
The enzyme in question is CYP3A4.  M6620 (VX-970, berzosertib) is metabolized 
by CYP3A4 and may be affected by other drugs that inhibit or induce this enzyme. 
Protein 
transporters
The proteins in questions are OATP1B3 and BCRP.  M6620 (VX-970, berzosertib) is 
a moderate inhibitor of these proteins and may affect drugs that are moved in and out 
of cells/organs by these transport proteins.
These are the things that you need to know:
The study drug M6620 (VX-970, berzosertib), may interact with other drugs which can cause side effects. 
For this reason, it is very important to tell your doctors about all your medicines, including: (a) medicines 
you are taking before this clinical trial, (b) medicines you start or stop taking during this study, (c) 
medicines you buy without a prescription (over-the-counter remedy), (d) herbals or supplements (e.g. St. 
John’s Wort). It is helpful to bring your medication bottles or an updated medication list with you. 
Before you enroll onto the clinical trial, your study doctor will work with your regular health care 
providers to review any medicines and herbal supplements that are considered strong inhibitors or 
inducers of CYP3A4 and sensitive substrates of CYP3A4, OATP1B3 and BCRP.
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 Apr2021
(Next page: Patient Drug Interaction Wallet Card)

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Patient Drug Interaction Wallet Card 
EMERGENCY 
INFORMATION
DRUG INTERACTIONS
Show this card to all of your 
healthcare providers. Keep it 
with you in case you go to the 
emergency room.
Tell your doctors before you start or 
stop any medicines.
Check with your doctor or 
pharmacist if you need to use an 
over-the-counter medicine or herbal 
supplement!
Carry this card with you at all times  
M6620 (VX-970, berzosertib) interacts with specific enzymes in your liver or 
other tissues like the gut and transport proteins that help move drugs in and 
out of cells and must be used very carefully with other medicines.
Patient Name:
Use caution and avoid the 
following drugs if possible:
Your healthcare providers should be aware of any medicines that are strong 
inhibitors or inducers of CYP3A4, and sensitive substrates of CYP3A4, 
OATP1B3, and BCRP.
x Strong inhibitors or inducers of CYP3A4 should be avoided.
x Sensitive substrates of CYP3A4, OATP1B3, and BCRP should be used 
with caution.
Diagnosis:
Study Doctor:
Study Doctor Phone #:
NCI Trial #:
Before prescribing new medicines, your health care provider should check a 
frequently updated medical reference for a list of drugs to avoid or contact 
your study doctor.
Study Drug(S):
             Version Apr/2021
For more information: 1-800-4-CANCER
For more information: 1-800-4-CANCER
For more information: 1-800-4-
CANCER
For more information: 1-800-4-CANCER
cancer.gov | clinicaltrials.gov
cancer.gov | clinicaltrials.gov
cancer.gov | clinicaltrials.gov
cancer.gov | clinicaltrials.gov

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APPENDIX D:PD SPECIMENSUBMISSIONFORMANDCHAINOFCUSTODY
If submitting more than 10 specimens, attach an additional copy of the Specimen Submission Form. Include a copy of the submission
form and signed, chain of custody section with every shipment.
Specimen Submission Form
NOTE:
Record times using military time (24-h designation); e.g., specify 16:15 to indicate 4:15 PM. If submitting more than 10
specimens, attach an additional Specimen Submission Form.
Total No. Specimens:
Shipment Date:
Item
No.
Patient/Sample ID
Protocol/
CTEP No.
Collection
Date
Collection
Time
Cycle/Day/
Hour
Clinical Diagnosis
Comments
Ex:
1234-001025-402
1234
10/24/2012
16:15
C1D1-2h
sarcoma
1
2
3
4
5
6
7
8
9
10

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Chain of Custody Signatures
Prior to shipping the Clinical Center Specimen Handling personnel should verify contents of and sign and date on line 1 below to
verify contents of container.
Task
Responsible Party
Signature
Date
1. Shipment of blood tubes (22°C ± 3°C controlled
temperature gel packs)
Clinical Center
/
/
2. Receipt of specimen: log receipt, verify specimen(s),
and verify shipping conditions.
NCI-F/FNLCR
/
/
3. Receipt of specimen for research use.
NCI-F/FNLCR
/
/

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APPENDIX E: TISSUE BIOPSY VERIFICATION
A copy of the diagnostic pathology report must be shipped with all tissue specimens sent to the
EET Biobank.
If the corresponding pathology report is not available for the biopsy, then a copy of the 
radiology report or operative report from the biopsy procedure and the diagnostic pathology 
report must be sent to the EET Biobank. A completed copy of this appendix (i.e., Tissue 
Biopsy Verification) must also be submitted to the EET Biobank.
Note: If this information is not provided with the biopsy specimen, then it will not be accepted by 
the EET Biobank.
Please have the Clinician* responsible for signing out this patient’s case complete the following:
ETCTN Universal Patient ID:
ETCTN Patient Study ID:
DateofProcedure (mm/dd/yyyy):
Tissue Type (circle one):
Primary
Metastatic
Time point (circleone): Baseline
Site Tissue Taken From:
Diagnosis:
I agree that this tissue may be released for research purposes only and that the release of this tissue 
will not have any impact on the patient’s care.
Clinician Signature
Date
Clinician Printed Name

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110 
*Note: For the purposes of this form, Clinician could include the Nurse Practitioner, Registered Nurse, 
Pathologist, Radiologist, Interventional Radiologist, Surgeon, Oncologist, Internist, or other medical 
professional responsible for the patient’s care.  
 
Version: 1 
Effective Date: 9/2019