A Phase 2 Study of M6620 (VX-970, Berzosertib) in Combination With Carboplatin Compared With Docetaxel in Combination With Carboplatin in Metastatic Castration-Resistant Prostate Cancer
Phase: PHASE2
Conditions: Castration-Resistant Prostate Carcinoma, Metastatic Prostate Carcinoma, Stage IV Prostate Cancer AJCC v8
Sponsor: National Cancer Institute (NCI)

i
SUMMARY OF CHANGES – Protocol
For Protocol Amendment #13 to:
NCI Protocol #: 10191
Local Protocol #: Dana-Farber/Harvard Cancer Center Protocol #19-715
NCI Version Date: August 24, 2024
Protocol Date: August 24, 2024
Please provide a list of changes from the previous CTEP approved version of the protocol. The
list shall identify by page and section each change made to a protocol document with hyperlinks 
to the section in the protocol document.  All changes shall be described in a point-by-point 
format (i.e., Page 3, section 1.2, replace ‘xyz’ and insert ‘abc’).  When appropriate, a brief 
justification for the change should be included.
Protocol Changes (from version May 4, 2021)
#
Section
Comments
1.
Header
Title
Page
1)
New Protocol Amendment/Version Date Included on the Title/Cover Page per 
Operations Office Policy:
Protocol Cover Page: Page Number(s):  __1____
Version Date: _22 August, 2024_________
2
Biomar
ker 
Table
Added DirectHRD assay to Biomarker Table
3
2.5.2
Added description of DirectHRD to “Tumor profiling from circulating free DNA 
(cfDNA)”
4
7.4.3
Updated AE Reporting Table
5
9.7.2
Added 50 x whole genome sequencing to exploratory correlative studies

ii
“Biomarker Table”
Priority
Biomarker
Name
Assay
(CLIA: 
Y/N)
Use in the Trial 
(Integral, 
integrated, or 
Exploratory) 
AND Purpose
Specimen
s Tested
Collection 
Time Points
Mandatory or 
Optional
Assay Laboratory and 
Lab PI
Tissue-Based Biomarkers
1
Whole 
Exome 
Sequencing
NGS
CLIA: No
Integrated
For identification 
of homologous 
recombination 
deficiency 
(baseline) and 
mediators of 
resistance 
(progression)
DNA from 
Metastatic 
biopsy 
tissue
Pre-study and
at the time of 
progression
M (baseline)
O (progression)
MoCha, Frederick 
National Laboratory for 
Cancer Research 
(FNLCR)
Mickey Williams, Ph.D.
mickey.williams@nih.gov
2
RAD51
focus 
formation
IHC
CLIA: N
Exploratory
Functional 
assessment of 
HRD
Slides 
from
Metastatic 
biopsy 
tissue
Pre-treatment
M (baseline)
Center for DNA Damage 
and Repair, Dana-Farber 
Cancer Institute (DFCI)
Bose Kochupurakkal, 
Ph.D.
bose kochupurakkal@df
ci.harvard.edu
Center for DNA Damage
and Repair, Dana-Farber 
Cancer Institute (DFCI)
Geoffrey Shapiro
geoffrey shapiro@dfci.h
arvard.edu
BWH Specialized 
Histopathology Services 
Core, Dana-Farber 
Cancer Institute (DFCI)
Jon Aster
jaster@partners.org

iii
Priority
Biomarker
Name
Assay
(CLIA: 
Y/N)
Use in the Trial 
(Integral, 
integrated, or 
Exploratory) 
AND Purpose
Specimen
s Tested
Collection 
Time Points
Mandatory or 
Optional
Assay Laboratory and 
Lab PI
3
ATM/p-
KAP1 IHC
IHC
CLIA: N
Exploratory
Functional 
assessment of 
HRD
Slides 
from
Metastatic 
biopsy 
tissue
Pre-treatment
M (baseline)
Center for DNA Damage 
and Repair, Dana-Farber 
Cancer Institute (DFCI)
Bose Kochupurakkal, 
Ph.D.
bose kochupurakkal@df
ci.harvard.edu
Center for DNA Damage 
and Repair, Dana-Farber 
Cancer Institute (DFCI)
Geoffrey Shapiro
geoffrey shapiro@dfci.h
arvard.edu
BWH Specialized 
Histopathology Services 
Core, Dana-Farber 
Cancer Institute (DFCI)
Jon Aster
jaster@partners.org
4
RNAseq
NGS
CLIA: No
Exploratory
Assessment of 
RB functional 
status
RNA from 
Metastatic 
biopsy 
tissue
Pre-study and
at the time of 
progression
M (baseline)
O (progression)
NCLN Genomics 
Laboratory 
Mickey Williams, Ph.D
mickey.williams@nih.gov
(analysis by Leigh Ellis, 
Cedars Sinai 
leigh.ellis@cshs.org)
Blood-Based Biomarkers
1
Whole 
Exome 
Sequencing
NGS
CLIA: No
Integrated
Germline Control
DNA from 
blood in 
cfDNA 
Streck 
tube
Pre-treatment
M
MoCha, Frederick 
National Laboratory for 
Cancer Research 
(FNLCR)
Mickey Williams, Ph.D.
mickey.williams@nih.gov

iv
Priority
Biomarker
Name
Assay
(CLIA: 
Y/N)
Use in the Trial 
(Integral, 
integrated, or 
Exploratory) 
AND Purpose
Specimen
s Tested
Collection 
Time Points
Mandatory or 
Optional
Assay Laboratory and 
Lab PI
1
Ultra low-
pass whole 
genome
sequencing 
(ULP-WGS) 
and
prostate 
cancer-
specific 
targeted
sequencing 
from cfDNA
0.1 x pass 
whole 
genome
sequencin
g and 
targeted
NGS
CLIA: N
Exploratory
To qualify plasma 
for whole exome 
sequencing and 
to determine if 
genetic 
alterations 
detected in the 
tumor specimen 
can also be 
detected in 
cfDNA.
Plasma
Arm B: C1D1,
C4D1, and 
every 3 cycles 
thereafter and 
at end of 
study
.
Arm
A/crossover:
C1D1, C4D1, 
and every 3 
cycles while 
on carbo+/-
docetaxel, 
then C1D1 
[crossover], 
C4D1
[crossover], 
and every 3 
cycles 
thereafter 
while on 
carbo+M6620 
and at end of 
study.  
M
Center for Cancer Precision 
Medicine, Dana-Farber 
Cancer Institute / Brigham 
& Women’s Hospital / 
Broad Institute 
Eliezer Van Allen, M.D.
eliezerm vanallen@dfci.
harvard.edu
1
DirectHRD
50 x whole 
genome
sequencin
g from 
cfDNA and 
15 x from 
germline
CLIA: N
Exploratory
To assess 
homologous 
recombination 
repair deficiency 
in cfDNA
Plasma
Arm B: C1D1,
C4D1, and 
every 3 cycles 
thereafter and 
at end of 
study
.
Arm
A/crossover:
C1D1, C4D1, 
and every 3 
cycles while 
on carbo+/-
docetaxel, 
then C1D1 
[crossover], 
C4D1
[crossover], 
and every 3 
cycles 
thereafter 
while on 
carbo+M6620 
and at end of 
study.  
M
Broad Institute
Viktor Adalsteinsson, PhD
viktor@broadinstitute.org
(Please retain the section break below, so that the Title Page is page “1” of the document.)

1
NCI Protocol #:
10191
Local Protocol #:
Dana-Farber/Harvard Cancer Center Protocol #19-715
ClinicalTrials.gov Identifier: NCT03517969
TITLE: A Phase 2 Study of M6620 (VX-970, berzosertib) in Combination with Carboplatin 
compared with Docetaxel in Combination with Carboplatin in Metastatic Castration-Resistant 
Prostate Cancer
Study Disease: Prostate Cancer 10036910
Corresponding Organization:
LAO-MA036 / Dana-Farber/Harvard Cancer Center
Principal Investigator:
Atish D Choudhury, MD PhD
Dana-Farber Cancer Institute
450 Brookline Ave, Dana 930
Boston, MA 02215
Telephone – (617) 632-6328
Fax – (617) 632-2165
achoudhury@partners.org
Participating Organizations (Only the participating LAOs should be listed.)
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-OH007 / Ohio State University Comprehensive Cancer Center LAO
LAO-PA015 / University of Pittsburgh Cancer Institute LAO
LAO-TX035 / University of Texas MD Anderson Cancer Center LAO
LAO-MD017/ JHU Sidney Kimmel Comprehensive Cancer Center LAO
PARTICIPATION LIMITED TO:
CO070 / University of Colorado Hospital
LAO-NCI / National Cancer Institute LAO
CATCHUP/ Creating Access to Targeted Cancer Therapy for Underserved Populations

NCI Protocol #: 10191
Version Date: 24 August 2024
2
Statistician:
Wanling Xie, MS
Dana Farber Cancer Institute
Dept. of Biostatistics and Computational Biology
450 Brookline, Boston, MA 02215
Telephone –(617) 582-7928
Fax –(617) 632-2444
wxie@jimmy.harvard.edu
Study Coordinator:
Matthew Bandel
Dana Farber Cancer Institute
450 Brookline, Boston, MA 02215
Telephone- (617) 632-4126
Fax- (617) 632-6220
Matthew_Banel@dfci.harvard.edu
Regulatory Coordinator: 
Hannah Gallo
Dana Farber Cancer Institute
450 Brookline, Boston, MA 02215
Telephone- (617) 632-5505
Fax- (617) 632-6220
Hannahe_gallo@dfci.harvard.edu
NCI-Supplied Agent(s):  M6620 (VX-970, berzosertib), NSC# 780162
Other Agent(s):  carboplatin, NSC# 241240, commercial; docetaxel, NSC# 628503, commercial
IND #:  
IND Sponsor: DCTD, NCI
Protocol Type / Version # / Version Date:
Amendment 13 / Version #18 / 24 August, 2024
*Protocol types:  Original, Revision, or Amendment

NCI Protocol #: 10191
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SCHEMA

NCI Protocol #: 10191
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TABLE OF CONTENTS
SCHEMA.........................................................................................................................................3 
1. 
OBJECTIVES......................................................................................................................7 
1.1 
Primary Objectives...................................................................................................7 
1.2 
Secondary Objectives...............................................................................................7 
1.3 
Exploratory Objectives ............................................................................................7 
2. 
BACKGROUND .................................................................................................................7 
2.1 
Study Disease – Prostate Cancer..............................................................................7 
2.2 
M6620 (VX-970, berzosertib) .................................................................................9 
2.3 
Carboplatin.............................................................................................................15 
2.4 
Rationale ................................................................................................................16 
2.5 
Correlative Studies Background ............................................................................17 
3. 
PATIENT SELECTION....................................................................................................20 
3.1 
Eligibility Criteria..................................................................................................20 
3.2 
Exclusion Criteria ..................................................................................................22 
3.3 
Inclusion of Women and Minorities ......................................................................24 
4. 
REGISTRATION PROCEDURES ...................................................................................24 
4.1 
Investigator and Research Associate Registration with CTEP..............................24 
4.2 
Site Registration.....................................................................................................25 
4.3 
Patient Registration................................................................................................28 
4.4 
General Guidelines.................................................................................................29 
5. 
TREATMENT PLAN........................................................................................................29 
5.1 
Agent Administration.............................................................................................29 
5.2 
General Concomitant Medication and Supportive Care Guidelines......................33 
5.3 
Crossover ...............................................................................................................34 
5.4 
Duration of Therapy...............................................................................................35 
5.5 
Duration of Follow Up...........................................................................................35 
6. 
DOSING DELAYS/DOSE MODIFICATIONS................................................................36 
7. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ............................40 
7.1 
Rave-CTEP-AERS Integration..............................................................................40 
7.2 
Comprehensive Adverse Events and Potential Risks List (CAEPR).....................42 
7.3 
Adverse Event Characteristics...............................................................................46 
7.4 
Expedited Adverse Event Reporting......................................................................46 
7.5 
Routine Adverse Event Reporting .........................................................................49 
7.6 
Pregnancy...............................................................................................................49 
7.7 
Secondary Malignancy...........................................................................................49 
7.8 
Second Malignancy................................................................................................49 

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8. 
PHARMACEUTICAL INFORMATION..........................................................................50 
8.1 
M6620 (VX-970, berzosertib) (NSC 780162).......................................................50 
8.2 
Carboplatin.............................................................................................................54 
8.3 
Docetaxel ...............................................................................................................55 
9. 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ........................................57 
9.1 
Collection of Specimens ........................................................................................57 
9.2 
Specimen Procurement Kits and Scheduling.........................................................58 
9.3 
Specimen Tracking System Instructions................................................................58 
9.4 
Specimen Collection..............................................................................................62 
9.5 
Shipping Specimens from Clinical Site to the EET Biobank ................................64 
9.6 
Integrated Correlative Study – Whole Exome Sequencing ...................................66 
9.7 
Exploratory/Ancillary Correlative Studies ............................................................67 
10. 
STUDY CALENDAR .......................................................................................................69 
11. 
MEASUREMENT OF EFFECT........................................................................................70 
11.1 
Antitumor Effect – Solid Tumors ..........................................................................70 
11.2 
PSA Response........................................................................................................78 
12. 
STUDY OVERSIGHT AND DATA REPORTING / REGULATORY 
REQUIREMENTS.............................................................................................................78 
12.1 
Study Oversight .....................................................................................................78 
12.2 
Data Reporting.......................................................................................................78 
12.3 
Data Quality Portal ................................................................................................81 
12.4 
CTEP Multicenter Guidelines................................................................................81 
12.5 
Collaborative Agreements Language.....................................................................81 
12.6 
Genomic Data Sharing Plan...................................................................................83 
13. 
STATISTICAL CONSIDERATIONS...............................................................................83 
13.1 
Study Design/Endpoints.........................................................................................83 
13.2 
Sample Size/Accrual Rate......................................................................................84 
13.3 
Analysis of Primary Endpoint................................................................................85 
13.4 
Analysis of Secondary/Exploratory/Correlative Endpoints...................................86 
13.5 
Reporting and Exclusions ......................................................................................87 
REFERENCES ..............................................................................................................................87 
APPENDIX A 
PERFORMANCE STATUS CRITERIA ..................................................91 
APPENDIX B 
CTEP MULTICENTER GUIDELINES....................................................92 
APPENDIX C   
PATIENT DRUG INFORMATION HANDOUT AND 
WALLET CARD...............................................................................................................93 
APPENDIX D - BIOASSAY TEMPLATES ................................................................................95 

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APPENDIX E 
PROCEDURE FOR COLLECTION OF BIOPSY TISSUE...................101 
APPENDIX F -TISSUE BIOPSY VERIFICATION ..............................................................103 

NCI Protocol #: 10191
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1. OBJECTIVES
1.1
Primary Objectives
The primary objective of this study is to assess the difference in response rate (either 
achievement of PSA reduction of greater than 50% or radiographic response by RECIST 1.1) of 
the combination of M6620 (VX-970, berzosertib) and carboplatin as compared to the 
combination of docetaxel and carboplatin.
1.2
Secondary Objectives
A secondary objective is to assess the difference in time to PSA progression by Prostate Cancer 
Working Group 2 (PCWG2) criteria1 of the combination of M6620 (VX-970, berzosertib) and
carboplatin as compared to the combination of docetaxel and carboplatin.  In addition, we plan to 
describe radiographic progression-free survival and progression-free survival by PCWG3 
criteria2 in both arms of the study. We will assess the relationship with homologous 
recombination deficiency (HRD) detected from baseline tumor biopsy with response to the 
combination of M6620 (VX-970, berzosertib) and carboplatin and the combination of docetaxel 
and carboplatin. We also plan to describe the safety and adverse events from the combination of
M6620 (VX-970, berzosertib)+carboplatin as well the combination of docetaxel+carboplatin.
1.3
Exploratory Objectives
Exploratory objectives include comparison of overall survival in the two arms of the study.  In 
addition, we will explore response rate, time to PSA progression, radiographic progression-free
survival, and progression-free survival by PCWG3 criteria in patients who initially receive 
docetaxel+carboplatin after crossover to M6620 (VX-970, berzosertib)+carboplatin. We also 
plan to assess the relationship with homologous recombination deficiency (HRD) detected from 
baseline circulating free DNA (cfDNA) with response to the combination of M6620 (VX-970,
berzosertib) and carboplatin and the combination of docetaxel and carboplatin, and describe 
alterations seen in cfDNA (and optional tumor biopsy) at end of study.
2. BACKGROUND
2.1
Study Disease – Prostate Cancer
Prostate cancer is the most common non-cutaneous malignancy in men in the United States, and 
despite significant progress in management and treatment of this disease, prostate cancer is the 
third most common cause of cancer death in men in the United States.3 The vast majority of 
these deaths is in patients with metastatic dissemination of their cancer and in whom their 
disease has become resistant to medical or surgical castrating therapies.  While genetic and 
molecular alterations in metastatic castration-resistant prostate cancer (mCRPC) have been well 
characterized,4 there has been limited progress in translating these findings into novel therapeutic 
strategies for these patients.  Specifically, there has been limited clinical benefit derived from 

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molecularly targeted agents (other than those targeting signaling through the androgen receptor) 
in mCRPC, and there is a paucity of validated predictive biomarkers to guide clinical 
management in these patients.  Recently, Mateo, et al.5 demonstrated that olaparib, an inhibitor 
of Poly (ADP-ribose) polymerase (PARP), has clinical activity in mCRPC, with clinical 
responses enriched in the population of patients identified by next generation sequencing to have 
homozygous deletions, deleterious mutations, or both in DNA-repair genes – 14 of the 16 
patients (88%) found to have one of these aberrations experienced a response to olaparib.  This 
study has been transformative to our understanding of therapeutic vulnerabilities in mCRPC, 
having demonstrated both that targeting defects in DNA repair pathways can lead to clinical 
benefit in these patients, and that sequencing-based biomarkers can provide predictive 
information for the likelihood of response to therapy.
However, there are multiple limitations in applying these findings broadly in clinical practice.  
The sequencing-based biomarker in this study was primarily obtained from biopsy of a 
metastatic lesion, which is a cumbersome and expensive process to apply broadly in the 
community.  The alterations implicated in conferring sensitivity to olaparib in the Mateo study 
were predominantly BRCA2, ATM, FANCA, BRCA1, PALB2 and HDAC2 – however the 
degree to which these alterations were causal to the sensitivity remain unclear.  In reality, 
hundreds of genes are involved in the response to and repair of DNA damage, and capturing and 
interpreting these data to understand the phenotypic relevance is a major challenge (e.g. whether 
specific alterations are truly pathogenic, and whether the presence of multiple hypomorphic or 
heterozygous mutations in combination can confer sensitivity).  The overall response rate in the 
unselected population of patients in this study was 33%, with 12 of 49 patients (24%) remaining 
on study treatment for greater than 6 months.  
The FDA initially granted breakthrough therapy designation to olaparib in patients with BRCA1,
BRCA2 or ATM mutations based on the TOPARP-A study5, and subsequently the Phase III 
PROfound study6 demonstrated improvement in radiographic progression-free survival, objective 
response rate and overall survival of olaparib compared to potent AR pathway inhibitor (ARPI) 
abiraterone or enzalutamide in patients with these mutations who progressed on the other ARPI 
agent. However, the degree to which patients with ATM mutations respond to PARP inhibitors 
remains unclear. Rucaparib was granted FDA breakthrough therapy designation in patients with 
BRCA1 or BRCA2 mutations based on results of the TRITON2 study7, but in this study 0 of 18 
patients with an ATM mutation responded to rucaparib. In other studies of olaparib, Marshall et 
al.8 reported responses in 0 of 6 patients with ATM mutation, and the TOPARP-B study9 reported 
2 of 19 patients with PSA or radiographic response in this population (the remaining 5 
“responders” with ATM mutations in this study were based on CTC conversion, which is not a 
commonly used criterion for clinical response in prostate cancer studies). The TOPARP-B study 
did demonstrate responses in patients with PALB2 mutations, but limited benefit in patients with 
mutations in CDK12 and in a basket of “other” genes involved in DNA damage repair. Thus, better 
biomarkers to predict response and resistance to PARP inhibitors are needed, and alternative 
therapeutic approaches are required for patients unlikely to respond to PARP inhibitor 
monotherapy.
One such targeted approach is through inhibiting the enzymatic activity of the Ataxia 
telangiectasia and Rad3 related (ATR) serine/threonine kinase.  ATR is activated by replication 

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9
protein A (RPA)-coated single-stranded DNA (ssDNA), a nucleoprotein structure commonly 
generated at sites of DNA damage and stressed replication forks.10 Whereas a related kinase 
ATM is primarily involved in the response to DNA double-stranded breaks, ATR responds to a 
wide range of DNA damage and DNA replication problems.  Thus, ATR inhibition is selectively 
toxic in cells with loss of genes involved in homologous recombination (HR) repair (ATM, 
XRCC1) and NER (ERCC1), but also in cells reliant on alternative lengthening of 
telomeres (ALT) as well as cells with high levels of replication stress induced by oncogenes (e.g. 
Ras isoforms, Myc, Cyclin E) and hypoxia.  Replication stress can be induced exogenously, such 
as through treatment with chemotherapeutics.11 This study seeks to assess the anti-tumor activity 
of the ATR inhibitor M6620 (VX-970, berzosertib) in combination with carboplatin in patients 
with metastatic castration-resistant prostate cancer.
2.2
M6620 (VX-970, berzosertib)
M6620 (VX-970, berzosertib) is a highly potent and selective ATP-competitive inhibitor of 
ATR, with an inhibition constant (Ki) <0.3 nmol/L (nM)12.  In comparison, M6620 (VX-970,
berzosertib) was >100-fold weaker inhibitor of ATM (Ki=34 nM) and >1000-fold less effective 
against other closely related kinases, such as DNA-dependent protein kinase (DNA-PK) (Ki>4 
mcM), mTOR (Ki>1 mcM), and PI3K-gamma (Ki=0.22 mcM).13 Overall, M6620 (VX-970,
berzosertib) selectivity was >50-fold higher for ATR than for 290 of 291 kinases tested and  
>25-fold over FLT412.  A cellular 50% inhibition of ATR was attained at a M6620 (VX-970,
berzosertib) concentration (IC50) of 0.019 mcM, demonstrating >100-fold greater selectivity 
against ATR compared to ATM or DNA-PK (IC50 of 2.6 mcM or 18.1 mcM, respectively).13
Effect of M6620 (VX-970, berzosertib) on DDR signaling and DNA damage
M6620 (VX-970, berzosertib) potentiated the activity of multiple DNA-damaging agents in 
numerous cancer cell lines from a range of indications12.  Concurrent treatment of cancer cell 
lines with M6620 (VX-970, berzosertib) and various DNA-damaging agents led to sustained 
M6620 (VX-970, berzosertib)-dose-dependent decreases in levels of chemotherapy-induced 
CHK1pS345, a major substrate of ATR13,14.  In the presence of DNA damage, primarily DSBs, 
histone H2AX is phosphorylated at serine 139 to produce γH2AX (H2AXpS139).  Although all 
three DDR regulatory kinases, ATM, ATR, and DNA-PK phosphorylate H2AX to γH2AX, they 
are variably activated during different DNA-damage repair mechanisms (e.g., HR repair, non-
homologous end joining [NHEJ] repair, base excision repair due induced by stalled replication 
forks, etc.)15.  In addition, for efficient DNA-damage repair, the DDR regulatory kinases must be 
able to access damaged sites in the chromatin environment.  ATM has been shown to 
phosphorylate the heterochromatin protein KAP1 at serine 824 (KAP1pS824) in response to DNA 
damage16.  Exposure of lung cancer cell lines as well as primary tumors to M6620 (VX-970,
berzosertib) in combination with DNA-damaging agents enhanced levels of the DNA-damage 
markers, i.e., γH2AX and KAP1pS824, as compared to DNA-damaging agent alone14.  Sequential 
treatment of cells with DNA-damaging agent followed 15 h later by M6620 (VX-970,
berzosertib) resulted in an initial inhibition of phospho-CHK1 (for 1 to 2 h)12.  However, over 
time, phospho-CHK1 re-appeared despite continued exposure to M6620 (VX-970, berzosertib).
The rebound of phospho-CHK1 has been attributed to non-specific phosphorylation by an 

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undefined kinase.  However, despite the transient inhibition of phospho-CHK1, the sustained 
accumulation of the DNA damage markers was observed.  Together these data suggest that 
disruption of ATR-mediated DDR signaling by M6620 (VX-970, berzosertib) leads to sustained 
accumulation of DNA damage in cancer cells exposed to DNA-damaging agents.  It has been 
suggested that the failure to repair chemotherapy-induced DNA damage in the presence of 
M6620 (VX-970, berzosertib) is the driver of enhanced cytotoxicity in cancer cells.  These data 
support using the DNA-damage markers as pharmacodynamic markers of M6620 (VX-970,
berzosertib) activity.  
M6620 (VX-970, berzosertib)-mediated radiosensitivity of pancreatic ductal adenocarcinoma 
cells was associated with inhibition of HR repair13. M6620 (VX-970, berzosertib) caused 
increased persistence of γH2AX levels both in vitro and in vivo.  Adding M6620 (VX-970,
berzosertib) to gemcitabine and ionizing radiation (IR) dramatically enhanced antitumor effects, 
with early and late apoptosis and abrogation of IR-induced G2 checkpoint in cell culture 
experiments.  It has been suggested that by promoting strong S-phase arrest, chemoradiation may 
further increase dependence of tumor cells on ATR-mediated homologous recombination (HR) 
repair of DNA double strand breaks (DSBs) and for survival.  
Nonclinical studies
In vitro antitumor activity
In the absence of exogenous DNA-damaging agents, M6620 (VX-970, berzosertib) demonstrated 
stronger antiproliferative effects against cancer cell lines tested (HCT116, NCI-H23, and HT29 
with IC50s of 35, 48, and 170 nM, respectively) than against noncancerous cells (e.g., fibroblasts 
or mammary epithelial cells (IC50=200 -1100 nM)12.  However, M6620 (VX-970, berzosertib) 
caused potent cytotoxicity only in the colorectal (CRC) cell line, HCT116, with 50% effective 
concentration (EC50) of 61 nM.  This suggests that certain cancer cells may be particularly reliant 
on ATR for survival even in the absence of an exogenous DNA-damaging agent.
In the cell proliferation assay with the HCT116 cell line, M6620 (VX-970, berzosertib) 
synergized with cisplatin (cross-linking agent), gemcitabine (anti-metabolite), irinotecan 
(topoisomerase I inhibitor), and etoposide (topoisomerase II inhibitor)12.  The most dramatic 
response was observed in combination with cisplatin (a 20-fold lower IC50 compared to the IC50
of cisplatin alone).  Preliminary data from cell proliferation studies with M6620 (VX-970,
berzosertib) + carboplatin suggests >10-fold reduction in carboplatin IC50 for two non-small cell 
lung cancer (NSCLC) cell lines (H23 and HT1299) tested.
The M6620 (VX-970, berzosertib) impact on chemotherapy-induced cytotoxicity was further 
examined against a panel of 37 lung cancer cell lines (including squamous NSCLC and small 
cell lung cancer [SCLC] histotypes) and 15 pancreatic cancer cell lines12.  Most lung cancer cell 
lines responded well to M6620 (VX-970, berzosertib) in combination with cisplatin (84% of cell 
lines) or gemcitabine (76% of cell lines), demonstrating ≥3-fold reduction in the IC50 compared 
to the cytotoxic agent alone.12,14,17 Enhanced sensitivity was also observed with etoposide (53% 
of cell lines), irinotecan (49% of cell lines) and oxaliplatin (39% of cell lines).  M6620 (VX-970,

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berzosertib) hypersensitized (caused >10-fold reduction in IC50) about 40% of cell lines to 
cisplatin14.  Marked synergy between the two agents was also seen against four of seven human 
NSCLC primary tumors tested in vitro.  The greatest antitumor synergistic effect was 
demonstrated by tumors with poor response to cisplatin alone.  Similarly, most pancreatic cancer 
lines responded well to combination of M6620 (VX-970, berzosertib) with cisplatin or 
gemcitabine: antitumor IC50 was ≥3-fold lower for the M6620 (VX-970, berzosertib) + cytotoxic 
agent in >70% of cell lines as compared to IC50 of cytotoxic agent alone.12
In addition, significant radiosensitization effects by M6620 (VX-970, berzosertib) were observed 
against two human pancreatic cancer cell lines with mutant KRAS and mutant p53 (MiaPaCa-2
and PSN1) (P<0.05), but not against non-cancerous fibroblast cell lines13.  In addition, M6620
(VX-970, berzosertib) profoundly sensitized pancreatic tumor cells to gemcitabine-based 
chemoradiation.
Impact of defective ATM signaling on sensitivity of cells to M6620 (VX-970, berzosertib) in
combination with a cytotoxic agent (cisplatin, gemcitabine, irinotecan, oxaliplatin, or etoposide) 
was examined in isogenic matched lung cancer cells (wild-type p53 A549 versus A549 
transfected with p53 shRNA), using a cell viability assay.12,14 Loss of p53 promoted sensitivity to 
ATR inhibition in combination with all five cytotoxic agents in contrast with the effects in the 
p53 wild-type A549.  M6620 (VX-970, berzosertib) also synergized with cisplatin resulting in 
cytotoxicity in ATM-null primary skin fibroblasts, but no cytotoxicity was observed against 
ATM wild-type fibroblasts.12 This suggests that the functional status of the ATM pathway is a 
contributing factor in the cellular response to the inhibition of ATR.
Of note, the response/p53 status relationship was unclear in the panel of heterogeneous cancer 
cell lines exposed to M6620 (VX-970, berzosertib) + chemotherapy14.  Although not significant, 
there was a trend of causality between response and p53 status (P=0.08) for M6620 (VX-970,
berzosertib) combined with cisplatin.  Furthermore, no clear relationship between cellular 
response to M6620 (VX-970, berzosertib) + cisplatin and p53 status was observed in seven 
primary lung tumors.  
In vivo antitumor activity
The in vivo activity of M6620 (VX-970, berzosertib) was tested in multiple mouse xenograft 
models derived from human lung cancer cell lines and primary human tumor cells12,14. M6620
(VX-970, berzosertib) potentiated antitumor effects of cisplatin, gemcitabine, irinotecan, and IR 
in a dose- and schedule-dependent manner.  Antitumor efficacy correlated with inhibition of 
phospho-CHK1 and an increase in DNA-damage markers.  This supports ATR inhibition as a 
primary mechanism of action for M6620 (VX-970, berzosertib).  Single-agent M6620 (VX-970,
berzosertib) had no significant effect on tumor growth in the experimental models.  M6620 (VX-
970, berzosertib) was generally well tolerated at efficacious doses in combination with DNA-
damaging agents.  Some body weight loss and enhanced changes in specific peripheral blood cell 
populations were observed with intensive and sustained dosing of M6620 (VX-970, berzosertib) 
in combination with cisplatin.  This effect could be attributed to an increased growth arrest, 
which was observed in vitro in normal cells for combinations of M6620 (VX-970, berzosertib) 

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with DNA-damaging agents.  This effect was reversed when ATR activity was restored.  M6620
(VX-970, berzosertib) sensitized pancreatic tumor xenografts to the cytotoxic effects of 
gemcitabine-based chemoradiation13.  The combination treatment was effective even at 
gemcitabine doses with no single-agent activity.  M6620 (VX-970, berzosertib) administered in 
combination with gemcitabine + IR was well tolerated.
In the sequence/schedule-optimization studies, M6620 (VX-970, berzosertib) was administered 
intravenously (IV) at 20 mg/kg (either as a single injection or as two 10 mg/kg injections 3 days 
apart) before (-2 h) or after cytotoxic agent (+12, 24, or 48 h) in human pancreatic cancer and 
NSCLC xenograft mouse models12. M6620 (VX-970, berzosertib) effectively enhanced 
antitumor activity of gemcitabine or cisplatin when administered 12 to 24 h after a cytotoxic 
agent.  M6620 (VX-970, berzosertib) administered before cytotoxic drug or greater than 48 h 
after a DNA-damaging agent had no impact on tumor growth compared to the effect of cytotoxic 
agent alone.  
A therapeutic dose for humans has been estimated based on the efficacious exposure achieved at 
20 mg/kg/week of M6620 (VX-970, berzosertib) (given either as a single IV injection or as two 
IV injections of 10 mg/kg per week) 12-24 h after cytotoxic agent (gemcitabine or cisplatin) in 
mice12.  The target M6620 (VX-970, berzosertib) plasma exposure, which corresponded to this 
dose, was an area under the concentration-time curve (AUC) of 4080 ng×h/mL/week.  Allometry 
predicts that a human dose of 2.5 mg/kg (100 mg/mg2) will be sufficient to achieve this 
exposure.  
Nonclinical Pharmacokinetics
In all nonclinical species (the mouse, rat, dog, and monkey), M6620 (VX-970, berzosertib) 
exhibited a high volume of distribution (Vd); tissue exposure, including tumor, was high12.  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 (VX-970, berzosertib) was extensively bound to plasma proteins; the free 
fraction of M6620 (VX-970, berzosertib) was only 2.1% in human blood.
M6620 (VX-970, berzosertib) is primarily eliminated by oxidative metabolism, with a 
cytochrome 450 (CYP) 3A4 isoform being the principle isoform responsible12.  Strong inducers 
or inhibitors of CYP3A4 may alter M6620 (VX-970, berzosertib) kinetics and blood levels.  
Based on its minimal inhibition or induction effects on CYPs, M6620 (VX-970, berzosertib) is
expected to have a low potential for drug-drug interactions.  M6620 (VX-970, berzosertib) 
metabolites were 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 (VX-970, berzosertib) following
IV administration was 26 and 13 mL/min/kg in the rat and dog, respectively.
Nonclinical Safety Pharmacology 
An manual patch-clamp human ether-a-go-go-related gene (hERG) assay demonstrated moderate 

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inhibition of the hERG channel12.  However, a telemetry dog study did not demonstrate any 
cardiovascular (CV) effects at exposures greatly exceeding the target human exposure.  
Nonclinical Toxicology
A severely toxic dose defined as causing a death in 10% of animals (STD10) in rats was 30 
mg/kg/day administered IV over 3 h12.  The highest non-severely toxic dose (HNSTD) in dogs 
was 20 mg/kg/day 3 h IV.  M6620 (VX-970, berzosertib) had no cardiovascular liabilities, was 
not genotoxic in mutagenicity assay, had no hemolytic potential in human blood or compatibility 
issues in human plasma, and was well tolerated in an acute rabbit parenteral injection study.  
M6620 (VX-970, berzosertib) absorbs in the ultraviolet (UV) spectrum and has high tissue 
distribution in rats.  
M6620 (VX-970, berzosertib) has yet not been assessed in developmental and reproductive 
toxicity studies12.  However, M6620 (VX-970, berzosertib) inhibits DNA-damage repair and will 
be administered in conjunction with cytotoxic chemotherapy, thus the potential for teratogenicity 
should be considered high.  
Clinical Studies
Preliminary clinical data for M6620 (VX-970, berzosertib) have been derived from company-
sponsored clinical studies evaluating M6620 (VX-970, berzosertib) in combination with various 
DNA-damaging agents, e.g., gemcitabine, cisplatin, or carboplatin12.  To test M6620 (VX-970,
berzosertib) single-agent PK, a single IV dose of M6620 (VX-970, berzosertib) alone, ranging 
from 18-210 mg/m2, was administered 7-14 days before M6620 (VX-970, berzosertib) was
combined with a DNA-damaging agent.  Combination of M6620 (VX-970, berzosertib) and a 
DNA-damaging agent were administered on a once-weekly schedule, with M6620 (VX-970,
berzosertib) being dosed 24 h after a DNA-damaging agent.  M6620 (VX-970, berzosertib) doses 
evaluated in combination with a DNA-damaging agent ranged from 90-240 mg/m2 IV.
Clinical Pharmacokinetics  
Clinical PK have been evaluated both in whole blood and plasma12.  Mean exposure (AUC) 
profiles were similar in whole blood and plasma.  Overall, the 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 (VX-970, berzosertib) PK.  The terminal elimination t1/2 was approximately 17 h across 
all doses.  In the M6620 (VX-970, berzosertib) single dose studies, M6620 (VX-970,
berzosertib) 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 (VX-970, berzosertib) administration did not appear to affect the PK of 
M6620 (VX-970, berzosertib).
Clinical Efficacy

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Preliminary analysis demonstrated objective responses for M6620 (VX-970, berzosertib) used in 
combination with a DNA-damaging agent(s) in treatment of patients with solid tumors12:  A 
summary of preliminary activity is as follows: 
x
M6620 (VX-970, berzosertib) + gemcitabine in advanced solid tumors:  Among 48 
patients, 4 (one each NSCLC, head and neck cancer, breast cancer, and unknown primary 
cancer) had partial response (PR) and 29 patients had stable disease (SD).  In an 
additional cohort of 18 patients with advanced NSCLC, 3 had PRs and 15 had SD.
x
M6620 (VX-970, berzosertib) + cisplatin in advanced solid tumors:  Among 26 patients, 
4 (1 each BRCA2+ ovarian cancer, epithelioid mesothelioma, TNBC, neuroendocrine 
prostate cancer) had PRs, and 15 patients had SD.  In an additional cohort of 18 patients 
with advanced TNBC, 7 had PR and 6 had SD. 
x
M6620 (VX-970, berzosertib) + carboplatin in advanced solid tumors refractory to 
standard therapy:  Among 21 evaluable patients, 1 had PR (ovarian cancer) and 14 had 
SD.  
x
M6620 (VX-970, berzosertib) + carboplatin or M6620 (VX-970, berzosertib) + cisplatin 
in platinum-resistant advanced SCLC:  There were no objective responses observed 
among nine evaluable patients and 4 had SD.
x
M6620 (VX-970, berzosertib) + gemcitabine + cisplatin in advanced solid tumors: Of 7 
evaluable patients, 1 had PR (CRC) and 4 had SD.
x
M6620 (VX-970, berzosertib) + carboplatin + paclitaxel in advanced solid tumors 
refractory to standard therapy:  Among 8 evaluable patients, 2 had PR (1 each 
adenosquamous carcinoma of the cervix and melanoma) 3 had SD.
Safety summary from studies with M6620 (VX-970, berzosertib) as single agent or in 
combination with cytotoxic therapy12
Infusion-related reactions (local or systemic), nausea, and vomiting are considered adverse drug 
reactions (ADRs) for M6620 (VX-970, berzosertib), and myelosuppression events are considered 
ADRs for M6620 (VX-970, berzosertib) in combination with carboplatin.  
x
Systemic infusion-related reactions to M6620 (VX-970, berzosertib) 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 (VX-970, berzosertib) 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 (VX-
970, berzosertib) and they included hypotension and mental status changes.  All 
subjects fully recovered with standard care procedures.
x
Local infusion-related reactions to M6620 (VX-970, berzosertib), 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 (VX-970,
berzosertib) should be administered through a large-bore catheter into large-caliber 
peripheral vein or central venous access.

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x
Nausea and vomiting have occurred commonly in patients receiving M6620 (VX-970,
berzosertib) monotherapy. Many of the affected subjects experienced these events on 
the same day as M6620 (VX-970, berzosertib) was administered, and there was some 
suggestion of a dose response. 
x
Hematologic AEs in subjects who received M6620 (VX-970, berzosertib) in
combination with carboplatin have included 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 (VX-970, berzosertib) 
inhibits DNA-damage repair and it will be administered in conjunction with cytotoxic 
chemotherapy; thus, the potential for teratogenicity should be M6620 (VX-970,
berzosertib) considered high.  Patients on M6620 (VX-970, berzosertib) studies must 
take stringent measures to avoid fathering or bearing children while on study drug and 
for 6 months after discontinuation of M6620 (VX-970, berzosertib).  Refer to the 
M6620 (VX-970, berzosertib) clinical study protocols for specific contraceptive 
requirements.
Guidance on prior and concomitant medications12
Because the drug interaction profile of M6620 (VX-970, berzosertib) has not been fully 
characterized, caution should be used when co-administering medications with M6620 (VX-970,
berzosertib).  As M6620 (VX-970, berzosertib) is primarily metabolized by CYP3A4, 
concomitant administration with potent inhibitors or inducers of CYP3A4 should be avoided.
The following list of potent CYP3A4 inhibitors and inducers is not exhaustive: 
x
Potent CYP3A4 inhibitors: clarithromycin, itraconazole, ketoconazole, hepatitis C virus 
and human immunodeficiency virus protease inhibitors, nefazodone, posaconazole, 
telithromycin, voriconazole. 
x
Potent CYP3A4 inducers: carbamazepine, rifampin, phenobarbital, phenytoin, St. John’s 
wort.
2.3
Carboplatin
Platinum compounds have demonstrated clinical responses in castration-resistant prostate cancer, 
suggesting their clinical utility in this setting.  In an unselected population, a Phase III trial of 
satraplatin in combination with prednisone demonstrated improved PFS as compared to placebo 
in combination with prednisone, but with no OS benefit seen.18 A wide range of clinical 
responses have been reported to platinum compounds (cisplatin, carboplatin and satraplatin) in 
the literature,19 with the highest response rates generally seen in combination with other 
chemotherapeutics in chemotherapy-naïve patients.  The response rate to carboplatin
combinations is ~20% overall in patients who progressed on docetaxel, and carboplatin in 
combination with docetaxel is a common regimen in taxane-refractory patients20. Recently, a 

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higher response rate has been demonstrated for carboplatin in combination with cabazitaxel21:
PSA > 50% reduction was 60% for carboplatin plus cabazitaxel vs. 44% for cabazitaxel alone; 
radiographic partial response rate was 52% (17/33) for carboplatin plus cabazitaxel vs. 14% 
(5/35) for cabazitaxel alone.  However, while these early data are promising, this is not 
considered a standard regimen at this point and is thus not yet universally covered by insurance.
Carboplatin use has previously been described in patients with “anaplastic” or “aggressive 
variant” prostate cancer.22 More recently, carboplatin has been shown to be an active agent in 
cancers with homologous recombination repair deficiency, with demonstrated activity in prostate 
cancer patients with known inherited BRCA2 mutations.23,24 However, now that olaparib has 
demonstrated responses in patients with mCRPC with alterations in genes involved in 
homologous recombination repair, PARP inhibitors have already been incorporated in clinical 
practice for off-label use and are often preferentially prescribed over carboplatin at centers where 
detection of these alterations is feasible.  Nonetheless, many questions remain in the utility of 
PARP inhibitors, including a better understanding of patients likely to respond, the proper 
sequencing/combination of this agent with others, and mechanisms of resistance.  
A variety of mechanisms have been proposed for how tumors that are resistant to PARP 
inhibition could remain sensitive to platinum agents, including loss of 53BP1, which leads to 
increased double strand break resection and thus leads to resistance to PARP inhibition in Brca1-
null cells, but maintenance of sensitivity to DNA-crosslinking agents25;  BRCA1 mutations that 
lead to defects in alternate DNA repair pathways such as nucleotide excision repair but retain 
proficiency in homologous recombination repair26; and mutation of other genes involved in 
nucleotide excision repair such as ERCC6 and ERCC4.27 As such, carboplatin remains a 
relevant agent in mCRPC and may lead to clinical responses even in patients who progress on a 
PARP inhibitor.
2.4
Rationale
ATR inhibition is selectively toxic in cells with high levels of replication stress induced by 
oncogenes (e.g. Ras isoforms, Myc, Cyclin E), hypoxia, and exogenous administration of 
chemotherapeutics.  In particular, platinum compounds increase replication stress by modifying 
DNA to produce intra- and inter-strand crosslinks between nucleotide bases.  Intra-strand
crosslinks induce DNA lesions in the template strand as well as misincorporate nucleotides, 
while inter-strand crosslinks induce defects in DNA unwinding—the very first step of DNA 
replication.  These crosslinks will delay the progression of replication forks and enhance 
replicative stress.  In pre-clinical studies, ATR inhibitor M6620 (VX-970, berzosertib) is
synergistic with a variety of DNA damaging agents in cancer cell lines, but the synergy was 
found to be most pronounced with cisplatin.14 In addition, M6620 (VX-970, berzosertib) was
found to enhance the therapeutic efficacy of cisplatin in patient-derived lung tumor xenografts.
We conjecture that the combination of carboplatin with M6620 (VX-970, berzosertib) would
provide clinical benefit to patients with metastatic castration-resistant prostate cancer with 
homologous recombination deficiency (even those who received prior PARP inhibitor) and a 
larger group of patients without HRD due to alternate mechanisms of action of carboplatin and 

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the synergistic activity of M6620 (VX-970, berzosertib) with platinum compounds related to 
induction of replication stress.
The recommended Phase II dose of M6620 (VX-970, berzosertib) in combination with 
carboplatin was informed by Part B of Study VX13-970-002 (Study 002).  Initial results of this 
study were reported at the 2016 ASCO Annual Meeting.28 M6620 (VX-970, berzosertib) was
tolerated as a single agent with mostly grade 1/grade 2 toxicities and no dose-limiting toxicities 
(DLTs), and the recommended Phase 2 dose of the single agent was 240 mg/m2.  Among 11 
treated patients, a patient with ATM loss colorectal cancer had RECIST complete response (19 
months+) and 4 pts had RECIST stable disease (SD).  In the combination of M6620 (VX-970,
berzosertib) + carboplatin, dose escalation was limited by neutropenia and/or thrombocytopenia.  
The recommended Phase 2 dose of the combination was carboplatin AUC 5 day 1 and M6620
(VX-970, berzosertib) 90 mg/m2 days 2,8 of a 21 day cycle.  Among 15 patients treated with the 
combination, a patient with germline BRCA1 mutant and platinum-refractory, PARP inhibitor-
resistant ovarian cancer with a somatic Y220C TP53 mutation had RECIST partial response for 6 
months and 8 pts had RECIST SD. We will thus compare the response rate of this combination 
against a standard docetaxel + carboplatin combination regimen20 in patients with metastatic 
CRPC.
2.5
Correlative Studies Background
2.5.1
Whole exome sequencing through Molecular Characterization (MoCha) laboratory at the 
Frederick National Laboratory for Cancer Research
Mandatory pre-treatment tumor biopsy specimens will be submitted for whole exome sequencing 
through the Molecular Characterization (MoCha) laboratory at the Frederick National Laboratory 
for Cancer Research. We plan to assess for the presence of homologous recombination repair 
deficiency as detected by a bone fide deleterious mutation or deletion in a gene known to be 
involved in homologous recombination repair from a fresh tumor biopsy.  In addition, whole
exome sequencing using the same assay will be performed from optional end of study tumor 
biopsies to assess for mediators of resistance.
This analysis is critical to understanding the relationship of response to carboplatin +/- M6620
(VX-970, berzosertib) with DNA damage repair defects detected in patients with metastatic 
CRPC.  Specifically, we would hypothesize that:
1. Patients with HRD who are previously untreated with PARPi or carboplatin would be 
expected to respond to either docetaxel+carboplatin or M6620 (VX-970, berzosertib) +
carboplatin.
2. Patients with HRD who were previously treated with PARPi and are found to have a 
secondary mutation in a gene involved in an alternate DNA damage repair pathway (such 
as nucleotide excision repair)27 would be expected to respond to docetaxel+carboplatin or 
M6620 (VX-970, berzosertib)+carboplatin.
3. Patients with HRD who were previously treated with PARPi and are found to have a 
reversion mutation in the gene originally conferring HRD (and thus no longer possessing 
an HRD phenotype) would not be expected to respond to docetaxel+carboplatin but could 

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respond to the combination of M6620 (VX-970, berzosertib)+carboplatin due to 
synergistic activity related to induction of replication stress.
4. Patients without HRD or other DNA damage repair defects would not be expected to 
respond to docetaxel+carboplatin but could respond to the combination of 
carboplatin+M6620 (VX-970, berzosertib) due to synergistic activity related to induction 
of replication stress.
Genetic alterations detected from end of study circulating free DNA or the optional end of study 
biopsy would allow us to understand mechanisms of resistance to carboplatin+M6620 (VX-970,
berzosertib) and thus design therapeutic strategies based on these mechanisms.
2.5.2
Tumor profiling from circulating free DNA (cfDNA)
DNA derived from tumor tissues can be detected in circulating free DNA (cfDNA) 
isolated from plasma from patients with metastatic cancer.  We plan to perform whole genome 
sequencing at 0.1x coverage, termed ultra-low pass whole genome sequencing (ULP-WGS).
The sequencing information derived from ULP-WGS can be used to identify copy number 
alterations (CNA) in the tumor using ichorCNA29, a probabilistic model that is an adaptation of 
TITAN.30 While other algorithms for assessing copy number changes from cfDNA have been 
described31,32, ichorCNA has the advantage of accounting for mixtures of cell populations to 
assess for subclonal events, while also estimating the fraction of DNA derived from tumor cells 
rather than normal tissues.
Our model can also use ULP-WGS to estimate the fraction of circulating free DNA 
derived from tumor rather than normal tissues (“tumor fraction”) based on an assumption that the 
cancer cells derive from a common precursor and thus have at least one truncal copy number 
alteration (other alterations being subclonal).  We estimate the lower limit for detection of tumor 
derived DNA by this method to be approximately 3%.  The tumor purity estimated by ULP-
WGS using ichorCNA demonstrates close concordance with that estimated from whole exome 
sequencing using a different method for deriving tumor fraction from somatic DNA alterations 
called ABSOLUTE33, thus validating this method for quantification.
This exploratory analysis will allow us to assess for the relationship of copy number 
alterations detected in cfDNA (particularly deletions in ATM and BRCA2) and tumor fraction at
baseline with response to therapy.  Changes in tumor fraction with treatment and then resistance 
to therapy could serve as an additional biomarker of response and resistance.
In addition, we plan to perform targeted next generation sequencing from circulating free 
DNA at baseline, at crossover (for patients randomized to arm A), and at end of study.  We have 
designed a custom bait set specifically for prostate cancer including allowing for identification of 
SSNVs in all genes known to be recurrently mutated in metastatic prostate cancer34, genes 
involved in DNA damage repair35, as well as sequencing of intronic and intergenic regions of 
genes known to be translocated or have complex structural alterations in prostate cancer (AR36,
ERG, TMPRSS2, ETV1, ETV4, SLC45A3, RAF1, PTEN, MSH2, MSH637).  This analysis will 
allow us to determine if genetic alterations detected in pre- and post-treatment tumor specimens 

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can be detected in cfDNA.  This analysis may also allow us to better sample global tumor burden 
better than a single biopsy due to tumor heterogeneity. In addition, longitudinal monitoring of 
cfDNA from patients while on study will allow us to monitor clonal dynamics over time.
Whole genome sequencing from cfDNA can be used to assess homologous 
recombination repair deficiency using an algorithm called DirectHRD.38 DirectHRD is a whole-
genome sequencing (WGS) scar-based classifier that makes use of a specific type of genomic 
scar–a small, microhomology deletion (mhDel) believed to be the direct evidence of 
microhomology-mediated end joining in the absence of HR due to its superior classification 
power and low error rate in next generation sequencing (NGS).39 We have demonstrated that 
DirectHRD is 10x more sensitive than state-of-the-art methods and can detect HRD at >=1% 
tumor fraction using 50x WGS of cell-free DNA.
2.5.3
RAD51 focus formation assay
Homologous recombination (HR) repair deficiency confers sensitivity to platinum-based 
chemotherapeutic agents and inhibitors of poly(ADP-ribose) polymerase (PARP). To date, the 
identification of tumors with impaired HR has relied on genomic features, including mutational 
signature, LOH-based HRD assays or gene expression analyses defining ‘BRCAness’. These 
tests analyze history of the tumor rather than providing a functional assessment of HR status at 
the time of diagnosis. Therefore, development of a functional assay for HR status in tumors is 
essential to make accurate treatment decisions. 
We have described a RAD51-based immunohistochemical (IHC) assay that identifies HR status
(Kochupurakkal BS, et al. AACR 2017 Abstract #2796). The presence or absence of RAD51 foci 
in cell lines and PDX models correlated with olaparib sensitivity and not with BRCA mutation 
status. Therefore, tumors that are HR-deficient and PARP inhibitor-sensitive are characterized by 
either high RAD51 nuclear staining without foci, or absence of RAD51 staining. We thus plan to 
assess RAD51 focus formation from biopsy specimens from patients participating in this trial to 
understand if this assay could serve as a superior or complementary biomarker to HRD+ status 
(by genomic characterization) in predicting for response to carboplatin in combination with 
docetaxel or M6620 (VX-970, berzosertib).
2.5.4
ATM and p-KAP1 Immunohistochemistry
The Ataxia Telangiectasia Mutated (ATM) and Ataxia telangiectasia and Rad3 related (ATR) 
serine/threonine kinases are both involved in the response to DNA damage, though ATM is 
primarily involved in the response to double strand breaks (DSBs) in DNA while ATR is 
involved in the response to a wide range of perturbations leading to DNA damage and replication 
defects.  These kinases appear to share a synthetic lethal relationship, as cells deficient in ATM 
expression have been shown to be sensitive to ATR inhibition in mantle cell lymphoma40, CLL41
and gastric cancer42,43 models.  In cell lines, the majority of cell lines sensitive to the ATR 
inhibitor BAY-1895344 were characterized by mutations in the ATM pathway.44
We have demonstrated that ATM-deficient human fibroblasts cell lines are sensitive to ATR 

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inhibition, and this sensitivity can be reversed by complementation with wild-type ATM.  We 
have also demonstrated in gastric cancer cell lines that ATM deficiency predicts for sensitivity to 
ATR inhibition, and we developed an immunohistochemistry assay for ATM demonstrating in 
208 primary gastric tumors that ATM expression is absent in 11% of samples with very low 
expression in 26%.43 As ATM alterations are highly enriched in mCRPC compared with 
locoregional prostate cancer45,46, targeting ATM alterations through inhibition of ATR is a 
promising therapeutic strategy in mCRPC.47
KAP1 (KRAB [Kruppel-Associated Box Domain]-Associated Protein 1) is a protein that in 
humans is encoded by the TRIM28 gene. KAP1 is phosphorylated by ATM in response to DNA 
damage.16,48 Unpublished data from the laboratory of Dr. Alan D’Andrea suggests that high 
basal levels of p-KAP1 (which is an indicator of DNA replication stress) in unirradiated tissue 
may also predict for sensitivity to an ATR inhibitor. 
2.5.5
RNA-Seq for RB loss of function
Recent data from patients with mCRPC identified RB genetic aberrations as the strongest 
predictor of poor outcome.49 Currently there is no therapeutic option to provide durable response 
in patients with RB loss-of function (LOF). The laboratory of Dr. Leigh Ellis has completed a 
genome-scale CRISPR-Cas9 pooled selection screen to identify genes that are required for 
proliferation or survival of an Rb-deficient prostate cancer cell line derived from an Rb-deficient
mouse model. The results from this screen have identified the ATR repair pathway as a 
vulnerability of RB-deficient cells. RB function may be a better predictor of M6620 (VX-970,
berzosertib) response than genomic RB loss, so RNA sequencing from pre-treatment tumor 
specimens would allow us to identify patients with decreased RB function due to a signature 
score derived from target gene expression. The Ellis lab has received funding through an RO1 
application to the NCI to assess whether RB functional status, at the DNA and/or functional 
level, can predict superior response to ATR inhibition combined with carboplatin compared to 
carboplatin combined with docetaxel.
3. PATIENT SELECTION
3.1
Eligibility Criteria 
3.1.1
Participants must have histologically or cytologically confirmed prostate cancer 
(code 10036910) with progressive disease at the time of study entry by either
x
Sequence of at least 2 rising PSA values at a minimum of 1-week intervals 
x
Radiographic progression per RECIST1.1 for soft tissue and/or per PCWG32
for bone, with or without PSA progression.

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3.1.2
Patients must have metastatic disease by bone scan or other nodal or visceral lesions 
on CT or MRI and a castrate level of testosterone (<50ng/dL) and evaluable for 
disease response by either
x
Baseline PSA ≥ 2.0 ng/mL OR
x
Measurable disease per RECIST 1.1
NOTE: Subjects must maintain a castrate state. If they have not had an orchiectomy,
they must continue to receive LHRH or GnRH agonists or antagonists unless 
intolerant.
3.1.3
At least 2 prior treatments for prostate cancer (in either hormone sensitive or 
castration-resistant disease) as follows:
x
Past progression or intolerance to at least one secondary hormonal therapy 
(abiraterone, enzalutamide, galeterone, apalutamide, darolutamide, orteronel, 
seviteronel or equivalent) 
x
Past progression or intolerance to taxane-based chemotherapy 
3.1.4
Age ≥18 years.  Children are excluded from this study as prostate cancer is a disease 
of adults
3.1.5
ECOG performance status ≤1 (Karnofsky ≥70%, see Appendix A).
3.1.6
Patients must have normal organ and marrow function as defined below:

leukocytes 
≥3,000/mcL

absolute neutrophil count ≥1,500/mcL

hemoglobin
≥9 g/dL (transfusion permitted)

platelets 
≥150,000/mcL (without transfusion or growth factor in 
prior 28 days)

total bilirubin
≤1.5 × institutional upper limit of normal, unless the 
subject has known or suspected Gilbert’s syndrome

AST(SGOT)/ALT(SGPT) ≤2.5 × institutional upper limit of normal or ≤5 × upper 
limit of normal if presence of liver metastases

creatinine clearance 
≥40 mL/min/1.73 m2
3.1.7
Prior treatment with mTOR inhibitors, cytostatic TKI, or biologic therapies allowed
3.1.8
Prior treatment with PARP inhibitors permitted.
3.1.9
Patients with allergy or intolerance to docetaxel or Grade 2 neuropathy are allowed on 
study, but if randomized to Arm A will receive carboplatin as a single agent (AUC 5) 
rather than docetaxel+carboplatin. They must be fit for carboplatin chemotherapy as 
determined by the treating investigator.

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3.1.10 Presence of a lesion (bone or soft tissue) amenable to image-guided percutaneous 
biopsy adequate for next generation sequencing (NGS), and planned to undergo core 
biopsy after trial registration but prior to cycle 1 day 1 of therapy. Confirmation of 
adequacy of this biopsy material for NGS is NOT required for initiation of therapy. If
elective biopsies are not being performed at the treating institution due to preparations 
or precautions related to COVID-19, this requirement can be waived on discussion 
with the trial PI.
3.1.11 The effects of M6620 (VX-970, berzosertib), carboplatin and docetaxel on the 
developing human fetus are unknown. For this reason and because DNA-damage 
response inhibitors and chemotherapeutic agents are known to be teratogenic, men 
must agree to use adequate contraception (hormonal or barrier method of birth 
control; abstinence) prior to study entry and for the duration of study participation.  
Should a woman become pregnant or suspect she is pregnant while 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 6 months after 
completion of carboplatin and M6620 (VX-970, berzosertib) administration.
3.1.12 Ability to understand and the willingness to sign a written informed consent 
document.
3.2
Exclusion Criteria
3.2.1
Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for 
nitrosoureas or mitomycin C) prior to planned cycle 1 day 1 of study treatment.
Patients on an oral anti-neoplastic such as an oral hormonal agent, PARP inhibitor 
or oral experimental agent should discontinue >=14 days prior to planned cycle 1 
day 1 of study treatment.
3.2.2
Patients who have not recovered from adverse events due to prior anti-cancer 
therapy (i.e., have residual toxicities > Grade 1), except for Grade 2 anorexia, 
alopecia, neuropathy, and fatigue, for which resolution is not required.
3.2.3
Patients who are receiving any other investigational agents.
3.2.4
Patients with known brain metastases or leptomeningeal disease should be 
excluded from this clinical trial because of their poor prognosis and because they 
often develop progressive neurologic dysfunction that would confound the 
evaluation of neurologic and other adverse events.

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3.2.5
History of allergic reactions attributed to compounds of similar chemical or 
biologic composition to M6620 (VX-970, berzosertib) or carboplatin. (Patients 
with allergy to docetaxel will be allowed on study, but docetaxel will be excluded 
from their treatment regimen.)
3.2.6
Subjects receiving treatment with ototoxic or nephrotoxic medications that cannot 
be discontinued at least 7 days before first dose of carboplatin and for the duration 
of the study. Inadvertent or short-term use on study will not cause a subject to be 
ineligible. If a short course of therapy with nephrotoxic or ototoxic medication is 
anticipated and required, carboplatin should be discontinued until 7 days after this 
course is completed. Patients on continuous medications that are potentially 
nephrotoxic who have had no evidence of nephrotoxicity from these medications 
at study entry are allowed to continue those medicines on trial.
M6620 (VX-970, berzosertib) is primarily metabolized by CYP3A4; therefore, 
concomitant administration with strong inhibitors of CYP3A4 (e.g., ketoconazole, 
itraconazole, clarithromycin, ritonavir, indinavir, nelfinavir and saquinavir) or 
inducers of CYP3A4 (e.g. rifampin, phenytoin, carbamazepine, phenobarbital, St. 
John’s Wort) is prohibited.  Because the lists of these agents are constantly 
changing, it is important to regularly consult a frequently-updated medical 
reference for a list of drugs to avoid or minimize use of.  APPENDIX C (Patient 
Drug Information Handout and Wallet Card) should be provided to patients.  As 
part of the enrollment/informed consent procedures, the patient will be counseled 
on the risk of interactions with other agents, and what to do if new medications 
need to be prescribed or if the patient is considering a new over-the-counter 
medicine or herbal product.
3.2.7
Uncontrolled intercurrent illness including, but not limited to, ongoing or active 
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac 
arrhythmia, or psychiatric illness/social situations that would limit compliance 
with study requirements.
3.2.8
Pregnant and nursing women are excluded from this study because they do not 
develop prostate cancer.
3.2.9
HIV-positive participants with detectable viral load and/or CD4 count ≤300 are 
ineligible due to increased risk of lethal infections when treated with marrow-
suppressive therapy.  HIV-positive patients with undetectable viral loads and CD4 
counts >300, and not on interacting antiretroviral therapy may be eligible after 
discussing with the principal investigator.  
3.2.10 Prior treatment with platinum-containing regimen or ATR inhibitor for prostate 
cancer

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following five criteria to complete processing of the IRB/REB approval record:
x
Holds an Active CTEP status,
x
Rostered at the site on the IRB/REB approval (applies to US and Canadian sites only) and 
on at least one participating roster,
x
If using NCI CIRB, rostered on the NCI CIRB Signatory record,
x
Includes the IRB number of the IRB providing approval in the Form FDA 1572 in the 
RCR profile, and
x
Holds the appropriate CTEP registration type for the protocol. 
Additional Requirements
Additional requirements to obtain an approved site registration status include:
x
An active Federalwide Assurance (FWA) number,
x
An active roster affiliation with the Lead Protocol Organization (LPO) or a Participating 
Organization, and
x
Compliance with all protocol-specific requirements (PSRs).
4.2.1
Downloading Regulatory Documents
Download the site registration forms from the protocol-specific page located on the CTSU 
members’ website.  Permission to view and download this protocol and its supporting documents 
is restricted based on person and site roster assignment.  To participate, the institution and its 
associated investigators and staff must be associated with the LPO or a Participating 
Organization on the protocol. 
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-MA036, and 
protocol number 10191,
x
Click on Documents, select Site Registration, and download and complete the forms 
provided.  (Note:  For sites under the CIRB initiative, IRB data will load automatically to 
the CTSU as described above.) 
4.2.2
Requirements For NCI protocol # 10191 Site Registration:
x
Site Initiation Visit
x
Specimen Tracking System Training Requirement:
x
All data entry users (Clinical Research Associate role) at each participating 

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site will need to complete the Theradex-led training.
x
Theradex will provide a certificate of completion, which will need to be 
submitted to the CTSU through the Regulatory Submission Portal.
x
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.
x
This training will need to be completed before the first patient enrollment at 
a given site.
x
Please contact STS Support at Theradex for the training 
(STS.Support@theradex.com, Theradex phone: 609-799-7580).
4.2.3
Submitting Regulatory Documents
Submit required forms and documents to the CTSU Regulatory Office via the Regulatory 
Submission Portal on the CTSU website. 
To access the Regulatory Submission Portal, log on to the CTSU members’ website Æ
Regulatory Æ Regulatory Submission.
Institutions with patients waiting that are unable to use the Regulatory Submission Portal should 
alert the CTSU Regulatory Office immediately at 1-866-651-2878 in order to receive further 
instruction and support.
4.2.4
Checking Site Registration Status
You can verify your site’s registration status on the members’ side of the CTSU website. 
x
Log on to the CTSU members’ website
x
Click on Regulatory at the top of your screen
x
Click on Site Registration 
x
Enter your 5-character CTEP Institution Code and click on Go
Note:  The status shown only reflects institutional compliance with site registration requirements 
as outlined above.  It does not reflect compliance with protocol requirements for individuals 
participating on the protocol or the enrolling investigator’s status with the NCI or their affiliated 
networks.

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4.3
Patient Registration
4.3.1
OPEN / IWRS
The Oncology Patient Enrollment Network (OPEN) is a web-based registration system available 
on a 24/7 basis.  OPEN is integrated with CTSU regulatory and roster data and with the 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:  Be on an LPO roster, ETCTN 
Corresponding roster, or Participating Organization roster with the role of Registrar.  
Registrars must hold a minimum of an AP registration type.
x
Have an approved site registration for a protocol prior to patient enrollment.
To assign an Investigator (IVR) or Non-Physician Investigator (NPIVR) as the treating, 
crediting, consenting, drug shipment (IVR only), or receiving investigator for a patient transfer in 
OPEN, the IVR or NPIVR must list the IRB number used on the site’s IRB approval on their 
Form FDA 1572 in RCR.  If a DTL is required for the study, the IVR or NPIVR must be 
assigned the appropriate OPEN-related tasks on the DTL.
Prior to accessing OPEN, site staff should verify the following:
x
Patient has met all eligibility criteria within the protocol stated timeframes, and 
x
All patients have signed an appropriate consent form and HIPAA authorization form (if
applicable).
Note: The OPEN system will provide the site with a printable confirmation of registration and 
treatment information. Please print this confirmation for your records.
Access OPEN at https://open.ctsu.org or from the OPEN link on the CTSU members’ website.  
Further instructional information is in the OPEN section of the CTSU website at 
https://www.ctsu.org or https://open.ctsu.org.  For any additional questions, contact the CTSU 
Help Desk at 1-888-823-5923 or ctsucontact@westat.com.

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4.3.2
Special Instructions for Patient Enrollment
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 special Rave user roles:  “CRA Specimen Tracking” 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 under the Rave/DQP tab.
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 can be found in Section Error! Reference source not found..
4.3.3
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.
4.4
General Guidelines
Following registration, patients should begin protocol treatment within 5 days.  Issues that would 
cause treatment delays should be discussed with the Principal Investigator.  If a patient does not 
receive protocol therapy following registration, the patient’s registration on the study may be 
canceled.  The Study Coordinator should be notified of cancellations as soon as possible.
5. TREATMENT PLAN
5.1
Agent Administration
M6620 (VX-970, berzosertib), carboplatin and docetaxel will be administered every 3 weeks, 
with 21 consecutive days defined as a treatment cycle. Treatment will be administered on an 
outpatient basis.  Reported adverse events and potential risks are described in Section 7.  
Appropriate dose modifications are described in Section 6.  No investigational or commercial 
agents or therapies other than those described below may be administered with the intent to treat 
the participant's malignancy.

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Arm A: Docetaxel + Carboplatin
Agent
Premedications; 
Precautions
Dose
Route***
Schedule
Cycle
Length
Docetaxel
Corticosteroid
premedication per 
institutional standard
60 mg/m2
administered 
per 
institutional 
guidelines
IV over 60 
minutes (± 10 
minutes)
Day 1
21 days 
(3 weeks)
Carboplatin Must be administered 
after docetaxel
Antiemetics should be 
administered per 
institution guidelines.
AUC 4
administered 
per 
institutional 
guidelines
IV over 30 
minutes (± 25% 
planned 
infusion time)
Day 1
21 days 
(3 weeks)
Arm A: Carboplatin alone (for Docetaxel-ineligible)
Agent
Premedications; 
Precautions
Dose
Route***
Schedule
Cycle
Length
Carboplatin Antiemetics should be 
administered per 
institution guidelines.
AUC 5
administered 
per 
institutional 
guidelines
IV over 30 
minutes (± 25% 
planned 
infusion time)
Day 1
21 days 
(3 weeks)
Arm B and Arm A crossover: M6620 (VX-970, berzosertib) + Carboplatin
Agent
Premedications; 
Precautions
Dose
Route***
Schedule
Cycle
Length
Carboplatin Antiemetics should be 
administered per 
institution guidelines.
AUC 5
administered 
per 
institutional 
guidelines
IV over 30 
minutes (± 25% 
planned 
infusion time)
Day 1
21 days 
(3 weeks)
M6620
(VX-970,
berzosertib)
For Day 2 dose, initiate 
~24 h (± 4 h) after 
cessation of carboplatin 
infusion.
Premedicate with 
hydrocortisone 100 mg 
IV (or oral equivalent 
if intravenous 
90 mg/m2  in 
D5W to a 
final 
concentration
between
0.075 mg/ml 
to 1 mg/ml
IV over 60 
minutes (± 10 
minutes) for
volumes < 600 
mL.  For 
volumes 600 –
900 mL, 
administer at 10 
Days 2 and 
9

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formulation is 
unavailable or IV 
administration is not 
feasible) ~ 60 mins (± 
15 min) before M6620
(VX-970, berzosertib) 
infusion, and 25 mg 
diphenhydramine IV
(or oral equivalent if 
intravenous 
formulation is 
unavailable or IV 
administration is not 
feasible) ~ 30 min (± 
10 min) before M6620
(VX-970, berzosertib) 
infusion
mL/min; for 
volumes > 900 
mL, administer 
over 90 min.
5.1.1
M6620 (VX-970, berzosertib)
Study drug may be dispensed only under the supervision of the investigator or an authorized 
designee and only for administration to the study subjects.  M6620 (VX-970, berzosertib) will be 
supplied as 20 mg/mL M6620 (VX-970, berzosertib) (in betadex sulfobutyl ether and acetate 
buffer) to be diluted in D5W before intravenous infusion.
M6620 (VX-970, berzosertib) solution will be constituted into the individual dosing containers 
by a qualified pharmacist. Details of dose preparation are listed in Section 8.1.7. Body surface 
area (BSA) is to be calculated per institutional standards of practice. In the event of changes in 
participant weight, institutional standards of practice should be followed for dose re-calculations.
The dose of M6620 (VX-970, berzosertib) will be infused intravenously over 60 minutes (± 10 
minutes). When the total volume of infusion exceeds 600 mL, the infusion time may be extended 
beyond 60 minutes (as tolerated), but no more than 90 minutes. If the infusion volume is 600 –
900 mL, the M6620 (VX-970, berzosertib) solution should be infused at 10 mL/minute; if the 
volume is >900 mL then it should be infused over 90 minutes. Details of dose administration for
M6620 (VX-970, berzosertib) are listed in section 8.1.1.11 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 (VX-970, berzosertib) should not 
come in contact with 0.9% Sodium Chloride due to incompatibility.
Intravenous administration of M6620 (VX-970, berzosertib) is independent of food intake. When 
M6620 (VX-970, berzosertib) is given the day after chemotherapy (i.e., Day 2) infusion of 
M6620 (VX-970, berzosertib) should be initiated approximately 24 hours (± 4 hours) after 
cessation of carboplatin infusion. 

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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. The 
intravenous infusion site should be monitored closely for the development of erythema, 
induration, purulence, tenderness, or warmth. If any subject develops phlebitis, or signs or 
symptoms of inflammation that may progress to phlebitis or that the patient cannot tolerate, 
standard measures should be employed to ameliorate these symptoms (including removal of the 
infusion catheter and resumption of infusion through a different vein).
Based on the observation of acute hypersensitivity in the Phase I trial, we will plan to 
premedicate with 100 mg hydrocortisone intravenously (or oral equivalent if intravenous 
formulation is unavailable or IV administration is not feasible) approximately 60 minutes (± 15 
minutes) before M6620 (VX-970, berzosertib) infusion, and 25 mg of diphenhydramine 
intravenously (or oral equivalent if intravenous formulation is unavailable or IV administration is 
not feasible) approximately 30 minutes (± 10 minutes) before M6620 (VX-970, berzosertib) 
infusion. In addition, treatment with an H2-blocker (e.g., ranitidine) may be considered for 
subjects not responsive to a regimen with an H1-blocker.
If standard procedures to limit symptoms of injection site reaction, or pruritus or acute 
hypersensitivity are insufficient, then the infusion time may be extended beyond 60 minutes, but 
no more than 90 minutes.
Treatment with granulocyte colony stimulating factors is not routinely recommended for patients 
receiving carboplatin + M6620 (VX-970, berzosertib), however can be used if felt to be indicated 
per investigator discretion.  Recommended timing of filgrastim (or biosimilar) is daily dosing 
starting the day after the second M6620 (VX-970, berzosertib) infusion (usually day 10) with last 
dose > 10 days prior to day 1 of the next cycle.  If pegfilgrastim (or biosimilar) is preferred, this 
should be administered the day after the second M6620 (VX-970, berzosertib) infusion (usually 
day 10), and day 1 of the next cycle should be > 10 days from pegfilgrastim (or biosimilar) dose.  
If the day 9 M6620 (VX-970, berzosertib) dose is skipped, filgrastim/pegfilgrastim (or 
biosimilar) can be initiated at visit for planned day 9.
5.1.2
Carboplatin
The subject specific dose should be calculated using the modified Cockcroft-Gault method per 
institutional policy for AUC calculation Carboplatin should be administered per institutional 
standards.
When administered as sequential infusions, docetaxel should be administered before the 
carboplatin to limit myelosuppression and to enhance efficacy. Time interval between docetaxel 
and carboplatin infusions is per institutional standard.
Acceptable window for infusion: ± 25% of the planned infusion time.
Anti-emetics and supportive therapies will be administered or dispensed to subjects for use in 

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combination with carboplatin according to individual site SOC. Anti-emetics and growth factors 
can be used per institutional guidelines for standard chemotherapy. (See section 5.1.1 for 
recommended timing of granulocyte colony stimulating factors in relation to M6620 (VX-970,
berzosertib) infusions for patients receiving carboplatin in combination with M6620 (VX-970,
berzosertib)). If a participant has an infusion reaction to carboplatin, standard of care for 
rechallenge should be followed.  
5.1.3
Docetaxel
Docetaxel should be prepared and administered per institutional standards or package insert. For 
one vial preparation: 
1. Docetaxel vials should be stored at room temperature, 25°C (77°F), and protected from light.
2. Aseptically withdraw the required amount of docetaxel injection concentrate (20 mg/mL) with 
a calibrated syringe and inject into a 250 mL infusion bag of either 0.9% Sodium Chloride 
solution to produce a final concentration of 0.3 to 0.74 mg/mL. If a dose greater than 200 mg of 
docetaxel is required, use a larger volume of the infusion vehicle so that a concentration of 0.74 
mg/mL docetaxel is not exceeded. Body surface area (BSA) is to be calculated per institutional 
standards of practice. In the event of changes in participant weight, institutional standards of 
practice should be followed for dose re-calculations.3. Thoroughly mix the infusion by manual 
rotation. 
4. Attach non-PVC, DEHP-free tubing 
5. As with all parenteral products, docetaxel should be inspected visually for particulate matter or 
discoloration prior to administration whenever the solution and container permit. If the docetaxel 
injection concentrate or final dilution for intravenous infusion is not clear or appears to have 
precipitation, these should be discarded. 
6. The final docetaxel dilution for infusion should be administered intravenously as a 1-hour
infusion (+/- 10 min) under ambient room temperature and lighting conditions. Docetaxel may be 
administered according to institutional standards or package insert.
Standard corticosteroid pre-medication per institutional standards should be administered (e.g.
dexamethasone 8 mg orally twice daily the day before, day of and day after docetaxel; 
dexamethasone 12 mg or methylprednisolone 50 mg IV bolus prior to docetaxel)
Anti-emetics and supportive therapies will be administered or dispensed to subjects for use in 
combination with docetaxel according to individual site SOC. Anti-emetics and growth factors 
can be used per institutional guidelines for standard chemotherapy. If a participant has an 
infusion reaction to docetaxel or carboplatin, standard of care for rechallenge should be 
followed.  
5.2
General Concomitant Medication and Supportive Care Guidelines
M6620 (VX-970, berzosertib) is metabolized by cytochrome P450 (CYP) 3A4 isoenzyme 
(CYP3A4); exposure to M6620 (VX-970, berzosertib) may be affected by concomitantly 
administered drugs that are strong inhibitors or inducers of CYP3A4.  Because there is a 
potential for interaction of M6620 (VX-970, berzosertib), carboplatin and docetaxel with other 
concomitantly administered drugs, the case report form must capture the concurrent use of all 

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other drugs, over-the-counter medications, or alternative therapies.  The Principal Investigator 
should be alerted if the patient is taking any agent known to affect or with the potential for drug 
interactions. The study team should check a frequently-updated medical reference for a list of 
drugs to avoid or minimize use of.  Appendix C (Patient Drug Information Handout and Wallet 
Card) should be provided to patients if available.
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.  
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.  The 
intravenous infusion site should be monitored closely for the development of erythema, 
induration, purulence, tenderness, or warmth.
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.
Palliative radiation is permitted for patients on trial.  Radiation should be initiated at least 14 
days after carboplatin is administered (i.e. day 15 of a cycle or after). Trial therapy is to be held 
until radiation treatment is completed, and can be resumed at least 7 days after last fraction of 
radiation.
5.3
Crossover
Patients randomized to arm A who have documented PSA progression (by PCWG2 criteria1) or
radiographic progression (by PCWG3 criteria2) should not receive further doses of treatment on 
the control arm (carboplatin+docetaxel or carboplatin alone).  Patients should be re-screened for 
meeting eligibility criteria for the protocol and the treating investigator must feel that the patient 
is appropriate for continued carboplatin therapy to crossover to the experimental arm of 
carboplatin+M6620 (VX-970, berzosertib). If a patient required a dose reduction on the control 
arm, they should initiate treatment with the experimental regimen at the same dose level per 
Table 6-1 (e.g. if a patient required dose reduction to the -2 dose level on the control arm, they 
should be treated at the -2 dose level of the experimental arm at the time of crossover).  If
patients do not meet criteria for crossover, they will be discontinued from study, but can continue 
carboplatin +/- docetaxel per standard of care per investigator discretion.
PSA progression by PCWG2 criteria1 is defined as the date that a 25% or greater increase and an 
absolute increase of 2 ng/mL or more from the nadir is documented, which is confirmed by a 
second value obtained 3 or more weeks later. Thus, for example if a patient has a PSA increase 
of 25% with an absolute increase of 2 ng/mL from nadir on labs obtained prior to C5D1, they 
should be advised that if this increase is confirmed prior to C6D1 then they will not receive 
C6D1 carboplatin +/- docetaxel treatment.  In this circumstance, carboplatin +/- docetaxel should 

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not be administered until pre-C6D1 PSA value returns (and is administered only if PSA 
progression is NOT confirmed).
Cycle 1 day 1 [crossover] of carboplatin+M6620 (VX-970, berzosertib) can be scheduled as soon 
as eligibility is confirmed, and should be scheduled within 42 days of the last dose of carboplatin 
+/- docetaxel.  Imaging studies should be repeated if not performed within 30 days of C1D1 
[crossover].
5.4
Duration of Therapy
In the absence of treatment delays due to adverse event(s), treatment may continue indefinitely
or until one of the following criteria applies:
x
Disease progression by PCWG3 criteria,2 including clinical progression. Patients 
should not be discontinued from study therapy for PSA progression alone (but
patients initially randomized to Arm A will cross over to the experimental arm at PSA 
progression or radiographic progression if eligible.) For patients initially randomized 
to Arm B, or those who cross over after PSA/radiographic progression on Arm A, 
PCWG3 criteria allow treatment beyond radiographic progression if the treating 
physician feels that the patient is continuing to derive clinical benefit from therapy, 
and the patient will continue until felt to be “no longer clinically benefiting” (NLCB).
x
Intercurrent illness that prevents further administration of treatment
x
Unacceptable adverse event(s)
x
Patient decides to withdraw from the study
x
General or specific changes in the patient's condition render the patient unacceptable 
for further treatment in the judgment of the investigator
x
Patient non-compliance
x
Termination of the study by sponsor
x
The drug manufacturer can no longer provide the study agent
The reason(s) for protocol therapy discontinuation, the reason(s) for study removal, and the 
corresponding dates must be documented in the Case Report Form (CRF).
5.5
Duration of Follow Up
An end of treatment and safety assessment should be performed 30-42 days after the last dose 
of study treatment to include any adverse events occurring within 30 days after the last dose of 

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study treatment. In the event subjects cannot be seen for the end treatment safety assessment at 
the site of enrollment due to the ongoing COVID-19 situation or other extenuating 
circumstances, safety assessments may be conducted at alternate locations if these assessments 
are deemed of adequate quality by the treating investigator.
Participants who stop study treatment prior to the time recommended in the protocol will 
continue follow-up visits according to the protocol.
If a patient wishes to stop the study visits, they will be requested to allow their ongoing health 
status to be periodically reviewed via continued study visits or phone contact or from their 
general practitioner, or medical records, country/region specific cancer and/or mortality 
registries.
6. DOSING DELAYS/DOSE MODIFICATIONS
Dose delays and modifications will be made as indicated. The descriptions and grading scales 
found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
5.0 will be utilized for dose delays and dose modifications. A copy of the CTCAE version 5.0
can be downloaded from the CTEP website
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.
Guidelines for dose modification for toxicity are provided below. The final dose reduction or 
delay for each subject may be determined by the investigator and sponsor. However, these 
guidelines provide the minimum dose reduction or delay criteria. Patients may hold treatment up 
to 3 weeks (i.e. day 1 of the subsequent cycle may be delayed up to 42 days from day 1 of prior 
cycle) until the completion of cycle 6, then up to 6 weeks (i.e. day 1 of the subsequent cycle may 
be delayed up to 63 days from day 1 of prior cycle) thereafter. If day 2 or day 9 M6620 (VX-
970, berzosertib) cannot be safely administered during the required window (see Section 10), 
then that dose will be skipped and the patient will resume treatment with day 1 of the next cycle 
as above.  If day 1 of the next cycle cannot be safely administered within the above windows, 
then the subject must be discontinued from trial.
Additionally, if a subject who is responding to treatment experiences toxicity even after 2 dose 
reductions, the subject may continue to receive treatment if in the judgment of the investigator it 
is in the best interest of the subject. In this case the patient will be treated at the -3 dose level in 
Table 6-1.  If the subject does not tolerate treatment at the -3 dose level (or -2 dose level for 
carboplatin alone), the subject will be discontinued from study treatment.
In case of Grade 3 or higher treatment-related toxicity (excluding fatigue or 
nausea/vomiting/diarrhea adequately managed by supportive care, or asymptomatic unrelated 
laboratory abnormalities that would not prevent safe administration of trial therapy in the opinion 
of the trial investigator), treatment will be interrupted and may be resumed when all toxicities 
have returned to Grade 2 or lower, at the discretion of the investigator at the same dose or with a 
dose reduction as detailed below. Dose re-escalation is allowed if an unrelated confounding 

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variable that contributed to the dose reduction (for example, an adverse effect of another agent 
that has since been discontinued) has resolved; dose re-escalation must be approved on a case-
by-case basis by the principal investigator.
For the following treatment-related hematologic toxicities, once the toxicity has returned to 
Grade 2 or lower (Grade 1 or lower for thrombocytopenia), dosing can be resumed with 1 dose 
level reduction (Table 6-1). If, after 1 dose level reduction, any of the below drug-related
hematologic toxicities are subsequently observed, then dosing may be resumed with 2 dose level 
reductions (Table 6-1). Platelet count is required to be ≥75,000/mcL to initiate a new cycle.
o Grade 4 thrombocytopenia
o Febrile neutropenia (growth factor support, per site protocol, may be used in lieu
of dose reduction)
o Grade 4 neutropenia lasting more than 7 days
o Any Grade 3 or lower hematologic toxicity requiring dose delay of more than
2 weeks
For the following treatment-related non-hematologic toxicities, dosing can be resumed with 1
dose level reduction (Table 6-1).
o Grade 3 non-hematologic toxicity (Except for fatigue or nausea, vomiting, or 
diarrhea adequately controlled by medication), after resolution to Grade 2 or lower.
o Any Grade 2 or lower non-hematologic toxicity requiring dose delay of more than
2 weeks, once felt safe to resume trial therapy by the treating investigator.
If, after 1 dose level reduction, the above drug-related non-hematologic toxicities are
subsequently observed, then dosing may be resumed with 2 dose level reductions (Table 6-1).
For Grade 4 treatment-related non-hematologic toxicity, treatment will be interrupted and may 
be resumed with 2 dose level reductions (Table 6-1) when toxicity has returned to Grade 2 or 
lower. If any toxicity not described above results in delay in dosing in any part of the study, but 
this section does not specifically mandate a dose reduction, then the doses of M6620 (VX-970,
berzosertib) or chemotherapy may be reduced by 1 dose level or continued without dose 
reduction at the discretion of the investigator.
Of note, the toxicity profiles of docetaxel, carboplatin, and M6620 (VX-970, berzosertib) are 
largely overlapping so in most cases it would be difficult to ascribe a particular adverse event to
a single agent.  However, for non-hematologic toxicities clearly related to one agent but not the 
other (e.g. ototoxicity for carboplatin) dose modifications can be made independently from the 
other agent. Treatment day is delayed until criteria to treat are met. If a patient in Arm A needs 
to be discontinued from docetaxel for toxicity specifically attributable to docetaxel (i.e. new 
onset allergic reaction), the patient can subsequently be treated with carboplatin alone at AUC 5 
– however, this would be unusual as per eligibility these patients are required to have previously 
tolerated docetaxel.  Patients in Arm A cannot be treated with docetaxel monotherapy, and those 
in Arm B cannot be treated with monotherapy of either agent – if carboplatin and/or M6620 
(VX-970, berzosertib) is not tolerated despite the appropriate dose reductions then the patient 
must be discontinued from study treatment.

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Table 6-1
Guidelines for Dose Modification for Toxicity
Arm A: Docetaxel plus Carboplatin
Dose Level
Docetaxel
(mg/m2)
Carboplatin
(mg∙min/mL)
0
60
AUC 4
-1
45
AUC 4
-2
45
AUC 3
-3
30
AUC 3
Arm A: Carboplatin alone (for docetaxel-ineligible)
Dose Level
Carboplatin
(mg∙min/mL)
0
AUC 5
-1
AUC 4
-2*
AUC 3
*Patients who require dose reduction from carboplatin AUC 3 should be discontinued from 
study treatment.
Arm B and Arm A Crossover: M6620 (VX-970, berzosertib) plus Carboplatin
Dose Level
M6620 (VX-970,
berzosertib) (mg/m2)
Carboplatin
(mg∙min/mL)
0
90
AUC 5
-1
90
AUC 4
-2
60
AUC 4
-3
60
AUC 3
Any patient on study treatment who develops visual symptoms should be referred for immediate 
ophthalmologic evaluation.  Investigators should be aware of potential ocular complications of 
docetaxel, including cystoid macular edema. 
Below are dose modification tables for the following adverse events:  nausea, vomiting, diarrhea,
neuropathy.  
Table 6-2
Nausea
Management/Next Dose for 
Arm A
Management/Next Dose for 
Arm B or Arm A Crossover
≤ Grade 1
No change in dose
No change in dose
Grade 2
Hold until ≤ Grade 1.  Resume at 
same dose level.
Hold until ≤ Grade 1.  Resume at 
same dose level.

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Nausea
Management/Next Dose for 
Arm A
Management/Next Dose for 
Arm B or Arm A Crossover
Grade 3
Hold* until < Grade 2.  Resume at 
one dose level lower, if indicated.** Hold* until < Grade 2.  Resume at 
one dose level lower, if indicated.**
Grade 4
Off protocol therapy
Off protocol therapy
*Participants requiring a delay of >3 weeks within 1st 6 cycles (or >6 weeks after 6 cycles)
should go off protocol therapy.
**Participants requiring > three dose reductions (or > two dose reductions for carboplatin alone)
should go off protocol therapy.
Recommended management:  antiemetics.
Table 6-3
Vomiting
Management/Next Dose for
Arm A
Management/Next Dose for 
Arm B or Arm A Crossover
≤ Grade 1
No change in dose
No change in dose
Grade 2
Hold until ≤ Grade 1.  Resume at 
same dose level.
Hold until ≤ Grade 1.  Resume at 
same dose level.
Grade 3
Hold* until < Grade 2.  Resume at 
one dose level lower, if indicated.** Hold* until < Grade 2.  Resume at 
one dose level lower, if indicated.**
Grade 4
Off protocol therapy
Off protocol therapy
* Participants requiring a delay of >3 weeks within 1st 6 cycles (or >6 weeks after 6 cycles) 
should go off protocol therapy.
** Participants requiring > three dose reductions (or > two dose reductions for carboplatin 
alone) should go off protocol therapy.
Recommended management:  antiemetics.
Table 6-4
Diarrhea
Management/Next Dose for 
Arm A
Management/Next Dose for 
Arm B or Arm A Crossover
≤ Grade 1
No change in dose
No change in dose
Grade 2
Hold until ≤ Grade 1.  Resume at 
same dose level.
Hold until ≤ Grade 1.  Resume at 
same dose level.
Grade 3
Hold* until < Grade 2.  Resume at 
one dose level lower, if indicated.** Hold* until < Grade 2.  Resume at 
one dose level lower, if indicated.**
Grade 4
Off protocol therapy
Off protocol therapy
* Participants requiring a delay of >3 weeks within 1st 6 cycles (or >6 weeks after 6 cycles) 
should go off protocol therapy.
** Participants requiring > three dose reductions (or > two dose reductions for carboplatin 
alone) should go off protocol therapy.
Recommended management:  Loperamide antidiarrheal therapy
Dosage schedule:  4 mg at first onset, followed by 2 mg with each loose motion until diarrhea-

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Diarrhea
Management/Next Dose for 
Arm A
Management/Next Dose for 
Arm B or Arm A Crossover
free for 12 hours (maximum dosage:  16 mg/24 hours)
Adjunct anti-diarrheal therapy is permitted and should be recorded when used.
Table 6-5
Neuropathy
Management/Next Dose for 
Arm A
Management/Next Dose for 
Arm B or Arm A Crossover
≤ Grade 1
No change in dose
No change in dose
Grade 2
Discontinue docetaxel and switch 
to carboplatin alone AUC 5.  If 
grade 2 on carboplatin alone, can 
continue unless progresses to 
Grade 3. 
No change in dose
Grade 3
Hold docetaxel until ≤ Grade 2.  
Resume on carboplatin alone AUC 
5.  If grade 3 on carboplatin alone, 
hold until ≤Grade 2 and resume at
one dose level lower.
Hold carboplatin until ≤ Grade 2 
(may continue M6620 (VX-970,
berzosertib)).  Resume at one dose 
level lower, if indicated.**
Grade 4
Off protocol therapy
Off protocol therapy
* Participants requiring a delay of >3 weeks within 1st 6 cycles (or >6 weeks after 6 cycles) 
should go off protocol therapy.
** Participants requiring > three dose reductions (or > two dose reductions for carboplatin 
alone) should go off protocol therapy.
Recommended management:  Gabapentin per physician discretion
Dose delays are permitted for recovery of adverse effects of therapy as detailed above, or for 
inclement weather, holidays, emergencies, non-study related procedures or interventions, or
other concerns regarding the health and well-being of the patient (such as concern for COVID-19
exposure) within the windows detailed in the protocol (delay of up to 3 weeks allowed in the first 
6 cycles, up to 6 weeks allowed after cycle 6). Dose delays outside of permitted windows must 
be approved by the trial PI and IND Sponsor (DCTD NCI).
7. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The 
following list of AEs (Section 7.2) and the characteristics of an observed AE (Sections 7.3 and
7.4) will determine whether the event requires expedited reporting via the CTEP Adverse Event 
Reporting System (CTEP-AERS) in addition to routine reporting.
7.1
Rave-CTEP-AERS Integration
The Cancer Therapy Evaluation Program Adverse Event Reporting System (CTEP-

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AERS) integration enables evaluation of post-baseline AEs entered in Rave to determine 
whether they require expedited reporting, and facilitates entry in CTEP-AERS for those 
AEs requiring expedited reporting.   
All AEs that occur after baseline are collected in Medidata Rave using the Adverse Event 
form, which is available for entry at each treatment or reporting period, and used to 
collect AEs that start during the period or persist from the previous reporting period.  The 
Clinical Research Associate (CRA) will enter AEs that occur prior to the start of 
treatment on a baseline form that is not included in the Rave-CTEP-AERS integration.  
AEs that occur prior to enrollment must begin and end on the baseline Adverse Event 
form and should not be included on the standard Adverse Events form that is available at 
treatment unless there has been an increase in grade.
Prior to sending AEs through the rules evaluation process, site staff should verify the 
following on the Adverse Event form in Rave:
x
The reporting period (course/cycle) is correct, and
x
AEs are recorded and complete (no missing fields) and the form is query-free 
(fields added to the form during study build do not need to be query-free for the 
integration call with CTEP-AERS to be a success).
The CRA reports AEs in Rave at the time the Investigator learns of the event.  If the CRA 
modifies an AE, it must be re-submitted for rules evaluation.
Upon completion of AE entry in Medidata Rave, the CRA submits the AE for rules 
evaluation by completing the Expedited Reporting Evaluation form.  Both NCI and 
protocol-specific reporting rules evaluate the AEs submitted for expedited reporting.  A 
report is initiated in CTEP-AERS using information entered in Medidata Rave for AEs 
that meet reporting requirements.  The CRA completes the report by accessing CTEP-
AERS via a direct link on the Medidata Rave Expedited Reporting Evaluation form.
In the rare occurrence that Internet connectivity is lost, a 24-hour notification is to be 
made to CTEP by telephone at 301-897-7497.  Once Internet connectivity is restored, the 
24-hour notification that was phoned in must be entered immediately into CTEP-AERS 
using the deep link from Medidata Rave.
Additional information about the CTEP-AERS integration is available on the CTSU 
website:

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x
Study specific documents:  Protocols > Documents > Education and Promotion, 
and
x
Expedited Safety Reporting Rules Evaluation user guide:  Resources > CTSU 
Operations Information > User Guides.
NCI requirements for SAE reporting are available on the CTEP website: 
x
NCI Guidelines for Investigators:  Adverse Event Reporting Requirements is 
available at 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguid
elines.pdf.
7.2
Comprehensive Adverse Events and Potential Risks List (CAEPR)
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single list of 
reported and/or potential adverse events (AE) associated with an agent using a uniform 
presentation of events by body system. In addition to the comprehensive list, a subset, the 
Specific Protocol Exceptions to Expedited Reporting (SPEER), appears in a separate column and 
is identified with bold and italicized text. This subset of AEs (SPEER) is a list of events that are 
protocol specific exceptions to expedited reporting to NCI (except as noted below).  Refer to the 
'CTEP, NCI Guidelines: Adverse Event Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf for 
further clarification.
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses next to 
the AE in the SPEER.  If this CAEPR is part of a combination protocol using multiple 
investigational agents and has an AE listed on different SPEERs, use the lower of the grades to 
determine if expedited reporting is required.
7.2.1
CAEPRs for CTEP IND Agent
7.2.1.1
CAEPR for M6620 (VX-970, berzosertib)
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. The CAEPR does not provide frequency data; refer to the Investigator's Brochure 
for this information. Below is the CAEPR for M6620 (VX-970, berzosertib).

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Adverse events reported on M6620 (VX-970, berzosertib) (NSC 780162) trials, but for which there is 
insufficient evidence to suggest that there was a reasonable possibility that M6620 (VX-970,
berzosertib) (NSC 780162) caused the adverse event:
CARDIAC DISORDERS - Palpitations
GASTROINTESTINAL DISORDERS - Abdominal pain; Ascites; Colonic obstruction; Mucositis oral
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Edema limbs; Fever
IMMUNE SYSTEM DISORDERS - Allergic reaction
INFECTIONS AND INFESTATIONS - Infections and infestations - Other (lower respiratory tract infection); 
Otitis externa; Sepsis; Soft tissue infection
INVESTIGATIONS - GGT increased; Hemoglobin increased; Weight loss
METABOLISM AND NUTRITION DISORDERS - Anorexia; Dehydration; Hypophosphatemia
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Generalized muscle weakness
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - Neoplasms 
benign, malignant and unspecified (incl cysts and polyps) - Other (malignant neoplasm progression)
NERVOUS SYSTEM DISORDERS - Lethargy; Spinal cord compression; Syncope
PSYCHIATRIC DISORDERS - Confusion
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Atelectasis; Dyspnea
VASCULAR DISORDERS - Hypertension; Hypotension; Thromboembolic event
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.
7.2.2
Adverse Event List(s) for Carboplatin
Very common side effects (>10%):
• Abdominal pain
• Anemia
• Decreased kidney function/kidney toxicity
• High blood uric acid levels
• Infection
• Abnormal liver function tests
• Electrolyte imbalance
• Low platelets
• Leukopenia
• Nausea
• Vomiting
Less common side effects (<10%):
• Allergic reaction (rash and hives)
• Bleeding
• Diarrhea
• Constipation
• Hearing impairment
• Infection
• Neuropathy (numbness or pain of the hands and/or feet)

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Refer to the package insert for a comprehensive list of adverse events.
7.1.3 Adverse Event List(s) for Docetaxel
Likely (> 50% chance)
• Hair loss
• Fatigue
• Low white blood cell count
• Low red blood cell count 
Frequent (10-50% chance)
• Low platelet count 
• Soreness or weakness of muscles or joints
• Diarrhea
• Upset stomach
• Nausea or vomiting
• Mouth or throat sores
• Loss of appetite
• Elevated blood levels of liver enzymes
• Fluid retention, usually just leg swelling, but rarely fluid collection surrounding the 
heart or lungs that could cause difficulty breathing
• Rash or hives
• Reactions at the infusion site including redness or darkening of the skin
• Nail changes including nail pain, bleeding under the nails and rarely loss of nails 
numbness and tingling of fingers and toes
• The dexamethasone that needs to be taken with docetaxel may increase blood sugars 
which may increase thirst or urination, may cause difficulty getting to sleep, and may 
be associated with abnormal changes in personality or mood swings
Occasional (1-10% chance)
• Allergic reaction, which can cause difficulty breathing, irregular heartbeat, low 
blood pressure and be life threatening
• Continuing, long-lasting numbness, tingling or burning in the hands and feet.
• Shortness of breath
• Cough
• Infusion reaction which may cause fever, chills or rigors
• Irritation of the tear ducts, tearing of the eyes – this may be permanent
• Peeling on hands and feet
• Nosebleeds
• Taste disturbance
• Alcohol intoxication. Docetaxel contains alcohol (ethanol), which may affect the 
central nervous system
Rare (< 1% chance)
• Changes in vision

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• Seizure
• Stevens-Johnson syndrome 
• Blood clots
• Pneumonia or inflammation involving the lungs
• Heart failure, heart attack, or irregular heart rhythm
• Colitis
Refer to the package insert for a comprehensive list of adverse events.
7.3
Adverse Event Characteristics 
x
CTCAE term (AE description) and grade:  The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
5.0 will be utilized for AE reporting.  All appropriate treatment areas should have access 
to a copy of the CTCAE version 5.0.  A copy of the CTCAE version 5.0 can be 
downloaded from the CTEP web site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.
x
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 7.1.1) should be reported through CTEP-AERS only if the 
grade is above the grade provided in the SPEER.
-
Other AEs for the protocol that do not require expedited reporting are outlined in 
section 7.3.4.
x
Attribution of the AE:
-
Definite – The AE is clearly related to the study treatment.
-
Probable – The AE is likely related to the study treatment.
-
Possible – The AE may be related to the study treatment.
-
Unlikely – The AE is doubtfully related to the study treatment.
-
Unrelated – The AE is clearly NOT related to the study treatment.
7.4
Expedited Adverse Event Reporting
7.4.1
Expedited AE reporting for this study must use CTEP-AERS (CTEP Adverse Event 
Reporting System), accessed via the CTEP Web site (https://eapps-
ctep.nci.nih.gov/ctepaers).  The reporting procedures to be followed are presented in the 
“NCI Guidelines for Investigators: Adverse Event Reporting Requirements for DCTD 
(CTEP and CIP) and DCP INDs and IDEs” which can be downloaded from the CTEP 
Web site 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.htm
).  These requirements are briefly outlined in the tables below (Section 7.3.3).
In the rare occurrence when 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, 10 Calendar Days
24-Hour notification, 5 Calendar Days
NOTE:
Protocol-specific exceptions to expedited reporting of SAEs are found in the Specific Protocol 
Exceptions to Expedited Reporting (SPEER) portion of the CAEPR.
Expedited AE reporting timeframes are defined as:
o
“24-Hour notification, 5 Calendar Days” - The SAE must initially be reported via CTEP-AERS within 
24 hours of learning of the SAE, followed by a complete expedited report within 5 calendar days of 
the initial 24-hour report.
o
“24-Hour notification, 10 Calendar Days” - The SAE must initially be reported via CTEP-AERS within 
24 hours of learning of the SAE, followed by a complete expedited report within 10 calendar days of 
the initial 24-hour report.
1SAEs 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 notifications are required for all SAEs followed by a complete report
x
Within 5 calendar days for Grade 4-5 SAEs
x
Within 10 calendar days for Grade 1-3 SAEs
2For studies using nuclear medicine or molecular imaging IND agents (NM, SPECT, or PET), the SAE 
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: August 30, 2024
7.4.4
Additional Protocol-Specific Expedited Adverse Event Reporting Exclusions
For this protocol only, the AEs/grades listed below do not require expedited reporting via 
CTEP-AERS.  However, they still must be reported through the routine reporting 
mechanism (Section 7.4):
CTCAE SOC
Adverse Event
Grade
≥24h 
Hospitalizationa
BLOOD AND LYMPHATIC 
SYSTEM DISORDERS
Anemia
2
Regardless
GASTROINTESTINAL 
DISORDERS
Nausea
2
Regardless
GENERAL DISORDERS AND 
ADMINISTRATION SITE 
CONDITIONS
Fatigue
2
Regardless
a Indicates that an adverse event required hospitalization for ≥24 hours or prolongation of 
hospitalization by ≥24 hours of a patient.

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7.5
Routine Adverse Event Reporting
All Adverse Events must be reported in routine study data submissions.  AEs reported 
expeditiously through CTEP-AERS must also be reported in routine study data 
submissions.
Adverse event data collection and reporting, which are required as part of every clinical trial, are 
done to ensure the safety of patients enrolled in the studies as well as those who will enroll in 
future studies using similar agents.  AEs are reported in a routine manner at scheduled times 
during the trial using Medidata Rave.  For this trial the Adverse Event CRF is used for routine 
AE reporting in Rave.
7.6
Pregnancy
Although not an adverse event in and of itself, pregnancy as well as its outcome must be 
documented via CTEP-AERS.  In addition, the Pregnancy Information Form included within 
the NCI Guidelines for Adverse Event Reporting Requirements must be completed and 
submitted to CTEP.  Any pregnancy occurring in a patient’s partner from the time of consent to 
90 days after the last dose of study drug must be reported and then followed for outcome.  
Newborn infants should be followed until 30 days old.  Please see the “NCI Guidelines for 
Investigators: Adverse Event Reporting Requirements for DCTD (CTEP and CIP) and DCP 
INDs and IDEs” (at http://ctep.cancer.gov/protocolDevelopment/adverse effects.htm) for more 
details on how to report pregnancy and its outcome to CTEP. 
7.7
Secondary Malignancy
A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g.,
treatment with investigational agent/intervention, radiation or chemotherapy). A secondary 
malignancy is not considered a metastasis of the initial neoplasm.
CTEP requires all secondary malignancies that occur following treatment with an agent under an 
NCI IND/IDE be reported expeditiously via CTEP-AERS. Three options are available to 
describe the event: 
x
Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic leukemia 
[AML]) 
x
Myelodysplastic syndrome (MDS) 
x
Treatment-related secondary malignancy 
Any malignancy possibly related to cancer treatment (including AML/MDS) should also be 
reported via the routine reporting mechanisms outlined in each protocol. 
7.8
Second Malignancy

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A second malignancy is one unrelated to the treatment of a prior malignancy (and is NOT a
metastasis from the initial malignancy).  Second malignancies require ONLY routine AE
reporting unless otherwise specified.
8. PHARMACEUTICAL INFORMATION
A list of the adverse events and potential risks associated with the investigational or commercial 
agents administered in this study can be found in Section 7.1.
8.1
M6620 (VX-970, berzosertib) (NSC 780162)
8.1.1.1
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
8.1.1.2
Classification: ATR inhibitor
CAS Registry Number: 1232416-25-9
8.1.1.3
Molecular Formula: C24H25N5O3S                 M.W.: 463.55 Da
8.1.1.4
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.
8.1.1.5
Description: The drug substance for M6620 (VX-970, berzosertib) is the free base.
8.1.1.6
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.

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8.1.1.7
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.  
8.1.1.8
Storage: Store intact vials protected from light inside cardboard boxes at room 
temperature, 25°C (77°F), with excursions allowed between 15 and 30°C (59 and 
86°F).
If a storage temperature excursion is identified, promptly return M6620 (VX-970,
berzosertib) to between 15 and 30°C and quarantine the supplies.  Provide a detailed 
report of the excursion (including documentation of temperature monitoring and 
duration of the excursion) to PMBAfterHours@mail.nih.gov for determination of 
suitability.
8.1.1.9
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).
8.1.1.10
Route of Administration: Intravenous (IV) infusion.
8.1.1.11
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.  If the infusion volume is 600 – 900
mL, the M6620 (VX-970, berzosertib) solution should be infused at 10 mL/minute; if 
the volume is >900 mL then it should be infused over 90 minutes.  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.

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8.1.1.12
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. M6620 (VX-
970, berzosertib) is not a vesicant drug. 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).
8.1.1.13
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 OATP1B3and BCRP transporters.
8.1.1.14
Availability:
M6620 is an investigational agent supplied to investigators by the Division of Cancer 
Treatment and Diagnosis (DCTD), NCI.
M6620 (VX-970, berzosertib) is provided to the NCI under a Collaborative 
Agreement between the Pharmaceutical Collaborator and the DCTD, NCI (see 
Section 12.4).
8.1.2
Agent Ordering and Agent Accountability
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 

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agents for the study should be ordered under the name of one lead participating 
investigator at that institution.
In general, sites may order initial agent supplies when a subject is being screened for 
enrollment onto the study.
Submit agent requests through the PMB Online Agent Order Processing (OAOP) 
application.  Access to OAOP requires the establishment of a CTEP Identity and Access 
Management (IAM) account and the maintenance of an “active” account status, a 
“current” password, and active person registration status.  For questions about drug 
orders, transfers, returns, or accountability, call or email PMB any time.  Refer to the 
PMB’s website for specific policies and guidelines related to agent management.  
8.1.3
Agent Inventory Records
The investigator, or a responsible party designated by the investigator, must maintain a 
careful record of the receipt, dispensing and final disposition of all agents received from 
the PMB using the appropriate NCI Investigational Agent (Drug) Accountability Record 
(DARF) available on the CTEP forms page.  Store and maintain separate NCI 
Investigational Agent Accountability Records for each agent, strength, formulation and 
ordering investigator on this protocol.
8.1.4
Investigator Brochure Availability
The current versions of the IBs for the agents 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.
8.1.5
Useful Links and Contacts
x
CTEP Forms, Templates, Documents:  http://ctep.cancer.gov/forms/
x
NCI CTEP Investigator Registration:  RCRHelpDesk@nih.gov
x
PMB policies and guidelines: 
http://ctep.cancer.gov/branches/pmb/agent_management.htm
x
PMB Online Agent Order Processing (OAOP) application: 
https://ctepcore.nci.nih.gov/OAOP
x
CTEP Identity and Access Management (IAM) account: 
https://ctepcore.nci.nih.gov/iam/
x
CTEP IAM account help:  ctepreghelp@ctep.nci.nih.gov
x
IB Coordinator:  IBCoordinator@mail.nih.gov
x
PMB email:  PMBAfterHours@mail.nih.gov
x
PMB phone and hours of service: (240) 276-6575 Monday through Friday 
between 8:30 am and 4:30 pm (ET)

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8.2
Carboplatin
8.2.1
Product description
Commercially available for injection as solution: 10 mg/mL (5 mL, 15 mL, 45 
mL, 60 mL)
8.2.2
Solution preparation
Refer to package insert for complete preparation and dispensing instructions.
8.2.3
Storage requirements
Store intact vials at room temperature and protect from light.
8.2.4
Stability
Further dilution to a concentration as low as 0.5 mg/mL is stable at room 
temperature for 8 hours in 0.9% NaCl; stable at room temperature or under 
refrigeration for at least 9 days in D5W, although the manufacturer states to use 
within 8 hours due to lack of preservative. Multidose vials are stable for up to 14 
days after opening when
stored at room temperature.
8.2.5
Route of administration
Refer to the treatment section for specific administration instructions. When 
administered as sequential infusions, taxane derivatives (docetaxel, paclitaxel) 
should be administered before the carboplatin to limit myelosuppression and to 
enhance efficacy.
8.2.6
Agent Ordering
Commercial supplies. Pharmacies or clinics shall obtain supplies from normal 
commercial supply chain or wholesaler.

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8.3
Docetaxel
8.3.1
Description
Docetaxel is an antineoplastic agent belonging to the taxoid family. It is prepared 
by semisynthesis beginning with a precursor extracted from the renewable needle 
biomass of yew plants. The chemical name for docetaxel is (2R,3S)-N-carboxy-3-
phenylisoserine,Ntert- butyl ester, 13-ester with 5β-20-epoxy-1,2α,4,7β,10β,13α-
hexahydroxytax-11-en-9-one 4- acetate 2-benzoate, trihydrate. 
Mechanism of Action
Docetaxel is an antineoplastic agent that acts by disrupting the microtubular 
network in cells that is essential for mitotic and interphase cellular functions. 
Docetaxel binds to free tubulin and promotes the assembly of tubulin into stable 
microtubules while simultaneously inhibiting their disassembly. This leads to the 
production of microtubule bundles without normal function and to the 
stabilization of microtubules, which results in the inhibition of mitosis in cells. 
Docetaxel’s binding to microtubules does not alter the number of protofilaments 
in the bound microtubules, a feature which differs from most spindle poisons
currently in clinical use.
8.3.2
Form
Docetaxel Injection Concentrate is supplied in glass vials as non-aqueous, clear, 
viscous, colorless to pale yellow solution at 20mg/mL concentration. Docetaxel 
injection concentrate is sterile, non-pyrogenic, and is available in single-dose vials 
as 20 mg/mL or 80mg/4mL. One vial formulation (Injection Concentrate)
Docetaxel injection concentrate (20mg/mL) requires no prior dilution with a 
diluent and is ready to add to the infusion solution. Docetaxel injection 
concentrate should be inspected visually for particulate matter or discoloration 
prior to preparation. If the injection concentrate is not clear or appears to have 
precipitation, then it should be discarded.
8.3.3
Storage and Stability
Store vials at 25°C (77°F); excursions permitted to 15°C to 30°C (36°F and 
77°F). Retain in the original package to protect from bright light. Docetaxel final 
dilution for infusion, if stored between 2°C and 25°C (36°F and 77°F) is stable for 
4 hours. Docetaxel final dilution for infusion (in 0.9% Sodium Chloride solution
or D5W), diluted to a final concentration of 0.3mg/ml to 0.74mg/ml, should be 
used within 4 hours (including the 1 hour intravenous administration).
8.3.4
Compatibility

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Contact of the docetaxel injection concentrate with plasticized PVC equipment or 
devices used to prepare solutions for infusion is not recommended. In order to 
minimize patient exposure to the plasticizer DEHP (di-2-ethylhexyl phthalate), 
which may be leached from PVC infusion bags or sets, the final docetaxel dilution 
for infusion should be stored in bottles (glass, polypropylene) or plastic bags 
(polypropylene, polyolefin) and administered through polyethylene-lined 
administration sets.
8.3.5
Handling
Qualified personnel, familiar with procedures that minimize undue exposure to 
themselves and the environment, should undertake the preparation, handling, and 
safe disposal of the chemotherapeutic agent in a self-contained and protective 
environment. Study treatment must only be dispensed by a Pharmacist or 
medically qualified staff. Study treatment is to be dispensed only to participants 
enrolled in this study. Once the study treatment is prepared for a participant, it can 
only be administered to that participant. Docetaxel is a cytotoxic anticancer drug 
and, as with other potentially toxic compounds, caution should be exercised when 
handling and preparing docetaxel solutions. The use of gloves is recommended. If
docetaxel injection concentrate or final dilution for infusion should come into 
contact with the skin, immediately and thoroughly wash with soap and water. If 
docetaxel injection concentrate or final dilution for infusion should come into 
contact with mucosa, immediately and thoroughly wash with water.
8.3.6
Availability
Docetaxel is commercially available.

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8.3.7
Preparation
Docetaxel may be prepared according to institutional standards or package insert.
Body surface area (BSA) is to be calculated per institutional standards of practice. 
In the event of changes in participant weight, institutional standards of practice 
should be followed for dose re-calculations. For one vial preparation: 1.
Docetaxel vials should be stored at room temperature, 25°C (77°F), and protected 
from light. 2. Aseptically withdraw the required amount of docetaxel injection 
concentrate (20 mg/mL) with a calibrated syringe and inject into a 250 mL 
infusion bag of either 0.9% Sodium Chloride solution or D5W to produce a final 
concentration of 0.3 to 0.74 mg/mL. If a dose greater than 200 mg of docetaxel is 
required, use a larger volume of the infusion vehicle so that a concentration of 
0.74 mg/mL docetaxel is not exceeded. 2. Thoroughly mix the infusion by manual 
rotation. 3. Attach non-PVC, DEHP-free tubing 3. As with all parenteral products, 
docetaxel should be inspected visually for particulate matter or discoloration prior 
to administration whenever the solution and container permit. If the docetaxel 
injection concentrate or final dilution for intravenous infusion is not clear or 
appears to have precipitation, these should be discarded.
8.3.8
Administration
The final docetaxel dilution for infusion should be administered intravenously as 
a 1-hour infusion (+/- 10 min) under ambient room temperature and lighting 
conditions. Docetaxel may be administered according to institutional standards or 
package insert.
8.3.9
Ordering
Docetaxel will not be provided by the sponsor. Commercial supply will be used.
9. BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES
9.1
Collection of Specimens 
Summary of Specimen Requirements: 
Time point
Specimen and Processing at Site
Send specimens to
Pre-treatment
x
Tumor tissue biopsies in formalin (minimum 
of 4)
x
10 mL blood in cfDNA Streck tube
EET Biobank
Every Third 
Cycle (Arm B: 
C1D1, C4D1, 
C7D1, etc.; Arm 
A: C1D1, C4D1, 
etc. then 
C1D1[crossover], 
x
10 mL blood in cfDNA Streck tube
EET Biobank

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C4D1[crossover], 
etc.)
Off Study
x
Tumor tissue biopsies in formalin (minimum 
of 4) [optional]
x
10 mL blood in cfDNA Streck tube
EET Biobank
*For new biopsies, the Tissue Biopsy Verification Form (Appendix G) and 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.
9.2
Specimen Procurement Kits and Scheduling
9.2.1
Specimen Kits
EET Biobank Kits for shipment can be ordered online via the Kit Management 
system (https://ricapps.nationwidechildrens.org/KitManagement).
Sites will need to set up an account in the Kit Management system and select a 
specific clinical trial protocol to request a kit. Each user may order two kit per kit 
type day (daily max = 6 kits). Kits are shipped ground, so please allow 5-7 days for 
receipt. Two kit types will be provided for this protocol: a single chamber for the 
submission of tissue from Pre-treatment or Off Study and an ambient shipper for the 
submission of blood in a cfDNA Streck tube.  A complete list of kit contents for each 
kit type is located on the Kit Management system website and in the instructions 
included with the kits.
9.2.2
Scheduling of Specimen Collections
Tumor tissue cores collected during biopsy procedures that are fixed must be shipped 
on the same day as collection. Tissue can be collected Monday through Wednesday,
and shipped overnight (FedEx Priority Overnight strongly preferred to avoid potential 
delays, which will negatively impact specimen quality) for arrival on Tuesday 
through Thursday at the EET Biobank at Nationwide Children’s Hospital. 
Fresh blood specimens may be collected and shipped Monday through Friday.  
Saturday delivery is only available for shipments of fresh blood.
9.3
Specimen Tracking System Instructions
9.3.1 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

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o
Investigator’s name
x
Eligibility Verification:  Patients must meet all the eligibility requirements listed in 
Section Error! Reference source not found..
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 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, 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 STS Support at
STS.Support@theradex.com.
A shipping manifest must be included with all sample submissions.
9.3.2 Specimen Labeling
9.3.2.1 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 (to be added by hand)

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9.3.2.2 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., Formalin Fixed Tissue)
x
Tissue type (P for primary, M for metastatic or N for normal)
x
Surgical pathology ID (SPID – if applicable) number
x
Collection date (to be added by hand)
9.3.2.3 Example of Specimen Label
The following image is an example of a tissue specimen label printed on a standard Avery label 
that is 1” high and 2.625” wide.
The QR code in the above example is for the Specimen ID shown on the second line.  
NOTE: The QR code label is currently under development at Theradex as of 31-Aug-2018;
therefore, labels generated by the STS for this study may not include a QR code.
The second line item from the end includes four 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. The last alpha-numeric code is protocol specific and is only included if the protocol requires 
an additional special code classification
The last line on the example label is for the handwritten date and optional time.
9.3.3 Overview of Process at Treating Site
9.3.3.1 OPEN Registration

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All registrations will be performed using the Oncology Patient Enrollment Network (OPEN) 
system. OPEN communicates automatically with the Interactive Web Response System (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.
9.3.3.2 Rave Specimen Tracking Process Steps
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:
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 report in EDC and collect specimen.
x
Label specimen containers and write collection date on each label.
x
After collection, labeled specimens can be kept at room temperature until ready 
for shipment.
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, mailing address, medical 
record number or social security number (SSN), redacted.  Do not redact SPID, 
block number or relevant dates (such as collection date), 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.

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x
Shipping Status CRF: Enter tracking number, your contact information, 
recipient, number of containers and ship date once for the 1st specimen in a 
shipment.
x
Copy Shipping CRF: Select additional specimens to add to an existing shipment 
referenced by the tracking number.
Step 5: Print shipping list report and prepare to ship. 
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).
9.4
Specimen Collection 
9.4.1
Formalin-fixed Tumor Biopsies
Biopsies will be performed by an interventional radiologist or other appropriate radiologist under 
CT guidance (ultrasound guidance is allowed if preferred by the radiologist.) Blood samples will 
be drawn within 28 days of the biopsy to document an acceptable coagulation profile (INR < 1.5, 
PTT < 45, platelets >50,000). Aspirin and/or Plavix should be discontinued 5 days prior to the 
biopsy. On the day of the biopsy, a short physical exam will be performed by the radiologist 
including assessing the patient’s general ASA score and airway rating. Informed written consent 
will be obtained following discussion of the risks (bleeding, infection, adjacent tissue injury, and 
pain) and benefits of the procedure. Biopsies will be performed using standard coaxial 
techniques under CT (or ultrasound) guidance without the administration of intravenous contrast. 
Conscious sedation will be administered by a trained radiology nurse using small doses of 
Versed and fentanyl titrated to the patient’s level of discomfort. Following the biopsy, patients 
will be observed for 2 hours following their last dose of conscious sedation for any 
complications (severe pain, hematoma, neurologic deficit) prior to departing with a chaperone.
The study investigator and interventional radiologist or other appropriate radiologist will decide 
on appropriate biopsy site likely to yield tissue amenable to NGS analysis51 while exposing the 
patient to acceptable risk (see Appendix E).  If such a site cannot be identified, the patient will be 
excluded from this study.  Large bore core biopsies will be performed per institutional standards.
9.4.2
Handling of Specimens(s) 
1.
Label formalin-filled containers according to instructions in Section 9.3.1.2.
2.
Obtain biopsy specimens and place one core in each cassette. 
3.
Snap the cassette lids closed and place cassettes into a formalin-filled pre-labeled 

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container as soon as possible after collection to prevent air drying.  Up to two cassettes may be 
placed in one formalin jar.
4.
Secure the container lids and package containers into the shipping kit according to 
instructions in Section 5.6.  Keep tissue in formalin jars at room temperature until shipment to 
the EET Biobank
Specimen size requirement is as follows:
• Surface area of 25mm2 is optimal. Minimum is 5mm2.
• Volume: 1mm3 optimal. Minimum volume is 0.2mm3
however the success of DNA extraction decreases at suboptimal tissue volume.
At least 4 biopsy cores should be obtained and placed in formalin: one for submission to 
the Pathology department at each institution, at least 3 for submission to the EET
Biobank to distribute to the MoCha laboratory for Whole Exome Sequencing and to 
Dana-Farber Cancer Institute for RAD51 Focus Formation Assay per section 9.2.2.  
Cores submitted to the EET Biobank will be prioritized for whole exome sequencing first 
and RAD51 focus formation second.
9.4.2.1
Collection of Blood
Collect 10 mL of blood in cfDNA Streck tube at the following time points: 
x
Pre-treatment (for genomic DNA)
x
For Arm B: Every third cycle on study (i.e. C1D1, C4D1, C7D1, 
etc.) 
x
For Arm A: C1D1, C4D1, C7D1, etc., then C1D1[crossover], 
C4D1[crossover] etc.
x
Off study.
9.4.2.2
Handling of Blood in cfDNA Streck Tube(s) 
1) Label one 10 mL cfDNA Streck tube per section 9.3.1.1.
2) Collect 10 mL blood into the pre-labeled tube and 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 may compromise the specimen.  Blood collected in 
cfDNA Streck tubes is stable at room temperature. 

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9.5
Shipping Specimens from Clinical Site to the EET Biobank
9.5.1.1
General Shipping Information:
Core biopsies that are fixed in formalin and fresh blood should be shipped as 
one shipment at ambient temperature, whenever possible.  The shipping 
container 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 formalin-fixed biopsies, if the corresponding anatomical pathology report 
is not available at the time of shipment, then the surgical and/or radiology 
reports from the tissue removal procedure and the diagnostic anatomic 
pathology report must be included in the package, or the specimen will not be 
processed.  Once completed, upload the corresponding pathology report to the 
ETCTN specimen tracking system and send a copy to the EET Biobank.
9.5.1.2
Specimen Shipping Instructions:
Tissue in formalin must be shipped on the day of collection.  Collect and ship 
on Monday through Wednesday.
Fresh blood may be shipped on Monday through Friday.  Please select 
“Saturday Delivery” when shipping fresh blood on a Friday. 

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9.5.1.3
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. 
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 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 below.  FedEx Priority 
Overnight is strongly recommended to prevent delays in package receipt. 
9.5.1.4
Shipping Ambient Tissue and Blood in a Single-Chamber Kit [used when 
tissue in formalin is included]
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.  The lids of formalin jars should be wrapped in 
parafilm.  Absorbent material must be placed around each primary container 
that holds liquid.  
2. Place the specimens in zip-lock bags.  Use a separate bag for each specimen 
type.
3. Place specimens into the secondary pressure vessel surrounded by bubble 
wrap.  Place the lid on the secondary pressure vessel and set it inside the kit 
chamber. 
4. Place a copy of the shipping manifest and corresponding reports such as 
pathology, surgical, or radiology reports into the insulated shipping container. 
5. Set the lid on top of the container.  Close the outer flaps and tape shut.
6. Attach a shipping label to the top of the shipping container. 
7. Attach an Exempt Human Specimen sticker to the side of the container.
8. Ship specimens via overnight courier to the address below.  FedEx Priority 
Overnight is strongly recommended to prevent delays in package receipt. 

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9.5.1.5
Shipping Address
Ship to the address below.  Ship formalin-fixed 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.
9.5.1.6
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
9.6
Integrated Correlative Study – Whole Exome Sequencing 
Whole exome sequencing will be performed through Molecular Characterization (MoCha) 
laboratory at the Frederick National Laboratory for Cancer Research.  Patients will be considered 
to have homologous recombination deficiency (HRD) from this assay if a bona fide mutation, 
deletion, or truncation predicted to be functionally deleterious in a gene involved in homologous 
recombination repair.  Statistical analysis comparing response rates to M6620 (VX-970,
berzosertib)+carboplatin and docetaxel+carboplatin in patients found to have HRD as compared 
to those who do not is described in section 13.6.2.
In patients who elect for optional post-treatment biopsy, whole exome sequencing will also be 
performed on this tissue to assess for genomic correlates of resistance to therapy.
9.6.1
Specimens and Processing at the EET Biobank
Formalin-fixed tissue at pre-treatment (mandatory) and Off Study (optional, if 
available) time points will be used for this assay. Tumor tissue will be processed 
and embedded upon receipt at the EET Biobank. Slides will be cut from 1 – 2
cores, and the first section will be stained with H&E for pathology quality control 
review to assess tumor content; unstained slides will be macrodissected, if 
needed, and then DNA and RNA will be co-extracted, aliquoted, and stored in a -
80°C freezer until distribution for testing.

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9.6.2
Site(s) Performing Correlative Study:
Whole exome sequencing will be performed through Molecular Characterization 
(MoCha) laboratory at the Frederick National Laboratory for Cancer Research.
9.7
Exploratory/Ancillary Correlative Studies
9.7.1
RNA Sequencing for RB loss of function
RNA-Seq from tumor biopsies is an exploratory biomarker in this study.  Background 
and Rationale for using RNA-Seq for assessment of RB loss of function are described in 
section 2.5.5.
9.7.1.1
Specimens and Processing at the EET Biobank
RNA will be co-extracted with DNA from tumor tissue as detailed in 
section 9.6.1, aliquoted, and stored in a -80°C freezer until distribution for 
testing.
9.7.1.2
Site(s) Performing Correlative Study:
RNA sequencing will be performed through the NCLN Genomics 
Laboratory. Data will be analyzed in the laboratory of Dr. Leigh Ellis at 
Cedars-Sinai Medical Center.
9.7.2
Ultra low-pass whole genome sequencing, 50 x whole genome sequencing, and
prostate cancer-specific targeted sequencing from circulating free DNA
Genomic analysis from cfDNA is an exploratory biomarker in this study.  Background 
and Rationale for genomic studies from cfDNA are described in section 2.5.2.
9.7.2.1
Specimens and Processing at the EET Biobank
All specimens will be processed to plasma and frozen per ETCTN standard 
operating procedures. Plasma will be aliquoted and stored in a -80°C freezer until 
distribution for testing. 
9.7.2.2
Site(s) Performing Correlative Study
Genomic DNA extracted from blood collected at the pre-treatment time point, as well as 
frozen plasma from C1D1, C1D1 [crossover] (for patients randomized to arm A), and Off
Study time points will be shipped in batches in by the ECTCN Biorepository to the
Genomics Platform at the Broad Institute at the following address:
Broad Institute
Attn: Genomics Platform – Samples Lab
320 Charles St – Lab 181
Cambridge, MA 02141
Phone: (617) 714-8952

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Remaining plasma samples (from C4D1, C7D1, C10D1, etc. time points as well 
as C4D1[crossover], C7D1[crossover], etc. time points) will remain banked in the 
EET Biobank for future studies.
9.7.3
RAD51 Focus Formation Assay, ATM/p-KAP1 Immunohistochemistry
9.7.3.1
Specimens and Processing at the EET Biobank
Formalin-fixed tissue at pre-treatment (mandatory) and end of treatment (optional, 
if available) time points will be used for this assay. Tumor tissue will be 
processed and embedded upon receipt at the EET Biobank. One of the embedded 
biopsies will be banked at room temperature until distribution for the RAD51 
Focus Formation Assay, ATM/p-KAP1 Immunohistochemistry.
9.7.3.2
Site performing correlative study
RAD51 Focus Formation Assay and ATM/p-KAP1 Immunohistochemistry will be 
performed at the Center for DNA Damage and Repair at Dana-Farber Cancer 
Institute. FFPE biopsy tissue blocks will be shipped in batches by the EET Biobank to 
the Dana Farber Cancer Institute: 
Bose Kochupurakkal, PhD
HIM208, Center for DNA Damage and Repair
Dana-Farber Cancer Institute
77 Avenue Louis Pasteur, Boston, MA 02115

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10. STUDY CALENDAR
Pre-study (screening) laboratory testing, imaging studies, and EKG must be done <4 weeks prior 
to the start of therapy. Packed red blood cell (PRBC) transfusions are permitted to meet 
eligibility criteria prior to screening but platelet transfusions and growth factors are not permitted 
within 28 days of screening.  Pre-treatment assessments (prior to day 1 and day 9 drug dosing for
each cycle) should be performed within 72 hours of planned treatment dose. Results from the 
patient’s complete blood counts and serum chemistry1 must be reviewed prior to drug dosing. 
The patient’s laboratory parameters must meet eligibility criteria (section 3.1.6) to initiate cycle 
1 day 1 of trial therapy; eligibility to receive subsequent doses is based on dose 
delay/modification criteria detailed in Section 6, with platelet count required to be ≥75,000/mcL
to initiate a new cycle. The acceptable window for start of day 1 of a cycle is 21 days +/- 3 days
in relation to day 1 of the prior cycle.  The acceptable window for day 2 is +2 days (i.e. day 2-4);
the acceptable window for day 9 is +/- 2 days in reference to day 2 (i.e. day 7-11 if M6620 (VX-
970, berzosertib) is administered on day 2 of the cycle, day 9-13 if administered on day 4 of the 
cycle). Administration outside of these windows may be permitted for weather or other 
emergencies after discussing with the principal investigator. Note that the study calendar is 
related to cycle, so assessments (radiologic evaluations, biomarker, etc.) are delayed when cycles 
are delayed.
Pre-
Study
Cycle 1
Cycle 2
Cycle 3
Subsequent 
cycles
Off Study4
C1
D1
C1
D2
C1
D9
C2
D1
C2
D2
C2
D9
C3
D1
C3
D2
C3
D9
C_
D1
C_
D2
C_
D9
Docetaxel
A
A
A
A
Carboplatin
A,B
A,B
A,B
A,B
M6620 (VX-970, 
berzosertib)
B
B
B
B
B
B
B
B
Informed consent
X
Demographics
X
Medical history
X
Concurrent meds
X
X----------------------------------------------------------------------------------------X
Physical exam
X
X
X
X
X
X
Vital signs
X
X
B
X
B
X
B
X
B
X
Height
X
Weight
X
X
X
X
X
X
Performance status
X
X
X
X
X
X
CBC w/diff, plts
X
X
B
X
B
X
B
X
B
X
Serum chemistry1
X
X
B
X
B
X
B
X
B
X
PSA
X
X
X
X
X
X
Testosterone
X
EKG (as indicated)
X

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Adverse event evaluation
X----------------------------------------------------------------------------------------X
X
Tumor measurements
X
Tumor measurements are repeated prior to every third cycle (i.e. prior to 
C4D1, C7D1, etc.).  For patients on Arm A who crossover, imaging studies 
are obtained within 30 days of C1D1[crossover] and then prior to 
C4D1[crossover], C7D1[crossover], etc. Documentation (radiologic) must 
be provided for participants removed from study for progressive disease.
X
Radiologic evaluation2
X
Radiologic measurements should be performed prior to every third cycle 
(i.e. prior to C4D1, C7D1, etc.) For patients on Arm A who crossover, 
imaging studies are obtained within 30 days of C1D1[crossover] and then 
prior to C4D1[crossover], C7D1[crossover], etc. Imaging is preferred within 
7 days of scheduled D1 of the subsequent cycle but a window of up to 14 
days prior to scheduled D1 of the subsequent cycle (and up to 30 days prior 
to C1D1[crossover]) is allowed.
X
Tumor biopsy
X
X4
Biomarker (blood in 
cfDNA Streck)3
X
X
X3
X
Other correlative studies
A:
Docetaxel 60 mg/m2 day 1 + Carboplatin AUC 4 day 1 (or Carboplatin AUC 5 alone, day 1 if docetaxel-ineligible)
B:
M6620 (VX-970, berzosertib) 90 mg/m2 on days 2 and 9 + Carboplatin AUC 5 day 1
1:
Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, LDH, 
phosphorus, potassium, total protein, SGOT [AST], SGPT [ALT], sodium.
2:
Cross-sectional imaging of Chest, Abdomen and Pelvis as well as bone scintigraphy
3:
Pre-study biomarker sample is for genomic DNA and can be drawn any time between and including screening and C1D1;
remaining biomarker samples are for cfDNA. For patients randomized to Arm B, cfDNA blood draws will be performed 
C1D1, C4D1, and every 3 cycles thereafter and at end of study.  For patients randomized to Arm A and then crossover, 
cfDNA blood draws will be performed on C1D1, C4D1, and every 3 cycles while on carbo+/-docetaxel, then C1D1 
[crossover], C4D1 [crossover], and every 3 cycles thereafter while on carbo+M6620 (VX-970, berzosertib) and at end of 
study
4:
Off-study evaluation. End of study biomarker blood draw is mandatory, but end of study tumor biopsy is optional. Note: 
for IND/IDE trials, follow up visits or other contact are required in order to identify SAEs during the 30 days following 
the end of study treatment. 
11. MEASUREMENT OF EFFECT
11.1
Antitumor Effect – Solid Tumors
For the purposes of this study, participants should be re-evaluated for response prior to every 
third cycle (i.e. prior to C4D1, C7D1, etc.); for patients on Arm A who crossover, imaging 
studies are obtained within 30 days of C1D1[crossover] and then prior to C4D1[crossover], 
C7D1[crossover], etc. Imaging is preferred within 7 days of scheduled D1 of the subsequent 
cycle but a window of up to 14 days prior to scheduled D1 of the subsequent cycle (and up to 30 
days prior to C1D1[crossover]) is allowed. In addition to a baseline scan, confirmatory scans 
should also be obtained not less than 4 weeks following initial documentation of objective 
response.
Response and progression of non-osseous disease will be evaluated in this study using the new 
international criteria proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) 
guideline (version 1.1) [Eur J Ca 45:228-247, 2009].  Changes in the largest diameter 

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(unidimensional measurement) of the tumor lesions and the shortest diameter in the case of 
malignant lymph nodes are used in the RECIST criteria. Response and progression of osseous 
disease by bone scintigraphy will be per Prostate Cancer Working Group 3 criteria.2
11.1.1 Definitions
Evaluable for toxicity.  All patients will be evaluable for toxicity from the time of their 
first treatment with M6620 (VX-970, berzosertib), carboplatin, and/or docetaxel.
Evaluable for PSA response: Only those patients with PSA ≥ 2.0 ng/mL at baseline, have 
received at least one cycle of therapy, and have had their PSA re-measured will be 
evaluable for PSA response per section 11.2.
Evaluable for radiographic 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 radiographic response.  These patients will 
have their response classified according to the definitions stated below.  (Note:  Patients 
who exhibit objective disease progression prior to the end of cycle 1 will also be 
considered evaluable.)
Evaluable Non-Target Disease Response.  Patients who have lesions present at baseline 
that are evaluable but do not meet the definitions of measurable disease, have received at 
least one cycle of therapy, and have had their disease re-evaluated will be considered 
evaluable for non-target disease.  The response assessment is based on the presence, 
absence, or unequivocal progression of the lesions. 
11.1.2 Disease Parameters
Measurable disease.  Measurable lesions are defined as those that can be accurately 
measured in at least one dimension (longest diameter to be recorded) as ≥20 mm (≥2 cm) 
by chest x-ray or as ≥10 mm (≥1 cm) with CT scan or MRI.  All tumor measurements 
must be recorded in millimeters (or decimal fractions of centimeters).
Note:  Tumor lesions that are situated in a previously irradiated area will not be 
considered measurable.  
Malignant lymph nodes. To be considered pathologically enlarged and measurable, a 
lymph node must be ≥15 mm (≥1.5 cm) in short axis when assessed by CT scan (CT scan 
slice thickness recommended to be no greater than 5 mm [0.5 cm]).  At baseline and in 
follow-up, only the short axis will be measured and followed.
Non-measurable disease.  All other lesions (or sites of disease), including small lesions 
(longest diameter <10 mm [<1 cm] or pathological lymph nodes with ≥10 to <15 mm [≥1 
to <1.5 cm] short axis), are considered non-measurable disease.  Bone lesions, 
leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis 

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

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Conventional CT and MRI This guideline has defined measurability of lesions on CT 
scan based on the assumption that CT slice thickness is 5 mm (0.5 cm) or less.  If CT 
scans have slice thickness greater than 5 mm (0.5 cm), the minimum size for a 
measurable lesion should be twice the slice thickness.  MRI is also acceptable in certain 
situations (e.g. for body scans).  
Use of MRI remains a complex issue.  MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which 
greatly impact image quality, lesion conspicuity, and measurement.  Furthermore, the
availability of MRI is variable globally.  As with CT, if an MRI is performed, the 
technical specifications of the scanning sequences used should be optimized for the 
evaluation of the type and site of disease.  Furthermore, as with CT, the modality used at 
follow-up should be the same as was used at baseline and the lesions should be 
measured/assessed on the same pulse sequence.  It is beyond the scope of the RECIST 
guidelines to prescribe specific MRI pulse sequence parameters for all scanners, body 
parts, and diseases.  Ideally, the same type of scanner should be used and the image 
acquisition protocol should be followed as closely as possible to prior scans.  Body scans 
should be performed with breath-hold scanning techniques, if possible.
PET-CT At present, the low dose or attenuation correction CT portion of a combined 
PET-CT is not always of optimal diagnostic CT quality for use with RECIST 
measurements.  However, if the site can document that the CT performed as part of a 
PET-CT is of identical diagnostic quality to a diagnostic CT (with IV and oral contrast), 
then the CT portion of the PET-CT can be used for RECIST measurements and can be 
used interchangeably with conventional CT in accurately measuring cancer lesions over 
time.  Note, however, that the PET portion of the CT introduces additional data which 
may bias an investigator if it is not routinely or serially performed.  
Ultrasound Ultrasound is not useful in assessment of lesion size and should not be used 
as a method of measurement.  Ultrasound examinations cannot be reproduced in their 
entirety for independent review at a later date and, because they are operator dependent, it 
cannot be guaranteed that the same technique and measurements will be taken from one 
assessment to the next.  If new lesions are identified by ultrasound in the course of the 
study, confirmation by CT or MRI is advised.  If there is concern about radiation
exposure at CT, MRI may be used instead of CT in selected instances.
Endoscopy, Laparoscopy The utilization of these techniques for objective tumor 
evaluation is not advised.  However, such techniques may be useful to confirm complete 
pathological response when biopsies are obtained or to determine relapse in trials where 
recurrence following complete response (CR) or surgical resection is an endpoint.
Tumor markers Refer to Section 11.2
Cytology, Histology These techniques can be used to differentiate between partial 

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responses (PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor 
types, such as germ cell tumors, where known residual benign tumors can remain).
The cytological confirmation of the neoplastic origin of any effusion that appears or 
worsens during treatment when the measurable tumor has met criteria for response or 
stable disease is mandatory to differentiate between response or stable disease (an 
effusion may be a side effect of the treatment) and progressive disease.
FDG-PET While FDG-PET response assessments need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in 
assessment of progression (particularly possible 'new' disease).  New lesions on the basis 
of FDG-PET imaging can be identified according to the following algorithm: 
a.
Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of 
PD based on a new lesion.
b. No FDG-PET at baseline and a positive FDG-PET at follow-up:  If the positive FDG-
PET at follow-up corresponds to a new site of disease confirmed by CT, this is PD.  If 
the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, 
additional follow-up CT  scans are needed to determine if there is truly progression 
occurring at that site (if so, the date of PD will be the date of the initial abnormal 
FDG-PET scan).  If the positive FDG-PET at follow-up corresponds to a pre-existing 
site of disease on CT that is not progressing on the basis of the anatomic images, this 
is not PD.
c.
FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy 
in cases where a residual radiographic abnormality is thought to represent fibrosis or 
scarring.  The use of FDG-PET in this circumstance should be prospectively 
described in the protocol and supported by disease-specific medical literature for the 
indication.  However, it must be acknowledged that both approaches may lead to false 
positive CR due to limitations of FDG-PET and biopsy resolution/sensitivity.
Note:  A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake 
greater than twice that of the surrounding tissue on the attenuation corrected image.
11.1.4 Response Criteria
11.1.4.1
Evaluation of Target Lesions
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 

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baseline sum if that is the smallest on study).  In addition to the relative increase of 
20%, the sum must also demonstrate an absolute increase of at least 5 mm (0.5 cm).  
(Note:  the appearance of one or more new lesions is also considered progressions).
Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum diameters while on 
study.
11.1.4.2
Evaluation of Non-Osseous Non-Target Lesions
Complete Response (CR):  Disappearance of all non-target lesions.  All lymph nodes 
must be non-pathological in size (<10 mm [<1 cm] short axis).
Non-CR/Non-PD: Persistence of one or more non-target lesion(s)
Progressive Disease (PD):  Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target lesions.  Unequivocal progression
should not normally trump target lesion status.  It must be representative of overall 
disease status change, not a single lesion increase.
Although a clear progression of “non-target” lesions only is exceptional, the opinion 
of the treating physician should prevail in such circumstances, and the progression 
status should be confirmed at a later time by the review panel (or Principal 
Investigator).
11.1.4.3
Evaluation of Osseous Disease by Bone scintigraphy per PCWG3 criteria2
Osseous disease will be monitored by bone scintigraphy.  The bone scan performed at 
9 weeks will serve as the baseline for assessment of radiographic progression of
osseous disease.  Bone scan progression will be defined as the appearance of at least 
two new lesions relative to the first post-treatment scan, confirmed on a subsequent 
scan.  Date of progression is the date of the scan that first documents the second 
lesion (and not the date of the confirmatory scan).  Changes in intensity of uptake 
alone do not constitute either progression or regression.
11.1.4.4
Evaluation of Best Overall Response
The best overall response is the best response recorded from the start of the treatment 
until disease progression/recurrence (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)

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

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reference for progressive disease the smallest measurements recorded since the treatment 
started).
The duration of radiographic CR is measured from the time measurement criteria are first 
met for CR until the first date that radiographic progression is objectively documented.
Duration of stable disease:  Stable disease is measured from the start of the treatment 
until the criteria for progression are met, taking as reference the smallest measurements 
recorded since the treatment started, including the baseline measurements. 
11.1.6 Time to Event Endpoints
Overall Survival: Overall Survival (OS) is defined as the time from randomization  to 
death due to any cause, or censored at date last known alive.
Progression-Free Survival: Progression-Free Survival (PFS) is defined as the time from 
randomization  to the earlier of progression by PCWG3 criteria2 or death due to any 
cause. PCWG3 progression is defined as when it is felt by the treating physician that the 
patient is “no longer clinically benefiting” (NLCB) from therapy.  Generally, this is 
understood as radiographic or clinical/symptomatic progression (i.e. not PSA progression
alone), but PCWG3 criteria allow treatment beyond radiographic progression if the 
treating physician feels that the patient is continuing to derive clinical benefit from 
therapy (compared to other available treatments or no treatment). Participants alive
without disease progression are censored at date of last disease evaluation.
Time to Progression: Time to Progression (TTP) is defined as the time from 
randomization  to progression by PCWG3 criteria2, or censored at date of last disease 
evaluation for those without progression reported.
Time to PSA Progression: Time to PSA Progression is defined as the time from 
randomization to PSA progression by PCWG2 criteria1, defined as the date that a 25% or 
greater increase and an absolute increase of 2 ng/mL or more from the nadir is 
documented, which is confirmed by a second value obtained 3 or more weeks later.
Radiographic Progression-Free Survival: rPFS is defined as the time from randomization  
to the earlier of progression of non-osseous disease by RECIST 1.1 criteria or bone scan 
progression by PCWG3 criteria2 or death due to any cause. Participants alive without 
disease progression are censored at date of last disease evaluation.
11.1.7 Response Review
Responses will be reviewed by an expert independent of the study at the study’s 
completion.

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11.2
PSA Response
Only patients with baseline PSA ≥ 2 ng/mL at baseline will be evaluable for PSA response.
Biochemical Response:52
The laboratory will utilize a consistent method to check serum PSA at baseline, on treatment as 
per the study calendar, and at study termination.
A PSA response will be defined as any PSA decline ≥50% from baseline during trial therapy.
Percent change in serum PSA1
The percent change (rise or fall) from baseline at 12 weeks, and separately, the maximal
change (rise or fall) at any time will be recorded using a waterfall plot.
12. STUDY OVERSIGHT AND DATA REPORTING / REGULATORY 
REQUIREMENTS
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7.0 
(Adverse Events: List and Reporting Requirements).
12.1
Study Oversight
This protocol is monitored at several levels, as described in this section.  The Protocol Principal 
Investigator is responsible for monitoring the conduct and progress of the clinical trial, including 
the ongoing review of accrual, patient-specific clinical and laboratory data, and routine and 
serious adverse events; reporting of expedited adverse events; and accumulation of reported 
adverse events from other trials testing the same drug(s).  The Protocol Principal Investigator and 
statistician have access to the data at all times through the CTMS web-based reporting portal.  
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.  
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.
12.2
Data Reporting
Medidata Rave is a clinical data management system being used for data collection for this 
trial/study.  Access to the trial in Rave is controlled through the CTEP-IAM system and role 

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assignments.  To access Rave via iMedidata:
x
Site staff will need to be registered with CTEP and have a valid and active CTEP-IAM
account, and 
x
Assigned one of the following Rave roles on the relevant Lead Protocol Organization 
(LPO) or Participating Organization roster at the enrolling site:  Rave CRA, Rave Read 
Only, Rave CRA (LabAdmin), Rave SLA, or Rave Investigator.  Refer to 
https://ctep.cancer.gov/investigatorResources/default.htm for registration types and 
documentation required.
o
To hold Rave CRA or Rave CRA (Lab Admin) role, site staff must hold a 
minimum of an AP registration type,
o
To hold Rave Investigator role, the individual must be registered as an NPIVR or 
IVR, and
o
To hold Rave Read Only role, site staff must hold an Associates (A) registration 
type.
Upon initial site registration approval for the study in Regulatory Support System (RSS), all 
persons with Rave roles assigned on the appropriate roster will be sent a study invitation e-mail
from iMedidata. To accept the invitation, site staff must log in to the Select Login 
(https://login.imedidata.com/selectlogin) using their CTEP-IAM username and password, and 
click on the accept link in the upper right-corner of the iMedidata page. Site staff will not be 
able to access the study in Rave until all required Medidata and study specific trainings are 
completed. Trainings will be in the form of electronic learnings (eLearnings), and can be 
accessed by clicking on the link in the upper right pane of the iMedidata screen.  If an eLearning 
is required and has not yet been taken, the link to the eLearning will appear under the study name 
in iMedidata instead of the Rave EDC link; once the successful completion of the eLearning has 
been recorded, access to the study in Rave will be granted, and a Rave EDC link will display 
under the study name. 
Site staff that have not previously activated their iMedidata/Rave account at the time of initial 
site registration approval for the study in RSS will also receive a separate invitation from 
iMedidata to activate their account. Account activation instructions are located on the CTSU 
website in the Rave section under the Rave resource materials (Medidata Account Activation and 
Study Invitation Acceptance).  Additional information on iMedidata/Rave is available on the 
CTSU members’ website in the Data Management > Rave section at www.ctsu.org/RAVE/ or by 
contacting the CTSU Help Desk at 1-888-823-5923 or by e-mail at ctsucontact@westat.com.
12.2.1 Method
This study will be monitored by the Clinical Trials Monitoring Service (CTMS).  Data 
will be submitted to CTMS at least once every two weeks via Medidata Rave (or other 
modality if approved by CTEP).  Information on CTMS reporting is available at:  

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http://www.theradex.com/clinicalTechnologies/?National-Cancer-Institute-NCI-11.  On-
site audits will be conducted on an 18-36 month basis as part of routine cancer center site 
visits. More frequent audits may be conducted if warranted by accrual or due to concerns 
regarding data quality or timely submission.  For CTMS monitored studies, after users 
have activated their accounts, please contact the Theradex Help Desk at (609) 619-7862 
or by email at CTMSSupport@theradex.com for additional support with Rave and 
completion of CRFs.
12.2.2 Responsibility for Data Submission
For ETCTN trials, it is the responsibility of the PI(s) at the site to ensure that all 
investigators at the ETCTN Sites understand the procedures for data submission for each 
ETCTN protocol and that protocol specified data are submitted accurately and in a timely 
manner to the CTMS via the electronic data capture system, Medidata Rave.  
Data are to be submitted via Medidata Rave to CTMS on a real-time basis, but no less 
than once every 2 weeks.  The timeliness of data submissions and timeliness in resolving 
data queries will be tracked by CTMS.  Metrics for timeliness will be followed and
assessed on a quarterly basis.  For the purpose of Institutional Performance Monitoring, 
data will be considered delinquent if it is greater than 4 weeks past due.
Data from Medidata Rave and CTEP-AERS is reviewed by the CTMS on an ongoing 
basis as data is received.  Queries will be issued by CTMS directly within Rave.  The 
queries will appear on the Task Summary Tab within Rave for the CRA at the ETCTN to 
resolve.  Monthly web-based reports are posted for review by the Drug Monitors in the 
IDB, CTEP.  Onsite audits will be conducted by the CTMS to ensure compliance with 
regulatory requirements, GCP, and NCI policies and procedures with the overarching 
goal of ensuring the integrity of data generated from NCI-sponsored clinical trials, as 
described in the ETCTN Program Guidelines, which may be found on the CTEP 
(http://ctep.cancer.gov/protocolDevelopment/electronic applications/adverse events.htm
)  and CTSU websites.
CTMS will utilize a core set of eCRFs that are Cancer Data Standards Registry and 
Repository (caDSR) compliant (http://cbiit.nci.nih.gov/ncip/biomedical-informatics-
resources/interoperability-and-semantics/metadata-and-models).  Customized eCRFs will 
be included when appropriate to meet unique study requirements.  The PI is encouraged 
to review the eCRFs, working closely with CTMS to ensure prospectively that all 
required items are appropriately captured in the eCRFs prior to study activation.  CTMS 
will prepare the eCRFs with built-in edit checks to the extent possible to promote data 
integrity.
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.

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Further information on data submission procedures can be found in the ETCTN Program 
Guidelines 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.htm
).
12.3
Data Quality Portal
The Data Quality Portal (DQP) provides a central location for site staff to manage 
unanswered queries and form delinquencies, monitor data quality and timeliness, 
generate reports, and review metrics. 
The DQP is located on the CTSU members’ website under Data Management.  The Rave 
Home section displays a table providing summary counts of Total Delinquencies and 
Total Queries.  DQP Queries, DQP Delinquent Forms, and the DQP Reports modules are 
available to access details and reports of unanswered queries, delinquent forms, and 
timeliness reports.  Review the DQP modules on a regular basis to manage specified 
queries and delinquent forms.
The DQP is accessible by site staff that are rostered to a site and have access to the CTSU 
website. Staff that have Rave study access can access the Rave study data using a direct 
link on the DQP.
To learn more about DQP use and access, click on the Help icon displayed on the Rave 
Home, DQP Queries, and DQP Delinquent Forms modules.
Note:  Some Rave protocols may not have delinquent form details or reports specified on 
the DQP. A protocol must have the Calendar functionality implemented in Rave by the 
Lead Protocol Organization (LPO) for delinquent form details and reports to be available
on the DQP. Site staff should contact the LPO Data Manager for their protocol regarding 
questions about Rave Calendaring functionality.
12.4
CTEP Multicenter Guidelines
N/A
12.5
Collaborative Agreements Language
The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the NCI 

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

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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.
12.6
Genomic Data Sharing Plan
De-identified samples and data (clinical as well as genomic or epigenomic) collected under this 
protocol will be shared with collaborators performing the biomarker studies and stored in the 
database of Genotypes and Phenotypes (dbGaP). Specimens will be de-identified using a Trial 
ID # that is different from the patient’s medical record number. Language regarding the 
acquisition and sharing of genomic data is included in the consent form for this trial.  Data at 
both the individual level (de-identified) and aggregate level may be shared in collaboration with 
other researchers.
13. STATISTICAL CONSIDERATIONS
13.1
Study Design/Endpoints
This is a randomized open-label of Phase 2 study of M6620 (VX-970, berzosertib) + carboplatin 
vs. docetaxel + carboplatin in patients with metastatic castration-resistant prostate cancer.  
Patients who have been treated with at least one secondary hormonal therapy and taxane-based 
chemotherapy will be randomized 1:1 to receive Arm A (docetaxel + carboplatin) or Arm B 

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(M6620 (VX-970, berzosertib) + carboplatin). Patients who are ineligible for docetaxel due to 1. 
Allergy or intolerance to docetaxel or 2. Gr 2 neuropathy and are randomized to the control arm 
will be treated with carboplatin as a single agent. Patients will be treated on study until the 
occurrence of progression by PCWG3 criteria2, unequivocal clinical progression, unacceptable 
side effects, withdrawal of consent, or death. Patients will be stratified by 1) whether they 
received prior PARP inhibitor (yes vs. no) at randomization, 2) whether they have evaluable 
disease by RECIST criteria at baseline (yes vs. no) at randomization, with a post-hoc analysis by 
whether or not they have a canonical pathogenic mutation in a gene involved in homologous 
recombination repair by whole exome sequencing from a mandatory pre-treatment tumor biopsy.
Patients on the docetaxel+carboplatin arm will be allowed to crossover to the M6620 (VX-970,
berzosertib)+carboplatin arm at the earlier of time of PSA progression (by PCWG2 criteria1) or 
radiographic progression (by RECIST 1.1 criteria for non-osseous disease or PCWG3 criteria2
for osseous disease) if the patient remains clinically stable and continues to meet the eligibility 
criteria of the protocol.  
The primary objective of this trial is to investigate the response rate (CR+PR as defined by  
radiographic response by RECIST 1.1 or PSA response defined in Section 11.2) in patients 
treated with a combination of M6620 (VX-970, berzosertib) and carboplatin as compared to a 
combination of docetaxel and carboplatin.  Patients who are evaluable for both PSA and 
radiographic response will be considered responders if they experience a response by either 
criterion.
Secondary objectives include comparison of time to PSA progression by PCWG2 criteria1
(defined in section 11.1.6) between the 2 arms. Patients who had radiographic progression prior 
to PSA progression (rare cases) will be counted as failures for time to PSA progression 
comparisons. Given that the crossover design does not allow for direct comparison of radiologic 
progression–free survival and progression-free survival by PCWG3 criteria between the arms of 
this study, these parameters in each arm will be reported separately. We will assess the 
relationship with homologous recombination deficiency (HRD) detected from baseline tumor 
biopsy with response to the combination of M6620 (VX-970, berzosertib) and carboplatin and 
the combination of docetaxel and carboplatin. Other secondary endpoints include safety of 
carboplatin+M6620 (VX-970, berzosertib) and adverse events in each arm.
13.2
Sample Size/Accrual Rate
For the primary endpoint, we anticipate a response rate of 20% in the docetaxel+carboplatin arm 
in this cohort of patients who have previously received at least 2 prior therapies19. If the response 
rate of carboplatin+M6620 (VX-970, berzosertib) is 40%, with 65 patients on each treatment 
arm (total N=130), there will be 80% power to distinguish a response rate of 40% versus 20% 
using a chi-square test (one sided a=0.05). 142 subjects will be enrolled to account for 10% of 
patients who never start treatment after randomization.
The study will be monitored for futility with one interim analysis, planned at approximately 50% 
information (i.e. 65 response evaluable patients). The decision for stopping the trial will be based 

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they have measurable disease per RECIST at baseline (yes versus no)) as well as HRD status 
from post-hoc analysis of collectively tissue after randomization (HRD(+), HRD(-), or unknown) 
will be applied to the stratified CMH test.
13.4
Analysis of Secondary/Exploratory/Correlative Endpoints
13.4.1 Analysis of secondary endpoints
Time to event endpoints (PFS, time to PSA progression and rPFS) will be estimated with 
the Kaplan Meier methodology. Median and event-free rate at selected time points will be 
provided with 95% confidence interval. Comparison of time to PSA progression between 
arms will be conducted using the log-rank test. Since patients will be allowed to 
crossover at the time of PSA progression, PFS and rPFS will not be compared between 
arms.
Safety analysis will be conducted using the Safety Population defined as any participant 
receiving one dose of study treatment. All safety endpoints will be summarized according 
to treatment arm. For toxicity reporting, all adverse events will be graded and analyzed 
using CTCAE version 5.0. Type of adverse events, intensity (grading), and attribution 
will be provided in a listing. All adverse events resulting in discontinuation, dose 
modification, and/or dosing interruption, and/or treatment delay of drug will also be 
summarized. Laboratory test results will be classified according to the CTCAE version 
5.0.
13.4.2 Analysis of exploratory endpoints 
OS will be estimated with the Kaplan Meier methodology. Comparison of OS between 
arms will be conducted using the log-rank test base on the intention-to-treat approach, 
where two treatment arms will be compared regardless of cross-over or any subsequent 
therapy.
We anticipate that ~50% of patients who progress on docetaxel+carboplatin will choose 
to crossover to the M6620 (VX-970, berzosertib)+carboplatin arm of the study, and the 
response rate, PFS, rPFS, and time to PSA progression after crossover will be 
descriptively assessed in this population.

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13.4.3 Analysis of correlative endpoints  
Gene mutation frequencies and mean ± SD of quantitative biomarkers will be 
summarized by arm and in overall population at baseline and/or at end of study. We
anticipate that about 75% of biopsy specimens will be evaluable for homologous 
recombination deficiency (HRD) status by next generation sequencing.  With a total of 98
evaluable samples, the 90% exact binominal CI width is 0.11 and 0.16 with the observed 
mutation rate of 0.1 and 0.3 respectively. We hypothesize that in both arms of the study, 
responses to carboplatin will be enriched in patients with HRD as determined by 
detection of alterations in genes involved in homologous recombination repair from the 
tumor. If 20% of patients harbor HRD, there is 83% power to detect a 30% difference in 
response (e.g. for a response rate 20% in HRD(-) versus 50% in HRD(+) patients) using a 
chi-square test (one sided a=0.05). Assuming 40~60% of patients with paired (pre- and 
post-treatment) biopsy available, there is 80% power to detect a 0.32~0.40 SD mean 
change in quantitative biomarkers between time points with n=52~78 using a paired t-test
(two-sided α=0.05).
13.5
Reporting and Exclusions
The following Analysis Populations are planned for this study:
Safety Analysis Set: Evaluation of toxicity will be done in the safety population, which
will include all patients who received at least one dose of study treatment. Patients will be 
analyzed in the treatment group according to the study treatment they actually received. 
Full Analysis Set (FAS): The FAS will include all randomized patients who are deemed
eligible and receive at least one dose of study treatment. FAS will be used for the primary 
comparison of response rate and other efficacy endpoints (time to PSA progression and 
OS) in an intent-to-treat analysis. Response unevaluable patients or early death from any 
causes prior to response evaluation will be included in the main analysis of the response 
rate as non-responders.
REFERENCES
1.
Scher HI, Halabi S, Tannock I, et al: Design and end points of clinical
trials for patients with progressive prostate cancer and castrate levels of testosterone: 
recommendations of the Prostate Cancer Clinical Trials Working Group. J Clin Oncol 26:1148-
59, 2008
2.
Scher HI, Morris MJ, Stadler WM, et al: Trial Design and Objectives for 
Castration-Resistant Prostate Cancer: Updated Recommendations From the Prostate Cancer 
Clinical Trials Working Group 3. J Clin Oncol 34:1402-18, 2016
3.
Society AC: Key Statistics for Prostate Cancer, 2017

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4.
Robinson D, Van Allen EM, Wu YM, et al: Integrative clinical genomics 
of advanced prostate cancer. Cell 161:1215-28, 2015
5.
Mateo J, Carreira S, Sandhu S, et al: DNA-Repair Defects and Olaparib in 
Metastatic Prostate Cancer. N Engl J Med 373:1697-708, 2015
6.
Sandhu S, Hussain M, Mateo J, et al: LBA8 PROfound: Phase III study of 
olaparib versus enzalutamide or abiraterone for metastatic castration-resistant prostate cancer 
(mCRPC) with homologous recombination repair (HRR) gene alterations. Annals of Oncology
30:mdz446. 007, 2019
7.
Abida W, Bryce AH, Balar AV, et al: TRITON2: An international, 
multicenter, open-label, phase II study of the PARP inhibitor rucaparib in patients with 
metastatic castration-resistant prostate cancer (mCRPC) associated with homologous 
recombination deficiency (HRD). Journal of Clinical Oncology 36:TPS388-TPS388, 2018
8.
Marshall CH, Sokolova AO, McNatty AL, et al: Differential response to 
olaparib treatment among men with metastatic castration-resistant prostate cancer harboring 
BRCA1 or BRCA2 Versus ATM Mutations. European urology, 2019
9.
Mateo J, Porta N, McGovern UB, et al: TOPARP-B: A phase II 
randomized trial of the poly (ADP)-ribose polymerase (PARP) inhibitor olaparib for metastatic 
castration resistant prostate cancers (mCRPC) with DNA damage repair (DDR) alterations, 
American Society of Clinical Oncology, 2019
10.
Karnitz LM, Zou L: Molecular Pathways: Targeting ATR in Cancer 
Therapy. Clin Cancer Res 21:4780-5, 2015
11.
Zhang J, Dai Q, Park D, et al: Targeting DNA Replication Stress for 
Cancer Therapy. Genes (Basel) 7, 2016
12.
Vertex Pharmaceuticals I: VX-970 Investigator’s Brochure (2017),  (ed 
Version 7.0), 2017
13.
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inhibitor VE-822 results in selective sensitization of pancreatic tumors to radiation. Cell Death 
Dis 3:e441, 2012
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Hall AB, Newsome D, Wang Y, et al: Potentiation of tumor responses to 
DNA damaging therapy by the selective ATR inhibitor VX-970. Oncotarget 5:5674-85, 2014
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Kuo LJ, Yang LX: Gamma-H2AX - a novel biomarker for DNA double-
strand breaks. In Vivo 22:305-9, 2008
16.
White D, Rafalska-Metcalf IU, Ivanov AV, et al: The ATM substrate 
KAP1 controls DNA repair in heterochromatin: regulation by HP1 proteins and serine 473/824 
phosphorylation. Mol Cancer Res 10:401-14, 2012
17.
Hall AB, Newsome D, Wang Y, et al: Potentiation of tumor responses to 
DNA damaging therapy by the selective ATR inhibitor VX-970, 2014 
18.
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prostate cancer progressing after prior chemotherapy: the SPARC trial. J Clin Oncol 27:5431-8,
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Hager S, Ackermann CJ, Joerger M, et al: Anti-tumour activity of 
platinum compounds in advanced prostate cancer-a systematic literature review. Ann Oncol 
27:975-84, 2016
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docetaxel in men with metastatic hormone-refractory prostate cancer who are refractory to 
docetaxel. Cancer 112:521-6, 2008
21.
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II study (NCT01505868) of cabazitaxel (CAB) plus or minus carboplatin (CARB) in men with 
metastatic castration-resistant prostate cancer (mCRPC), ASCO Annual Meeting Proceedings,
2015, pp 5010
22.
Aparicio AM, Harzstark AL, Corn PG, et al: Platinum-based 
chemotherapy for variant castrate-resistant prostate cancer. Clin Cancer Res 19:3621-30, 2013
23.
Cheng HH, Pritchard CC, Boyd T, et al: Biallelic Inactivation of BRCA2 
in Platinum-sensitive Metastatic Castration-resistant Prostate Cancer. Eur Urol 69:992-5, 2016
24.
Pomerantz MM, Spisak S, Jia L, et al: The association between germline 
BRCA2 variants and sensitivity to platinum-based chemotherapy among men with metastatic 
prostate cancer. Cancer 123:3532-3539, 2017
25.
Bunting SF, Callen E, Kozak ML, et al: BRCA1 functions independently 
of homologous recombination in DNA interstrand crosslink repair. Mol Cell 46:125-35, 2012
26.
Johnson SF, Cruz C, Greifenberg AK, et al: CDK12 Inhibition Reverses 
De Novo and Acquired PARP Inhibitor Resistance in BRCA Wild-Type and Mutated Models of 
Triple-Negative Breast Cancer. Cell Rep 17:2367-2381, 2016
27.
Ceccaldi R, O'Connor KW, Mouw KW, et al: A unique subset of epithelial 
ovarian cancers with platinum sensitivity and PARP inhibitor resistance. Cancer Res 75:628-34,
2015
28.
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as monotherapy (mono) or in combination (combo) with carboplatin (CP) incorporating 
pharmacodynamics (PD) studies. J Clin Oncol 34, 2016
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sequencing of cell-free DNA reveals high concordance with metastatic tumors. Nature 
Communications 8:1324, 2017
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architectures in clonal cell populations from tumor whole-genome sequence data. Genome Res 
24:1881-93, 2014
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somatic copy number alterations by liquid biopsies. Mol Oncol 10:494-502, 2016
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focal amplifications as a driving force in metastatic prostate cancer. Nat Commun 7:12008, 2016
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Carter SL, Cibulskis K, Helman E, et al: Absolute quantification of 
somatic DNA alterations in human cancer. Nat Biotechnol 30:413-21, 2012
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5:4988, 2014
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Davies H, Glodzik D, Morganella S, et al: HRDetect is a predictor of 
BRCA1 and BRCA2 deficiency based on mutational signatures. Nat Med 23:517-525, 2017
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enhanced sensitivity to ATR inhibitor treatment in mantle cell lymphoma with ATM loss-of-
function. Molecular Cancer Research 13:120-129, 2015
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Kwok M, Davies N, Agathanggelou A, et al: ATR inhibition induces 
synthetic lethality and overcomes chemoresistance in TP53-or ATM-defective chronic 
lymphocytic leukemia cells. Blood 127:582-595, 2016
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Min A, Im S-A, Jang H, et al: AZD6738, a novel oral inhibitor of ATR, 
induces synthetic lethality with ATM-deficiency in gastric cancer cells. Molecular cancer 
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Cai M-Y, Reavis HD, Chen J-W, et al: ATR inhibition for the treatment of 
ATM-deficient gastric cancer, AACR, 2018
44.
Wengner AM, Siemeister G, Luecking U, et al: ATR inhibitor BAY 
1895344 shows potent anti-tumor efficacy in monotherapy and strong combination potential with 
the targeted alpha therapy radium-223 dichloride in preclinical tumor models, AACR, 2017
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Abida W, Armenia J, Gopalan A, et al: Prospective Genomic Profiling of 
Prostate Cancer Across Disease States Reveals Germline and Somatic Alterations That May 
Affect Clinical Decision Making. JCO Precis Oncol 2017, 2017
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Armenia J, Wankowicz SAM, Liu D, et al: The long tail of oncogenic 
drivers in prostate cancer. Nat Genet, 2018
47.
Rafiei S, Fitzpatrick K, Liu D, et al: ATM Loss Confers Greater 
Sensitivity to ATR Inhibition than PARP Inhibition in Prostate Cancer. Cancer Res, 2020
48.
Hu C, Zhang S, Gao X, et al: Roles of Kruppel-associated Box (KRAB)-
associated Co-repressor KAP1 Ser-473 Phosphorylation in DNA Damage Response. J Biol 
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Abida W, Cyrta J, Heller G, et al: Genomic correlates of clinical outcome 
in advanced prostate cancer. Proc Natl Acad Sci U S A 116:11428-11436, 2019
50.
Sharp A, Coleman I, Yuan W, et al: Androgen receptor splice variant-7
expression emerges with castration resistance in prostate cancer. J Clin Invest 129:192-208, 2019
51.
McKay RR, Zukotynski KA, Werner L, et al: Imaging, procedural and 
clinical variables associated with tumor yield on bone biopsy in metastatic castration-resistant 
prostate cancer. Prostate Cancer Prostatic Dis 17:325-31, 2014
52.
Bubley GJ, Carducci M, Dahut W, et al: Eligibility and response 
guidelines for phase II clinical trials in androgen-independent prostate cancer: recommendations 
from the Prostate-Specific Antigen Working Group. J Clin Oncol 17:3461-7, 1999

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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
CTEP MULTICENTER GUIDELINES
N/A

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APPENDIX C
PATIENT DRUG INFORMATION HANDOUT AND WALLET CARD
Information for Patients, Their Caregivers and Non-Study Healthcare Team on Possible 
Interactions with Other Drugs and Herbal Supplements 
Patient 
Name:
Diagnosis:
Trial #:
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.  

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APPENDIX D - BIOASSAY TEMPLATES
WHOLE EXOME SEQUENCING
Whole exome sequencing will be performed through Molecular Characterization (MoCha) 
laboratory at the Frederick National Laboratory for Cancer Research.  At least two research core 
biopsies placed in formalin are shipped overnight to the EET Biobank for rapid embedding and 
subsequent nucleic acid extraction. These procedures are summarized in Section 9.4.
Whole Exome Sequencing will be performed at the Molecular Characterization Laboratory on 
the purified DNA aliquots provided by the Biorepository.
WES DNA libraries will be generated using the Agilent SureSelect XT Target Enrichment
System, and quantitated via digital droplet PCR (ddPCR). Library samples are denatured, diluted 
and sequenced on the
Illumina NovaSeq 6000.
RNA SEQ
RNA sequencing will be performed through the NCLN Genomics Laboratory. At least two 
research core biopsies placed in formalin are shipped overnight to the EET Biobank for rapid 
embedding and subsequent nucleic acid extraction. These procedures are summarized in Section 
9.4.
RNA-Seq will be performed at the the NCLN Genomics Laboratory on the purified RNA
aliquots provided by the Biobank.
Reverse transcription to cDNA is primed with random hexamers, and the TruSeq RNA Exome 
kit from Illumina is used to specifically capture the coding regions of the transcriptome for 
cDNA sequencing.

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in WES of tumor biopsies and confirmed (i.e. supported by ≥ 3 variant reads) in WES of cfDNA. 
This demonstrates that the vast majority of clonal events detected in a metastasis biopsy are 
detectable in cfDNA, suggesting cfDNA as a reasonable proxy for metastasis biopsy.  Subclonal 
events are less commonly detected in cfDNA, suggesting that cfDNA is composed of DNA 
derived from multiple metastatic sites.   E. Mutational signatures in whole-exome sequencing of 
cfDNA and tumor biopsies were predicted using a Bayesian non-negative matrix factorization 
(NMF) approach. Samples with predicted homozygous loss of BRCA1/2 through whole exome 
sequencing are indicated in red and blue.  This demonstrates that a BRCA-like signature 
(compatible with deficiency in homologous recombination repair deficiency) can be detected 
from cfDNA, and that there are patients with this signature who do not have known loss of 
BRCA1 and BRCA2.
Assay Details for ultra low pass whole genome sequencing (ULP-WGS): Frozen aliquots of 
plasma are thawed at room temperature. Cell-free DNA is extracted from 2 mL of plasma and 
eluted into 60 uL of resuspension buffer using the Qiagen Circulating DNA kit on the 
QIAsymphony liquid handling system. Extracted cell-free DNA is frozen at -20 C until ready for 
further processing. Quantification of extracted cfDNA and gDNA is performed using the 
PicoGreen (Life Technologies) assay on a Hamilton STAR-line liquid handling system.  Library 
construction of cell-free DNA is performed using the Kapa HyperPrep kit with custom adapters 
(IDT). Generally, 5 ng of cfDNA input is used for ultra low-pass whole-genome sequencing 
(ULP-WGS).  A Hamilton STAR-line liquid handling system is used to automate and perform 
this method. Constructed sequencing libraries are pooled (2 uL of each x 96 per pool) and 
sequenced using 100bp paired-end runs over 1 x lane on a HiSeq2500 (Illumina) for ULP-WGS.
The genome is divided into T non-overlapping windows, or bins, of 1Mb. Aligned reads are 
counted based on overlap within each bin using the tools in HMMcopy Suite 
(http://compbio.bccrc.ca/software/hmmcopy/). The read counts are then normalized to correct for 
GC-content and mappability biases using HMMcopy R package.  This data is used to generate a 
Hidden Markov Model to derive copy number alterations and Tumor DNA purity using 
TitanCNA R package v1.9.0 (https://github.com/gavinha/TitanCNA) 8.  Samples must pass a 
quality threshold (median absolute deviation score < 0.115) for accurate purity estimate. 
Assay details for whole exome sequencing: When possible, 20ng of cfDNA input is used to 
construct another cfDNA library for WES, which affords greater library complexity and reduced 
the depth of sequencing required to achieve the desired mean target coverage. Library 
construction was performed using the Kapa HyperPrep kit with custom adapters (IDT) on a 
Hamilton STAR-line liquid handling system. Libraries are then quantified using the PicoGreen 
(Life Technologies) assay on a Hamilton STAR-line liquid handling system and pooled up to 12-
plex. Hybrid selection of cfDNA libraries is performed using the Nextera Rapid Capture Exome 
kit (Illumina) with custom blocking oligos (IDT and Broad Institute). Sequencing to generate 
100bp paired-end reads is performed on the Illumina HiSeq2500 in high-output mode with 2-4
libraries per lane.  Single nucleotide variants are identified using MuTect and cancer cell 
fractions of these variants are derived using ABSOLUTE.

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RAD51 Focus Formation Assay
Kochupurakkal/D’Andrea/Shapiro/Dana-Farber Cancer Institute
RAD51 staining pattern correlates with HR repair status and PARP--inhibitor response in 
breast cancer cell line models. We screened commercially available RAD51 antibodies by (1) 
detection of a single band on a western blot of whole cell extract in either non--irradiated or 
irradiated cells; (2) determination that only nuclear staining was present, without cytoplasmic 
staining, even at high concentrations of antibody, since RAD51 is a nuclear protein; and (3) 
detection of Rad51 foci in normal fibroblasts and lack of foci--like structures in BRCA2--/--
fibroblasts following irradiation. This screen identified a monoclonal rabbit antibody that 
recognizes RAD51 with high specificity.  
We next tested RAD51 staining patterns in non--irradiated and irradiated FFPE sections of breast 
cancer cell lines. The BRCA--deficient cells lines used were MDA--MB--436 and HCC1395;; 
BRCA--proficient cell lines included BT20, HCC1569 and MDA--MB--468. MDA--MB436 and 
HCC1395 are highly sensitive to the PARP inhibitor olaparib compared to the BRCA--proficient 
cell lines. Immunohistochemical (IHC) staining conditions were optimized using paraffin 
sections containing these cell lines. Analysis of RAD51 staining pattern revealed three features: 
(1) RAD51 levels were high in BRCA--deficient lines in comparison to cell lines with wild--type 
BRCA; (2) Foci were observed in cell lines with wild--type BRCA and the number of cells with 
foci and the number of foci/cell increased with irradiation; in contrast, foci were absent in 
BRCA-- deficient cell lines irrespective of irradiation; and (3) only a fraction of cells stained for 
RAD51 irrespective of irradiation (Figure 1).
Figure 1. RAD51 staining pattern correlates with HR repair status. FFPE blocks were 
prepared of the indicated cell lines grown as spheroids embedded in a collagen--laminin matrix 
that were either un--irradiated or exposed to 10 Gy g -- irradiation. Sections from these blocks 
were stained for RAD51 using a standardized protocol. RAD51 staining was observed in a 
fraction of the cells. (A) BRCA wild--type cell lines have low levels of RAD51, with foci 
evident in both unirradiated and irradiated cells, whereas, BRCA--mutant cell lines have high 
levels of diffuse nuclear RAD51 without evidence of foci. (B) Example of nuclei at higher 

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magnification from indicated cells lines with either RAD51 foci (HCC1569, BRCA wild--type),
or diffuse high levels of RAD51 without foci (MDA--MB--436, BRCA1 mutant). Based on these 
results, it is possible to construct a matrix for evaluation of HR repair proficiency and deficiency, 
as shown below.
Analytical characteristics of the assay 
Accuracy. We believe our screening conditions and criteria for selecting the best RAD51 
antibody were appropriate. The staining patterns we observe using the selected antibody are 
consistent with current knowledge about the HR repair pathway. Therefore, the results obtained 
using the antibody are expected to have a high degree of accuracy. The staining conditions were 
standardized using the Leica auto--staining platform, which minimizes human error in 
performing the stains. The Aperio Scanscope image acquisition and analysis platform offers the 
ability to generate analysis--specific standardized macros that can be used consistently across 
samples and minimize human error/estimation discordance. This platform has proved successful 
in analyzing clinical samples. Accurate estimation of the functional HR repair score will require 
further validation. 
Precision. The stains were done on the Leica auto--stainer platform and the stains of different 
batches of control samples were consistent. Staining using the standardized protocol, using 
Aperio ScanScope for image acquisition and analysis using standardized macros is expected to 
ensure a high degree of precision and minimize batch--to--batch variation. Precision in 
estimating the functional HR repair score will require further validation in expanded cohorts of 
samples. 
Analytical Sensitivity. Since the RAD51 nucleofilament (foci) contains multiple molecules of 
RAD51 concentrated at a specific sub--nuclear location, we diluted the antibody such that only 
foci are visible in HR repair--proficient samples. At this dilution, HR repair--deficient cells have 
strong diffuse nuclear RAD51 staining. Testing larger cohorts of samples will help establish the 
exact dilution of the antibody for the staining. Although RAD51 nucleofilament (focus) 
formation is an essential step in HR repair, other steps downstream of RAD51 loading are 
necessary to complete HR. At this point, we are unsure if high RAD51 levels and presence of 
RAD51 foci indicate disruption of HR events downstream of RAD51 loading. The functional HR 
repair score is expected to identify tumors with disruption in HR repair upstream of RAD51 
loading. The sensitivity of HR repair--deficient calls requires further validation. 
Analytical specificity. This monoclonal antibody was generated in rabbits using recombinant 
full length RAD51. Western blot containing whole cell lysates of multiple cell lines detected a 
single ~37kDa band. Moreover, the staining pattrn observed in immunofluorescence--based and 
IHC-- based assays are consistent with high--specificity of the antibody to detect RAD51. The 
antibody is commercially available from Cell Signaling Technology, Danvers, MA. Cell 
Signaling Technology has procedures in place to provide Good Manufacturing Practice (GMP) 
certified antibody. Currently, the antibody is used at a dilution of 1:75. Our plan is to procure a 
GMP certified custom batch of the antibody and establish multiple parameters, including storage 
stability, assay sensitivity, and precision. Since Rad51 loading is an intermediate step in HR 

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repair, it is possible that presence of RAD51 foci may not indicate HR repair competence when 
genes encoding proteins downstream from RAD51 loading are altered. For example, cell lines in 
which RAD52 is disrupted fail to remove RAD51 nucleofilaments and complete HR repair 
(unpublished results). In such cases, the functional HR repair score may not correlate with HR 
repair proficiency, leading to a false--positive result. 
Reportable range of results for the test system. A low functional HR repair score indicates HR 
repair deficiency, whereas a high score indicates proficiency. The percentage of foci--positive 
nuclei is the major component of the functional HR repair score. However, in HR repair-
-proficient tumors, cells with high levels of RAD51 are rare and this may inflate the functional 
HR repair score depending on the number of nuclei analyzed. Nevertheless, the functional HR 
repair scores observed in the five cell lines (un--irradiated and irradiated) range from 0.07 to 
28.87 with scores ≤ 1.06 indicative of HR repair deficiency.
Controls for assay harmonization at multiple locations, quality controls and other 
performance characteristics. A paraffin block containing irradiated and un--irradiated cell lines 
described earlier in a Tissue MicroArray (TMA) format will be used as the control for staining 
and analysis using Aperio ScanScope. A section from this block will be included with all batches
of samples that are stained and analyzed. Since the cell lines are an unlimited resource, duplicate 
blocks can be prepared, certified and shared with all locations where the staining will be 
performed. The macro used to analyze images of stains will also be shared. Alternatively, the 
stains can be performed at a centralized location.

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APPENDIX E
PROCEDURE FOR COLLECTION OF BIOPSY TISSUE
Introduction
The majority of the tissue/tumor collections for this project will occur via an image-
guided (CT scan or US-guided) needle biopsy of a soft tissue or bone lesion. Biopsy 
of soft tissue is preferred when possible. Excisional biopsy of a lymph node or tissue 
from a surgical procedure (e.g. repair of a pathological fracture, liver nodule resection 
samples, cord compression samples, brain metastasis, etc. that are usually large 
samples) could be allowed as the pre-treatment tissue specimen if performed within 
the screening window and tissue specimens are preserved with formalin for biomarker 
analysis as described in the protocol.
Blood samples will be drawn within 4 weeks of the biopsy to document an acceptable 
coagulation profile (INR < 1.5, PTT < 45, platelets > 50,000). Aspirin and/or Plavix 
should be discontinued 5 days prior to the biopsy (continuation of aspirin 81 mg may 
be permitted based on institutional guidelines). On the day of the biopsy, a short 
physical exam will be performed by the radiologist including assessing the 
participant’s general ASA score and airway rating.
Bone Biopsies:
Bone biopsies will be performed using standard coaxial techniques under CT 
guidance without the administration of intravenous contrast. Bone biopsies should not 
be performed on irradiated lesions. Bone sites include lumbar vertebrae, pelvic bones 
and long bones. Excluded sites are thoracic, cervical vertebrae, skull and rib lesions. 
11G needle is preferred to be used for bone biopsies. Given lower yield on bone 
biopsy special attention should be given to the following parameters which may 
correlate with tumor yield on bone biopsy51:
· Size (larger size correlated with greater yield)
· Degree of sclerosis (more sclerosis correlating with more difficulty with biopsy and 
nucleic acid extraction)
· Distance from the skin to the lesion (lower yield for lesions farther from the skin)
· Distance from the cortex to the lesion (lower yield for lesions farther from the 
cortex)
· Presence of a bone scan correlate (greater yield with positive bone scan correlate)

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· Area to target for biopsy (potentially greater yield at the periphery vs. center of the 
lesion)
Soft Tissue Biopsies:
Soft tissue biopsies will be performed using standard coaxial techniques under CT 
guidance without the administration of intravenous contrast or US-guidance. Soft 
tissue biopsy sites include: lymph node or visceral metastases. 18G or larger is 
preferred to be used for soft tissue biopsies. Fine Needle Aspirate (FNA) samples are 
not acceptable. Same radiological parameters above will be noted.
Cores and Core Size:
For each tissue collection procedure, the intent is to acquire 4 needle cores for 
formalin fixation. Size of these biopsy cores can be variable (0.1-1.0 cm). Good 
quality cores are usually at least 0.3- 0.4 cm in size. While larger cores are preferable 
to optimize tumor capture, cores of any size should be processed.
Pre-Biopsy Labeling of Tubes and Cryomolds
Following information must be included:
· Biopsy date
· Specimen ID
· Biopsy type
· Clinical protocol number
· Sample #, 1, 2, 3, 4, 5, 6
Attach the labels to the mega-cassettes and formalin container. You can always 
remove them later for future use if not used this time.
Biopsy Notice
Research staff should communicate with Interventional Radiology team in advance of 
the biopsy to ensure that specimens are collected according to the laboratory manual.
Tumor Needle Biopsy Collection

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Research staff should arrive at the biopsy site at least 15 minutes ahead of the 
scheduled time to allow sufficient time to set up laboratory supplies.
APPENDIX F -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:
Dateof Procedure (mm/dd/yyyy):
Tissue Type (circle one):
Metastatic
Time point (circleone):     Pre-Treatment
       Off-Study
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.

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